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GOOD MORNING, EVERYONE.

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MY NAME IS STEPHANIE GOFF AND I

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WAS CHAIR OF THE PLANNING

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COMMITTEE FOR THIS CONFERENCE SO

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ON BEHALF OF DR. ROSENBERG AND

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MYSELF, THANK YOU ALL FOR

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ATTENDING.

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I'D LIKE TO ASK DR. JAMES GULLE

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TO GIVE US SOME OPENING REMARKS,

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CO-DIRECTOR OF THE CENTER FOR

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IMMUNOONCOLOGY, THE CLINICAL

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DIRECTOR HERE AT THE NCI AND

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ACTING CO-CHAIR OF THE CENTER

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FOR CANCER RESEARCH.

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PLEASE WELCOME DR. GULLE.

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[APPLAUSE]

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>> THANK YOU SO MUCH.

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IT'S REALLY A DELIGHT TO BE HERE

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TODAY AND ON BEHALF OF THE

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INCREDIBLE INVESTIGATORS DOING

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OUTSTANDING RESEARCH HERE AT THE

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CENTER FOR CANCER RESEARCH, I'D

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LIKE TO BOTH WELCOME YOU AND I'M

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DELIGHTED AND HONORED TO KICK

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OFF THIS SYMPOSIUM ON THE PAST,

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PRESENT AND FUTURE OF CELLULAR

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IMMUNOTHERAPY.

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SO AS SOMEONE WHO EARLY IN MY

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CAREER REALLY DRANK THE KOOL-AID

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OF IMMUNOTHERAPY, IT'S BEEN SUCH

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AN INCREDIBLE RIDE TO SEE US

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GOING FROM THE APPROVAL OF IL-2

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AS YOU'RE GOING TO HEAR ABOUT IN

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A LITTLE BIT FROM DR. LOTZE

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THROUGH WHERE WE ARE TODAY, WITH

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A MULTIBILLION DOLLAR INDUSTRY

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AIMED AT HELPING PATIENTS, BUT

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MORE IMPORTANTLY, ALL THE LIVES

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IMPACTED, AND ALL THE PATIENTS

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CURED.

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AS ONE OF THE PRIMARY DRIVERS OF

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THIS WORK WAS RIGHT HERE IN THE

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INTRAMURAL PROGRAM IN THE NIH.

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AND THIS MORNING, WE ARE MEETING

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HERE IN THE AUDITORIUM OF THE

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NIH CLINICAL CENTER, AND I JUST

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WANT TO SAY THAT THE NIH

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CLINICAL CENTER IS THE LARGEST

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CLINICAL RESEARCH CENTER IN THE

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WORLD, AND THE NCI'S CENTER FOR

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CANCER RESEARCH IS ONE OF ITS

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MAJOR USERS.

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THE NIH CLINICAL CENTER IS NOT A

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REGULAR HOSPITAL, IT'S REALLY

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DEDICATED TO PATIENT RESEARCH

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AND INTENSIVE PATIENT RESEARCH,

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AND ALL OF THE PATIENT TREATED

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HERE ARE TREATED ON CLINICAL

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TRIALS.

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THE NCI INTRAMURAL CLINICAL

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PROGRAM IS A RESOURCE FOR BOTH

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THE BASIC SCIENCE AND CLINICAL

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SCIENTISTS AND REALLY WHAT WE

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EXCEL IN IS TRANSLATING THESE

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BASIC DISCOVERIES INTO FIRST IN

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HUMAN CLINICAL TRIALS.

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I WANT TO JUST SHARE A LITTLE

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BIT MORE ABOUT THE CENTER FOR

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CANCER RESEARCH.

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WE HAVE CENTRAL FUNDING WHICH

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ALLOWS US TO FLEXIBLY SPEED

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THINGS INTO THE CLINIC.

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IT ALLOWS US THE INDEPENDENCE TO

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ALLOW HIGH RISK RESEARCH.

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WE ALSO HAVE CLINICAL RESOURCES

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THAT WE DON'T BILL PATIENTS OR

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INSURANCE.

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WE WILL PAY FOR PATIENTS TO

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TRAVEL FROM ANYWHERE IN THE

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UNITED STATES TO COME HERE ON

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CLINICAL TRIALS, AND THIS REALLY

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ALSO AFFORDS EXCELLENT

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OPPORTUNITIES TO TRAIN PHYSICIAN

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SCIENTISTS BECAUSE WE DON'T HAVE

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AN RVU-BASED SYSTEM.

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IN ADDITION, OUR COLLABORATIVE

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ATMOSPHERE REALLY ENCOURAGES

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TEAM SCIENCE AND PARTNERING.

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MORE ON THAT IN A LITTLE BIT.

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SO THIS IS A SNAPSHOT OF SOME OF

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OUR METRICS ON OUR CLINICAL

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RESEARCH ACTIVITY.

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WE HAVE ABOUT 1700 NEW PATIENT A

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YEAR HERE, AND IN ADDITION TO

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OUR NATURAL HISTORY STUDIES AND

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NON-TREATMENT STUDY, WE HAVE

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ABOUT A THOUSAND PATIENTS THAT

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ARE ACCRUED TO INTERVENTIONAL

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STUDIES EACH YEAR HERE.

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TYPICALLY THESE ARE IN PHASE ONE

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OR PHASE TWO FIRST IN HUMAN

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STUDIES.

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IN TERMS OF CELL THERAPIES,

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THERE ARE CURRENTLY 29 OPEN CELL

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THERAPY STUDIES IN HERE, AND

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WE'RE TALKING ABOUT CAR T, TCR

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Ts, TILs, BUT ALSO NK CELLS,

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MYELOID CELLS AND MONOCYTES.

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THESE CELL THERAPY STUDIES ARE

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ONGOING IN SIX DIFFERENT

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BRANCHES HERE, WHICH IS ABOUT A

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THIRD OF THE GROUPS DOING

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CLINICAL TRIALS.

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SO I'M PROUD OF THIS SLIDE HERE.

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THIS SLIDE OUTLINES SOME OF THE

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RESEARCH THAT HAS LED TO NEW

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TREATMENTS BEING APPROVED FOR

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PATIENTS AS A TESTAMENT TO SOME

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OF THE CLINICAL SCIENCE GOING ON

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HERE.

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YOU CAN SEE THAT OVER THE PAST

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SEVEN YEARS, WE'VE HAD 12 NEW

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THERAPIES THAT WERE

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FDA-APPROVED, AND WHAT I'VE

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OUTLINED IN RED HERE ARE THE

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IMMUNOTHERAPIES THAT HAVE BEEN

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APPROVED BY THE FDA.

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IN ADDITION, THERE'S BEEN

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MULTIPLE BREAKTHROUGH THERAPY

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AND ORPHAN DRUG DESIGNATION

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BASED ON WORK GOING ON HERE.

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BUT I'D JUST LIKE TO HIGHLIGHT

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THESE TWO CELL THERAPIES BASED

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ON WORK THAT CAME OUT OF THE

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SURGERY BRANCH.

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AND YOU'RE GOING TO HEAR MORE

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ABOUT THESE, I'M SURE, LATER ON

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TODAY.

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SO WE'VE COME FROM CYTOKINES TO

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IMMUNE CHECKPOINT INHIBITORS AND

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CELL THERAPY, BUT WHERE ARE WE

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GOING TO GO NEXT?

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AND SO THIS IS A PAPER THAT WAS

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PUT TOGETHER AUTHORED BY EMENS

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AND COLLEAGUES THAT OUTLINES

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SOME OF THE CHALLENGES AND

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OPPORTUNITIES IN THE FIELD.

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I WANTED TO BRING UP SOME OF THE

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THINGS THAT WAS BROUGHT OUT IN

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THIS PAPER AND REALLY ONE OF THE

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POINTS THAT WAS BROUGHT OUT WAS

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THE POTENTIAL FOR PARTNERSHIPS.

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HERE.

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SO PARTNERSHIPS BETWEEN ACADEMIC

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INSTITUTIONS, PARTNERSHIPS WITH

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COMPLEMENTARY SCIENCE

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DISCIPLINES AND PARTNERSHIPS

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BETWEEN PHARMA AND BIOTECH.

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ON THE LATTER, I'D JUST LIKE TO

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MENTION THAT ABOUT 70% OF NEW

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DRUGS COME FROM BIOTECH.

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SO BASED IN PART ON THAT, THE

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SOCIETY FOR IMMUNOTHERAPY OF

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CANCER OUTLINED THEIR

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BIOTECHNICIANTIVE, WHICH REALLY

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WHAT OUR GOAL IS, IS TO GET 100

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NEW APPROVALS WITHIN THE NEXT

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DECADE.

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AND SO FAR THIS YEAR, YOU CAN

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SEE THERE'VE BEEN FOUR

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APPROVALS, AND THESE ARE

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HIGHLIGHTED HERE BELOW, AND YOU

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CAN SEE THAT TWO OF THESE ARE IN

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CELL THERAPIES.

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SO ONCE AGAIN, I'D LIKE TO

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WELCOME EACH AND EVERY ONE OF

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YOU TO THIS SYMPOSIUM, AND I'D

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LIKE TO THANK MY FRIEND AND

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COLLEAGUE, DR. STEVE ROSENBERG,

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FOR HIS TENACIOUS BELIEF IN

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LIVING THERAPIES THAT HAVE

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BROUGHT US ALL HERE.

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THANK YOU.

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[APPLAUSE]

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>> HELLO, EVERYONE.

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THANK YOU SO MUCH FOR COMING.

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I'M NICK CLEMEN, I'LL BE

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MODERATING THE FIRST SESSION.

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THE TALKS ARE ONLY 15 MINUTES

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LONG AND WE'RE TRYING TO KEEP ON

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SCHEDULE SO WE'LL HOLD THE

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QUESTIONS FOR THE END.

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SO WITHOUT FURTHER ADO, FIRST UP

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IS DR. MICHAEL LOTZE FROM THE

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UNIVERSITY OF PITTSBURGH.

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>> WELL, FIRST OF ALL,
IT'S AN

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UNUSUAL PLEASURE AND HONOR TO BE

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ABLE TO BE HERE AND GIVE THE

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FIRST TALK.

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I WOULD LIKE TO SAY THAT ALL

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RHODES LEAD TO IL-2 AND LED FROM

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IL-2 FOR CELL THERAPY.

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BUT I'M BIASED.

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AND THANKS, JAMES GULLEY, FOR

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THAT NICE INTRODUCTION.

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I THINK WE STILL HAVE A LONG WAY

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TO GO TO GET 100 APPROVALS, BUT

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WE'RE ON OUR WAY.

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SO I CALL THIS A PROVOCATIVE

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TITLE, THE FIRST EFFECTIVE

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CHECKPOINT THERAPY WAS IL-2, IN

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PART BECAUSE AT THE TIME WHEN WE

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DID IT, WE DIDN'T KNOW THAT WE

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HAD TO GET OVER ALL THOSE

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GLUTTONOUST REGS THAT ATE OUR

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IL-2, IT MEANT WE HAD TO GO TO

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HIGH DOSE.

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THE UNIVERSITY OF PITTSBURGH IS

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NOW PUTTING UP, FINALLY, AFTER

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35 YEARS THERE, A CELL THERAPY

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FACILITY.

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I DO WANT TO PAUSE A MINUTE AND

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SAY ONE OF THE GRADUATES OF OUR

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PROGRAM HERE AT THE SURGERY

225
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BRANCH OF THE NCI, JEFF WEBBER,

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SADLY PASSED JUST A FEW MONTHS

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AGO, AND HE MOVED FROM BEING ONE

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OF OUR FELLOWS INTO A POSITION

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ON THE SENIOR STAFF, AND THEN AN

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ILLUSTRIOUS CAREER THAT TOOK HIM

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THROUGH MOFFITT AT ONE POINT AND

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THEN ALSO TO NYU, WHERE HE

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FINISHED HIS CAREER.

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I SHOULD SAY THAT I CAME TO THE

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BRANCH IN 1978.

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THE LAST MILLENNIUM, THE LAST

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CENTURY.

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AND TWO PEOPLE WHO TAUGHT ME HOW

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TO DO RESEARCH WERE ELANA RNA IN

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WHO STARAND SUSIE SCHWARTZ.

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I HAD MY OWN SMALL GROUP IN THE

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BRANCH.

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THIS IS JOSH REUBEN, HE JUST

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RETIRED AS A SURGEON.

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MARY, ALL THE WAY UP TO THE TOP

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OF THE NCI.

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DAVE JABLINS WHO RAN A BAGEL

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BUSINESS IN SAN FRANCISCO AS

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WELL AS BEING HEAD OF THORACIC

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SURGERY AT UCSF.

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AND YUTAKA KAWAKAMI, WHO I'M

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DELIGHTED TO SEE HERE AFTER SO

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MANY YEARS.

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AND THIS IS A GROUP THAT I WAS

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ABLE TO BUILT AT UNIVERSITY IN

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00:09:32,238 --> 00:09:33,807
PITTSBURGH WHEN I LEFT IN 1990

257
00:09:33,807 --> 00:09:34,908
BUT IT WAS ALL PREDICATED ON

258
00:09:34,908 --> 00:09:35,975
THIS EARLY GROUP THAT STEVE PUT

259
00:09:35,975 --> 00:09:36,342
TOGETHER.

260
00:09:36,342 --> 00:09:39,779
THIS IS A PICTURE FROM HIS BOOK

261
00:09:39,779 --> 00:09:40,914
IN 1982, MANY OF YOU WILL

262
00:09:40,914 --> 00:09:42,348
RECOGNIZE SOME OF THE PEOPLE

263
00:09:42,348 --> 00:09:44,951
THERE, BUT IT INCLUDED FRED

264
00:09:44,951 --> 00:09:51,424
CHANG, LIZ GRIM, STEVE

265
00:09:51,424 --> 00:09:54,661
EDINGHAUSEN AND JIM WHO YOU'LL

266
00:09:54,661 --> 00:09:55,428
HEAR FROM LATER.

267
00:09:55,428 --> 00:09:58,631
I HAVE SOME DISCLOSURES, HERE

268
00:09:58,631 --> 00:09:59,265
THEY ARE.

269
00:09:59,265 --> 00:10:01,668
THIS IS A 50 YEAR CELEBRATION

270
00:10:01,668 --> 00:10:03,403
FOR STEVE ROSENBERG BUT AN

271
00:10:03,403 --> 00:10:04,737
ORGANIZATION THAT I'VE BEEN

272
00:10:04,737 --> 00:10:08,475
ASSOCIATED WITH FOR MUCH OF MY

273
00:10:08,475 --> 00:10:10,510
CAREER IS GOING TO ITS 39TH

274
00:10:10,510 --> 00:10:13,813
MEETING IN HOUSTON, SITC, I

275
00:10:13,813 --> 00:10:14,948
ENCOURAGE YOU ALL TO CONSIDER

276
00:10:14,948 --> 00:10:16,316
IT, AND ALSO COME BACK WHEN IT'S

277
00:10:16,316 --> 00:10:17,750
BACK IN WASHINGTON FOR THE 40TH

278
00:10:17,750 --> 00:10:18,985
ANNIVERSARY.

279
00:10:18,985 --> 00:10:22,455
I SHOULD SAY THAT TUMOR

280
00:10:22,455 --> 00:10:23,857
IMMUNOLOGY IS REALLY COMPLICATED

281
00:10:23,857 --> 00:10:24,657
AND CONFUSING.

282
00:10:24,657 --> 00:10:27,494
THIS IS A PICTURE FROM GLEN

283
00:10:27,494 --> 00:10:30,363
DRANOFF FROM 20 YEARS AGO WHERE

284
00:10:30,363 --> 00:10:32,298
YOU SEE ALL THIS BLISTERING

285
00:10:32,298 --> 00:10:36,903
ARRAY OF CELLS, CYTOKINES AND

286
00:10:36,903 --> 00:10:37,971
CHEMOKINES AND IT'S REALLY

287
00:10:37,971 --> 00:10:38,872
CONFUSING BUT IF YOU REALLY LOOK

288
00:10:38,872 --> 00:10:41,174
AT IT, YOU EITHER GET ENDOGENOUS

289
00:10:41,174 --> 00:10:45,211
IL-2 BEING MADE OR GIVE

290
00:10:45,211 --> 00:10:47,814
EXOGENOUS IL-2 AS THE ENDOGENOUS

291
00:10:47,814 --> 00:10:49,682
COMING FROM SIGNAL 1 AND SIGNAL

292
00:10:49,682 --> 00:10:53,186
2, OR AS I DID WHEN I WAS AT

293
00:10:53,186 --> 00:10:56,122
NEREX USE A B INHIBITOR BUT THE

294
00:10:56,122 --> 00:10:57,757
REAL PROBLEM WAS WE DIDN'T KNOW

295
00:10:57,757 --> 00:10:59,359
ABOUT IT. REGS AND GIVING

296
00:10:59,359 --> 00:11:00,860
EXOGENOUS IL-2 WAS ALWAYS A

297
00:11:00,860 --> 00:11:02,195
DICEY PROPOSITION AS WE LEARNED.

298
00:11:02,195 --> 00:11:04,764
SO THE FIRST 40 YEARS OF CANCER

299
00:11:04,764 --> 00:11:07,066
IMMUNOTHERAPY FROM MY STANDPOINT

300
00:11:07,066 --> 00:11:09,736
IS WE ACTIVATED WITH WHAT WAS

301
00:11:09,736 --> 00:11:12,338
THEN CALLED T-CELL GROWTH

302
00:11:12,338 --> 00:11:14,741
FACTOR, SUBSEQUENTLY CALLED

303
00:11:14,741 --> 00:11:15,608
IL-2, LYMPHOKINE ACTIVATED

304
00:11:15,608 --> 00:11:15,942
KILLER CELLS.

305
00:11:15,942 --> 00:11:17,310
I DID THAT AS A CLINICAL

306
00:11:17,310 --> 00:11:19,445
ASSOCIATE WORKING WITH STEVE IN

307
00:11:19,445 --> 00:11:19,913
1980.

308
00:11:19,913 --> 00:11:22,549
WE STARTED OUR IL-2 CLINICAL

309
00:11:22,549 --> 00:11:26,119
TRIALS IN THE MID 80s.

310
00:11:26,119 --> 00:11:27,754
SUZANNE TOOK OVER MY LAB WHEN I

311
00:11:27,754 --> 00:11:30,723
LEFT THE NIH, HAD AN ILLUSTRIOUS

312
00:11:30,723 --> 00:11:32,792
CAREER HERE, ADVANCING TUMOR

313
00:11:32,792 --> 00:11:34,527
INFILTRATING LYMPHOCYTES, SHOWN

314
00:11:34,527 --> 00:11:36,496
IN RED, SUBSEQUENTLY BECAME A

315
00:11:36,496 --> 00:11:39,999
GREAT CHAMPION FOR PD-1 AND

316
00:11:39,999 --> 00:11:40,333
PDL1.

317
00:11:40,333 --> 00:11:42,635
YUTAKA KAWAKAMI DID WONDROUS

318
00:11:42,635 --> 00:11:44,571
STUDIES EVALUATING ANOTHER

319
00:11:44,571 --> 00:11:48,107
T-CELL GROWTH FACTOR, IL-4 BUT

320
00:11:48,107 --> 00:11:54,113
THEN WENT ON TO CLONE MART1 AND

321
00:11:54,113 --> 00:12:04,657
M 1 ANDMELAN A.

322
00:12:05,458 --> 00:12:06,593
DENDRITIC CELLS BEING GIVEN TO

323
00:12:06,593 --> 00:12:07,894
PATIENTS, WENT ON TO DEFINE THE

324
00:12:07,894 --> 00:12:10,330
ROLE OF THE MICROBIOME AND

325
00:12:10,330 --> 00:12:15,001
IMMUNOGENIC CELL DEATH, AND THEN

326
00:12:15,001 --> 00:12:17,370
DAL WIN TONG.

327
00:12:17,370 --> 00:12:18,805
THAT'S A 40 YEAR HISTORY.

328
00:12:18,805 --> 00:12:20,239
BUT ALONG THE WAY AND THANKFULLY

329
00:12:20,239 --> 00:12:22,375
FOR ALL OF US, THE CHECKPOINTS

330
00:12:22,375 --> 00:12:24,844
CAME ALONG IN 2010 AND 2014.

331
00:12:24,844 --> 00:12:26,713
SO IF YOU LOOK AT IT, WE HAD T

332
00:12:26,713 --> 00:12:28,681
CELLS AND T-CELL GROWTH FACTOR,

333
00:12:28,681 --> 00:12:30,416
IL-2 IN THE BEGINNING.

334
00:12:30,416 --> 00:12:32,485
A LONG PERIOD TESTING TUMOR

335
00:12:32,485 --> 00:12:34,554
VACCINES, AND THEN THE

336
00:12:34,554 --> 00:12:37,023
RENAISSANCE OF IMMUNOTHERAPY

337
00:12:37,023 --> 00:12:40,393
WITH CAR-T CELLS, TIL AND

338
00:12:40,393 --> 00:12:41,294
CHECKPOINT BLOCKADE.

339
00:12:41,294 --> 00:12:42,562
CELL THERAPY WAS NOT NEW, IT

340
00:12:42,562 --> 00:12:46,599
GOES BACK TO DONALD THOMAS'

341
00:12:46,599 --> 00:12:48,668
STUDY WITH BONE MARROW

342
00:12:48,668 --> 00:12:50,570
TRANSPLANT, WHICH HE DID IN

343
00:12:50,570 --> 00:12:53,840
COOPERS TOWN, NEW YORK AT THE

344
00:12:53,840 --> 00:12:56,342
MARY IMAGING BASSETT HOSPITAL, A

345
00:12:56,342 --> 00:12:57,243
LITTLE 200-BED COMMUNITY

346
00:12:57,243 --> 00:12:57,610
HOSPITAL.

347
00:12:57,610 --> 00:12:59,178
I'D LIKE TO GIVE YOU A REALLY

348
00:12:59,178 --> 00:13:01,080
QUICK UPDATE ON IL-2 AND HOW IT

349
00:13:01,080 --> 00:13:01,714
CAME ABOUT.

350
00:13:01,714 --> 00:13:06,753
THIS IS A PICTURE OF A WHALE

351
00:13:06,753 --> 00:13:08,855
CRESTING THE GOLDEN GATE BRIDGE.

352
00:13:08,855 --> 00:13:16,029
IT SAT IN THE BOARDROOM FOR

353
00:13:16,029 --> 00:13:18,998
CETUS TRYING TO CLEAN UP OIL

354
00:13:18,998 --> 00:13:20,733
SLICKS TO SAVE THE WHALES.

355
00:13:20,733 --> 00:13:22,602
ALSO CLONED IL-2.

356
00:13:22,602 --> 00:13:23,970
STEVE AND I DID OUR FIRST

357
00:13:23,970 --> 00:13:25,104
STUDIES WITH NATURAL PRODUCT

358
00:13:25,104 --> 00:13:26,539
IL-2 WITH A COLLABORATION WITH

359
00:13:26,539 --> 00:13:27,740
DU PONT WHERE THEY PUT 30 PEOPLE

360
00:13:27,740 --> 00:13:30,243
IN A MA HA TAN-LAKE PROJECT

361
00:13:30,243 --> 00:13:32,445
MAKING IL-2, BUT THAT SAME YEAR,

362
00:13:32,445 --> 00:13:36,582
THEY CLONED IL-2 AND

363
00:13:36,582 --> 00:13:38,251
OUT-LICENSED TO ROCHE.

364
00:13:38,251 --> 00:13:41,521
ROCHE MADE A FAUSTIAN DEAL WITH

365
00:13:41,521 --> 00:13:43,556
CETUS TO TRADE PCR RIGHTS SO

366
00:13:43,556 --> 00:13:46,793
THAT CETUS COULD GET IL-2.

367
00:13:46,793 --> 00:13:47,860
WHEN IT FIRST WENT IN FOR

368
00:13:47,860 --> 00:13:50,263
APPROVAL IN 1990, I REMEMBER THE

369
00:13:50,263 --> 00:13:52,131
MEETING AT THE FDA IN AUGUST,

370
00:13:52,131 --> 00:13:53,399
THEY FAILED TO GET APPROVAL SO

371
00:13:53,399 --> 00:13:56,636
IT WAS ACQUIRED BY CHIRON.

372
00:13:56,636 --> 00:13:59,338
NOVARTIS ACQUIRED CHIRON,

373
00:13:59,338 --> 00:14:02,942
NOVARTIS OUTLICENSED IL-2 TO

374
00:14:02,942 --> 00:14:03,976
PROMETHEUS, PROMETHEUS WAS

375
00:14:03,976 --> 00:14:08,314
ACQUIRED B NESTLE, IT WAS THEN

376
00:14:08,314 --> 00:14:11,184
CLINGEN DID IT, AND MOST

377
00:14:11,184 --> 00:14:13,453
RECENTLY IOVANCE ACQUIRED IT FLO

378
00:14:13,453 --> 00:14:18,057
YE40YEARS LATER IN 2023.

379
00:14:18,057 --> 00:14:19,859
THE GREAT PROMISE OF IL-2 WAS

380
00:14:19,859 --> 00:14:20,993
DRIVEN BY THE FACT THAT YOU

381
00:14:20,993 --> 00:14:22,395
COULD SEE EXTRAORDINARY LONG

382
00:14:22,395 --> 00:14:25,832
LIVED RESPONSES, REALLY PROVING

383
00:14:25,832 --> 00:14:27,166
THAT IMMUNOTHERAPY WORKS, SUCH

384
00:14:27,166 --> 00:14:27,934
AS THIS GENTLEMAN WE TREATED

385
00:14:27,934 --> 00:14:30,069
HERE IN THE BRANCH AT THE

386
00:14:30,069 --> 00:14:31,504
CLINICAL CENTER WHO HAD A LIVER

387
00:14:31,504 --> 00:14:33,373
THAT LOOKED JUST AS BAD AS HIS

388
00:14:33,373 --> 00:14:34,674
LUNGS AND AFTER A SINGLE COURSE

389
00:14:34,674 --> 00:14:38,845
OF IL-2, HAD LONG-LIVED COMPLETE

390
00:14:38,845 --> 00:14:40,713
RESPONSE.

391
00:14:40,713 --> 00:14:42,782
THERE WERE SOME RANDOMIZED

392
00:14:42,782 --> 00:14:43,649
TRIALS ALONG THE WAY.

393
00:14:43,649 --> 00:14:46,052
THE SECOND ONE WAS THIS

394
00:14:46,052 --> 00:14:46,819
RANDOMIZED PHASE 3 TRIAL IN WHAT

395
00:14:46,819 --> 00:14:49,889
WAS CALLED THE LACIL2 WORKING

396
00:14:49,889 --> 00:14:52,158
GROUP THAT WAS SET UP BY VINCE

397
00:14:52,158 --> 00:14:53,159
DAVITA TO TRY AND PROVE THAT

398
00:14:53,159 --> 00:14:54,694
STEVE AND I AND OTHER PEOPLE IN

399
00:14:54,694 --> 00:14:56,162
THE BRANCH WERE NOT CRIMINALS,

400
00:14:56,162 --> 00:14:57,530
THAT WE WERE NOT MAKING UP ALL

401
00:14:57,530 --> 00:14:59,232
THIS STUFF, THAT IT REALLY DID

402
00:14:59,232 --> 00:15:00,066
WORK.

403
00:15:00,066 --> 00:15:03,035
AND THIS WAS A STUDY DONE

404
00:15:03,035 --> 00:15:05,304
SHOWING -- COMPARING HIGH DOSE

405
00:15:05,304 --> 00:15:08,074
IL-2 TO A LOWER DOSE IL-2 AND

406
00:15:08,074 --> 00:15:10,443
INTERFERON REGIMEN.

407
00:15:10,443 --> 00:15:12,078
BUT THAT WAS THE SECOND

408
00:15:12,078 --> 00:15:13,346
RANDOMIZED TREATMENT.

409
00:15:13,346 --> 00:15:14,814
THE FIRST ONE WAS ONE DONE BY

410
00:15:14,814 --> 00:15:16,582
JIM YANG, WHERE HE COMPARED HIGH

411
00:15:16,582 --> 00:15:22,455
DOSE AND LOW DOSE IL-2 AND IL-2Y

412
00:15:22,455 --> 00:15:23,456
CANCER PATIENTS AND SHOWED THAT

413
00:15:23,456 --> 00:15:25,658
THOSE CRs WERE MUCH MORE

414
00:15:25,658 --> 00:15:26,626
DURABLE THAN PATIENTS GETTING

415
00:15:26,626 --> 00:15:27,493
HIGH DOSE IL-2.

416
00:15:27,493 --> 00:15:29,262
SO FOR THOSE -- THIS IS A LITTLE

417
00:15:29,262 --> 00:15:31,330
ADVERTISEMENT, WE JUST DID A

418
00:15:31,330 --> 00:15:34,534
REPORT IN NATURE IMMUNOLOGY ON

419
00:15:34,534 --> 00:15:35,168
CD28.

420
00:15:35,168 --> 00:15:38,337
MY PERCEPTION OF IMMUNOLOGY AND

421
00:15:38,337 --> 00:15:39,705
TUMOR IMMUNOLOGY IS THAT ALL

422
00:15:39,705 --> 00:15:42,041
RHODES LEAD TO CD28 AND COSTIM,

423
00:15:42,041 --> 00:15:44,477
WHETHER THAT BE CHECKPOINTS,

424
00:15:44,477 --> 00:15:46,679
REQUIREMENT FOR CD28 IN CAR-T

425
00:15:46,679 --> 00:15:48,481
CELLS, THE SMALL MOLECULE

426
00:15:48,481 --> 00:15:50,283
INHIBITORS, OR NOW NEW

427
00:15:50,283 --> 00:15:51,918
GENERATION OF COSTIMULATORY

428
00:15:51,918 --> 00:15:53,519
MOLECULES, AND THEY ALL LEAD

429
00:15:53,519 --> 00:15:55,188
ULTIMATELY TO IL-2 PRODUCTION.

430
00:15:55,188 --> 00:15:58,491
SO I LIKE TO SAY THAT THE EARLY

431
00:15:58,491 --> 00:16:00,560
INTUITION THAT IL-2 WAS

432
00:16:00,560 --> 00:16:01,727
IMPORTANT WAS CORRECT.

433
00:16:01,727 --> 00:16:05,565
THIS GOES BACK TO THE SIGNAL

434
00:16:05,565 --> 00:16:07,433
1 SIGNAL 2 OF BRECHER AND COHEN,

435
00:16:07,433 --> 00:16:09,302
THE DISASTROUS USE OF ANTIBODIES

436
00:16:09,302 --> 00:16:11,804
TO CD28 WHICH CAUSED THE

437
00:16:11,804 --> 00:16:12,238
CYTOKINE STORM.

438
00:16:12,238 --> 00:16:13,639
SOME OF YOU MAY BE AWARE OF

439
00:16:13,639 --> 00:16:13,840
THAT.

440
00:16:13,840 --> 00:16:15,608
THE USE OF CHECKPOINT INHIBITORS

441
00:16:15,608 --> 00:16:18,277
WHICH LARGELY WORK BY LIBERATING

442
00:16:18,277 --> 00:16:20,546
CD28 SIGNALING, THE ABILITY OF

443
00:16:20,546 --> 00:16:22,748
CAR-T CELLS TO WORK.

444
00:16:22,748 --> 00:16:25,685
THE FIRST GENERATION DONE BY PAT

445
00:16:25,685 --> 00:16:27,220
HU HERE AT THE BRANCH DIDN'T

446
00:16:27,220 --> 00:16:29,188
WORK ALL THAT WELL BUT WHEN YOU

447
00:16:29,188 --> 00:16:31,157
PUT A CD28 SIGNALING DOMAIN IN,

448
00:16:31,157 --> 00:16:32,692
ALL OF A SUDDEN THEY START

449
00:16:32,692 --> 00:16:34,427
WORKING, WE NOW HAVE A NEW

450
00:16:34,427 --> 00:16:35,328
GENERATION.

451
00:16:35,328 --> 00:16:36,329
IL-2 IS NOT OVER.

452
00:16:36,329 --> 00:16:39,699
JONATHAN WARY IS GOING TO COME

453
00:16:39,699 --> 00:16:41,334
VISIT THE BRANCH, I GUESS, FOR

454
00:16:41,334 --> 00:16:43,736
THE NEXT SITE VISIT, SHOWED THAT

455
00:16:43,736 --> 00:16:46,472
MANY OF THE SENESCENCE MARKERS

456
00:16:46,472 --> 00:16:51,611
SEEN WITH EXPRESSION OF TOX

457
00:16:51,611 --> 00:16:55,715
DRIVING PD-1, LAG3, TIM 3, ET

458
00:16:55,715 --> 00:16:58,184
CETERA CAN BE OVERCOME IN PART

459
00:16:58,184 --> 00:17:00,186
BY PHOSPHOSTAT5 EXPRESSION AS

460
00:17:00,186 --> 00:17:02,021
THE ANECDOTE DRIVEN LARGELY BY

461
00:17:02,021 --> 00:17:03,022
IL-2.

462
00:17:03,022 --> 00:17:05,591
IN A MODEL, IN A MURINE MODEL

463
00:17:05,591 --> 00:17:08,527
WHERE HE ADOPTIVELY TRANSFERRED

464
00:17:08,527 --> 00:17:11,530
CELLS, THOSE CELLS THAT HAD

465
00:17:11,530 --> 00:17:12,431
PHOSPHOSTAT5 CONSTITUTIVELY

466
00:17:12,431 --> 00:17:13,499
ACTIVE WERE MUCH MORE EFFECTIVE

467
00:17:13,499 --> 00:17:15,568
IN MEDIATING ANTITUMOR EFFECTS

468
00:17:15,568 --> 00:17:18,304
THAN THOSE WITHOUT.

469
00:17:18,304 --> 00:17:22,708
AL, TWO GROUPS REPORTED RECENTLY

470
00:17:22,708 --> 00:17:26,212
IN NATURE THAT PG2 INHIBITS IL-2

471
00:17:26,212 --> 00:17:27,813
SIGNALING AND IT DOES THIS

472
00:17:27,813 --> 00:17:29,482
THROUGH A VERY INTERESTING

473
00:17:29,482 --> 00:17:31,450
PATHWAY OF DOWN REGULATING THE

474
00:17:31,450 --> 00:17:34,587
ILIL-2 RECEPTOR GAMMA CHAIN.

475
00:17:34,587 --> 00:17:36,489
SO AGAIN, SIGNALING THE

476
00:17:36,489 --> 00:17:38,991
IMPORTANT ROLE OF IL-2 IN THE

477
00:17:38,991 --> 00:17:39,458
BIOLOGY.

478
00:17:39,458 --> 00:17:40,893
I SHOULD SAY IT'S BEEN A REALLY

479
00:17:40,893 --> 00:17:46,098
LONELY TIME IN SIGHT KINE IN CYY

480
00:17:46,098 --> 00:17:47,099
OSMGHT WE HAVEN'T HAD A NEW

481
00:17:47,099 --> 00:17:49,902
APPROVAL IN CYTOKINE SINCE 1994,

482
00:17:49,902 --> 00:17:55,575
UNTIL THE APPROVAL OF THE IL 15,

483
00:17:55,575 --> 00:17:58,878
ANKTIVA FOR BLADDER CANCER.

484
00:17:58,878 --> 00:18:00,947
I WROTE BOOKS ON CYTOKINES, I

485
00:18:00,947 --> 00:18:01,814
THOUGHT THAT WAS GOING TO BE THE

486
00:18:01,814 --> 00:18:03,015
WAY HOME BUT IT ACTUALLY TURNED

487
00:18:03,015 --> 00:18:07,320
OUT TO BE CELL THERAPY.

488
00:18:07,320 --> 00:18:11,557
MATT KIEVER AND -- CHAMPIONED

489
00:18:11,557 --> 00:18:12,758
THIS IN MOUSE MODELS BUT THE

490
00:18:12,758 --> 00:18:15,294
WORK THAT WAS DONE HERE IN THE

491
00:18:15,294 --> 00:18:15,928
BRANCH WAS SEMINAL.

492
00:18:15,928 --> 00:18:20,866
SOME OF YOU MAY NOT KNOW IT, BUT

493
00:18:20,866 --> 00:18:21,968
THE FIRST CELL THERAPIES WERE

494
00:18:21,968 --> 00:18:23,269
ACTUALLY SENSITIZED BIG

495
00:18:23,269 --> 00:18:25,471
LYMPHOCYTES TO HUMAN TUMORS THAT

496
00:18:25,471 --> 00:18:26,339
NORM WALLMARK DID.

497
00:18:26,339 --> 00:18:30,176
THIS WAS NEVER PUBLISHED.

498
00:18:30,176 --> 00:18:32,378
THEN SUBSEQUENTLY THE LAK

499
00:18:32,378 --> 00:18:34,680
STUDIES THAT WE CONDUCTED

500
00:18:34,680 --> 00:18:36,282
PUBLISHED IN '80, THEN THE THING

501
00:18:36,282 --> 00:18:38,250
THAT OPENED UP THE DOORS, THE

502
00:18:38,250 --> 00:18:40,987
COMBINATION OF IL-2 AND LAK IN

503
00:18:40,987 --> 00:18:42,054
1985 WITH THIS NEW ENGLAND

504
00:18:42,054 --> 00:18:43,422
JOURNAL PAPER.

505
00:18:43,422 --> 00:18:44,590
YUTAKA KAWAKAMI AND I SHOWED

506
00:18:44,590 --> 00:18:46,792
THAT IL 4 WAS INDEED A T-CELL

507
00:18:46,792 --> 00:18:49,095
GROWTH FACTOR, AND IT HELPED

508
00:18:49,095 --> 00:18:51,931
LAUNCH THE TIL PROGRAMS, AND

509
00:18:51,931 --> 00:18:54,767
THEN SINCE THEN, IT'S BEEN

510
00:18:54,767 --> 00:18:56,869
AMAZING THAT THE CELL THERAPY

511
00:18:56,869 --> 00:18:58,604
LANDSCAPE IS REALLY INCREDIBLY

512
00:18:58,604 --> 00:18:59,372
CROWDED AND COMPLEX NOW.

513
00:18:59,372 --> 00:19:02,875
I WAS AT A LITTLE COMPANY CALLED

514
00:19:02,875 --> 00:19:04,744
IOVANCE, I'M GLAD TO SEE SOME OF

515
00:19:04,744 --> 00:19:06,145
MY COLLEAGUES STILL HERE, HELPED

516
00:19:06,145 --> 00:19:07,747
TO DEVELOP THE PROPOSAL THAT

517
00:19:07,747 --> 00:19:09,448
JUST GOT APPROVED THIS LAST

518
00:19:09,448 --> 00:19:09,715
FEBRUARY.

519
00:19:09,715 --> 00:19:11,984
IF YOU LOOK AT ALL THE TIL

520
00:19:11,984 --> 00:19:12,618
COMPANIES, THERE WAS SOMETHING

521
00:19:12,618 --> 00:19:15,121
LIKE 20 OF THEM THAT HAD BEEN

522
00:19:15,121 --> 00:19:16,222
DEVELOPED AGAIN LARGELY COMING

523
00:19:16,222 --> 00:19:17,656
OUT OF WORK BY STEVE AND HIS

524
00:19:17,656 --> 00:19:19,492
COLLEAGUES HERE AT THE BRANCH.

525
00:19:19,492 --> 00:19:21,894
WE GOT OUT OF THE BUSINESS ONLY

526
00:19:21,894 --> 00:19:23,763
BECAUSE OF ITS COSTLINESS.

527
00:19:23,763 --> 00:19:26,832
THERE ARE NEW ENTREES, CONTROL

528
00:19:26,832 --> 00:19:29,268
THERAPEUTICS IN CHICAGO, AND

529
00:19:29,268 --> 00:19:31,470
KENDALL SQUARE, MICHAEL BENSON

530
00:19:31,470 --> 00:19:35,341
IS HERE FROM THERE, BUT I NSTILL

531
00:19:35,341 --> 00:19:36,909
BIOJUST GOT OUT AND ACHILLES

532
00:19:36,909 --> 00:19:37,977
JUST GOT OUT OF THE BUSINESS.

533
00:19:37,977 --> 00:19:39,779
I'D LIKE TO THANK JAMES GULLEY,

534
00:19:39,779 --> 00:19:43,482
WHO HELPED PREPARE ME FOR MY NEW

535
00:19:43,482 --> 00:19:46,419
ROLE, WHICH IS AS NEW EDITOR AND

536
00:19:46,419 --> 00:19:48,754
CHIEF FOR GITSI AND ENCOURAGE

537
00:19:48,754 --> 00:19:50,923
ANY OF YOU WHO HAVE GOOD

538
00:19:50,923 --> 00:19:52,525
MANUSCRIPTS TO SEND THEM MY WAY.

539
00:19:52,525 --> 00:19:52,858
AND THAT'S IT.

540
00:19:52,858 --> 00:19:53,893
THANK YOU FOR YOUR ATTENTION.

541
00:19:53,893 --> 00:20:02,134
[APPLAUSE]

542
00:20:02,134 --> 00:20:03,836
>> WE HAVE A FEW MINUTES
SO IF

543
00:20:03,836 --> 00:20:05,704
THERE ARE QUESTIONS, WE CAN TAKE

544
00:20:05,704 --> 00:20:07,106
THEM, OTHERWISE WE'LL GO TO THE

545
00:20:07,106 --> 00:20:17,349
NEXT SPEAKER.

546
00:20:18,784 --> 00:20:19,719
OKAY, SO OUR NEXT SPEAKER IS

547
00:20:19,719 --> 00:20:24,256
GOING TO BE JAMES MULE FROM THE

548
00:20:24,256 --> 00:20:34,266
MOFFITT CANCER INSTITUTE.

549
00:20:34,266 --> 00:20:35,868
>> STEVE, IT'S WONDERFUL
TO SEE

550
00:20:35,868 --> 00:20:36,535
YOU AGAIN.

551
00:20:36,535 --> 00:20:39,105
I JOINED THE BRANCH COMING OUT

552
00:20:39,105 --> 00:20:42,041
OF THE FRED HUTCH IN SEATTLE.

553
00:20:42,041 --> 00:20:47,713
I JOINED THE BRANCH IN '83, AND

554
00:20:47,713 --> 00:20:49,782
IT CHANGED MY LIFE

555
00:20:49,782 --> 00:20:51,817
PROFESSIONALLY FOR SURE.

556
00:20:51,817 --> 00:20:53,519
AND SO IT'S A SPECIAL HONOR TO

557
00:20:53,519 --> 00:20:57,957
BE HERE TO CELEBRATE THIS 50TH

558
00:20:57,957 --> 00:20:58,290
ANNIVERSARY.

559
00:20:58,290 --> 00:20:59,625
IT'S REALLY A WONDERFUL

560
00:20:59,625 --> 00:21:01,694
EXPERIENCE.

561
00:21:01,694 --> 00:21:03,429
SO I'M GOING TO GIVE YOU SORT OF

562
00:21:03,429 --> 00:21:05,397
A QUICK HISTORY OF THE

563
00:21:05,397 --> 00:21:09,368
DEVELOPMENT OF IL IL-2

564
00:21:09,368 --> 00:21:10,369
PRECLINICALLY, AND THEN ALSO

565
00:21:10,369 --> 00:21:12,505
TALK ABOUT THE PRE-CLINICAL WORK

566
00:21:12,505 --> 00:21:14,473
WITH LAK CELLS, AND IF TIME

567
00:21:14,473 --> 00:21:15,808
PERMITS, I'LL GIVE YOU A SENSE

568
00:21:15,808 --> 00:21:18,144
OF SOME OF THE THINGS I'M DOING

569
00:21:18,144 --> 00:21:23,115
NOW.

570
00:21:23,115 --> 00:21:25,384
SO WE USED TO CALL THE CYTOKINE

571
00:21:25,384 --> 00:21:29,655
OF THE MONTH CLUB, AND AFTER WE

572
00:21:29,655 --> 00:21:33,092
STARTED THE WORK WITH CETUS, A

573
00:21:33,092 --> 00:21:34,193
NUMBER OF OTHER COMPANIES

574
00:21:34,193 --> 00:21:36,495
STARTED COMING TO DR. ROSENBERG

575
00:21:36,495 --> 00:21:39,565
ABOUT OPPORTUNITIES WITH OTHER

576
00:21:39,565 --> 00:21:40,032
CYTOKINES.

577
00:21:40,032 --> 00:21:40,966
THIS IS JUST A PARTIAL LIST

578
00:21:40,966 --> 00:21:42,268
DURING THE TIME I WAS AT THE

579
00:21:42,268 --> 00:21:45,337
BRANCH.

580
00:21:45,337 --> 00:21:46,639
A NUMBER OF PUBLICATIONS HAD

581
00:21:46,639 --> 00:21:51,477
COME OUT OF THAT.

582
00:21:51,477 --> 00:21:53,112
DEANX, A CORPORATION IN PALO

583
00:21:53,112 --> 00:21:54,880
ALTO WAS INVOLVED, GENETICS

584
00:21:54,880 --> 00:21:56,282
INSTITUTE IN BOSTON AND OTHER

585
00:21:56,282 --> 00:21:57,917
COMPANIES.

586
00:21:57,917 --> 00:21:59,451
BUT I WANT TO -- AS I SAID

587
00:21:59,451 --> 00:22:01,520
EARLIER, I'M GOING TO FOCUS MOST

588
00:22:01,520 --> 00:22:05,991
OF THE TIME ON IL-2.

589
00:22:05,991 --> 00:22:07,760
SOME OF YOU MAY NOT KNOW THIS,

590
00:22:07,760 --> 00:22:11,931
BUT CETUS WAS ACTUALLY THE FIRST

591
00:22:11,931 --> 00:22:13,465
BIOTECH COMPANY ON THE PLANET.

592
00:22:13,465 --> 00:22:16,502
IT WAS NOT GENENTECH ACTUALLY,

593
00:22:16,502 --> 00:22:20,873
CETUS STARTED FIVE YEARS BEFORE

594
00:22:20,873 --> 00:22:23,409
GENENTECH IN THIS SMALL BUILDING

595
00:22:23,409 --> 00:22:26,245
IN BERKELEY, CALIFORNIA.

596
00:22:26,245 --> 00:22:31,150
IT QUICKLY, AS MIKE POINTED OUT,

597
00:22:31,150 --> 00:22:32,484
EXPANDED DURING THE TIME OF

598
00:22:32,484 --> 00:22:38,524
THEIR WORK WITH US WITH THE

599
00:22:38,524 --> 00:22:42,661
ACQUISITION OF CETUS BY KI CHIR.

600
00:22:42,661 --> 00:22:47,066
THIS WAS THE BUILDING IN

601
00:22:47,066 --> 00:22:48,667
EMERYVILLE WHICH MANY OF US HAD

602
00:22:48,667 --> 00:22:49,468
SPENT TIME VISITING.

603
00:22:49,468 --> 00:22:51,070
NOW YOU LOOK TODAY AT EMERYVILLE

604
00:22:51,070 --> 00:22:53,172
AND YOU CAN SEE THE CIRCLE WHERE

605
00:22:53,172 --> 00:22:55,374
THE OLD CETUS CHIRON BUILDING

606
00:22:55,374 --> 00:22:59,511
USED TO BE, AND THE REMARKABLE

607
00:22:59,511 --> 00:23:03,515
BIOTECH EXPLOSION THAT HAS OCC 

608
00:23:03,515 --> 00:23:04,216
OCCURRED OVER THE YEARS.

609
00:23:04,216 --> 00:23:10,356
IT'S NOW CALLED EMERY YARDS.

610
00:23:10,356 --> 00:23:12,324
SO THIS LAUNCHED EVERYTHING,

611
00:23:12,324 --> 00:23:14,727
THIS PAPER WITH STEVE IN SCIENCE

612
00:23:14,727 --> 00:23:16,929
WITH COLLEAGUES AT CETUS.

613
00:23:16,929 --> 00:23:18,864
WHICH WAS THE FIRST USE OF

614
00:23:18,864 --> 00:23:23,035
RECOMBINANT IL-2 PRODUCED IN

615
00:23:23,035 --> 00:23:23,903
E. COLI.

616
00:23:23,903 --> 00:23:25,671
WE WERE OFF TO THE RACES.

617
00:23:25,671 --> 00:23:27,873
THIS WAS ONE OF THE FIGURES IN

618
00:23:27,873 --> 00:23:32,011
THE PAPER, THE CLOAPING OF THE E

619
00:23:32,011 --> 00:23:35,881
IL-2 GENE BY ACRYLAMIDE GEL, IT

620
00:23:35,881 --> 00:23:37,116
WAS ABLE TO BE PURIFIED IN THE

621
00:23:37,116 --> 00:23:39,218
COMPANY USING THESE MEGA COLUMNS

622
00:23:39,218 --> 00:23:41,086
THAT STOOD FROM THE FLOOR TO THE

623
00:23:41,086 --> 00:23:43,322
CEILING OF THREE STORIES IN THE

624
00:23:43,322 --> 00:23:47,493
BUILDING.

625
00:23:47,493 --> 00:23:51,063
BUT STEVE MAY REMEMBER THIS.

626
00:23:51,063 --> 00:23:52,765
THE FIRST OR SECOND OR THIRD LOT

627
00:23:52,765 --> 00:23:54,633
THEY SENT US, WE PUT IN MICE AND

628
00:23:54,633 --> 00:23:56,669
ALL THE MICE DIED.

629
00:23:56,669 --> 00:24:01,640
AND IT WAS BECAUSE OF THE

630
00:24:01,640 --> 00:24:03,409
CONTAMINATION WITH ENDO TOXIN,

631
00:24:03,409 --> 00:24:04,710
WHICH, AGAIN, THEY QUICKLY TOOK

632
00:24:04,710 --> 00:24:08,647
CARE OF THAT PROBLEM AND SENT US

633
00:24:08,647 --> 00:24:11,116
THE BEST STUFF.

634
00:24:11,116 --> 00:24:13,519
AND YOU CAN SEE THE 15KD CLEANED

635
00:24:13,519 --> 00:24:18,824
UP SAMPLE OF IL-2.

636
00:24:18,824 --> 00:24:19,625
SO STEVE SHOWED THAT THE

637
00:24:19,625 --> 00:24:21,093
MATERIAL COULD, IN FACT,

638
00:24:21,093 --> 00:24:23,896
REPLICATE WHICH WAS DONE IN

639
00:24:23,896 --> 00:24:28,067
NATURAL IL-2, THE CREATION OR

640
00:24:28,067 --> 00:24:30,169
GENERATION OF LAK CELLS, BOTH IN

641
00:24:30,169 --> 00:24:32,104
THE MOUSE AND THE HUMAN.

642
00:24:32,104 --> 00:24:39,111
AND AS I MENTIONED, THIS WAS A

643
00:24:39,111 --> 00:24:39,545
REVOLUTION.

644
00:24:39,545 --> 00:24:43,549
I MEAN, TO LOOK AT THE ABILITY

645
00:24:43,549 --> 00:24:45,484
OF THIS EQUIPMENT IN THE COMPANY

646
00:24:45,484 --> 00:24:49,621
IN THE EARLY YEARS OF BIOTECH

647
00:24:49,621 --> 00:24:51,056
WAS PRETTY ASTONISHING.

648
00:24:51,056 --> 00:24:53,025
THIS WAS ONE EXAMPLE OF THE

649
00:24:53,025 --> 00:24:54,993
PRODUCTION OF THE E. COLI AT THE

650
00:24:54,993 --> 00:24:57,696
COMPANY.

651
00:24:57,696 --> 00:24:59,798
STEVE MAY NOT HAVE SEEN THIS

652
00:24:59,798 --> 00:25:03,836
ONE, BUT THIS WAS -- I TOOK A

653
00:25:03,836 --> 00:25:07,573
LIST OF ALL THE IL-2 THAT WAS ON

654
00:25:07,573 --> 00:25:10,209
THE FREEZER DOOR OUTSIDE THE

655
00:25:10,209 --> 00:25:13,345
LAB, AND THE LOT NUMBERS ARE

656
00:25:13,345 --> 00:25:14,546
SHOWN, DURING THE TIME I WAS IN

657
00:25:14,546 --> 00:25:15,547
THE BRANCH.

658
00:25:15,547 --> 00:25:18,217
NOW THINK ABOUT THIS.

659
00:25:18,217 --> 00:25:20,452
FOUR TIMES 10 TO THE 11TH

660
00:25:20,452 --> 00:25:21,887
INTERNATIONAL UNITS OF IL-2 WERE

661
00:25:21,887 --> 00:25:24,189
USED DURING THAT TIME.

662
00:25:24,189 --> 00:25:26,158
AND THIS WAS PURELY FOR THE

663
00:25:26,158 --> 00:25:27,259
PRE-CLINICAL WORK.

664
00:25:27,259 --> 00:25:28,560
AND I REMEMBER STEVE SAYING TO

665
00:25:28,560 --> 00:25:31,497
ME ONE DAY, HE SAYS, JIM, IF WE

666
00:25:31,497 --> 00:25:33,932
EVER COME BACK AS MICE, WE'RE IN

667
00:25:33,932 --> 00:25:35,334
TROUBLE.

668
00:25:35,334 --> 00:25:40,205
[LAUGHTER]

669
00:25:40,205 --> 00:25:43,108
SO THEN WE WENT ON WITH THIS

670
00:25:43,108 --> 00:25:44,643
JOURNAL OF EXPERIMENTAL MEDICINE

671
00:25:44,643 --> 00:25:48,113
PAPER, WHICH REALLY SHOWED THE

672
00:25:48,113 --> 00:25:51,417
ABILITY OF RECOMBINANT IL-2 AT

673
00:25:51,417 --> 00:25:52,951
HIGH DOSE TO IMPACT ESTABLISHED

674
00:25:52,951 --> 00:25:54,920
TUMORS IN MICE.

675
00:25:54,920 --> 00:25:57,956
AND THIS WAS THE RESULT OF 36

676
00:25:57,956 --> 00:25:59,858
CONSECUTIVE EXPERIMENTS THAT

677
00:25:59,858 --> 00:26:02,561
WE'VE SHOWN IN THE PAPER WITH

678
00:26:02,561 --> 00:26:03,996
THREE-DAY EARLY MULL KNOWARY

679
00:26:03,996 --> 00:26:04,430
METASTASES.

680
00:26:04,430 --> 00:26:10,436
YOU CAN SEE THAT MORE IL-2,

681
00:26:10,436 --> 00:26:13,071
BETTER EVENT IN MICE.

682
00:26:13,071 --> 00:26:14,072
 -- BETTER EFFECT IN MICE.

683
00:26:14,072 --> 00:26:15,040
AND THAT'S WHERE I THINK WE CAME

684
00:26:15,040 --> 00:26:18,343
UP WITH THE ONE MORE DOSE LOTZE

685
00:26:18,343 --> 00:26:24,583
FOR IL-2.

686
00:26:24,583 --> 00:26:26,084
AND THIS WAS 15 CONSECUTIVE

687
00:26:26,084 --> 00:26:29,288
EXPERIMENTS IN ALREADY ESTABL 

688
00:26:29,288 --> 00:26:30,589
ESTABLISHED LUNG TUMORS WITH

689
00:26:30,589 --> 00:26:31,690
SARCOMA, AND AGAIN, YOU CAN SEE

690
00:26:31,690 --> 00:26:37,162
THE EFFICACY OF RECOMBINANT IL-2

691
00:26:37,162 --> 00:26:38,464
IMPACTING AND CAUSING REGRESSION

692
00:26:38,464 --> 00:26:42,768
OF ACTUALLY ESTABLISHED CANCERS.

693
00:26:42,768 --> 00:26:43,836
AND THIS WAS SHOWN AS WELL NOT

694
00:26:43,836 --> 00:26:46,338
ONLY IN THE LUNGS BUT

695
00:26:46,338 --> 00:26:46,905
SUBCUTANEOUS TUMORS.

696
00:26:46,905 --> 00:26:48,173
YOU COULD SEE THE REGRESSION OF

697
00:26:48,173 --> 00:26:52,044
ALREADY ESTABLISHED TUMORS AT

698
00:26:52,044 --> 00:26:52,911
SUBCUTANEOUS SITES.

699
00:26:52,911 --> 00:26:56,181
WITH STEVE EDINGHAUSEN JOINING

700
00:26:56,181 --> 00:26:59,451
US IN THE LAB, STEVE HAD HIM ON

701
00:26:59,451 --> 00:27:04,089
THIS PROJECT, WAS TO LOOK AT

702
00:27:04,089 --> 00:27:05,190
STIMULATION OF LYMPHOCYTES

703
00:27:05,190 --> 00:27:07,493
WITHIN THE MOUSE WHEN ONE WAS

704
00:27:07,493 --> 00:27:10,128
GIVEN IL-2 TO START TO GET A

705
00:27:10,128 --> 00:27:12,664
SENSE OF THE MECHANISMS INVOLVED

706
00:27:12,664 --> 00:27:17,436
IN THE REGRESSION OF TUMORS BY

707
00:27:17,436 --> 00:27:17,936
THAT INTERLEUKIN.

708
00:27:17,936 --> 00:27:19,104
I WON'T GO THROUGH ALL THE

709
00:27:19,104 --> 00:27:22,040
SPECIFICS OTHER THAN TO SAY THAT

710
00:27:22,040 --> 00:27:23,542
HE DID SHOW THAT IL-2 COULD

711
00:27:23,542 --> 00:27:27,779
CAUSE THE PROLIFERATION OF

712
00:27:27,779 --> 00:27:28,981
LYMPHOCYTES IN THE

713
00:27:28,981 --> 00:27:30,082
IMMUNE-RELATED ORGANS, BUT AS

714
00:27:30,082 --> 00:27:35,754
YOU WOULD EXPECT, NOT ELSEWHERE

715
00:27:35,754 --> 00:27:36,755
AND SO FORTH.

716
00:27:36,755 --> 00:27:41,994
SO IL-2 COULD CAUSE SIGNIFICANT

717
00:27:41,994 --> 00:27:43,195
PROLIFERATION IN THE ANIMAL

718
00:27:43,195 --> 00:27:46,598
SYSTEMICALLY AT MULTIPLE

719
00:27:46,598 --> 00:27:50,736
LYMPHOID ORGAN SITES.

720
00:27:50,736 --> 00:27:53,505
HE ALSO SHOWED NOT ONLY DID IT

721
00:27:53,505 --> 00:27:54,873
CAUSE PROLIFERATION BUT IT

722
00:27:54,873 --> 00:27:56,208
PRODUCED LAK CELLS IN VIVO.

723
00:27:56,208 --> 00:27:57,242
SO THIS WAS TO SHOW THAT YOU

724
00:27:57,242 --> 00:28:02,681
COULD TAKE CELLS OUT OF THOSE

725
00:28:02,681 --> 00:28:03,882
MICE, EXPOSE THEM TO FRESH TUMOR

726
00:28:03,882 --> 00:28:05,284
CELLS IN CULTURE AND SHOW THAT

727
00:28:05,284 --> 00:28:08,387
THEY COULD, IN FACT, LYSE

728
00:28:08,387 --> 00:28:09,454
MULTIPLE TYPES OF FRESH TUMOR

729
00:28:09,454 --> 00:28:12,958
CELLS.

730
00:28:12,958 --> 00:28:15,494
WE THEN WENT ON TO GIVE A MORE

731
00:28:15,494 --> 00:28:20,832
IN DEPTH ANALYSIS OF WHAT WAS

732
00:28:20,832 --> 00:28:26,538
GOING ON IN THERAPEUTIC EFFICACY

733
00:28:26,538 --> 00:28:27,039
OF MICE.

734
00:28:27,039 --> 00:28:30,676
THIS TO ME WAS ONE OF THE MORE

735
00:28:30,676 --> 00:28:31,877
ASTONISHING FINDINGS THAT WE HAD

736
00:28:31,877 --> 00:28:35,147
WHERE STEVE ASKED US TO COMPARE

737
00:28:35,147 --> 00:28:36,014
NON-IMMUNOGENIC SARCOMAS THAT WE

738
00:28:36,014 --> 00:28:40,519
HAD IN THE LAB, WHICH WAS MCA101

739
00:28:40,519 --> 00:28:42,154
AND 102, WHICH WAS

740
00:28:42,154 --> 00:28:43,155
NON-IMMUNOGENIC DEFINED BY THE

741
00:28:43,155 --> 00:28:44,756
INABILITY OF THESE TUMOR CELLS

742
00:28:44,756 --> 00:28:46,658
BY DIFFERENT MEANS TO IMMUNIZE

743
00:28:46,658 --> 00:28:49,695
THE MICE TO REJEBT VIABLE TUMOR.

744
00:28:49,695 --> 00:28:51,330
SO THESE WERE CLASSICALLY

745
00:28:51,330 --> 00:28:52,764
NON-IMMUNOGENIC.

746
00:28:52,764 --> 00:28:56,134
AND MCA-105 AND 106, WHICH WERE

747
00:28:56,134 --> 00:28:59,638
CLASSICALLY DEFINED AS WEAKLEY

748
00:28:59,638 --> 00:29:00,205
IMMUNOGENIC.

749
00:29:00,205 --> 00:29:03,041
GIVE IL-2 AND YOU COULD SEE THAT

750
00:29:03,041 --> 00:29:06,979
THREE DAY METS, RARTLESS IF THE

751
00:29:06,979 --> 00:29:08,947
TEU NOR WAS NON-IMMUNOGENIC OR

752
00:29:08,947 --> 00:29:09,848
IMMUNOGENIC, YOU COULD CAUSE

753
00:29:09,848 --> 00:29:10,182
REGRESSION.

754
00:29:10,182 --> 00:29:11,049
HOWEVER, WITH THE MORE

755
00:29:11,049 --> 00:29:14,653
ESTABLISHED TUMORS, IT WAS ONLY

756
00:29:14,653 --> 00:29:17,155
THE WEAKLY IMMUNOGENIC TUMORS

757
00:29:17,155 --> 00:29:19,558
THAT RESPONDED TO HIGH DOSE IL-2

758
00:29:19,558 --> 00:29:21,426
AND DURING THAT 10-DAY PERIOD,

759
00:29:21,426 --> 00:29:23,395
ALLOWED THE IMMUNE SYSTEM TO

760
00:29:23,395 --> 00:29:24,396
GENERATE T CELLS THAT THEN COULD

761
00:29:24,396 --> 00:29:26,798
REACT TO THE IL-2 AND CAUSE

762
00:29:26,798 --> 00:29:27,099
REGRESSION.

763
00:29:27,099 --> 00:29:30,736
SO IN THIS STUDY, IMMUNOGENIC

764
00:29:30,736 --> 00:29:32,838
TUMORS, IL-2 WAS EFFECTIVE.

765
00:29:32,838 --> 00:29:34,640
NON-IMMUNOGENIC TUMORS, ONLY

766
00:29:34,640 --> 00:29:37,075
EARLY ON DURING THE EARLY

767
00:29:37,075 --> 00:29:38,210
METASTATIC STAGE, AND THOSE WERE

768
00:29:38,210 --> 00:29:41,980
DUE TO THE PRO TU PRODUCTION OFK

769
00:29:41,980 --> 00:29:42,514
CELLS.

770
00:29:42,514 --> 00:29:44,883
SO LAK CELLS EARLY ON, WE SHOWED

771
00:29:44,883 --> 00:29:47,452
YOU COULD ELIMINATE THESE LAK

772
00:29:47,452 --> 00:29:50,422
CELLS WITH ANTI-ACGM1, AND YOU

773
00:29:50,422 --> 00:29:52,724
COULD LOSE THE EFFECT ON

774
00:29:52,724 --> 00:29:54,026
THREE-DAY METS OF HIGH DOSE

775
00:29:54,026 --> 00:29:58,196
IL-2.

776
00:29:58,196 --> 00:29:59,898
THE OPPOSITE WAS TRUE ON 10-DAY

777
00:29:59,898 --> 00:30:01,600
METS SO IF YOU ELIMINATE IT, AT

778
00:30:01,600 --> 00:30:03,468
THAT TIME IT WAS CALLED LY2, WAS

779
00:30:03,468 --> 00:30:05,971
THE MARKER FOR CD8 CELLS.

780
00:30:05,971 --> 00:30:07,939
SO WE HAD THE ABILITY TO

781
00:30:07,939 --> 00:30:11,743
ELIMINATE THOSE CELLS IN MICE,

782
00:30:11,743 --> 00:30:13,211
AND THAT ELIMINATED THE IMPACT

783
00:30:13,211 --> 00:30:17,516
OF HIGH DOSE IL-2 ON ESTABLISHED

784
00:30:17,516 --> 00:30:18,016
TUMORS.

785
00:30:18,016 --> 00:30:20,952
SO THAT REALLY MOCKED DOWN THE

786
00:30:20,952 --> 00:30:23,121
ABILITY OF US TO DISTINGUISH THE

787
00:30:23,121 --> 00:30:25,123
IMPACT OF LAK CELLS EARLY ON

788
00:30:25,123 --> 00:30:26,758
WITH T CELLS LATER ON DURING THE

789
00:30:26,758 --> 00:30:30,162
PROGRESSION OF TUMOR.

790
00:30:30,162 --> 00:30:32,898
ALONG THE SAME PATH, STEVE ASKED

791
00:30:32,898 --> 00:30:36,168
ME TO WORK WITH HIM AND OTHERS

792
00:30:36,168 --> 00:30:40,005
ON LAK CELLS AND THE ABILITY TO

793
00:30:40,005 --> 00:30:41,973
USE THOSE AT LOWER DOSES OF IL-2

794
00:30:41,973 --> 00:30:43,842
AND TO SEE IF THAT COULD IMPACT

795
00:30:43,842 --> 00:30:47,012
ON TUMORS IN MICE.

796
00:30:47,012 --> 00:30:49,514
SO THIS WAS A PAPER IN SCIENCE

797
00:30:49,514 --> 00:30:51,583
IN 1984.

798
00:30:51,583 --> 00:30:53,885
AND, IN FACT, YOU COULD SEE HERE

799
00:30:53,885 --> 00:30:57,723
THE LAK CELLS BY THEMSELVES HAD

800
00:30:57,723 --> 00:31:00,459
SOME IMPACT ON EARLY TUMOR, BUT

801
00:31:00,459 --> 00:31:03,295
WITH IL-2, YOU COULD SEE A

802
00:31:03,295 --> 00:31:04,596
DRAMATIC REDUCTION IN THE NUMBER

803
00:31:04,596 --> 00:31:07,032
OF METASTASES.

804
00:31:07,032 --> 00:31:09,101
AND THIS WAS THE FIRST PHOTO

805
00:31:09,101 --> 00:31:13,271
THAT WAS SHOWN OF THE EFFICACY

806
00:31:13,271 --> 00:31:17,342
OF LAK CELLS IN LUNG TUMORS.

807
00:31:17,342 --> 00:31:17,509
 IN

808
00:31:17,509 --> 00:31:24,516
THAT SCIENCE PAPER.

809
00:31:24,516 --> 00:31:26,284
THIS WENT ON TO SHOW THAT YOU

810
00:31:26,284 --> 00:31:29,020
COULD GENRES LAK CELLS AS EARLY

811
00:31:29,020 --> 00:31:35,127
AS -- IN CULTURE, SO NOW I'M

812
00:31:35,127 --> 00:31:36,528
GOING TO END JUST BY SHOWING YOU

813
00:31:36,528 --> 00:31:38,830
A SNAPSHOT OF WHAT WE'VE BEEN

814
00:31:38,830 --> 00:31:41,566
DEVELOPING SINCE.

815
00:31:41,566 --> 00:31:42,667
SO I'VE BEEN INTERESTED IN

816
00:31:42,667 --> 00:31:44,870
CHEMOKINES FOR A NUMBER OF

817
00:31:44,870 --> 00:31:49,141
YEARS, AND I WAS ASKED BY JCO TO

818
00:31:49,141 --> 00:31:52,878
HAVE A COMMENTARY ON A PAPER BY

819
00:31:52,878 --> 00:31:57,315
WOLF FRIDMAN'S GROUP WHICH

820
00:31:57,315 --> 00:31:59,618
SHOWED THE ACTIVITY OF WHAT WAS

821
00:31:59,618 --> 00:32:01,787
CALLED ECTOPIC LYMPH NODES AT

822
00:32:01,787 --> 00:32:06,525
THE TIME, CONNECTING TO CLINICAL

823
00:32:06,525 --> 00:32:07,392
RESPONSE IN LUNG CANCER.

824
00:32:07,392 --> 00:32:12,130
SO WHEN I WAS ASKED TO HAVE THE

825
00:32:12,130 --> 00:32:15,133
COMMENTARY, I DID A QUICK

826
00:32:15,133 --> 00:32:19,971
SEARCH, AND IF YOU GOOGLE THAT

827
00:32:19,971 --> 00:32:21,840
WITH WHATEVER SEARCH ENGINE YOU

828
00:32:21,840 --> 00:32:24,876
USE AND YOU PUT IN TERTIARY

829
00:32:24,876 --> 00:32:27,479
LYMPHOID STRUCTURES OR ECTOPIC

830
00:32:27,479 --> 00:32:29,581
LYMPH NODE TUMORS, NOTHING CAME

831
00:32:29,581 --> 00:32:29,915
UP.

832
00:32:29,915 --> 00:32:31,016
FAST FORWARD TODAY, YOU CAN SEE

833
00:32:31,016 --> 00:32:33,084
THE EXPLOSION OF ACTIVITY OF

834
00:32:33,084 --> 00:32:35,387
INDIVIDUALS NOW WORKING TO

835
00:32:35,387 --> 00:32:37,122
UNCOVER WHAT IT MEANS TO HAVE

836
00:32:37,122 --> 00:32:38,790
THESE TERTIARY LYMPHOID

837
00:32:38,790 --> 00:32:39,958
STRUCTURES IN SOLID TUMOR

838
00:32:39,958 --> 00:32:42,594
MASSES.

839
00:32:42,594 --> 00:32:47,933
SO WITH MERCK BIOINFORMATACIST,

840
00:32:47,933 --> 00:32:49,501
WE HIT ON A GENE EXPRESSION

841
00:32:49,501 --> 00:32:51,236
SIGNATURE YEARS AGO.

842
00:32:51,236 --> 00:32:55,207
THIS IS 12 YEARS AGO WHEN WE

843
00:32:55,207 --> 00:32:56,708
PUBLISHED THIS, THAT COULD

844
00:32:56,708 --> 00:32:58,009
DISTINGUISH TUMORS AS YOU CAN

845
00:32:58,009 --> 00:33:00,679
SEE GREEN VERSUS RED.

846
00:33:00,679 --> 00:33:04,382
THIS WAS FROM THE META GENE

847
00:33:04,382 --> 00:33:06,151
GROUPING OF ABOUT 96 GENES THAT

848
00:33:06,151 --> 00:33:09,221
MERCK UNCOVERED.

849
00:33:09,221 --> 00:33:11,056
WITHIN THAT GROUPING WERE A HOT

850
00:33:11,056 --> 00:33:13,892
SPOT OF 12 CHEMOKINES.

851
00:33:13,892 --> 00:33:16,428
WE THEN TOOK IT ACROSS THOUSANDS

852
00:33:16,428 --> 00:33:20,699
OF SOLID TUMOR ARRAYS.

853
00:33:20,699 --> 00:33:23,101
THIS SHOWS ONE EXAMPLE IN

854
00:33:23,101 --> 00:33:26,538
MELANOMA, WHICH, IN FACT, THE

855
00:33:26,538 --> 00:33:28,039
SIGNATURE COULD RELIABLY

856
00:33:28,039 --> 00:33:31,309
IDENTIFY WITHIN MELANOMA

857
00:33:31,309 --> 00:33:38,316
COLORECTAL CANCER, FRIDMAN USED

858
00:33:38,316 --> 00:33:39,484
IT, TERTIARY STRUCTURES WHICH

859
00:33:39,484 --> 00:33:40,719
YOU SEE SURROUNDING A TUMOR MASS

860
00:33:40,719 --> 00:33:45,957
IN A HUMAN MELANOMA.

861
00:33:45,957 --> 00:33:50,562
YOU KNOW, WHEN WE FIRST

862
00:33:50,562 --> 00:33:52,731
UNCOVERED THIS, I ASKED THE

863
00:33:52,731 --> 00:33:53,398
PATHOLOGIST, I SAID HAVE YOU

864
00:33:53,398 --> 00:33:54,699
EVER LOOKED AT THIS, HAVE YOU

865
00:33:54,699 --> 00:33:55,467
EVER SEEN THIS?

866
00:33:55,467 --> 00:33:56,001
THEY SAID NO.

867
00:33:56,001 --> 00:33:57,335
I SAID, WELL, WHY NOT?

868
00:33:57,335 --> 00:33:58,870
THEY SAID, WELL, NO ONE EVER

869
00:33:58,870 --> 00:34:03,341
ASKED US TO LOOK FOR THEM.

870
00:34:03,341 --> 00:34:08,813
AND HISTORICALLY THEY WOULD

871
00:34:08,813 --> 00:34:10,749
SCORE IMMUNE ILL FILTRATE FROM A

872
00:34:10,749 --> 00:34:11,650
1 PLUS TO A 4 PLUS.

873
00:34:11,650 --> 00:34:13,518
SO NOW YOU CAN SEE THAT THESE

874
00:34:13,518 --> 00:34:17,589
UNIQUE STRUCTURES ACTUALLY MIMIC

875
00:34:17,589 --> 00:34:18,556
PERIPHERAL LYMPH NODES TO

876
00:34:18,556 --> 00:34:23,695
SOME DEGREE WHERE YOU SEE A

877
00:34:23,695 --> 00:34:25,430
DENSE B CELL FOLLICLE IDENTIFIED

878
00:34:25,430 --> 00:34:30,802
BY CD20 SURROUNDED BY T CELLS,

879
00:34:30,802 --> 00:34:33,238
MARGINS AROUND T CELLS, 4s AND

880
00:34:33,238 --> 00:34:36,608
8s, AS WELL AS THE UNDERLYING

881
00:34:36,608 --> 00:34:40,645
FOLLICULAR RETICULAR SITES OR

882
00:34:40,645 --> 00:34:41,079
DENDRITIC CELLS.

883
00:34:41,079 --> 00:34:42,714
THIS PAPER WILL BE APPEARING IN

884
00:34:42,714 --> 00:34:43,715
NATURE MEDICINE.

885
00:34:43,715 --> 00:34:46,418
WE CONDUCTED A MOFFITT -- A

886
00:34:46,418 --> 00:34:49,054
CLINICAL TRIAL WITH AN ONCOLYTIC

887
00:34:49,054 --> 00:34:52,457
VIRUS WITH A COMPANY CALLED CG

888
00:34:52,457 --> 00:34:55,527
ONCOLOGY WITH PEMBRO.

889
00:34:55,527 --> 00:34:58,463
DRAMATIC REGRESSION OR

890
00:34:58,463 --> 00:35:00,899
ELIMINATION OF A

891
00:35:00,899 --> 00:35:01,566
NON-MUSCLE-INVASIVE BLADDER

892
00:35:01,566 --> 00:35:03,835
CANCER BY THIS THERAPY, WHICH IN

893
00:35:03,835 --> 00:35:06,037
THIS PAPER SHOWS A DIRECT

894
00:35:06,037 --> 00:35:09,307
LINKAGE WITH THE ACTIVITY AND

895
00:35:09,307 --> 00:35:11,943
PRESENCE OF TLSs IN THOSE

896
00:35:11,943 --> 00:35:15,246
BIOPSIES.

897
00:35:15,246 --> 00:35:17,816
SO I'LL END HERE BY SAYING

898
00:35:17,816 --> 00:35:20,552
CONGRATULATIONS, DR. ROSENBERG,

899
00:35:20,552 --> 00:35:21,653
AND IT A DELIGHT TO BE HERE.

900
00:35:21,653 --> 00:35:22,554
SO THANK YOU VERY MUCH.

901
00:35:22,554 --> 00:35:32,731
[APPLAUSE]

902
00:35:37,268 --> 00:35:38,837
>> WE'RE DOING GREAT ON
TIME.

903
00:35:38,837 --> 00:35:39,871
IF ANYBODY HAS A QUESTION, WE

904
00:35:39,871 --> 00:35:43,108
COULD TAKE ONE NOW.

905
00:35:43,108 --> 00:35:43,541
ALL RIGHT.

906
00:35:43,541 --> 00:35:44,976
SO LET'S MOVE ON TO OUR NEXT

907
00:35:44,976 --> 00:35:45,510
SPEAKER THEN.

908
00:35:45,510 --> 00:35:48,013
WE HAVE STEPHANIE GOFF, A MEMBER

909
00:35:48,013 --> 00:35:49,547
OF OUR CURRENT SENIOR STAFF HERE

910
00:35:49,547 --> 00:35:51,583
IN THE SURGERY BRANCH, TO TALK

911
00:35:51,583 --> 00:35:53,351
ABOUT THE EVOLVING THERAPEUTIC

912
00:35:53,351 --> 00:36:00,592
LANDSCAPE OF MELANOMA.

913
00:36:00,592 --> 00:36:01,426
>> THANK YOU ALL.

914
00:36:01,426 --> 00:36:02,727
I HAVE BEEN TASKED WITH SORT OF

915
00:36:02,727 --> 00:36:04,295
GIVING YOU AN OVERVIEW OF ALL OF

916
00:36:04,295 --> 00:36:06,264
THE FANTASTIC WORK, STARTED

917
00:36:06,264 --> 00:36:08,099
OBVIOUSLY BY DR. ROSENBERG IN

918
00:36:08,099 --> 00:36:10,068
CONJUNCTION WITH MIKE AND JAMES

919
00:36:10,068 --> 00:36:11,803
AND HOW IT REALLY HAS CHANGED

920
00:36:11,803 --> 00:36:14,572
THE LANDSCAPE FOR MELANOMA OVER

921
00:36:14,572 --> 00:36:15,640
THE COURSE OF THE 50 YEARS THAT

922
00:36:15,640 --> 00:36:16,908
HE'S BEEN HERE.

923
00:36:16,908 --> 00:36:18,476
SO THE FIRST THING IS THAT IT'S

924
00:36:18,476 --> 00:36:19,811
GREAT NEWS, RIGHT?

925
00:36:19,811 --> 00:36:21,413
MORTALITY FOR PATIENTS WITH

926
00:36:21,413 --> 00:36:23,181
METATATIC MELANOMA HAS BEEN

927
00:36:23,181 --> 00:36:24,382
DROPPING.

928
00:36:24,382 --> 00:36:26,051
UNFORTUNATELY, THAT WASN'T DUE

929
00:36:26,051 --> 00:36:27,218
TO INTERLEUKIN NECESSARILY

930
00:36:27,218 --> 00:36:28,219
BECAUSE OF THE SMALL RATES, BUT

931
00:36:28,219 --> 00:36:29,421
REALLY THE REVOLUTION THAT

932
00:36:29,421 --> 00:36:33,158
HAPPENED WHEN CHECKPOINT

933
00:36:33,158 --> 00:36:33,892
INHIBITORS CAME ON BOARD.

934
00:36:33,892 --> 00:36:35,326
I'M NOT GOING TO EMBARRASS

935
00:36:35,326 --> 00:36:37,062
MYSELF ABOUT TRYING TO TALK TO

936
00:36:37,062 --> 00:36:38,696
YOU ABOUT THAT WHEN WE HAVE

937
00:36:38,696 --> 00:36:39,798
OTHERS TO TALK ABOUT THAT

938
00:36:39,798 --> 00:36:40,265
TOMORROW.

939
00:36:40,265 --> 00:36:41,566
BUT I DID WANT TO TALK YOU

940
00:36:41,566 --> 00:36:42,934
THROUGH SORT OF HOW LONG THIS

941
00:36:42,934 --> 00:36:44,769
TAKES TO HAPPEN.

942
00:36:44,769 --> 00:36:47,072
WHEN DR. ROSENBERG FIRST GOT

943
00:36:47,072 --> 00:36:48,540
HERE, DECASH SEEN WAS REALLY THE

944
00:36:48,540 --> 00:36:49,574
ONLY THING BEING USED FOR

945
00:36:49,574 --> 00:36:50,075
PATIENTS WITH METATATIC

946
00:36:50,075 --> 00:36:50,341
MELANOMA.

947
00:36:50,341 --> 00:36:51,943
THE ONE-YEAR SURVIVAL RATE WAS

948
00:36:51,943 --> 00:36:55,180
IN THE 5 TO 10%.

949
00:36:55,180 --> 00:36:57,449
IT TOOK FROM 1985 WHEN THAT

950
00:36:57,449 --> 00:36:59,851
FIRST CLINICAL EXPERIENCE WAS

951
00:36:59,851 --> 00:37:02,887
PUBLISHED TO 1998 TO GET

952
00:37:02,887 --> 00:37:03,822
INTERLEUKIN 2 APPROVED FOR

953
00:37:03,822 --> 00:37:06,291
PATIENTS WITH METATATIC

954
00:37:06,291 --> 00:37:09,661
MELANOMA.

955
00:37:09,661 --> 00:37:11,663
CTLA4 WAS FIRST DESCRIBED OF AS

956
00:37:11,663 --> 00:37:16,434
1987.

957
00:37:16,434 --> 00:37:17,435
THE FIRST CLINICAL TRIAL STARTED

958
00:37:17,435 --> 00:37:19,104
HERE IN 2001, WASN'T PUBLISHED

959
00:37:19,104 --> 00:37:20,371
UNTIL 2003 AND TOOK AN

960
00:37:20,371 --> 00:37:21,473
ADDITIONAL EIGHT YEARS TO GET

961
00:37:21,473 --> 00:37:27,145
THAT APPROVED BY THE FDA.

962
00:37:27,145 --> 00:37:30,215
PD-1 WAS FIRST DESCRIBED IN

963
00:37:30,215 --> 00:37:30,915
1992, FIRST CLINICAL EXPERIENCE

964
00:37:30,915 --> 00:37:32,117
WASN'T PUBLISHED FOR 10 YEARS

965
00:37:32,117 --> 00:37:33,418
AND IT TOOK FORTUNATELY JUST A

966
00:37:33,418 --> 00:37:35,053
FEW SHORT YEARS FOR THAT TO GET

967
00:37:35,053 --> 00:37:37,789
APPROVED IN BOTH ITS VERSIONS.

968
00:37:37,789 --> 00:37:41,392
WE LEARNED A LOT ABOUT TUMORS

969
00:37:41,392 --> 00:37:42,393
DURING THIS TIME.

970
00:37:42,393 --> 00:37:44,028
NO ONE WOULD HAVE EVER THOUGHT

971
00:37:44,028 --> 00:37:46,197
ABOUT SEQUENCING A TUMOR BACK IN

972
00:37:46,197 --> 00:37:48,166
1975 BUT IN 2002 WE STARTED TO

973
00:37:48,166 --> 00:37:49,501
UNDERSTAND ABOUT ACTIVATING BRAF

974
00:37:49,501 --> 00:37:51,136
IN PATIENTS WITH MELANOMA AND

975
00:37:51,136 --> 00:37:51,870
THE FIRST CLINICAL EXPERIENCE

976
00:37:51,870 --> 00:37:53,738
WITH THE BRAF DRUGS WAS IN 2010.

977
00:37:53,738 --> 00:37:58,243
IT WAS ABLE TO GET APPROVAL IN

978
00:37:58,243 --> 00:37:58,443
2011.

979
00:37:58,443 --> 00:37:59,777
THEN THE COMBINATIONS OF THOSE

980
00:37:59,777 --> 00:38:00,678
THERAPIES STARTED TO GET

981
00:38:00,678 --> 00:38:01,646
APPROVED.

982
00:38:01,646 --> 00:38:05,150
2016, 2020, 2022, THE ADDITION

983
00:38:05,150 --> 00:38:06,284
OF LAG 3.

984
00:38:06,284 --> 00:38:07,752
THROUGH ALL OF THIS DEVELOPMENT

985
00:38:07,752 --> 00:38:08,786
AS ALL OF THIS WAS HAPPENING IN

986
00:38:08,786 --> 00:38:12,123
THE FIELD OF MEL N MELANOMA, THE

987
00:38:12,123 --> 00:38:13,525
BRANCH TO BEGIN WITH AND THEN

988
00:38:13,525 --> 00:38:14,359
OTHERS, MOSTLY PEOPLE WHO HAD

989
00:38:14,359 --> 00:38:16,461
BEEN AT THE BRANCH AND

990
00:38:16,461 --> 00:38:17,662
METASTASIZED ACROSS THE WORLD,

991
00:38:17,662 --> 00:38:19,864
THEN LED TO THIS GREAT

992
00:38:19,864 --> 00:38:23,768
ACHIEVEMENT THIS PAST YEAR WHEN

993
00:38:23,768 --> 00:38:25,503
IOVANCE WAS ABLE TO GET THE

994
00:38:25,503 --> 00:38:27,605
FIRST TIL THERAPY APPROVED FOR

995
00:38:27,605 --> 00:38:28,106
PATIENTS WITH METATATIC

996
00:38:28,106 --> 00:38:28,373
MELANOMA.

997
00:38:28,373 --> 00:38:29,040
SO WHY?

998
00:38:29,040 --> 00:38:31,442
YOU KNOW, YOU'VE HEARD US TALK

999
00:38:31,442 --> 00:38:32,544
ABOUT LAK CELLS, YOU'VE HEARD

1000
00:38:32,544 --> 00:38:33,845
THE WORK ABOUT IL-2 AND

1001
00:38:33,845 --> 00:38:34,546
CYTOKINES.

1002
00:38:34,546 --> 00:38:35,914
A BEAUTIFUL THING ABOUT MELANOMA

1003
00:38:35,914 --> 00:38:37,515
IS WHEN YOU LOOK AT THE TUMORS,

1004
00:38:37,515 --> 00:38:39,450
ALMOST ALL OF THEM ARE HEAVILY

1005
00:38:39,450 --> 00:38:45,056
IMMUNE ILL FILTR INFILTRATEED WH

1006
00:38:45,056 --> 00:38:46,591
CD3, ALL THESE BEAUTIFUL T CELLS

1007
00:38:46,591 --> 00:38:48,293
LIVING IN THERE.

1008
00:38:48,293 --> 00:38:49,394
SO THE SCHEME THAT MANY OF US

1009
00:38:49,394 --> 00:38:50,728
HAVE COME TO KNOW SO WELL, THE

1010
00:38:50,728 --> 00:38:52,363
CIRCLE OF LIFE.

1011
00:38:52,363 --> 00:38:54,432
YOU EXCISE A TUMOR, YOU PLATE

1012
00:38:54,432 --> 00:38:57,402
THE FRAGMENTS, YOU THEN TRY TO

1013
00:38:57,402 --> 00:38:59,604
CULTURE THOSE IN HIGH DOSE IL-2,

1014
00:38:59,604 --> 00:39:04,642
YOU TEST FOR SOME REACTIVITY.

1015
00:39:04,642 --> 00:39:06,578
SO WE DON'T ALWAYS PLATE THEM.

1016
00:39:06,578 --> 00:39:07,912
ANYBODY WHO'S BEEN HERE OVER THE

1017
00:39:07,912 --> 00:39:09,781
TIME KNOWS THAT WE'VE

1018
00:39:09,781 --> 00:39:10,848
EXPERIMENTED WITH DIGEST THAT WE

1019
00:39:10,848 --> 00:39:12,550
THEN PLATED, WE EXPERIMENTED

1020
00:39:12,550 --> 00:39:15,453
WITH BAGS THAT WE GREW THEM IN,

1021
00:39:15,453 --> 00:39:17,855
WE EXPERIMENTED WITH THE GAS

1022
00:39:17,855 --> 00:39:19,424
PERMEABLE FLASKS.

1023
00:39:19,424 --> 00:39:23,761
OUR CURRENT ME THIS HA METHOD IK

1024
00:39:23,761 --> 00:39:24,762
TO THE FRAGMENTS.

1025
00:39:24,762 --> 00:39:26,831
IN THE DAYS OF MELANOMA, WE

1026
00:39:26,831 --> 00:39:28,132
WOULD TEST AGAINST CELL LINES

1027
00:39:28,132 --> 00:39:30,668
THAT HAD BEEN VERY THOROUGHLY

1028
00:39:30,668 --> 00:39:32,136
CHARACTERIZE.

1029
00:39:32,136 --> 00:39:32,503
CHARACTERIZED.

1030
00:39:32,503 --> 00:39:34,072
WE COULD EXPRESS WHICH ONES WE

1031
00:39:34,072 --> 00:39:34,739
WANTED.

1032
00:39:34,739 --> 00:39:36,174
NOW IN THOSE DAYS WE THOUGHT WE

1033
00:39:36,174 --> 00:39:38,009
WANTED THE MELANOMA

1034
00:39:38,009 --> 00:39:38,676
DIFFERENTIATION ANTIGEN SO WE

1035
00:39:38,676 --> 00:39:41,312
LOOKED FOR REACTIVITY AGAINST

1036
00:39:41,312 --> 00:39:42,981
THINGS LIKE MART, WE WOULD ALSO

1037
00:39:42,981 --> 00:39:45,049
BE ABLE TO GROW THE PATIENT'S

1038
00:39:45,049 --> 00:39:46,451
OWN TUMOR CELL LINE, A GREAT

1039
00:39:46,451 --> 00:39:48,987
MODEL TO TEST TO SEE IF THE TIL

1040
00:39:48,987 --> 00:39:50,388
WERE REACTIVE TO THAT.

1041
00:39:50,388 --> 00:39:52,390
WE WOULD PICK THE FRAGMENTS WE

1042
00:39:52,390 --> 00:39:53,258
WANTED, EXPAND THEM UP TO THE

1043
00:39:53,258 --> 00:39:54,592
ORDER OF 10 TO THE TENTH, AND

1044
00:39:54,592 --> 00:39:55,760
THEN GIVE THE PATIENT A LITTLE

1045
00:39:55,760 --> 00:39:56,895
BIT OF CHEMOTHERAPY IN THE

1046
00:39:56,895 --> 00:39:58,429
BEGINNING, A LOT OF CHEMOTHERAPY

1047
00:39:58,429 --> 00:39:59,897
LATER ON, AND THEN GIVE THE

1048
00:39:59,897 --> 00:40:02,500
PATIENTS THEIR CELLS AND IL-2.

1049
00:40:02,500 --> 00:40:07,205
SO THE FIRST PUBLICATION OF

1050
00:40:07,205 --> 00:40:08,273
THIS, 1988, THESE WERE PATIENTS

1051
00:40:08,273 --> 00:40:09,741
WITH METASTATIC MELANOMA, AND

1052
00:40:09,741 --> 00:40:11,909
YOU CAN SEE THE BEFORE AND AFTER

1053
00:40:11,909 --> 00:40:13,578
CHEST X-RAYS HERE.

1054
00:40:13,578 --> 00:40:15,213
THIS IS PRE-C T SCAN.

1055
00:40:15,213 --> 00:40:17,415
SO IF YOU CAN IMAGINE DOING ALL

1056
00:40:17,415 --> 00:40:18,616
THE ADVANCED CLINICAL WORK WE DO

1057
00:40:18,616 --> 00:40:19,951
TODAY, TRYING TO MAKE

1058
00:40:19,951 --> 00:40:22,020
MEASUREMENTS OFF CHEST X-RAYS

1059
00:40:22,020 --> 00:40:24,555
AND CHEST TOMOGRAMS.

1060
00:40:24,555 --> 00:40:26,424
9 OF THE 15 PATIENTS NAIVE TO

1061
00:40:26,424 --> 00:40:27,492
IL-2 HAD RESPONSE TO THIS

1062
00:40:27,492 --> 00:40:28,660
THERAPY, AND TWO OF THE FIVE

1063
00:40:28,660 --> 00:40:30,795
PATIENTS HAD BEEN REFRACTORY TO

1064
00:40:30,795 --> 00:40:31,996
IL-2, ALSO DEVELOPED A RESPONSE

1065
00:40:31,996 --> 00:40:33,298
TO THIS THERAPY.

1066
00:40:33,298 --> 00:40:34,565
BUT UNFORTUNATELY, THOSE

1067
00:40:34,565 --> 00:40:36,634
RESPONSES WERE NOT VERY DURABLE.

1068
00:40:36,634 --> 00:40:38,369
SO THE NEXT QUESTION WAS, A

1069
00:40:38,369 --> 00:40:40,972
SINGLE DOSE OF CYCLOPHOSPHAMIDE

1070
00:40:40,972 --> 00:40:42,206
DIDN'T GIVE US SORT OF THE

1071
00:40:42,206 --> 00:40:44,809
IMMUNE MILIEU THAT WE WANTED.

1072
00:40:44,809 --> 00:40:47,045
INCREASE THE LYMPHODEPLETION, AT

1073
00:40:47,045 --> 00:40:50,748
FLEW DARE BEAN, GET RID OF THE

1074
00:40:50,748 --> 00:40:52,483
ENDOGENOUS T CELLS AND THEN GIVE

1075
00:40:52,483 --> 00:40:53,151
THESE CELLS AGAIN.

1076
00:40:53,151 --> 00:40:54,953
THIS WAS PUBLISHED BY DR. DUDLEY

1077
00:40:54,953 --> 00:40:55,219
IN 2005.

1078
00:40:55,219 --> 00:40:56,254
YOU CAN SEE A PATIENT WITH

1079
00:40:56,254 --> 00:40:57,221
DISEASE IN THE LUNG AND IN THE

1080
00:40:57,221 --> 00:41:00,958
LEG THAT DISAPPEARED.

1081
00:41:00,958 --> 00:41:02,360
49% OBJECTIVE RESPONSE RATE, AND

1082
00:41:02,360 --> 00:41:04,062
MORE IMPORTANTLY, A 12% COMPLETE

1083
00:41:04,062 --> 00:41:05,129
RESPONSE RATE.

1084
00:41:05,129 --> 00:41:07,932
SO WHEN YOU COMPARE THAT, IL-2

1085
00:41:07,932 --> 00:41:09,367
WAS RUNNING IN A COMPLETE

1086
00:41:09,367 --> 00:41:14,205
RESPONSE RATE OF ABOUT 4%.

1087
00:41:14,205 --> 00:41:14,872
LYMPHODEPLETION WORKED.

1088
00:41:14,872 --> 00:41:16,441
IT HELPED MAKE THESE THINGS

1089
00:41:16,441 --> 00:41:17,408
DURABLE.

1090
00:41:17,408 --> 00:41:19,410
IS MORE LYMPHODEPLETION BETTER?

1091
00:41:19,410 --> 00:41:20,812
SO A NUMBER OF SEQUENTIAL

1092
00:41:20,812 --> 00:41:21,479
STUDIES WERE DONE.

1093
00:41:21,479 --> 00:41:23,848
MANY OF YOU TOOK PART IN A LOT

1094
00:41:23,848 --> 00:41:25,083
OF THESE STUDIES.

1095
00:41:25,083 --> 00:41:27,485
AND IN 2011, DR. ROSENBERG

1096
00:41:27,485 --> 00:41:29,020
PULLED TOGETHER THE 93 PATIENTS

1097
00:41:29,020 --> 00:41:31,222
THAT WE TALKED ABOUT FOR SO MANY

1098
00:41:31,222 --> 00:41:31,656
YEARS.

1099
00:41:31,656 --> 00:41:35,593
43 OF THEM HAD GOTTEN STANDARD

1100
00:41:35,593 --> 00:41:36,627
NON-MYELOABLATIVE CHEMOTHERAPY.

1101
00:41:36,627 --> 00:41:38,229
ANOTHER GROUP HAD GOTTEN 200

1102
00:41:38,229 --> 00:41:39,997
SENT DWRAID OF TOTAL BODY EE

1103
00:41:39,997 --> 00:41:43,167
RADIATION TO DEEPEN THEIR

1104
00:41:43,167 --> 00:41:44,135
LYMPHODEPLETION AND ANOTHER

1105
00:41:44,135 --> 00:41:46,437
GROUP HAD GOT A HIGHER DOSE THAT

1106
00:41:46,437 --> 00:41:47,438
REQUIRED STEM CELL RESCUE.

1107
00:41:47,438 --> 00:41:49,073
SO WHAT WE YOU A SAW WAS THAT

1108
00:41:49,073 --> 00:41:51,709
THE OVERALL RESPONSE RATE, THE

1109
00:41:51,709 --> 00:41:53,244
PARTIAL RESPONSE RATE WAS NOT

1110
00:41:53,244 --> 00:41:54,445
THAT DIFFERENT BUT THE COMPLETE

1111
00:41:54,445 --> 00:41:56,114
RESPONSE RATE APPEARED TO JUMP.

1112
00:41:56,114 --> 00:41:58,416
IT SEEMED LIKE YOU DID NEED THAT

1113
00:41:58,416 --> 00:41:59,117
DEEPER LYMPHODEPLETION EVEN

1114
00:41:59,117 --> 00:42:00,184
THOUGH IT DID COME AT THE COST

1115
00:42:00,184 --> 00:42:02,487
OF SOME EXTRA SIDE EFFECTS.

1116
00:42:02,487 --> 00:42:03,821
THESE AGAIN WERE SEQUENTIAL, AND

1117
00:42:03,821 --> 00:42:05,523
IN THE MATTER OF ALL GOOD

1118
00:42:05,523 --> 00:42:06,958
SCIENCE, YOU HAVE TO GO BACK AND

1119
00:42:06,958 --> 00:42:08,426
THEN TEST IN A RANDOMIZED

1120
00:42:08,426 --> 00:42:08,726
FASHION.

1121
00:42:08,726 --> 00:42:10,261
WHEN WE DID THAT, IT TURNED OUT

1122
00:42:10,261 --> 00:42:12,463
YOU DON'T ACTUALLY NEED THE

1123
00:42:12,463 --> 00:42:13,064
LYMPHODEPLETION, WHICH TURNED

1124
00:42:13,064 --> 00:42:14,098
OUT TO BE A GREAT THING FOR OUR

1125
00:42:14,098 --> 00:42:14,532
PATIENTS.

1126
00:42:14,532 --> 00:42:16,634
YOU DON'T NEED THAT TBI.

1127
00:42:16,634 --> 00:42:18,069
THE RESPONSE RATES WERE

1128
00:42:18,069 --> 00:42:19,137
IDENTICAL, THE COMPLETE RESPONSE

1129
00:42:19,137 --> 00:42:20,705
RATES WERE NEARLY IDENTICAL.

1130
00:42:20,705 --> 00:42:23,408
AND WE PUBLISHED THIS IN 2016.

1131
00:42:23,408 --> 00:42:25,710
WE ALL KNOW WHAT THESE RESPONSES

1132
00:42:25,710 --> 00:42:26,210
CAN LOOK LIKE.

1133
00:42:26,210 --> 00:42:27,545
IT CAN HAPPEN IN THE

1134
00:42:27,545 --> 00:42:28,546
SUBCUTANEOUS DISEASE, IT CAN

1135
00:42:28,546 --> 00:42:29,614
HAPPEN IN VISCERAL DISEASE IN

1136
00:42:29,614 --> 00:42:30,948
THE LIVER, AND IT CAN EVEN

1137
00:42:30,948 --> 00:42:32,583
HAPPEN IN THE BRAIN.

1138
00:42:32,583 --> 00:42:34,685
THIS IS A YOUNG MAN JUST 12 DAYS

1139
00:42:34,685 --> 00:42:36,421
LATER, YOU SEE THAT LARGE MET IS

1140
00:42:36,421 --> 00:42:37,321
GONE.

1141
00:42:37,321 --> 00:42:38,823
HE HAD UPWARDS OF 40 OF THEM ALL

1142
00:42:38,823 --> 00:42:41,592
OVER HIS BODY, ALL OF WHICH

1143
00:42:41,592 --> 00:42:42,126
RESOLVED.

1144
00:42:42,126 --> 00:42:43,694
HE ASKED US TO STOP CALLING HIM

1145
00:42:43,694 --> 00:42:44,662
ABOUT SEVEN YEARS LATER, SO I

1146
00:42:44,662 --> 00:42:46,330
HOPE HE'S STILL OUT THERE ALIVE

1147
00:42:46,330 --> 00:42:47,165
WITHOUT DISEASE.

1148
00:42:47,165 --> 00:42:48,699
BUT HE NO LONGER WANTED TO BE A

1149
00:42:48,699 --> 00:42:50,401
PATIENT.

1150
00:42:50,401 --> 00:42:52,336
NOT THAT I CAN BLAME HIM.

1151
00:42:52,336 --> 00:42:53,838
THIS GENTLEMAN WITH LIVER

1152
00:42:53,838 --> 00:42:55,006
DISEASE, YOU CAN SEE SEVEN YEARS

1153
00:42:55,006 --> 00:42:57,041
LATER, THE LIVER IS CLEAR.

1154
00:42:57,041 --> 00:42:58,709
AND THIS GENTLEMAN WITH BRAIN

1155
00:42:58,709 --> 00:43:00,144
METS, FOUR OF THEM, THAT YOU CAN

1156
00:43:00,144 --> 00:43:02,213
SEE ENHANCED BY CONTRAST, ALL

1157
00:43:02,213 --> 00:43:05,416
RESOLVED WITHIN THREE MONTHS.

1158
00:43:05,416 --> 00:43:06,984
THESE REGRESSIONS WERE DURABLE,

1159
00:43:06,984 --> 00:43:08,052
AND THAT'S REALLY BEEN THE

1160
00:43:08,052 --> 00:43:08,586
HALLMARK OF THIS.

1161
00:43:08,586 --> 00:43:10,455
SO WHEN WE LOOKED AT ALL OF OUR

1162
00:43:10,455 --> 00:43:11,456
PATIENTS HERE AT THE NCI THAT

1163
00:43:11,456 --> 00:43:13,624
GOT CELLS GROWN IN A SIMILAR WAY

1164
00:43:13,624 --> 00:43:15,193
BY OTHER FRAGMENTS OR DIGESTS

1165
00:43:15,193 --> 00:43:17,295
THAT WERE GROWN IN PLATES, WE

1166
00:43:17,295 --> 00:43:19,931
LOOKED AT 226 OF THEM AND WE HAD

1167
00:43:19,931 --> 00:43:21,632
A 22-MONTH SURVIVAL WITH A

1168
00:43:21,632 --> 00:43:23,734
5-YEAR SURVIVAL OF 35%.

1169
00:43:23,734 --> 00:43:25,269
BUT WHAT WAS MOST IMPRESSIVE, AT

1170
00:43:25,269 --> 00:43:27,772
LEAST TO ME, IS THAT GREEN LINE.

1171
00:43:27,772 --> 00:43:29,440
OUR COMPLETE RESPONDERS HAD A

1172
00:43:29,440 --> 00:43:33,911
10-YEAR SURVIVAL RATE OF 96%.

1173
00:43:33,911 --> 00:43:35,913
SO WE WENT INTO THAT COHORT TO

1174
00:43:35,913 --> 00:43:37,882
TRY TO DECIDE WHAT MADE PATIENTS

1175
00:43:37,882 --> 00:43:42,353
GET TO THAT GREEN LINE.

1176
00:43:42,353 --> 00:43:43,588
WELL INFUSION PRODUCTS THAT HAD

1177
00:43:43,588 --> 00:43:45,790
MORE CELLS APPEARED MORE LIKELY

1178
00:43:45,790 --> 00:43:48,125
TO BE ABLE TO MEDIATE RESPONSE.

1179
00:43:48,125 --> 00:43:50,061
WE IMREU AS MANY AS WE COULD.

1180
00:43:50,061 --> 00:43:52,129
MAYBE IT WAS AN UNDERLYING

1181
00:43:52,129 --> 00:43:53,331
FEATURE THAT WE WERE ABLE TO

1182
00:43:53,331 --> 00:43:54,899
GROW SO MANY CELLS BUT THERE WAS

1183
00:43:54,899 --> 00:43:56,434
A SIGNIFICANT DIFFERENCE BETWEEN

1184
00:43:56,434 --> 00:43:57,735
OBJECTIVE RESPONDERS AND

1185
00:43:57,735 --> 00:43:59,203
NON-RESPONDER WHEN IS YOU LOOK

1186
00:43:59,203 --> 00:44:01,038
BY MEDIAN AND IF YOU START TO --

1187
00:44:01,038 --> 00:44:04,208
IT OUT IN GROUPS BY 2 TO THE 10,

1188
00:44:04,208 --> 00:44:06,410
WHERE THE HIGHER OBJECTIVE

1189
00:44:06,410 --> 00:44:07,345
RESPONSE RATE IN THE HIGHEST

1190
00:44:07,345 --> 00:44:08,513
GROUP OF CELLS.

1191
00:44:08,513 --> 00:44:10,348
WHAT WE DID FIND WAS THAT PRIOR

1192
00:44:10,348 --> 00:44:12,049
THERAPY HAD A BIG IMPACT ON

1193
00:44:12,049 --> 00:44:12,950
WHETHER OR NOT THESE PATIENT

1194
00:44:12,950 --> 00:44:15,052
WOULD DEVELOP A RESPONSE TO TIL.

1195
00:44:15,052 --> 00:44:20,091
IF YOU LACKED AT OUR PATIENTS LT

1196
00:44:20,091 --> 00:44:21,158
RECEIVED IPIMIBULAB AND COMPARED

1197
00:44:21,158 --> 00:44:23,394
THEM TO THOSE THAT WERE

1198
00:44:23,394 --> 00:44:25,263
REFRACTORY, THERE WASN'T A

1199
00:44:25,263 --> 00:44:26,797
DIFFERENCE IN RESPONSE RATE,

1200
00:44:26,797 --> 00:44:27,765
ABOUT 49 TO 60%.

1201
00:44:27,765 --> 00:44:28,633
HOWEVER IF YOU LOOKED AT

1202
00:44:28,633 --> 00:44:30,501
PATIENTS WHO RECEIVED ANTIPD #

1203
00:44:30,501 --> 00:44:31,836
AND YOU LOOKED AT THE GROUP THAT

1204
00:44:31,836 --> 00:44:35,006
WAS NAIVE YOU HAD A 56 RESPONSE

1205
00:44:35,006 --> 00:44:36,574
RATE WITH A HEFTY NUMBER OF

1206
00:44:36,574 --> 00:44:37,241
COMPLETE RESPONDERS.

1207
00:44:37,241 --> 00:44:39,310
WHEN YOU LOOKED AT THE SMALLER

1208
00:44:39,310 --> 00:44:41,279
GROUP OF 34 PATIENTS THAT HAD

1209
00:44:41,279 --> 00:44:42,613
GOTTEN ANTIPD-1 BEFORE YOU HAD A

1210
00:44:42,613 --> 00:44:43,614
MUCH LOWER COMPLETE RESPONSE

1211
00:44:43,614 --> 00:44:45,216
RATE AND AT THAT TIME ONLY ONE

1212
00:44:45,216 --> 00:44:45,917
COMPLETE RESPONSE.

1213
00:44:45,917 --> 00:44:46,884
SIMILARLY WITH THE PATIENTS WHO

1214
00:44:46,884 --> 00:44:49,220
HAD BRAF MUTATED TUMORS, IF YOU

1215
00:44:49,220 --> 00:44:51,956
LOOKED AT THOSE THAT HAD

1216
00:44:51,956 --> 00:44:53,324
RECEIVED MAP KINASE INHIBITORS,

1217
00:44:53,324 --> 00:44:55,259
YOU HAD A LOWER RESPONSE RATE IN

1218
00:44:55,259 --> 00:44:56,894
THOSE PATIENTS THAT WERE

1219
00:44:56,894 --> 00:44:57,194
REFRACTORY.

1220
00:44:57,194 --> 00:44:58,663
AND THAT IMPACTED ON THEIR

1221
00:44:58,663 --> 00:44:59,096
SURVIVAL AS WELL.

1222
00:44:59,096 --> 00:45:00,398
YOU CAN SEE THE DIFFERENCES

1223
00:45:00,398 --> 00:45:01,699
BETWEEN THE PATIENTS THAT WERE

1224
00:45:01,699 --> 00:45:03,501
NAIVE AND REFRACTORY IN THESE

1225
00:45:03,501 --> 00:45:03,834
CURVES.

1226
00:45:03,834 --> 00:45:05,136
NOW THE PRESENCE OR ABSENCE OF

1227
00:45:05,136 --> 00:45:06,771
THAT ACTIVATING BRAF MUTATION

1228
00:45:06,771 --> 00:45:08,472
DIDN'T HAVE AN EFFECT ON WHETHER

1229
00:45:08,472 --> 00:45:10,107
TIL THERAPY WAS ABLE TO BE

1230
00:45:10,107 --> 00:45:11,509
USEFUL, BUT IF THEY HAD GOTTEN

1231
00:45:11,509 --> 00:45:12,810
THE DRUGS TO TRY TO BREAK DOWN

1232
00:45:12,810 --> 00:45:15,246
THE BRAF MEK THEN YOU SAW THE

1233
00:45:15,246 --> 00:45:19,216
DIFFERENCE IN RESPONSE.

1234
00:45:19,216 --> 00:45:21,052
HOWEVER, COMPLETE RESPONSES WERE

1235
00:45:21,052 --> 00:45:23,721
STILL POSSIBLE WHEN YOU USED TIL

1236
00:45:23,721 --> 00:45:25,056
AFTER PD-1.

1237
00:45:25,056 --> 00:45:28,125
THIS IS A GENTLEMAN WHO HAD GONE

1238
00:45:28,125 --> 00:45:29,794
THROUGH COMBINATION THERAPY, HAD

1239
00:45:29,794 --> 00:45:31,295
DEVELOPED A GROWING PARARENAL

1240
00:45:31,295 --> 00:45:32,496
MASS THAT WAS RESENTED AS THE

1241
00:45:32,496 --> 00:45:33,931
SOURCE OF HIS TIL.

1242
00:45:33,931 --> 00:45:35,299
AT THE TIME HE WAS TREATED YOU

1243
00:45:35,299 --> 00:45:36,534
SEE THE LUNG DISEASE THERE AS

1244
00:45:36,534 --> 00:45:38,069
WELL AS THE DISEASE THAT WAS

1245
00:45:38,069 --> 00:45:39,437
SORT OF WRAPPING AROUND THE

1246
00:45:39,437 --> 00:45:40,504
ILIAC BONE AND YOU CAN SEE FIVE

1247
00:45:40,504 --> 00:45:41,973
YEARS LATER, THAT DISEASE IS

1248
00:45:41,973 --> 00:45:45,142
GONE, AND IN FACT THE BONE HAS

1249
00:45:45,142 --> 00:45:46,377
RECALCIFIED.

1250
00:45:46,377 --> 00:45:47,712
SIMILARLY, THIS IS A GENTLEMAN

1251
00:45:47,712 --> 00:45:52,116
WHO CAME TO US WITH UNMANAGEABLE

1252
00:45:52,116 --> 00:45:53,050
AXILLARY DISEASE TO THE POINT HE

1253
00:45:53,050 --> 00:45:54,752
COULDN'T LOWER HIS ARMS, IT WAS

1254
00:45:54,752 --> 00:45:55,953
AFFECTING HIS DAILY ACTIVITY,

1255
00:45:55,953 --> 00:45:58,356
AND CAN YOU SEE WE RESPECTED A

1256
00:45:58,356 --> 00:45:59,590
SMALL NODULE OF THAT TUMOR

1257
00:45:59,590 --> 00:46:00,358
SEPARATE FROM THE REST,

1258
00:46:00,358 --> 00:46:01,959
DEVELOPED TIL FROM THAT, AND

1259
00:46:01,959 --> 00:46:03,294
EIGHT YEARS LATER, HE HAS A

1260
00:46:03,294 --> 00:46:05,329
CLEAN PET SCAN.

1261
00:46:05,329 --> 00:46:07,298
AND ACTUALLY HAS JUST BEEN

1262
00:46:07,298 --> 00:46:08,232
RECENTLY DISCHARGED FROM THERAPY

1263
00:46:08,232 --> 00:46:09,800
BECAUSE HE, TOO, NO LONGER WANTS

1264
00:46:09,800 --> 00:46:10,635
TO BE A PATIENT.

1265
00:46:10,635 --> 00:46:13,404
SO TIL FOR CHECKPOINT REFRACTORY

1266
00:46:13,404 --> 00:46:14,005
METATATIC MELANOMA IS STILL

1267
00:46:14,005 --> 00:46:14,272
EFFECTIVE.

1268
00:46:14,272 --> 00:46:15,773
THIS IS THE RESULTS THAT CAME

1269
00:46:15,773 --> 00:46:18,843
OUT OF THE IOVANCE STUDY OF

1270
00:46:18,843 --> 00:46:20,444
66 PATIENTS DEMONSTRATING A 22

1271
00:46:20,444 --> 00:46:23,347
MONTH SURVIVAL AND A 5-YEAR

1272
00:46:23,347 --> 00:46:24,749
SURVIVAL THERE.

1273
00:46:24,749 --> 00:46:27,752
SIMILARLY ACROSS THE POND IN

1274
00:46:27,752 --> 00:46:29,086
EUROPE, THERE WAS A RANDOMIZED

1275
00:46:29,086 --> 00:46:31,355
TRIAL OF 'TIL VERSUS IPIMIBULAB

1276
00:46:31,355 --> 00:46:32,323
IN PATIENTS WITH METATATIC

1277
00:46:32,323 --> 00:46:32,590
MELANOMA.

1278
00:46:32,590 --> 00:46:34,825
WE HAD A 25-MONTH SURVIVAL AN

1279
00:46:34,825 --> 00:46:36,227
OBJECTIVE RESPONSE OF 49%.

1280
00:46:36,227 --> 00:46:38,295
THESE ARE NOW APPROVED BOTH HERE

1281
00:46:38,295 --> 00:46:39,964
IN THE UNITED STATES OBVIOUSLY

1282
00:46:39,964 --> 00:46:41,766
AS WE ALL KNOW IN FEBRUARY, AND

1283
00:46:41,766 --> 00:46:44,468
FOR USE THROUGH THE EUROPEAN

1284
00:46:44,468 --> 00:46:46,237
HEALTH AGENCY IN I BELIEVE

1285
00:46:46,237 --> 00:46:50,508
DENMARK AND COPENHAGEN.

1286
00:46:50,508 --> 00:46:52,276
SO WHAT IS THE IMPACT OF THAT

1287
00:46:52,276 --> 00:46:52,710
PRIOR THERAPY?

1288
00:46:52,710 --> 00:46:54,445
ONE OF OUR FELLOWS WENT BACK TO

1289
00:46:54,445 --> 00:46:55,646
ALL THE INDIVIDUAL FRAGMENTS

1290
00:46:55,646 --> 00:46:56,781
GROWN FOR ALL OF THOSE

1291
00:46:56,781 --> 00:46:57,381
INDIVIDUAL PATIENTS, SO WHAT

1292
00:46:57,381 --> 00:46:58,516
YOU'RE LOOKING AT HERE ARE

1293
00:46:58,516 --> 00:46:59,550
MEDIANS OF MEDIANS.

1294
00:46:59,550 --> 00:47:01,619
SO PATIENT MAY HAVE HAD ANYWHERE

1295
00:47:01,619 --> 00:47:03,254
FROM 2 TO 24 FRAGMENTS GROWN FOR

1296
00:47:03,254 --> 00:47:04,822
THEM AND IT LOOKED AT THE

1297
00:47:04,822 --> 00:47:05,790
PERCENTAGE -- HE LOOKED AT THE

1298
00:47:05,790 --> 00:47:10,728
PERCENTAGE OF CD3s AS WELL AS

1299
00:47:10,728 --> 00:47:12,430
CD8 AND NK CELLS.

1300
00:47:12,430 --> 00:47:14,031
IT WAS AFFECTED BY PD-1.

1301
00:47:14,031 --> 00:47:16,667
THERE WERE FEWER CD3s, FEWER

1302
00:47:16,667 --> 00:47:19,637
CD8s AND MORE NKs IN THOSE.

1303
00:47:19,637 --> 00:47:21,072
INTERESTINGLY, ANTICTLA4 DIDN'T

1304
00:47:21,072 --> 00:47:22,073
HAVE THAT SAME EFFECT.

1305
00:47:22,073 --> 00:47:23,641
THERE WERE NO DIFFERENCES IN THE

1306
00:47:23,641 --> 00:47:24,675
BULK PHENOTYPE OF THE INITIAL

1307
00:47:24,675 --> 00:47:25,943
TIL PRODUCTS THAT WE WERE

1308
00:47:25,943 --> 00:47:26,377
GROWING.

1309
00:47:26,377 --> 00:47:27,778
BUT THE INITIAL TIL PRODUCTS ARE

1310
00:47:27,778 --> 00:47:28,979
NOT ALWAYS THE FINAL TIL

1311
00:47:28,979 --> 00:47:29,246
PRODUCT.

1312
00:47:29,246 --> 00:47:31,115
SO WHEN YOU LK AT THE FINAL TIL

1313
00:47:31,115 --> 00:47:32,583
PRODUCT, WHAT WE FOUND WAS THAT

1314
00:47:32,583 --> 00:47:34,452
PATIENTS THAT WERE PD-1

1315
00:47:34,452 --> 00:47:37,488
REFRACTORY HAD MORE CD4 CELLS IN

1316
00:47:37,488 --> 00:47:38,923
THEIR BAGS, AND THAT WAS THE

1317
00:47:38,923 --> 00:47:41,525
ONLY REAL DIFFERENCE BETWEEN THE

1318
00:47:41,525 --> 00:47:42,660
TWO GROUPS.

1319
00:47:42,660 --> 00:47:44,261
TIL GREW EQUALLY WELL UNDER THE

1320
00:47:44,261 --> 00:47:48,499
UNIFORM CONDITIONS WITH MORE CD.

1321
00:47:48,499 --> 00:47:49,867
WHEN YOU LOOK AT THE GENOMICS OF

1322
00:47:49,867 --> 00:47:51,102
THE TUMOR, THIS WAS DONE BY

1323
00:47:51,102 --> 00:47:52,036
ANOTHER FELLOW HERE IN THE

1324
00:47:52,036 --> 00:47:54,338
AUDIENCE TODAY, THE TMB OF THESE

1325
00:47:54,338 --> 00:47:55,940
TUMORS IS LOWER.

1326
00:47:55,940 --> 00:47:56,774
EVERYONE SHOULD HAVE EXPECTED

1327
00:47:56,774 --> 00:47:57,108
THAT.

1328
00:47:57,108 --> 00:47:58,309
WE'RE ONLY GETTING PATIENTS NOW

1329
00:47:58,309 --> 00:48:00,911
THAT ARE REFRACTORY TO PD-1.

1330
00:48:00,911 --> 00:48:02,179
WHO ARE THE PATIENTS THAT ARE

1331
00:48:02,179 --> 00:48:03,714
RESPONDING TO PD-1?

1332
00:48:03,714 --> 00:48:05,249
THOSE THAT HAVE HIGH TMB.

1333
00:48:05,249 --> 00:48:06,350
SO WE'RE ONLY GETTING THE

1334
00:48:06,350 --> 00:48:07,251
PATIENTS FOR WHOM THAT THERAPY

1335
00:48:07,251 --> 00:48:08,018
HAS NOT WORKED.

1336
00:48:08,018 --> 00:48:09,987
SO BY OUR REFERRAL PATTERN, OUR

1337
00:48:09,987 --> 00:48:11,222
TMB IS LOWER.

1338
00:48:11,222 --> 00:48:13,424
WHAT WE'VE ALSO NOTICED, THOUGH,

1339
00:48:13,424 --> 00:48:14,525
IS THAT IT AFFECTS THE ABILITY

1340
00:48:14,525 --> 00:48:16,127
TO FIND NEOANTIGENS.

1341
00:48:16,127 --> 00:48:17,161
I'M NOT GOING TO GO INTO THE

1342
00:48:17,161 --> 00:48:18,562
DETAILS OF HOW WE FIND OUR

1343
00:48:18,562 --> 00:48:19,296
NEOANTIGENS.

1344
00:48:19,296 --> 00:48:20,097
YOU'RE GOING TO HEAR FROM A LOT

1345
00:48:20,097 --> 00:48:21,499
OF DIFFERENT SPEAKERS LATER HOW

1346
00:48:21,499 --> 00:48:23,367
WE'VE TAKEN THIS FROM MELANOMA

1347
00:48:23,367 --> 00:48:24,935
INTO OUR EPITHELIAL CANCER

1348
00:48:24,935 --> 00:48:28,406
SPACE.

1349
00:48:28,406 --> 00:48:30,474
INTERESTINGLY, ANNA PASETTA HAD

1350
00:48:30,474 --> 00:48:31,408
GONE BACK TO THE INFUSION BAGS

1351
00:48:31,408 --> 00:48:32,676
OF A NUMBER OF PATIENTS.

1352
00:48:32,676 --> 00:48:33,778
SHE ACTUALLY LOOKED AT THE MOST

1353
00:48:33,778 --> 00:48:35,546
FREQUENT CLONES IN THOSE BAGS,

1354
00:48:35,546 --> 00:48:36,614
RECONSTRUCTED THE TCRs THAT

1355
00:48:36,614 --> 00:48:38,382
CAME FROM THEM AND THEN TESTED

1356
00:48:38,382 --> 00:48:39,717
THEM TO SEE WHETHER THEY WERE

1357
00:48:39,717 --> 00:48:41,419
TISSUE CULTURE REACTIVE, SHARED

1358
00:48:41,419 --> 00:48:42,720
ANTIGEN REACTIVE, MUTATION

1359
00:48:42,720 --> 00:48:44,021
REACTIVE.

1360
00:48:44,021 --> 00:48:45,990
THE ONLY ONE OF THESE PATIENTS

1361
00:48:45,990 --> 00:48:47,658
THAT WAS PD-1 REFRACTORY WAS THE

1362
00:48:47,658 --> 00:48:49,093
PATIENT FOR WHOM SHE COULD NOT

1363
00:48:49,093 --> 00:48:50,094
IDENTIFY ANY REACTIVITY.

1364
00:48:50,094 --> 00:48:52,563
SO THAT'S JUST AN ANECDOTE BUT

1365
00:48:52,563 --> 00:48:54,165
MAYBE A HINT OF WHAT WE MAY BE

1366
00:48:54,165 --> 00:48:55,733
FACING IN THESE PATIENTS THAT

1367
00:48:55,733 --> 00:48:56,901
ARE ANTIPD-1 REFRACTORY.

1368
00:48:56,901 --> 00:48:59,470
SO WHEN IT COMES TO THE WHOLE

1369
00:48:59,470 --> 00:49:00,237
EVOLVING LANDSCAPE OF OUR

1370
00:49:00,237 --> 00:49:02,840
PATIENTS WITH METASTATIC

1371
00:49:02,840 --> 00:49:04,041
MELANOMA, THESE WERE THE

1372
00:49:04,041 --> 00:49:05,843
THERAPIES AVAILABLE TO THEM NOW.

1373
00:49:05,843 --> 00:49:07,244
ANTIPD-1, DUAL CHECKPOINT

1374
00:49:07,244 --> 00:49:08,379
BLOCKADE, TRIPLET THERAPY FOR

1375
00:49:08,379 --> 00:49:11,148
THOSE PATIENTS THAT HAVE BRAF

1376
00:49:11,148 --> 00:49:11,682
MUTATIONS, OR TIL.

1377
00:49:11,682 --> 00:49:16,854
CAN YOU SEEYOU CAN SEETHE RYE SL

1378
00:49:16,854 --> 00:49:18,289
VERY SIMILAR, YOU CAN SEE THE

1379
00:49:18,289 --> 00:49:19,623
COMPLETE RESPONSE RATES THERE,

1380
00:49:19,623 --> 00:49:20,291
ALL VERY SIMILAR.

1381
00:49:20,291 --> 00:49:22,793
YOU SEE THE GRADE 3 ADVERSE

1382
00:49:22,793 --> 00:49:23,127
EVENTS.

1383
00:49:23,127 --> 00:49:26,096
THAT HE IS WHERE TIL WILL ALWAYS

1384
00:49:26,096 --> 00:49:26,964
TAKE A HIT.

1385
00:49:26,964 --> 00:49:29,500
WE DESIGN OUR THERAPY -- ALL OF

1386
00:49:29,500 --> 00:49:32,002
OUR PATIENTS WILL HAVE A GRADE

1387
00:49:32,002 --> 00:49:32,703
III/4 AE.

1388
00:49:32,703 --> 00:49:33,938
WHEN YOU STOP TO LOOK AT THOSE

1389
00:49:33,938 --> 00:49:35,039
ONLY DUAL TO THE CELL PRODUCT

1390
00:49:35,039 --> 00:49:36,540
AND PERHAPS THE IL-2, YOU'RE

1391
00:49:36,540 --> 00:49:38,008
LOOKING AT A MORE REASONABLE

1392
00:49:38,008 --> 00:49:38,709
36%.

1393
00:49:38,709 --> 00:49:40,778
AND AGAIN THE HALLMARK.

1394
00:49:40,778 --> 00:49:42,313
THE DURABILITY OF THIS IS THE

1395
00:49:42,313 --> 00:49:43,180
FIVE-YEAR OVERALL SURVIVAL.

1396
00:49:43,180 --> 00:49:44,849
SO WHEN YOU LOOK AT THE

1397
00:49:44,849 --> 00:49:45,516
QUALITATIVE THINGS THAT OUR

1398
00:49:45,516 --> 00:49:47,785
PATIENTS ARE THINKING ABOUT, GO

1399
00:49:47,785 --> 00:49:49,620
TO AN INFUSION CENTER EVERY TWO

1400
00:49:49,620 --> 00:49:51,488
TO THREE WEEKS, IT'S VERY

1401
00:49:51,488 --> 00:49:53,123
CONVENIENT, ALTHOUGH IT DOES PUT

1402
00:49:53,123 --> 00:49:56,627
A HAMPER ON YOUR SCHEDULE,

1403
00:49:56,627 --> 00:49:58,395
VERSUS OURS WHICH IS INCREDIBLY

1404
00:49:58,395 --> 00:50:00,264
COMPLICATED, YOU HAVE TO HAVE AN

1405
00:50:00,264 --> 00:50:01,866
OPERATION, COME BACK TO THE

1406
00:50:01,866 --> 00:50:02,566
HOSPITAL IN THREE TO FOUR WEEKS

1407
00:50:02,566 --> 00:50:04,668
BUT YOU ONL HAVE TO DO IT ONCE.

1408
00:50:04,668 --> 00:50:05,669
SO IT A TRADEOFF THAT MANY

1409
00:50:05,669 --> 00:50:06,704
PATIENTS ARE FACING.

1410
00:50:06,704 --> 00:50:07,905
PATIENTS WITH LYMPHOMA ARE

1411
00:50:07,905 --> 00:50:09,340
FACING THIS AS WELL, DO YOU TAKE

1412
00:50:09,340 --> 00:50:11,175
THE DRUG YOU TAKE EVERY DAY OR

1413
00:50:11,175 --> 00:50:12,543
DO YOU GET THE EXPENSIVE CAR

1414
00:50:12,543 --> 00:50:13,277
THERAPY THAT REQUIRES YOU TO BE

1415
00:50:13,277 --> 00:50:14,812
IN THE HOSPITAL FOR TWO WEEKS?

1416
00:50:14,812 --> 00:50:17,715
THESE TRADEOFFS ARE GOING TO BE

1417
00:50:17,715 --> 00:50:18,816
WHAT DRIVES PATIENTS WITH CANCER

1418
00:50:18,816 --> 00:50:19,917
ARE CHOOSING IN THE FUTURE.

1419
00:50:19,917 --> 00:50:30,694
SO THIS SOMEWHERE W IS WHERE WE.

1420
00:50:30,694 --> 00:50:33,063
THE NEW PD-1 LAG 3 DRUG, THEN

1421
00:50:33,063 --> 00:50:34,732
THEY COME IN TO GET TIL

1422
00:50:34,732 --> 00:50:35,833
RESECTION, THEN THEY GET THEIR

1423
00:50:35,833 --> 00:50:36,500
CELL THERAPY.

1424
00:50:36,500 --> 00:50:37,601
WHERE WE STAND TO LEARN THE MOST

1425
00:50:37,601 --> 00:50:38,836
IN MY OPINION IS IF WE GET THE

1426
00:50:38,836 --> 00:50:40,170
OPPORTUNITY TO RESECT A TUMOR

1427
00:50:40,170 --> 00:50:41,472
BEFORE THEY HAVE ANY OF THOSE

1428
00:50:41,472 --> 00:50:41,839
THERAPIES.

1429
00:50:41,839 --> 00:50:43,574
SO THAT WE CAN UNDERSTAND

1430
00:50:43,574 --> 00:50:44,542
WHETHER THOSE THERAPIES ARE

1431
00:50:44,542 --> 00:50:46,410
ACTUALLY IMPACTING HOW WE GROW

1432
00:50:46,410 --> 00:50:47,711
THE TIL OR IMPACTING HOW THE TIL

1433
00:50:47,711 --> 00:50:52,249
ARE AFFE ABLE TO AFFECT THEIR CR

1434
00:50:52,249 --> 00:50:53,150
AFTERWARDS AND IN THE FUTURE,

1435
00:50:53,150 --> 00:50:56,553
DOG THE CELL THERAPY FIRST.

1436
00:50:56,553 --> 00:51:00,824
DOING THE CELL THERAPY FIRST.

1437
00:51:00,824 --> 00:51:03,327
IOVANS HAS LOOKED AT THAT AND

1438
00:51:03,327 --> 00:51:05,696
NOW RUNNING A TRIAL OF TIL

1439
00:51:05,696 --> 00:51:06,897
VERSUS PEMBROLIZUMAB AND IN

1440
00:51:06,897 --> 00:51:08,265
THEIR SMALL COHORT OF I BELIEVE

1441
00:51:08,265 --> 00:51:09,767
IT'S 20 OR SO PATIENTS, YOU CAN

1442
00:51:09,767 --> 00:51:11,802
GET THESE GREAT RESPONSES.

1443
00:51:11,802 --> 00:51:13,971
A 30% COMPLETE RESPONSE RATE TO

1444
00:51:13,971 --> 00:51:17,908
TIL PLUS PEMBRO IN

1445
00:51:17,908 --> 00:51:18,509
TREATMENT-NAIVE PATIENTS.

1446
00:51:18,509 --> 00:51:19,877
SO THAT IN MY OPINION IS WHERE

1447
00:51:19,877 --> 00:51:22,379
WE COULD BE GOING IF PATIENTS

1448
00:51:22,379 --> 00:51:24,014
ARE WILLING TO WORK THERE WITH

1449
00:51:24,014 --> 00:51:26,050
US.

1450
00:51:26,050 --> 00:51:28,619
SO THE EVOLVING THERAPEUTIC

1451
00:51:28,619 --> 00:51:30,587
LANDSCAPE OF MELANOMA, IT CANNOT

1452
00:51:30,587 --> 00:51:32,156
BE SAID ENOUGH THAT CHECKPOINT

1453
00:51:32,156 --> 00:51:33,457
BLOCKADE HAS REVOLUTIONIZED THE

1454
00:51:33,457 --> 00:51:34,191
CARE OF THESE PATIENTS.

1455
00:51:34,191 --> 00:51:36,460
IT IS RESPONSIBLE FOR A NEAR

1456
00:51:36,460 --> 00:51:37,628
HALVING OF THE MORTALITY RATE

1457
00:51:37,628 --> 00:51:38,963
OVER THE LAST FIVE YEARS IN

1458
00:51:38,963 --> 00:51:40,531
PATIENTS WHO HAVE METASTATIC

1459
00:51:40,531 --> 00:51:42,399
DISEASE.

1460
00:51:42,399 --> 00:51:45,269
FAST, ACCESSIBLE TUMOR

1461
00:51:45,269 --> 00:51:46,570
SEQUENCING HAS CHANGED OUR

1462
00:51:46,570 --> 00:51:47,237
THERAPIES AND RESEARCH.

1463
00:51:47,237 --> 00:51:48,706
WE NOW KNOW ABOUT DRIVER

1464
00:51:48,706 --> 00:51:50,007
MUTATIONS, WE UNDERSTAND BETTER

1465
00:51:50,007 --> 00:51:52,009
THE TUMOR-TIL RELATIONSHIP.

1466
00:51:52,009 --> 00:51:54,144
TIL CAN MEDIATE LONG TERM

1467
00:51:54,144 --> 00:51:54,945
DURABLE RESPONSES AND I THINK

1468
00:51:54,945 --> 00:51:56,380
THAT IS REALLY THE KEY.

1469
00:51:56,380 --> 00:51:57,881
TIL AS WE ALL KNOW IS NOW

1470
00:51:57,881 --> 00:52:00,050
APPROVED IN TREATMENT REFRACTORY

1471
00:52:00,050 --> 00:52:01,352
DISEASE, HOWEVER, PRIOR THERAPY

1472
00:52:01,352 --> 00:52:03,253
DOES LOWER THE LIKELIHOOD OF

1473
00:52:03,253 --> 00:52:04,788
THAT RESPONSE, SO IS THERE ROOM

1474
00:52:04,788 --> 00:52:06,423
FOR TIL AS A FRONT-LINE

1475
00:52:06,423 --> 00:52:06,890
STRATEGY?

1476
00:52:06,890 --> 00:52:07,891
BECAUSE IN MY OPINION, WE WANT

1477
00:52:07,891 --> 00:52:09,560
TO GET ALL OUR PATIENTS TO THIS

1478
00:52:09,560 --> 00:52:13,297
GREEN LINE.

1479
00:52:13,297 --> 00:52:15,933
THIS WAS ONE OF MY FONDEST

1480
00:52:15,933 --> 00:52:16,767
MEMORIES.

1481
00:52:16,767 --> 00:52:18,669
IT'S NOT OFTEN THAT YOU GET TO

1482
00:52:18,669 --> 00:52:20,137
SURPRISE DR. ROSENBERG, BUT WE

1483
00:52:20,137 --> 00:52:21,438
ACTUALLY MADE A WORKING

1484
00:52:21,438 --> 00:52:22,940
OPERATION GAME FOR OUR HOLIDAY

1485
00:52:22,940 --> 00:52:24,775
DOOR CONTEST A FEW YEARS BACK.

1486
00:52:24,775 --> 00:52:26,143
AND I KNOW ANYONE THAT'S WORKED

1487
00:52:26,143 --> 00:52:27,778
WITH HIM HAS HEARD HIM SAY THIS

1488
00:52:27,778 --> 00:52:29,413
MORE THAN ONCE, EVERY PATIENT

1489
00:52:29,413 --> 00:52:30,948
DESERVES AN OPTIMISTIC

1490
00:52:30,948 --> 00:52:31,248
ONCOLOGIST.

1491
00:52:31,248 --> 00:52:33,517
AND SO WITH THAT, I'LL TAKE ANY

1492
00:52:33,517 --> 00:52:33,951
QUESTIONS.

1493
00:52:33,951 --> 00:52:35,352
AND CERTAINLY WANT TO

1494
00:52:35,352 --> 00:52:36,353
ACKNOWLEDGE EVERYONE AT THE

1495
00:52:36,353 --> 00:52:37,788
BRANCH AND MOST PARTICULARLY OUR

1496
00:52:37,788 --> 00:52:43,427
PATIENTS AND THEIR FAMILIES.

1497
00:52:43,427 --> 00:52:51,769
[APPLAUSE]

1498
00:52:51,769 --> 00:52:53,337
I GOT OFF EASY.

1499
00:52:53,337 --> 00:52:53,670
NO QUESTIONS.

1500
00:52:53,670 --> 00:52:56,907
>> WHAT ABOUT CLASS 1 --
TUMORS?

1501
00:52:56,907 --> 00:53:01,045
>> WHAT ABOUT CLASS 1 LOSS

1502
00:53:01,045 --> 00:53:01,378
TUMORS?

1503
00:53:01,378 --> 00:53:03,347
YOU KNOW, WE'VE EXPLORED THAT

1504
00:53:03,347 --> 00:53:04,615
MORE IN OUR PATIENTS WITH

1505
00:53:04,615 --> 00:53:05,816
EPITHELIAL CANCER THAN WE HAVE

1506
00:53:05,816 --> 00:53:07,351
WITH MELANOMA, SO WE'RE STARTING

1507
00:53:07,351 --> 00:53:08,919
TO GO BACK AND LOOK AT THAT MORE

1508
00:53:08,919 --> 00:53:10,354
DEEPLY.

1509
00:53:10,354 --> 00:53:12,656
WHAT WE HAVE FOUND IS THAT A

1510
00:53:12,656 --> 00:53:13,457
SIGNIFICANT NUMBER OF OUR

1511
00:53:13,457 --> 00:53:16,193
PATIENTS HAVE ACTUALLY LOST

1512
00:53:16,193 --> 00:53:17,961
CLASS 1 AND WE NOW USE IT AS A

1513
00:53:17,961 --> 00:53:19,563
SCREENING BEFORE WE DO SOME OF

1514
00:53:19,563 --> 00:53:20,931
OUR GENE ENGINEERED THERAPIES

1515
00:53:20,931 --> 00:53:22,132
BECAUSE WE KNOW IT'S A MECHANISM

1516
00:53:22,132 --> 00:53:22,633
OF REEF CYST TANS.

1517
00:53:22,633 --> 00:53:23,667
WHAT HE WITH HOPE IS THAT

1518
00:53:23,667 --> 00:53:25,169
BECAUSE WE'RE GIVING A

1519
00:53:25,169 --> 00:53:26,670
POLYCLONAL PRODUCT THAT EVEN IF

1520
00:53:26,670 --> 00:53:28,372
THEY LOSE ONE OF THEIR ALLELES,

1521
00:53:28,372 --> 00:53:30,307
THEY'VE GOT THE OTHER AND

1522
00:53:30,307 --> 00:53:33,610
HOPEFULLY THEY'VE GOT A

1523
00:53:33,610 --> 00:53:34,178
POLYCLONAL POLYTARGETTED

1524
00:53:34,178 --> 00:53:34,478
THERAPY.

1525
00:53:34,478 --> 00:53:37,981
WHICH IS WHY I THINK TIL PLAY

1526
00:53:37,981 --> 00:53:40,017
HAVE IN MY OPINION AN ADVANTAGE

1527
00:53:40,017 --> 00:53:41,718
OVER SINGLE CELL THERAPIES.

1528
00:53:41,718 --> 00:53:42,853
>> [INAUDIBLE]

1529
00:53:42,853 --> 00:53:44,154
>> THEY DON'T GROW WELL IN
THE

1530
00:53:44,154 --> 00:53:45,756
CONDITIONS, BUT THAT'S BECAUSE

1531
00:53:45,756 --> 00:53:46,824
WE DRIVE OUR GROWTH THAT WAY.

1532
00:53:46,824 --> 00:53:48,792
IF WE WANTED TO GROW

1533
00:53:48,792 --> 00:53:49,793
GAMMA-DELTA, WE'D HAVE TO CHANGE

1534
00:53:49,793 --> 00:53:52,696
THE WAY WE GROW OUR CELLS.

1535
00:53:52,696 --> 00:53:57,634
>> [INAUDIBLE]

1536
00:53:57,634 --> 00:54:03,173
>> PAUL ROBBINS, EVERYONE.

1537
00:54:03,173 --> 00:54:04,408
AND YOU'LL GET A CHANCE TO HEAR

1538
00:54:04,408 --> 00:54:05,609
FROM HIM A LITTLE BIT LATER

1539
00:54:05,609 --> 00:54:08,712
TODAY.

1540
00:54:08,712 --> 00:54:10,581
>> STEPHANIE, GREAT TALK.

1541
00:54:10,581 --> 00:54:12,549
I'D LIKE TO JUST FOLLOW UP ON

1542
00:54:12,549 --> 00:54:14,651
THIS ISSUE OF THE PD-1

1543
00:54:14,651 --> 00:54:15,652
REFRACTORY MELANOMAS.

1544
00:54:15,652 --> 00:54:17,588
DO YOU THINK THE ANTIPD-1

1545
00:54:17,588 --> 00:54:20,057
THERAPY IS JUST IDENTIFYING

1546
00:54:20,057 --> 00:54:21,925
MELANOMAS THAT ARE POORLY

1547
00:54:21,925 --> 00:54:23,360
IMMUNOGENIC SO THAT EVEN IF YOU

1548
00:54:23,360 --> 00:54:25,562
TREAT THEM IN THE FIRST LINE

1549
00:54:25,562 --> 00:54:26,697
WITH TIL, THEY'RE NOT GOING TO

1550
00:54:26,697 --> 00:54:28,098
BE GOOD RESPONDERS?

1551
00:54:28,098 --> 00:54:29,900
>> I THINK IT'S -- I THINK
IT'S

1552
00:54:29,900 --> 00:54:30,767
A LITTLE BIT OF BOTH.

1553
00:54:30,767 --> 00:54:32,503
SO I THINK IF WE WEREN'T SEEING

1554
00:54:32,503 --> 00:54:34,705
ANY RESPONSES IN THE POST PD-1

1555
00:54:34,705 --> 00:54:37,741
PATIENTS, I WOULD THINK THAT

1556
00:54:37,741 --> 00:54:39,810
IT'S THAT IT'S IMMUNOEDITING TO

1557
00:54:39,810 --> 00:54:40,911
A POINT THAT WE CAN NO LONGER

1558
00:54:40,911 --> 00:54:41,445
EXPRESS IT.

1559
00:54:41,445 --> 00:54:42,713
THAT'S WHY I'D LIKE TO STUDY

1560
00:54:42,713 --> 00:54:44,915
MORE TEU NORS BEFORE PD-1 TO BE

1561
00:54:44,915 --> 00:54:45,315
ABLE TO COMPARE.

1562
00:54:45,315 --> 00:54:48,218
WE HAVE BEEN ABLE TO FIND

1563
00:54:48,218 --> 00:54:49,086
NEOANTIGENS IN THOSE PATIENTS,

1564
00:54:49,086 --> 00:54:50,454
WE JUST HAVEN'T BEEN ABLE TO

1565
00:54:50,454 --> 00:54:53,323
FIND THEM AS ROBUSTLY.

1566
00:54:53,323 --> 00:54:54,825
I KNOW THAT'S A NEW WAY WE'VE

1567
00:54:54,825 --> 00:54:55,926
STARTED SCREENING THEM.

1568
00:54:55,926 --> 00:54:57,728
ONE THING I DO WANT TO TRY TO

1569
00:54:57,728 --> 00:54:58,795
PUT FORWARD CLINICALLY NOW IS

1570
00:54:58,795 --> 00:55:00,497
NOT ONLY TAKING PART IN THE

1571
00:55:00,497 --> 00:55:01,665
RANDOMIZED TRIAL OF GROWING TIL

1572
00:55:01,665 --> 00:55:03,467
IN A STANDARD FASHION, BUT

1573
00:55:03,467 --> 00:55:04,935
TAKING WHAT WE'VE LEARNED FROM

1574
00:55:04,935 --> 00:55:05,702
EPITHELIAL AND ACTUALLY

1575
00:55:05,702 --> 00:55:07,471
SCREENING FOR NEOANTIGEN

1576
00:55:07,471 --> 00:55:08,839
REACTIVITY TO SEE IF WE CAN

1577
00:55:08,839 --> 00:55:11,542
ENRICH AND MAKE THE TIL FOR POST

1578
00:55:11,542 --> 00:55:12,943
PD-1 PATIENTS MORE EFFECTIVE.

1579
00:55:12,943 --> 00:55:15,779
>> THANK YOU.

1580
00:55:15,779 --> 00:55:18,916
>> VERY NICE TALK.

1581
00:55:18,916 --> 00:55:22,152
SAMIR KALIFF FOUND IN CANCER

1582
00:55:22,152 --> 00:55:24,888
VACCINE STUDY IN MICE THAT

1583
00:55:24,888 --> 00:55:26,957
PRE-TREATMENT WITH ANTIPD-1 LED

1584
00:55:26,957 --> 00:55:28,659
TO LESS EFFECTIVE VACCINE

1585
00:55:28,659 --> 00:55:32,029
RESPONSE THAN TREATING

1586
00:55:32,029 --> 00:55:33,597
CONCURRENTLY, AND WAS ASSOCIATED

1587
00:55:33,597 --> 00:55:40,304
WITH MORE CD8 -- CD38-POSITIVE

1588
00:55:40,304 --> 00:55:42,272
CD-8 T CELLS THAT WERE SO-CALLED

1589
00:55:42,272 --> 00:55:43,473
SUBPRIMED.

1590
00:55:43,473 --> 00:55:46,476
AND WE TESTED THAT IN OUR

1591
00:55:46,476 --> 00:55:47,477
VACCINE SYSTEM AND FOUND

1592
00:55:47,477 --> 00:55:50,013
SOMETHING VERY SIMILAR, THAT

1593
00:55:50,013 --> 00:55:51,782
PRE-TREATING WITH ANTIPD-1

1594
00:55:51,782 --> 00:55:53,050
ACTUALLY REDUCED THE

1595
00:55:53,050 --> 00:55:54,518
EFFECTIVENESS OR ELIMINATED THE

1596
00:55:54,518 --> 00:55:56,186
EFFECTIVENESS OF THE VACCINE

1597
00:55:56,186 --> 00:55:57,588
COMPARED TO GIVING IT

1598
00:55:57,588 --> 00:55:59,089
CONCURRENTLY OR AFTER THE

1599
00:55:59,089 --> 00:55:59,423
VACCINE.

1600
00:55:59,423 --> 00:56:01,625
SO I WONDER IF THAT'S RELATED AT

1601
00:56:01,625 --> 00:56:03,660
ALL TO WHAT YOU'RE DESCRIBING

1602
00:56:03,660 --> 00:56:06,029
HERE WITH THE TILs, AND HAVE

1603
00:56:06,029 --> 00:56:08,432
YOU HAD THE OPPORTUNITY TO LOOK

1604
00:56:08,432 --> 00:56:13,136
AT CD38 EXPRESSION IN THE PEOPLE

1605
00:56:13,136 --> 00:56:17,040
WHO ARE PRE-TREATED WITH

1606
00:56:17,040 --> 00:56:17,307
ANTIPD-1?

1607
00:56:17,307 --> 00:56:18,775
>> WHAT I WILL SAY IS IN
THE

1608
00:56:18,775 --> 00:56:19,910
RECENT TWO TRIALS OF USING

1609
00:56:19,910 --> 00:56:20,811
CANCER VACCINES IN PATIENTS,

1610
00:56:20,811 --> 00:56:22,846
BOTH WITH MELANOMA AND WITH

1611
00:56:22,846 --> 00:56:24,615
PANCREAS CANCER, THOSE ARE GIVEN

1612
00:56:24,615 --> 00:56:27,818
IN CONJUNCTION WITH AN ANTIPD-1

1613
00:56:27,818 --> 00:56:29,286
OR ANTIPDL1 INHIBITOR.

1614
00:56:29,286 --> 00:56:31,788
SO THE PATIENTS WILL GET THE

1615
00:56:31,788 --> 00:56:33,690
DRUG, THEN GET THE VACCINE, AND

1616
00:56:33,690 --> 00:56:36,760
BOTH IN THE PAPER THAT DR. WEBER

1617
00:56:36,760 --> 00:56:38,061
PUBLISHED RECENTLY BEFORE HIS

1618
00:56:38,061 --> 00:56:39,363
PASSING AND IN THE WORK THAT

1619
00:56:39,363 --> 00:56:41,632
CAME OUT OF MEMORIAL SLOAN

1620
00:56:41,632 --> 00:56:42,299
KETTERING, THOSE PATIENTS WERE

1621
00:56:42,299 --> 00:56:44,201
ABLE TO BE VACCINATED.

1622
00:56:44,201 --> 00:56:45,936
AND SO THE EFFECT OF THAT

1623
00:56:45,936 --> 00:56:47,904
CHECKPOINT INHIBITOR IN HUMANS

1624
00:56:47,904 --> 00:56:49,439
DOES NOT SEEM TO DIMINISH THE

1625
00:56:49,439 --> 00:56:51,041
ABILITY TO RAISE THAT

1626
00:56:51,041 --> 00:56:52,476
IMMUNOGENIC RESPONSE.

1627
00:56:52,476 --> 00:56:54,444
ONE THING THAT WE HAVE LOOKED AT

1628
00:56:54,444 --> 00:56:57,447
IS NOT CD38 SPECIFICALLY, BUT

1629
00:56:57,447 --> 00:56:59,616
CD39 AND 69, AND I THINK RATHER

1630
00:56:59,616 --> 00:57:02,586
THAN STEAL THE THUNDER OF EITHER

1631
00:57:02,586 --> 00:57:03,887
DR. LOWRY OR DR. KRISHNA WHO

1632
00:57:03,887 --> 00:57:05,489
WILL PROBABLY PRESENT THAT MORE

1633
00:57:05,489 --> 00:57:06,690
FULLY LATER THIS AFTERNOON, WE

1634
00:57:06,690 --> 00:57:07,924
DID FIND THAT THOSE CELLS THAT

1635
00:57:07,924 --> 00:57:09,393
WERE NEGATIVE WERE LESS PRESENT

1636
00:57:09,393 --> 00:57:11,695
IN THE PD-1 GROUP.

1637
00:57:11,695 --> 00:57:12,429
>> OKAY.

1638
00:57:12,429 --> 00:57:13,363
THANK YOU.

1639
00:57:13,363 --> 00:57:17,701
>> THANK YOU ALL.

1640
00:57:17,701 --> 00:57:18,068
OH.

1641
00:57:18,068 --> 00:57:19,736
>> ONE COMMENT I'D LIKE TO
MAKE

1642
00:57:19,736 --> 00:57:21,071
IS THAT WHEN YOU LOOK AT THE

1643
00:57:21,071 --> 00:57:24,207
COMPARISON BETWEEN THE VARIOUS

1644
00:57:24,207 --> 00:57:25,275
IMMUNOTHERAPIES AVAILABLE AND

1645
00:57:25,275 --> 00:57:27,544
THE -- THE -- ONE THING THAT'S

1646
00:57:27,544 --> 00:57:30,213
NOT MEASURED IS THE TIME OFF

1647
00:57:30,213 --> 00:57:30,480
TREATMENT.

1648
00:57:30,480 --> 00:57:31,748
THE AMOUNT OF TIME THE PATIENT

1649
00:57:31,748 --> 00:57:33,350
DOES NOT SEE A DOCTOR OR A

1650
00:57:33,350 --> 00:57:34,217
HOSPITAL OR A CLINIC.

1651
00:57:34,217 --> 00:57:36,920
THAT'S SOMETHING THAT WE NEED TO

1652
00:57:36,920 --> 00:57:39,589
CAPTURE, THE DIFFERENCE BETWEEN

1653
00:57:39,589 --> 00:57:41,124
THE -- PRETTY MUCH ALL OTHER

1654
00:57:41,124 --> 00:57:41,525
THERAPIES.

1655
00:57:41,525 --> 00:57:43,160
>> I AGREE, AND THE GROUP
IN

1656
00:57:43,160 --> 00:57:44,194
EUROPE ACTUALLY INCORPORATED

1657
00:57:44,194 --> 00:57:46,029
QUALITY OF LIFE STUDIES IN THEIR

1658
00:57:46,029 --> 00:57:48,398
RANDOMIZED TRIAL AND FOUND THAT

1659
00:57:48,398 --> 00:57:49,599
QUALITY OF LIFE WAS BETTER IN

1660
00:57:49,599 --> 00:57:51,335
THE PATIENTS THAT HAD GOTTEN THE

1661
00:57:51,335 --> 00:57:52,636
TIL PRODUCT THAN THOSE THAT WENT

1662
00:57:52,636 --> 00:57:54,938
ON TO IPIMIBULAB.

1663
00:57:54,938 --> 00:57:56,073
THANK YOU FOR YOUR ATTENTION.

1664
00:57:56,073 --> 00:57:57,407
AND AGAIN, DR. ROSENBERG, I

1665
00:57:57,407 --> 00:57:58,842
WOULDN'T BE HERE WITHOUT YOU,

1666
00:57:58,842 --> 00:57:59,376
QUITE LITERALLY.

1667
00:57:59,376 --> 00:57:59,843
THANK YOU.

1668
00:57:59,843 --> 00:58:09,319
[APPLAUSE]

1669
00:58:09,319 --> 00:58:10,520
>> OKAY, THANK YOU,
EVERYBODY.

1670
00:58:10,520 --> 00:58:11,722
THAT'S IT FOR OUR FIRST SESSION.

1671
00:58:11,722 --> 00:58:13,623
SO WE HAVE TIME FOR A 15-MINUTE

1672
00:58:13,623 --> 00:58:16,259
BREAK AND THEN WE'LL COME BACK

1673
00:58:16,259 --> 00:58:20,530
AT 9:50 FOR ANTIGEN DISCOVERY

1674
00:58:20,530 --> 00:58:21,898
WITH DR. PRIETO.

1675
00:58:21,898 --> 00:58:22,466
THANK YOU.

1676
00:58:22,466 --> 00:58:23,433
MORNING SO WE'RE GOING TO START

1677
00:58:23,433 --> 00:58:25,202
WITH OUR SECOND SESSION, WHICH

1678
00:58:25,202 --> 00:58:27,404
IS DEALING WITH ANTIGEN

1679
00:58:27,404 --> 00:58:31,174
DISCOVERY.

1680
00:58:31,174 --> 00:58:33,610
WE HAVE WITH US FIRST DR. YUTAKA

1681
00:58:33,610 --> 00:58:35,312
KAWAKAMI FROM THE INTERNATIONAL

1682
00:58:35,312 --> 00:58:37,647
HEALTH AND WELLNESS UNIVERSITY

1683
00:58:37,647 --> 00:58:41,518
FROM SHIBA, JAPAN.

1684
00:58:41,518 --> 00:58:51,762
DR. KAWAKAMI.

1685
00:58:59,569 --> 00:59:02,506
>> GOOD MORNING.

1686
00:59:02,506 --> 00:59:04,941
THANK YOU, CHAIRMAN AND THOSE

1687
00:59:04,941 --> 00:59:06,109
MEETING ORGANIZERS.

1688
00:59:06,109 --> 00:59:08,812
THIS IS MY GREAT HONOR FOR ME TO

1689
00:59:08,812 --> 00:59:12,449
GIVE A TALK AT THIS SPECIAL

1690
00:59:12,449 --> 00:59:15,352
SYMPOSIUM CELEBRATING

1691
00:59:15,352 --> 00:59:17,421
DR. ROSENBERG'S 50 YEARS AT NCI.

1692
00:59:17,421 --> 00:59:22,692
I STILL REMEMBER WHEN I WAS A

1693
00:59:22,692 --> 00:59:25,162
PHYSICIAN, HEMATOONCOLOGIST

1694
00:59:25,162 --> 00:59:26,329
TRAINED AT UNIVERSITY OF TOKYO,

1695
00:59:26,329 --> 00:59:27,798
I WAS VERY INTERESTED WITH ONE

1696
00:59:27,798 --> 00:59:32,002
PAPER WRITTEN BY DR. ROSENBERG

1697
00:59:32,002 --> 00:59:35,305
DISCUSSING POTENTIAL NEW CANCER

1698
00:59:35,305 --> 00:59:37,040
TREATMENT THAT WAS -- TRANSFER

1699
00:59:37,040 --> 00:59:41,678
OF LYMPHOCYTE.

1700
00:59:41,678 --> 00:59:44,648
SO I HAD A CHANCE TO JOIN THE

1701
00:59:44,648 --> 00:59:44,881
BRANCH.

1702
00:59:44,881 --> 00:59:48,018
I WAS HERE '87 TO '97, FOR 10

1703
00:59:48,018 --> 00:59:48,351
YEARS.

1704
00:59:48,351 --> 00:59:52,355
SO TODAY, I'M GOING TO TALK

1705
00:59:52,355 --> 00:59:55,725
ABOUT TUMOR ANTIGEN ISOLATION, A

1706
00:59:55,725 --> 00:59:56,426
HISTORICAL VIEW AND ALSO A

1707
00:59:56,426 --> 01:00:02,799
LITTLE BIT ABOUT FURTHER STUDY

1708
01:00:02,799 --> 01:00:03,834
AND RESEARCH.

1709
01:00:03,834 --> 01:00:07,070
SO THIS SLIDE SHOWS OUR CANCER

1710
01:00:07,070 --> 01:00:10,106
IMMUNOLOGY RESEARCH HISTORY.

1711
01:00:10,106 --> 01:00:15,479
SO ANTITUMOR ACTIVITY OF

1712
01:00:15,479 --> 01:00:19,716
CD8 POSITIVE TUMOR LYMPHOCYTE

1713
01:00:19,716 --> 01:00:21,218
WAS DISCOVERED AT THE BRANCH, WE

1714
01:00:21,218 --> 01:00:25,055
TRIED TO ISOLATE TUMOR ANTIGEN

1715
01:00:25,055 --> 01:00:26,523
RECOGNIZED BY -- TO UNDERSTAND

1716
01:00:26,523 --> 01:00:28,325
MECHANISM OF ANTITUMOR IMMUNE

1717
01:00:28,325 --> 01:00:31,461
RESPONSE AND THOSE MECHANISMS OF

1718
01:00:31,461 --> 01:00:31,862
IMMUNORESISTANCE.

1719
01:00:31,862 --> 01:00:36,733
SO LATER, 2010, LATER

1720
01:00:36,733 --> 01:00:39,736
CHECKPOINT -- WAS AVAILABLE,

1721
01:00:39,736 --> 01:00:41,438
COMPARATIVE ANALYSIS BETWEEN THE

1722
01:00:41,438 --> 01:00:43,874
RESPONDER AND NON-RESPONDER

1723
01:00:43,874 --> 01:00:47,477
ACTUALLY PROMOTED FURTHER CANCER

1724
01:00:47,477 --> 01:00:49,212
IMMUNOLOGY RESEARCH.

1725
01:00:49,212 --> 01:00:52,616
NOW WE KNOW MANY IMMUNOLOGICAL

1726
01:00:52,616 --> 01:00:53,750
SUBTYPE VARIETY OF CANCER AND

1727
01:00:53,750 --> 01:00:55,852
THUS A POTENTIAL GOOD

1728
01:00:55,852 --> 01:00:56,987
COMBINATION IMMUNOTHERAPY.

1729
01:00:56,987 --> 01:01:00,724
SO THIS IS A PICTURE, I WAS HERE

1730
01:01:00,724 --> 01:01:01,391
AT THE NIH.

1731
01:01:01,391 --> 01:01:05,195
SOME OF THE PEOPLE ACTUALLY HERE

1732
01:01:05,195 --> 01:01:05,795
TODAY.

1733
01:01:05,795 --> 01:01:10,200
THIS IS THE TUMOR ISOLATION,

1734
01:01:10,200 --> 01:01:11,668
ACTUAL MORE ANTIGEN ISOLATION

1735
01:01:11,668 --> 01:01:14,905
GROUP.

1736
01:01:14,905 --> 01:01:17,374
ALSO WE COLLABORATED WITH MANY

1737
01:01:17,374 --> 01:01:19,943
RESEARCHERS AT NIH AND AS AN

1738
01:01:19,943 --> 01:01:23,480
INSTITUTE FOR C D EXPRESSION

1739
01:01:23,480 --> 01:01:29,786
CLONING, BINDING PEP TIGHTS,

1740
01:01:29,786 --> 01:01:32,656
SPECTROMETRY ANALYSIS, NEW

1741
01:01:32,656 --> 01:01:33,623
TECHNOLOGY WAS ESSENTIAL AND

1742
01:01:33,623 --> 01:01:36,493
EVEN NOW IT'S MORE IMPORTANT TO

1743
01:01:36,493 --> 01:01:39,496
COLLABORATE WITH MANY PEOPLE.

1744
01:01:39,496 --> 01:01:43,466
SO WE FIRST ACTUALLY FOUND THREE

1745
01:01:43,466 --> 01:01:48,371
STRATEGIES, CLONING -- USED

1746
01:01:48,371 --> 01:01:53,009
FIRST STABLE EXPRESSION SYSTEM,

1747
01:01:53,009 --> 01:01:56,646
THEN COS CELL TRANSIENT SYSTEM.

1748
01:01:56,646 --> 01:01:57,981
TESTING KNOWN OR NEW CANDIDATE

1749
01:01:57,981 --> 01:02:00,016
IDENTIFIED BY A VARIETY OF

1750
01:02:00,016 --> 01:02:01,084
DIFFERENT METHODS.

1751
01:02:01,084 --> 01:02:02,886
THE THIRD ONE IS ISOLATION,

1752
01:02:02,886 --> 01:02:06,723
DIRECT ISOLATION OF HLA BINDING

1753
01:02:06,723 --> 01:02:11,428
PEPTIDES ON HLA MELANOMA CELL,

1754
01:02:11,428 --> 01:02:14,864
USING HPLC AND MASS

1755
01:02:14,864 --> 01:02:15,465
SPECTROMETRY.

1756
01:02:15,465 --> 01:02:18,301
UNFORTUNATELY I COULD NOT --

1757
01:02:18,301 --> 01:02:19,803
ISOLATE THIS WAY BUT LATER, THIS

1758
01:02:19,803 --> 01:02:21,605
IS VERY IMPORTANT TO JUST

1759
01:02:21,605 --> 01:02:23,073
CONFIRM THE PRESENCE OF PEPTIDE

1760
01:02:23,073 --> 01:02:26,142
ON HLA ON MELANOMA CELL.

1761
01:02:26,142 --> 01:02:28,878
WHEN I WENT BACK TO JAPAN, I

1762
01:02:28,878 --> 01:02:34,417
ALSO TRIED CD EXPRESSION CRO

1763
01:02:34,417 --> 01:02:40,557
CREXPRESSIONCLONING.

1764
01:02:40,557 --> 01:02:41,524
TUMOR ANTIGEN AND

1765
01:02:41,524 --> 01:02:43,760
CHARACTERIZATION OF ANTIGEN FOR

1766
01:02:43,760 --> 01:02:46,162
PREPARATION OF -- FOR

1767
01:02:46,162 --> 01:02:47,063
ANTISCREENING, WE'RE SCREENING

1768
01:02:47,063 --> 01:02:49,132
SO MANY TIL, RESULT IN TUMOR

1769
01:02:49,132 --> 01:02:50,400
REGRESSION.

1770
01:02:50,400 --> 01:02:53,770
HERE SHOW GP100 REACTIVE T-CELL

1771
01:02:53,770 --> 01:02:54,437
VERY GOOD RESPONSE.

1772
01:02:54,437 --> 01:02:59,676
WE ALSO EVALUATED -- OF

1773
01:02:59,676 --> 01:03:01,111
AUTOLOGOUS AND ALLOGENIC

1774
01:03:01,111 --> 01:03:02,178
MELANOMA CELL, ACTUALLY WE

1775
01:03:02,178 --> 01:03:09,319
PROVED THE PRESENCE OF SHARED --

1776
01:03:09,319 --> 01:03:15,158
ALSO -- BY VERY COMMON HLA-A2.1,

1777
01:03:15,158 --> 01:03:19,095
LATER A20, 1/3 INTSH 26,

1778
01:03:19,095 --> 01:03:26,069
SOMETHING LIKE THAT.

1779
01:03:26,069 --> 01:03:29,906
THIS WAS PRETTY NEW AT THE TIME,

1780
01:03:29,906 --> 01:03:31,074
IF YOU REMEMBER, THE STRUCTURE

1781
01:03:31,074 --> 01:03:37,213
OF HLA-ASM 26789 -- WAS JUST

1782
01:03:37,213 --> 01:03:37,714
PUBLISHED 1987.

1783
01:03:37,714 --> 01:03:40,350
TWO YEARS BEFORE I STARTED THE

1784
01:03:40,350 --> 01:03:41,751
TUMOR ANTIGEN PROJECT.

1785
01:03:41,751 --> 01:03:45,789
WE ALSO MADE SURE THE ENDODGE

1786
01:03:45,789 --> 01:03:47,557
JUST EXPRESSION OF EPITOPE, WE

1787
01:03:47,557 --> 01:03:50,360
CONFIRMED THE PRESENCE OF

1788
01:03:50,360 --> 01:03:55,932
EPITOPE PEPTIDE AND ALSO TUMOR

1789
01:03:55,932 --> 01:03:58,768
DEACTIVE T-CELL BY STIMULATION

1790
01:03:58,768 --> 01:03:59,703
WITH PEPTIDE.

1791
01:03:59,703 --> 01:04:01,071
TO CHARACTERIZATION OF TUMOR

1792
01:04:01,071 --> 01:04:04,207
ANTIGENS AND EP TOTALS, SELF OR

1793
01:04:04,207 --> 01:04:06,409
MUTATED, OR SHARED OR UNIQUE BY

1794
01:04:06,409 --> 01:04:09,112
DNA SEQUENCING AND ALSO HLA

1795
01:04:09,112 --> 01:04:10,547
BINDING AFFINITY OF PEPTIDES,

1796
01:04:10,547 --> 01:04:14,417
MANY OF THEM IT'S INTERMEDIATE

1797
01:04:14,417 --> 01:04:14,918
AFFINITY.

1798
01:04:14,918 --> 01:04:16,753
WE CAN MODIFY TO MAKE

1799
01:04:16,753 --> 01:04:20,323
IMMUNOGENIC PEPTIDE, AND ALSO

1800
01:04:20,323 --> 01:04:25,161
THE AVIDITY OF TCR TO

1801
01:04:25,161 --> 01:04:26,563
PEPTIDE/HLA COMPLEX, WE CAN MAKE

1802
01:04:26,563 --> 01:04:29,499
A HIGH AVIDITY TCR.

1803
01:04:29,499 --> 01:04:30,834
AND BIOLOGICAL FUNCTION OF

1804
01:04:30,834 --> 01:04:32,068
ANTIGEN, THIS IS ALSO IMPORTANT

1805
01:04:32,068 --> 01:04:37,674
RELATED TO THE UNDERSTANDING OF

1806
01:04:37,674 --> 01:04:38,975
IMMUNOLOGIST -- ME CANNISTS AND

1807
01:04:38,975 --> 01:04:40,076
TARGET THERAPY.

1808
01:04:40,076 --> 01:04:42,178
OF COURSE INVIE VO ANTITUMOR

1809
01:04:42,178 --> 01:04:43,813
ACTIVITY WAS CONFIRMED IN

1810
01:04:43,813 --> 01:04:47,150
CLINICAL TRIAL.

1811
01:04:47,150 --> 01:04:49,786
NOW MANY PEOPLE TRYING TO

1812
01:04:49,786 --> 01:04:51,221
GENERATE ALGORITHM PREDICTING I

1813
01:04:51,221 --> 01:04:53,123
MU KNOWGENIC NEOANTIGEN, ALSO

1814
01:04:53,123 --> 01:04:55,225
MAKING A LIBRARY OF TUMOR

1815
01:04:55,225 --> 01:04:56,659
ANTIGEN AND THEY'RE RECOGNIZING

1816
01:04:56,659 --> 01:04:57,627
TCR.

1817
01:04:57,627 --> 01:05:03,166
NOW THIS IS WHERE I JUST SHOW

1818
01:05:03,166 --> 01:05:04,033
REPRESENTATIVE -- WE FIRST

1819
01:05:04,033 --> 01:05:09,539
ACTUALLY ISOLATED TISSUE --

1820
01:05:09,539 --> 01:05:09,973
ANTIGEN.

1821
01:05:09,973 --> 01:05:13,443
LATER THE NEOANTIGEN DID WITH

1822
01:05:13,443 --> 01:05:17,714
MYSELF ISOLATED SINGLE --

1823
01:05:17,714 --> 01:05:18,348
PINPOINT MUTATION.

1824
01:05:18,348 --> 01:05:20,617
THIS MUTATION CREATES HIGHER HLA

1825
01:05:20,617 --> 01:05:22,585
BINDING PEPTIDE, WHICH ACTUALLY

1826
01:05:22,585 --> 01:05:24,754
INDUCED T-CELL.

1827
01:05:24,754 --> 01:05:29,659
WE ALSO ISOLATE -- VERY SIMILAR

1828
01:05:29,659 --> 01:05:30,093
MECHANISM.

1829
01:05:30,093 --> 01:05:32,929
THEN LATER WE ALSO FOUND IN

1830
01:05:32,929 --> 01:05:38,635
COLON CANCER -- DEFECTIVE ONE,

1831
01:05:38,635 --> 01:05:40,670
WE FOUND THE IMMUNE SYSTEM

1832
01:05:40,670 --> 01:05:43,540
ACTUALLY RECOGNIZED -- PEPTIDE.

1833
01:05:43,540 --> 01:05:45,475
THIS IS VERY IMPORTANT TOO.

1834
01:05:45,475 --> 01:05:50,046
NOW, THIS IS -- I MADE LATE NIEP

1835
01:05:50,046 --> 01:06:00,957
LATE90s SHOWING -- ON CANCER CE.

1836
01:06:03,126 --> 01:06:03,726
TRANSLATION, MODIFICATION,

1837
01:06:03,726 --> 01:06:06,896
VARIETY OF MECHANISMS TO

1838
01:06:06,896 --> 01:06:08,698
GENERATE T-CELL EPITOPE ON

1839
01:06:08,698 --> 01:06:09,699
CANCER CELL.

1840
01:06:09,699 --> 01:06:11,000
I WILL NOT GET IN DETAIL.

1841
01:06:11,000 --> 01:06:18,741
THIS IS ALSO LATE N LATE '90S, G

1842
01:06:18,741 --> 01:06:23,646
HLA PEPTIDE, AFFINITY MEANS --

1843
01:06:23,646 --> 01:06:26,482
CRYPTIC NATURE OF EPITOPE, WHICH

1844
01:06:26,482 --> 01:06:27,584
MEANS MAYBE WE CAN MAKE A

1845
01:06:27,584 --> 01:06:28,218
MODIFICATION.

1846
01:06:28,218 --> 01:06:33,156
AND ALSO WE MADE SURE -- PRESENT

1847
01:06:33,156 --> 01:06:39,896
OF THIS ANTIGEN OF -- MELANOMA.

1848
01:06:39,896 --> 01:06:41,631
SHOWING TARGET USED FOR CLINICAL

1849
01:06:41,631 --> 01:06:42,398
TRIAL.

1850
01:06:42,398 --> 01:06:46,302
 -- T-CELL, THIS PEPTIDE, THIS

1851
01:06:46,302 --> 01:06:50,340
PEPTIDE MODIFIED GP100 USED FOR

1852
01:06:50,340 --> 01:06:50,840
VACCINE TRIAL.

1853
01:06:50,840 --> 01:06:54,811
THIS PEPTIDE IS ACTUALLY

1854
01:06:54,811 --> 01:06:57,647
BIOSTATISTIC -- CD3 AND THIS

1855
01:06:57,647 --> 01:07:00,216
PEPTIDE -- WAS ACTUALLY APPROVED

1856
01:07:00,216 --> 01:07:01,818
BY FDA.

1857
01:07:01,818 --> 01:07:05,722
THIS IS ACTUALLY EXPERIMENT OF

1858
01:07:05,722 --> 01:07:07,056
CANCER VACCINE WITH HIGHLY I YOU

1859
01:07:07,056 --> 01:07:09,325
MOO KNOWGENIC MODIFIED GP100

1860
01:07:09,325 --> 01:07:09,959
PEPTIDE.

1861
01:07:09,959 --> 01:07:12,028
THE SERIES OF STUDIES SHOW

1862
01:07:12,028 --> 01:07:17,166
ANTI-TUMOR ACTIVITY OF SHARED --

1863
01:07:17,166 --> 01:07:20,536
OR WE CAN SEE THE -- BUT ANYWAY,

1864
01:07:20,536 --> 01:07:24,474
IT IS A VERY NICE -- TUMOR

1865
01:07:24,474 --> 01:07:26,542
ANTIGEN MADE AS POSSIBLE TO

1866
01:07:26,542 --> 01:07:29,812
DEVELOP ANTIGEN-SPECIFIC 

1867
01:07:29,812 --> 01:07:30,580
IMMUNOTHERAPY IN A VERY

1868
01:07:30,580 --> 01:07:31,147
SCIENTIFIC WAY.

1869
01:07:31,147 --> 01:07:32,782
THIS IS WHAT'S GOOD.

1870
01:07:32,782 --> 01:07:38,121
AND I THINK STILL THAT EVEN

1871
01:07:38,121 --> 01:07:40,523
THE -- T-CELL IN MELANOMA NEED

1872
01:07:40,523 --> 01:07:42,358
TO BE CLARIFIED.

1873
01:07:42,358 --> 01:07:47,830
LIKE VACCINE STUDY AND ALSO

1874
01:07:47,830 --> 01:07:50,333
TRANSFER OF MART 1 -- TRANSDUCED

1875
01:07:50,333 --> 01:07:55,605
T-CELL AND ALSO OLD PAPER BUT --

1876
01:07:55,605 --> 01:07:57,707
CORRELATE RESPONSE TO

1877
01:07:57,707 --> 01:08:00,310
INTERLEUKIN 2 THERAPY AND ALSO

1878
01:08:00,310 --> 01:08:05,615
RECENTLY THIS IS JEFF WEBER'S

1879
01:08:05,615 --> 01:08:07,383
PAPERS IN RESPONSE TO PD-1

1880
01:08:07,383 --> 01:08:08,484
TREATMENT.

1881
01:08:08,484 --> 01:08:12,288
SO MAYBE THERE WILL BE SOME LOAD

1882
01:08:12,288 --> 01:08:13,589
OVER -- ANTIGEN SPECIFIC T-CELL.

1883
01:08:13,589 --> 01:08:16,526
THIS IS A VERY INTERESTING

1884
01:08:16,526 --> 01:08:19,696
CLINICAL HISTORY ON A PATIENT

1885
01:08:19,696 --> 01:08:26,703
TREATED WITH -- SO ONE THING

1886
01:08:26,703 --> 01:08:28,438
INTERESTING -- TIL THERAPY --

1887
01:08:28,438 --> 01:08:29,839
NEOANTIGEN WAS VERY EFFECTIVE

1888
01:08:29,839 --> 01:08:32,709
DND MULTIPLE METASTASES.

1889
01:08:32,709 --> 01:08:36,045
 -- HLA LOSS OCCUR.

1890
01:08:36,045 --> 01:08:37,914
PREVIOUSLY WE REPORTED IN THE

1891
01:08:37,914 --> 01:08:39,582
INTERLEUKIN 2 THERAPY.

1892
01:08:39,582 --> 01:08:42,952
AND INTERESTINGLY -- CANCER CELL

1893
01:08:42,952 --> 01:08:45,088
STILL EXPRESSING NEOANTIGEN

1894
01:08:45,088 --> 01:08:46,856
REMAINING EVEN IN COMPLETE

1895
01:08:46,856 --> 01:08:48,658
RESPONSE PATIENT.

1896
01:08:48,658 --> 01:08:51,894
THEN THREE YEARS LATER, TWICE,

1897
01:08:51,894 --> 01:08:55,164
THAT MEANS -- IMMUNORESISTANT

1898
01:08:55,164 --> 01:08:57,000
DOMINANT CANCER CELERY MAINING.

1899
01:08:57,000 --> 01:08:59,635
THEN THAT LED US ANALYSIS OF

1900
01:08:59,635 --> 01:09:01,537
CANCER STEM CELL EMT, LATER WE

1901
01:09:01,537 --> 01:09:05,108
FOUNT EMT CANCER CELL INCREASED

1902
01:09:05,108 --> 01:09:07,643
METASTASES PARTLY DUE TO VERY

1903
01:09:07,643 --> 01:09:08,544
STRONG IMMUNOSUPPRESSION.

1904
01:09:08,544 --> 01:09:12,682
NOW, THIS IS A PROTOTYPE OF

1905
01:09:12,682 --> 01:09:13,783
IMMUNOLOGICAL SUBTYPE IN

1906
01:09:13,783 --> 01:09:14,417
MELANOMA.

1907
01:09:14,417 --> 01:09:16,185
AS YOU ALREADY KNOW,

1908
01:09:16,185 --> 01:09:17,787
HYPERMUTATION TYPE -- AND

1909
01:09:17,787 --> 01:09:21,991
VARIETY OF IMMUNOSUPPRESSION.

1910
01:09:21,991 --> 01:09:28,164
ACTIVATED ONCO -- MUTATION --

1911
01:09:28,164 --> 01:09:32,735
RELATED TO EMT, CAF, ALTERED

1912
01:09:32,735 --> 01:09:36,205
METABOLISM, WE'RE NOW LOOKING ON

1913
01:09:36,205 --> 01:09:38,841
FATTY ACID, CHOLESTEROL AND ALSO

1914
01:09:38,841 --> 01:09:42,011
GUT MICROBIOTA -- MEDICINE.

1915
01:09:42,011 --> 01:09:47,383
NOW, THIS IS ONE -- OUR

1916
01:09:47,383 --> 01:09:49,552
RESEARCH -- DENDRITIC CELL

1917
01:09:49,552 --> 01:09:51,721
T-CELL ACCESS AFTER -- MUTATION

1918
01:09:51,721 --> 01:09:54,757
WAS DISCOVERED WE ACTUALLY WORK

1919
01:09:54,757 --> 01:09:58,194
ON BETA -- INDUCE

1920
01:09:58,194 --> 01:09:59,095
IMMUNOSUPPRESSION.

1921
01:09:59,095 --> 01:10:01,531
DIFFERENT MECHANISM THAN

1922
01:10:01,531 --> 01:10:05,034
INHIBITOR ACTIVATE ANTITUMOR

1923
01:10:05,034 --> 01:10:07,003
DENDRITIC CELLS -- NOW

1924
01:10:07,003 --> 01:10:09,305
DOWNSTREAM OF THE -- IS CD1,

1925
01:10:09,305 --> 01:10:12,909
THIS IS A FATTY ACID --

1926
01:10:12,909 --> 01:10:15,211
INHIBITOR ACTIVATE TUMOR --

1927
01:10:15,211 --> 01:10:26,022
AGAIN 16ER J SYNERGIZE WITH PD-.

1928
01:10:28,791 --> 01:10:31,794
THEN WE ARE FOCUSING INTRATUMOR

1929
01:10:31,794 --> 01:10:34,297
DENDRITIC CELL.

1930
01:10:34,297 --> 01:10:37,900
JIM MULE DISCUSSED ABOUT -- IN

1931
01:10:37,900 --> 01:10:39,302
CANCER, MANY PEOPLE WORKING ON

1932
01:10:39,302 --> 01:10:40,336
THAT.

1933
01:10:40,336 --> 01:10:44,207
NOW, WE ACTUALLY ARE WORKING

1934
01:10:44,207 --> 01:10:47,844
ON -- DENDRITIC CELL,

1935
01:10:47,844 --> 01:10:50,746
MICROBIOTA -- INHIBITOR -- THOSE

1936
01:10:50,746 --> 01:10:53,282
ACTUALLY ACTIVATE INTERTUMOR

1937
01:10:53,282 --> 01:10:55,017
DENDRITIC CELLS AND FINALLY

1938
01:10:55,017 --> 01:10:57,820
ACTIVATE T-CELL -- PD-1.

1939
01:10:57,820 --> 01:11:01,124
THIS IS ONE EXAMPLE WE

1940
01:11:01,124 --> 01:11:04,827
PREVIOUSLY IDENTIFIED --

1941
01:11:04,827 --> 01:11:05,228
IMMUNOSUPPRESSION.

1942
01:11:05,228 --> 01:11:09,532
THIS IN MOUSE -- MELANOMA,

1943
01:11:09,532 --> 01:11:11,367
INHIBITOR ANTIPD-1 ANTIBODY IS

1944
01:11:11,367 --> 01:11:12,568
EFFECTIVE BUT NOT ENOUGH.

1945
01:11:12,568 --> 01:11:15,404
IN ADDITION OF -- AGONIST IS

1946
01:11:15,404 --> 01:11:19,876
COMPLETELY ERADICATE ACTIVATION

1947
01:11:19,876 --> 01:11:22,245
OF INTRATUMOR DENDRITIC CELL,

1948
01:11:22,245 --> 01:11:32,722
CDC, PDC -- THIS WAS USED --

1949
01:11:33,156 --> 01:11:33,856
SIMILAR 2003.

1950
01:11:33,856 --> 01:11:38,094
NOW ACTUALLY INTERESTING

1951
01:11:38,094 --> 01:11:42,031
SITUATION, IL-2 RESPONSE

1952
01:11:42,031 --> 01:11:44,634
CANCER -- DEFICIENT CANCER,

1953
01:11:44,634 --> 01:11:45,935
VIRAL ASSOCIATED CANCER.

1954
01:11:45,935 --> 01:11:49,005
SO ONE IS BACK TO 2003, ACTUALLY

1955
01:11:49,005 --> 01:11:54,777
WE ANALYZED COLON CANCER WITH --

1956
01:11:54,777 --> 01:11:58,080
DEFECTIVE COLON CANCER -- T-CELL

1957
01:11:58,080 --> 01:11:58,948
INFILTRATION.

1958
01:11:58,948 --> 01:12:03,419
WE COULD REPORT IMMUNE

1959
01:12:03,419 --> 01:12:04,754
RECOGNITION AGAINST -- PEPTIDE,

1960
01:12:04,754 --> 01:12:06,389
THIS IS COMPLETELY CHANGED

1961
01:12:06,389 --> 01:12:10,760
BECAUSE OF DNA -- BY -- THEN

1962
01:12:10,760 --> 01:12:17,633
ACTUALLY CANCER RESEARCH -- WITH

1963
01:12:17,633 --> 01:12:19,368
DEFECTIVE -- IT TYPE OF TUMOR IS

1964
01:12:19,368 --> 01:12:20,136
PARTICULARLY INTERESTING IN

1965
01:12:20,136 --> 01:12:21,037
TERMS OF -- VIEW.

1966
01:12:21,037 --> 01:12:22,872
THEN LATER ACTUALLY PD-1

1967
01:12:22,872 --> 01:12:25,608
ANTIBODY WAS FOUND TO BE VERY

1968
01:12:25,608 --> 01:12:27,009
EFFECTIVE FOR -- CANCER,

1969
01:12:27,009 --> 01:12:29,812
ALTHOUGH SOME OF THEM STILL DO

1970
01:12:29,812 --> 01:12:32,615
NOT RESPOND SO -- CLASS 1 LOSS

1971
01:12:32,615 --> 01:12:35,218
OR IMMUNOSUPPRESSION -- TO ONE

1972
01:12:35,218 --> 01:12:36,185
OF THE MECHANISMS OF

1973
01:12:36,185 --> 01:12:36,485
SUPPRESSION.

1974
01:12:36,485 --> 01:12:43,192
NOW IN TERMS OF -- RECOGNIZE --

1975
01:12:43,192 --> 01:12:47,597
TUMOR ORGANOID AND THOSE ARE

1976
01:12:47,597 --> 01:12:49,098
FREQUENTLY -- HBV67.

1977
01:12:49,098 --> 01:12:52,602
CLINICAL TRIAL -- SIMILAR TO THE

1978
01:12:52,602 --> 01:12:55,538
PROTOCOL ACTUALLY -- PATIENT WAS

1979
01:12:55,538 --> 01:12:56,439
ALMOST COMPLETE RESPONSE.

1980
01:12:56,439 --> 01:13:03,312
NOW, THIS IS SHOWING -- I TOLD

1981
01:13:03,312 --> 01:13:05,815
YOU I WAS SO AMAZED BUT --

1982
01:13:05,815 --> 01:13:09,085
PROTEIN WHICH RECOGNIZED CD3 AND

1983
01:13:09,085 --> 01:13:11,854
GP100 PEPTIDE -- THIS ONE WAS

1984
01:13:11,854 --> 01:13:15,658
ACTUALLY APPROVED BY FDA FOR --

1985
01:13:15,658 --> 01:13:16,058
MELANOMA.

1986
01:13:16,058 --> 01:13:18,694
SO WE ALSO IDENTIFY MANY

1987
01:13:18,694 --> 01:13:24,166
ANTIGEN, ONE IS ONCOANTIGEN,

1988
01:13:24,166 --> 01:13:26,235
VERY EFFECTIVE PARTICULARLY IN

1989
01:13:26,235 --> 01:13:28,304
COMBINATION WITH ANTIPD-1 OR --

1990
01:13:28,304 --> 01:13:31,140
WE NOW TRY TO DEVELOP A CLINICAL

1991
01:13:31,140 --> 01:13:31,574
TRIAL.

1992
01:13:31,574 --> 01:13:34,510
SO THIS IS A SUMMARY OF ANTIGEN.

1993
01:13:34,510 --> 01:13:39,649
I'M NOT GOING TO -- THE ANTIGEN

1994
01:13:39,649 --> 01:13:42,718
ISOLATION, SCIENTIFIC -- T-CELL

1995
01:13:42,718 --> 01:13:47,990
NEO -- IS VERY IMPORTANT AND --

1996
01:13:47,990 --> 01:13:49,792
TARGETING TUMOR ANTIGEN IS VERY

1997
01:13:49,792 --> 01:13:50,059
PROMISING.

1998
01:13:50,059 --> 01:13:57,800
SO THIS IS -- MY COLLEAGUES, AND

1999
01:13:57,800 --> 01:13:59,001
TUMOR ISOLATION TEAM.

2000
01:13:59,001 --> 01:13:59,669
THANK YOU VERY MUCH.

2001
01:13:59,669 --> 01:14:07,977
[APPLAUSE]

2002
01:14:07,977 --> 01:14:10,046
>> ARE THERE ANY QUESTIONS
FOR

2003
01:14:10,046 --> 01:14:10,913
DR. KAWAKAMI BEFORE WE MOVE ON

2004
01:14:10,913 --> 01:14:12,214
TO OUR NECK SPEAKER?

2005
01:14:12,214 --> 01:14:12,682
OKAY.

2006
01:14:12,682 --> 01:14:14,950
THE NEXT SPEAKER IS DR. PAUL

2007
01:14:14,950 --> 01:14:16,452
ROBBINS FROM THE CENTER FOR

2008
01:14:16,452 --> 01:14:17,320
CANCER RESEARCH AND MEMBER OF

2009
01:14:17,320 --> 01:14:27,830
THE SURGERY BRANCH.

2010
01:14:27,830 --> 01:14:28,497
>> ALL RIGHT.

2011
01:14:28,497 --> 01:14:31,000
I'M VERY HAPPY TO PRESENT TODAY.

2012
01:14:31,000 --> 01:14:33,102
ON THE USE OF PERSONALIZED

2013
01:14:33,102 --> 01:14:34,170
T-CELL ANTIGEN SCREENING

2014
01:14:34,170 --> 01:14:37,239
APPROACHES TO DEVELOP EFFECTIVE

2015
01:14:37,239 --> 01:14:38,541
ADOPTIVE IMMUNOTHERAPIES.

2016
01:14:38,541 --> 01:14:41,711
NOW, I WANTED TO START WITH THIS

2017
01:14:41,711 --> 01:14:44,213
SLIDE, WHERE I SHOW AN IMAGE OF

2018
01:14:44,213 --> 01:14:46,349
A CHARACTER IN GREEK MYTHOLOGY

2019
01:14:46,349 --> 01:14:48,351
AS EVERYBODY KNOWS, WHO WAS

2020
01:14:48,351 --> 01:14:49,885
PUNISHED BY THE GODS FOR KILLING

2021
01:14:49,885 --> 01:14:51,954
VISITORS ACTUALLY, BY BEING

2022
01:14:51,954 --> 01:14:53,222
FORCED FOR ETERNITY TO ROLL A

2023
01:14:53,222 --> 01:14:57,426
ROCK UP A HILL THAT THEN RODE

2024
01:14:57,426 --> 01:14:58,527
BACK DOWN AGAIN.

2025
01:14:58,527 --> 01:15:03,099
HIS WIFE GAVE HIM THIS FIGURE I

2026
01:15:03,099 --> 01:15:05,201
THINK WHEN HE FIRST CAME HERE.

2027
01:15:05,201 --> 01:15:07,603
APART FROM THE OBVIOUS THAT

2028
01:15:07,603 --> 01:15:09,672
STEVE HAS WELCOME AND CARED FOR

2029
01:15:09,672 --> 01:15:10,373
MORE PEOPLE THROUGH HIS WORK

2030
01:15:10,373 --> 01:15:13,042
THAN ANYBODY LISTENING IN THE

2031
01:15:13,042 --> 01:15:14,009
AUDIENCE, I BELIEVE THIS IMAGE

2032
01:15:14,009 --> 01:15:18,180
ALSO REALLY DOESN'T CAPTURE HIM.

2033
01:15:18,180 --> 01:15:20,950
AND THIS IS, I THINK, EVIDENT

2034
01:15:20,950 --> 01:15:21,150
HERE.

2035
01:15:21,150 --> 01:15:25,121
IF YOU LOOK AT PROGRESS IN

2036
01:15:25,121 --> 01:15:29,558
IMMUNOTHERAPY, OVER MEAN YEARS,

2037
01:15:29,558 --> 01:15:31,994
I THINK STEVE HAS REALLY PLAYED

2038
01:15:31,994 --> 01:15:33,295
A MAJOR ROLE IN ADVANCING

2039
01:15:33,295 --> 01:15:33,529
THERAPY.

2040
01:15:33,529 --> 01:15:34,830
SO THIS IS REALLY THE IMAGE THAT

2041
01:15:34,830 --> 01:15:40,703
I HAVE WHEN THINKING OF HIM.

2042
01:15:40,703 --> 01:15:42,037
HE'S ROLLING THE ROCK UP THE

2043
01:15:42,037 --> 01:15:43,139
HILL, WE HAVEN'T REACHED THE

2044
01:15:43,139 --> 01:15:44,373
TOP, WE'RE STILL ON OUR WAY,

2045
01:15:44,373 --> 01:15:45,441
STILL MAKING PROGRESS BUT I

2046
01:15:45,441 --> 01:15:49,345
THINK HE'S PLAYED A MAJOR ROLE

2047
01:15:49,345 --> 01:15:51,347
IN ROLLING THAT ROCK UP THE

2048
01:15:51,347 --> 01:15:51,547
HILL.

2049
01:15:51,547 --> 01:15:53,315
YOU CAN SEE HIS NAMEPLATE HERE

2050
01:15:53,315 --> 01:15:58,854
NEXT TO THIS FIGURE.

2051
01:15:58,854 --> 01:16:00,156
SO I WANT TO DISCUSS HERE WHAT

2052
01:16:00,156 --> 01:16:03,125
SOME OF THE MAIN ISSUES FOR THE

2053
01:16:03,125 --> 01:16:04,427
DEVELOPMENT OF EFFECTIVE

2054
01:16:04,427 --> 01:16:05,327
ADOPTIVE T-CELL THERAPIES.

2055
01:16:05,327 --> 01:16:06,829
I THINK UNDERSTANDING THE

2056
01:16:06,829 --> 01:16:07,696
FACTORS ASSOCIATED WITH THE

2057
01:16:07,696 --> 01:16:10,332
RESPONSE IS CRITICAL.

2058
01:16:10,332 --> 01:16:11,534
THE NATURE OF THE FUNCTION OF

2059
01:16:11,534 --> 01:16:12,535
THE ANTIGEN TARGET WHICH IS WHAT

2060
01:16:12,535 --> 01:16:14,837
I'M REALLY GOING TO FOCUS ON,

2061
01:16:14,837 --> 01:16:16,906
EXPRESSION, MHC BINDING, THE

2062
01:16:16,906 --> 01:16:18,174
CLASS OF T CELLS, YOU CAN

2063
01:16:18,174 --> 01:16:19,175
PROBABLY COME UP WITH A VERY

2064
01:16:19,175 --> 01:16:23,145
LONG LIST OF THINGS THAT ARE

2065
01:16:23,145 --> 01:16:26,081
IMPORTANT FOR THERAPY.

2066
01:16:26,081 --> 01:16:27,583
DEVELOPING STRATEGIES FOR

2067
01:16:27,583 --> 01:16:28,451
OVERCOMING TUMOR RESISTANCE.

2068
01:16:28,451 --> 01:16:30,119
I THINK WE NEED TO BROADEN THE

2069
01:16:30,119 --> 01:16:33,055
REP TRREPERTOIRE OF ANTIGENS TOL

2070
01:16:33,055 --> 01:16:35,591
WITH ANTIGEN AND/OR MHC LOSS.

2071
01:16:35,591 --> 01:16:37,526
AS I MENTIONED, WE DON'T SEE

2072
01:16:37,526 --> 01:16:41,030
COMPLETE LOSS OF MHC CLASS 1 IN

2073
01:16:41,030 --> 01:16:42,531
GI CANCERS, AT LEAST IN THE

2074
01:16:42,531 --> 01:16:43,399
COHORT OF PATIENTS THAT WE'VE

2075
01:16:43,399 --> 01:16:44,500
LOOKED AT.

2076
01:16:44,500 --> 01:16:46,602
IT'S VERY RARE, IN FACT, I CAN'T

2077
01:16:46,602 --> 01:16:47,837
EVEN RECALL A PATIENT WHO HAS

2078
01:16:47,837 --> 01:16:54,977
HAD A BA BETA 2 MICRO GLOBULIN T

2079
01:16:54,977 --> 01:16:55,911
RESULTS IN LOSS.

2080
01:16:55,911 --> 01:16:58,047
BUT I THINK WE NEED TO FOCUS ON

2081
01:16:58,047 --> 01:17:00,649
DRIVER MUTATIONS, SINCE THESE

2082
01:17:00,649 --> 01:17:01,650
WILL BE ESSENTIAL FOR THE

2083
01:17:01,650 --> 01:17:02,751
PHENOTYPE OF THE TUMOR.

2084
01:17:02,751 --> 01:17:04,186
I'M NOT GOING TO TALK ABOUT

2085
01:17:04,186 --> 01:17:06,655
EVALUATING T-CELL STATES, BUT

2086
01:17:06,655 --> 01:17:07,556
SEVERAL OTHER SPEAKERS ARE GOING

2087
01:17:07,556 --> 01:17:11,460
TO TALK ABOUT THAT.

2088
01:17:11,460 --> 01:17:12,461
NOW THE EXPRESSION CLONING

2089
01:17:12,461 --> 01:17:15,397
SYSTEM THAT I AND YUTAKA WORKED

2090
01:17:15,397 --> 01:17:17,800
ON WAS FIRST ACTUALLY DESCRIBED

2091
01:17:17,800 --> 01:17:23,772
IN 1987 WH 1987 BY BRIAN SEED, D

2092
01:17:23,772 --> 01:17:27,977
FROM HIS APPROACH.

2093
01:17:27,977 --> 01:17:30,012
INTERESTINGLY ENOUGH THE

2094
01:17:30,012 --> 01:17:32,214
MOLECULE HE FIRST DISCOVERED WAS

2095
01:17:32,214 --> 01:17:33,883
CD28, SO A VERY RELEVANT

2096
01:17:33,883 --> 01:17:35,151
MOLECULE TO A LOT OF THE STUDIES

2097
01:17:35,151 --> 01:17:35,618
THAT WE'VE DONE.

2098
01:17:35,618 --> 01:17:36,719
I DON'T NEED TO GO THROUGH THIS

2099
01:17:36,719 --> 01:17:39,455
SLIDE IN DETAIL, I THINK, BUT

2100
01:17:39,455 --> 01:17:40,222
BASICALLY EVERYBODY PROBABLY IS

2101
01:17:40,222 --> 01:17:42,424
FAMILIAR WITH THIS.

2102
01:17:42,424 --> 01:17:45,561
WE ISOLATE RNA FROM TUMOR CELLS,

2103
01:17:45,561 --> 01:17:47,096
MAKE A CDA LIBRARY, GENERATE

2104
01:17:47,096 --> 01:17:52,468
POOLS OF BARACK TI IN BACTERIA,N

2105
01:17:52,468 --> 01:17:55,404
TRANSFECT THEM AND ISOLATE THOSE

2106
01:17:55,404 --> 01:17:58,107
CLONES FROM THOSE CELLS.

2107
01:17:58,107 --> 01:17:59,575
THIS LED TO THE IDENTIFICATION

2108
01:17:59,575 --> 01:18:01,744
OF MULTIPLE CATEGORIES OF

2109
01:18:01,744 --> 01:18:02,478
ANTIGENS.

2110
01:18:02,478 --> 01:18:04,580
YUTAKA WENT OVER THESE IN MORE

2111
01:18:04,580 --> 01:18:07,216
DETAIL.

2112
01:18:07,216 --> 01:18:08,317
BUT ONE OF THE IMPORTANT

2113
01:18:08,317 --> 01:18:10,286
PRODUCTS THAT WERE IDENTIFIED

2114
01:18:10,286 --> 01:18:12,922
EARLY ON ARE THE NEOANTIGENS,

2115
01:18:12,922 --> 01:18:14,557
THE PRODUCT OF MUTATED GENES.

2116
01:18:14,557 --> 01:18:18,027
NOW THE AGNOSTIC NATURE OF THIS

2117
01:18:18,027 --> 01:18:19,328
CLONING SYSTEM REALLY LED TO

2118
01:18:19,328 --> 01:18:20,796
IDENTIFICATION OF SOME

2119
01:18:20,796 --> 01:18:22,298
NON-CANONICAL PRODUCTS AS WELL.

2120
01:18:22,298 --> 01:18:23,599
AGAIN, YUTAKA MENTIONED SOME OF

2121
01:18:23,599 --> 01:18:24,366
THESE TOO.

2122
01:18:24,366 --> 01:18:25,668
BUT I LIKE TO THINK OF THESE AS

2123
01:18:25,668 --> 01:18:27,636
THE DARK MATTER OF THE IMMUNE

2124
01:18:27,636 --> 01:18:29,271
SYSTEM, WHICH IS A POPULAR TERM

2125
01:18:29,271 --> 01:18:32,808
NOW OBVIOUSLY.

2126
01:18:32,808 --> 01:18:35,177
THE PEPTIDE SPICING WAS SHOWN

2127
01:18:35,177 --> 01:18:42,751
FIRST ACTUALLY BY KEN, WHERE

2128
01:18:42,751 --> 01:18:45,688
THEY'RE SPLICED POST

2129
01:18:45,688 --> 01:18:47,556
TRANSLATIONALLY IN THE

2130
01:18:47,556 --> 01:18:48,657
PROTEASOME, SUBSEQUENTLY SHOWN

2131
01:18:48,657 --> 01:18:49,959
THAT THIS OCCURS IN THE

2132
01:18:49,959 --> 01:18:51,460
PROTEASOME, AND THESE PEPTIDES

2133
01:18:51,460 --> 01:18:53,329
CAN BE SPLICED IN EITHER ORDER.

2134
01:18:53,329 --> 01:18:55,965
SO THE END TERMINAL PART OF THE

2135
01:18:55,965 --> 01:19:00,002
PEPTIDE CAN BE AT THE N-TERMINUS

2136
01:19:00,002 --> 01:19:02,738
OF THE PROTEIN OR AS THE 

2137
01:19:02,738 --> 01:19:04,039
C-TERMINUS AS YOU CAN SEE BY THE

2138
01:19:04,039 --> 01:19:05,841
ARROW HOW THESE PEPTIDES ARE

2139
01:19:05,841 --> 01:19:06,475
JOINED.

2140
01:19:06,475 --> 01:19:08,110
EPITOPES ARE ALSO GENERATED BY

2141
01:19:08,110 --> 01:19:09,945
THE TRANSLATION OF ALTERNATIVE

2142
01:19:09,945 --> 01:19:10,846
OPEN READING FRAMES.

2143
01:19:10,846 --> 01:19:14,350
AS YOU CAN SEE HERE, THE

2144
01:19:14,350 --> 01:19:15,317
SEQUENCE SHOWN BELOW.

2145
01:19:15,317 --> 01:19:17,519
YOU HAVE TWO ALTERNATIVE OPEN

2146
01:19:17,519 --> 01:19:19,254
READING FRAMES DOWNSTREAM OPEN

2147
01:19:19,254 --> 01:19:21,056
READING FRAME THAT IS USED TO

2148
01:19:21,056 --> 01:19:22,691
INITIATE THE PRODUCTION OF A

2149
01:19:22,691 --> 01:19:24,593
PROTEIN THAT'S THEN PROCESSED

2150
01:19:24,593 --> 01:19:25,961
INTO A PEPTIDE.

2151
01:19:25,961 --> 01:19:28,263
THEN EPITOPES WITHIN INTRONS,

2152
01:19:28,263 --> 01:19:29,665
EITHER PARTIALLY OR ENTIRELY

2153
01:19:29,665 --> 01:19:31,033
WITH INTRONS.

2154
01:19:31,033 --> 01:19:32,735
ACTUALLY THE FIRST MUTANT TUMOR

2155
01:19:32,735 --> 01:19:35,571
ANTIGEN THAT WAS IDENTIFIED IN

2156
01:19:35,571 --> 01:19:40,209
HUMANS, FIRST CALLED MUM1 WAS

2157
01:19:40,209 --> 01:19:41,510
ACTUALLY THE PRODUCT OF AN

2158
01:19:41,510 --> 01:19:42,811
INTRON, WAS TRANSLATED FROM AN

2159
01:19:42,811 --> 01:19:44,480
INTRON.

2160
01:19:44,480 --> 01:19:47,049
NOW, THE ADVANTAGES OF THE CDNA

2161
01:19:47,049 --> 01:19:48,284
LIBRARY SCREENING APPROACH I

2162
01:19:48,284 --> 01:19:51,220
THINK, THOUGH, NEED TO BE

2163
01:19:51,220 --> 01:19:53,088
BALANCED BY THE LIMITATIONS.

2164
01:19:53,088 --> 01:19:54,823
ANTIGENS WERE READILY IDENTIFIED

2165
01:19:54,823 --> 01:19:56,358
IN THIS SYSTEM BECAUSE THEY WERE

2166
01:19:56,358 --> 01:19:57,793
HIGHLY REPRESENTED, HIGHLY

2167
01:19:57,793 --> 01:19:58,661
EXPRESSED IN MOST OF THE CELL

2168
01:19:58,661 --> 01:20:00,129
LINES AND A, THEREFORE, IN THE

2169
01:20:00,129 --> 01:20:00,963
LIBRARIES THAT WE MADE.

2170
01:20:00,963 --> 01:20:03,032
SO WE INITIALLY FOCUSED ON

2171
01:20:03,032 --> 01:20:05,034
MDAs AS TARGETS FOR THERAPY,

2172
01:20:05,034 --> 01:20:07,870
BUT IN TRIALS CARRIED OUT USING

2173
01:20:07,870 --> 01:20:11,573
TCRs DIRECTED AGAINST MAR1,

2174
01:20:11,573 --> 01:20:13,075
GP100, WE SAW DURABLE RESPONSES

2175
01:20:13,075 --> 01:20:15,344
IN ONLY A VERY SMALL MINORITY OF

2176
01:20:15,344 --> 01:20:15,778
PATIENTS.

2177
01:20:15,778 --> 01:20:17,680
BUT I THINK ANOTHER IMPORTANT

2178
01:20:17,680 --> 01:20:20,316
POINT IS THAT THE NEED FOR CELL

2179
01:20:20,316 --> 01:20:22,217
LINES AND LENGTHY PROCEDURES

2180
01:20:22,217 --> 01:20:23,852
INVOLVED WITH SCREENING MAKE

2181
01:20:23,852 --> 01:20:25,487
THIS ROUTINE SCREENING DIFFICULT

2182
01:20:25,487 --> 01:20:27,022
TO CARRY OUT.

2183
01:20:27,022 --> 01:20:28,590
CERTAINLY NOT PROSPECTIVELY ON A

2184
01:20:28,590 --> 01:20:29,858
PATIENT WHO WE WISH TO TREAT,

2185
01:20:29,858 --> 01:20:32,695
BECAUSE THIS CAN TAKE --

2186
01:20:32,695 --> 01:20:33,729
GENERALLY TAKES MANY MONTHS TO

2187
01:20:33,729 --> 01:20:34,363
CARRY OUT.

2188
01:20:34,363 --> 01:20:36,565
NOW, THE DRAMATIC DECLINE IN

2189
01:20:36,565 --> 01:20:38,067
SEQUENCING COSTS, THOUGH, IN THE

2190
01:20:38,067 --> 01:20:40,502
LATE TWO THOUSANDS, LED TO THE

2191
01:20:40,502 --> 01:20:42,705
DEVELOPMENT OF A NEW ANTIGEN

2192
01:20:42,705 --> 01:20:44,673
DISCOVERY PLATFORM, AND I'D LIKE

2193
01:20:44,673 --> 01:20:45,874
TO SHOW THIS BECAUSE IT SHOWS

2194
01:20:45,874 --> 01:20:48,811
YOU THE COST PER MEGABASE OF DNA

2195
01:20:48,811 --> 01:20:50,345
SEQUENCING AND THE DECLINE OF

2196
01:20:50,345 --> 01:20:53,115
THAT COST PARTICULARLY OVER THE

2197
01:20:53,115 --> 01:20:53,415
2000s.

2198
01:20:53,415 --> 01:20:55,918
YOU CAN SEE MOORE'S LAW PLOTTED

2199
01:20:55,918 --> 01:20:59,421
HERE, WHICH BASICALLY WAS

2200
01:20:59,421 --> 01:21:00,322
DEVELOPED BY GORDON MOORE, I

2201
01:21:00,322 --> 01:21:02,758
THINK BACK IN 1965, WHERE HE

2202
01:21:02,758 --> 01:21:08,397
PREDICTED THAT THE CAPACITY OF

2203
01:21:08,397 --> 01:21:09,965
CHIPS WOULD INCREASE BY TWOFOLD

2204
01:21:09,965 --> 01:21:11,066
EVERY TWO YEARS BASICALLY.

2205
01:21:11,066 --> 01:21:13,001
AND AMAZINGLY ENOUGH, MOORE'S

2206
01:21:13,001 --> 01:21:14,436
LAW HAS HELD FOR A LONG TIME.

2207
01:21:14,436 --> 01:21:15,537
I THINK FOR MANY DECADES.

2208
01:21:15,537 --> 01:21:18,374
BUT WHAT YOU CAN SEE HERE IS

2209
01:21:18,374 --> 01:21:19,775
THAT THERE WAS A PRECIPITOUS

2210
01:21:19,775 --> 01:21:21,310
DROP IN THE COST OF SEQUENCING

2211
01:21:21,310 --> 01:21:22,745
IN THE LATE 2000s.

2212
01:21:22,745 --> 01:21:24,913
SO OBVIOUSLY OTHER THINGS WERE

2213
01:21:24,913 --> 01:21:25,180
INVOLVED.

2214
01:21:25,180 --> 01:21:27,249
OBVIOUSLY COMPUTING TECHNOLOGY

2215
01:21:27,249 --> 01:21:31,520
IMPROVED, BUT THEN ADVANCED --

2216
01:21:31,520 --> 01:21:33,622
OTHER ADVANCED TECHNOLOGIES

2217
01:21:33,622 --> 01:21:37,092
ALLOWED I THE SEQUENCING COST TO

2218
01:21:37,092 --> 01:21:38,527
DECLINE QUITE PRECIPITOUSLY, AND

2219
01:21:38,527 --> 01:21:40,262
THIS ALLOWED US TO CARRY OUT A

2220
01:21:40,262 --> 01:21:41,897
VARIETY OF STUDIES AND OTHERS

2221
01:21:41,897 --> 01:21:45,334
BEGAN TO LOOK AT TUMORS, TUMOR

2222
01:21:45,334 --> 01:21:46,301
MUTATIONAL BURDEN, AND IN THIS

2223
01:21:46,301 --> 01:21:50,539
PAPER PUBLISHED IN 2017, WHICH I

2224
01:21:50,539 --> 01:21:52,841
THINK IS A LANDMARK PAPER

2225
01:21:52,841 --> 01:21:54,309
BASICALLY THIS GROUP SHOWED THAT

2226
01:21:54,309 --> 01:21:56,712
THE TUMOR MUTATIONAL BURDEN

2227
01:21:56,712 --> 01:21:57,813
CORRELATED WITH OBJECTIVE

2228
01:21:57,813 --> 01:22:00,215
RESPONSE TO PD-1 DIRECTED

2229
01:22:00,215 --> 01:22:00,482
THERAPY.

2230
01:22:00,482 --> 01:22:04,052
YOU CAN SEE MELANOMA OVER HERE

2231
01:22:04,052 --> 01:22:05,687
IS OBVIOUSLY HIGHLY RESPONSIVE

2232
01:22:05,687 --> 01:22:09,424
TO PD-1.

2233
01:22:09,424 --> 01:22:11,527
BUT AS WELL AS MISMATCH REPAIR

2234
01:22:11,527 --> 01:22:13,796
DEFICIENT COLORECTAL CANCER.

2235
01:22:13,796 --> 01:22:18,934
HOWEVER, MISMATCH REPAIR STABLE

2236
01:22:18,934 --> 01:22:19,601
COLORECTAL CANCER DOES NOT

2237
01:22:19,601 --> 01:22:21,136
RESPOND TO CHECKPOINT THERAPY AT

2238
01:22:21,136 --> 01:22:24,673
ANY APPRECIABLE LEVEL.

2239
01:22:24,673 --> 01:22:26,308
SO THE EXPRESSION CLONING SYSTEM

2240
01:22:26,308 --> 01:22:28,177
THAT WAS DEVELOPED BY OUR GROUP

2241
01:22:28,177 --> 01:22:32,381
AND THE GROUP IN BRUSSELS AS

2242
01:22:32,381 --> 01:22:33,582
WELL AS SEVERAL OTHER GROUPS WAS

2243
01:22:33,582 --> 01:22:35,417
BASICALLY A MODIFIED VERSION OF

2244
01:22:35,417 --> 01:22:37,452
THE EXPRESSION CLONING SYSTEM,

2245
01:22:37,452 --> 01:22:39,988
SO GENOMIC DNA IS ISOLATED, RNA

2246
01:22:39,988 --> 01:22:44,827
AS WELL FROM THE TUMOR,

2247
01:22:44,827 --> 01:22:46,595
GENOMIC -- IS -- WHOLE EXOME

2248
01:22:46,595 --> 01:22:48,197
SEQUENCE SOMETHING CARRIED OUT,

2249
01:22:48,197 --> 01:22:50,299
SOMATIC MUTATIONS ARE IDENTIFIED

2250
01:22:50,299 --> 01:22:53,302
AND THEN YOU CAN GENERATE MINI

2251
01:22:53,302 --> 01:22:55,537
GENES, TANDEM MINI GENES OR

2252
01:22:55,537 --> 01:22:58,607
PEPTIDES CORRESPONDING TO THESE

2253
01:22:58,607 --> 01:23:00,375
MUTANT TRANSCRIPTS, TRANSFECT

2254
01:23:00,375 --> 01:23:02,978
THEM OR PULSE THEM ON TO

2255
01:23:02,978 --> 01:23:05,647
AUTOLOGOUS DENDRITIC CELLS,

2256
01:23:05,647 --> 01:23:06,215
CO-CULTURE THOSE CELLS AND

2257
01:23:06,215 --> 01:23:08,917
IDENTIFY THE REACTIVE T CELLS OR

2258
01:23:08,917 --> 01:23:10,686
SHOWN ON THE RIGHT, USING AN

2259
01:23:10,686 --> 01:23:12,087
ALTERNATIVE PROCESS, IDENTIFY

2260
01:23:12,087 --> 01:23:13,722
THE T CELLS AND THE T-CELL

2261
01:23:13,722 --> 01:23:17,025
RECEPTORS THAT MEDIATE

2262
01:23:17,025 --> 01:23:18,494
RECOGNITION OF THOSE

2263
01:23:18,494 --> 01:23:19,561
NEOANTIGENS.

2264
01:23:19,561 --> 01:23:21,563
NOW NEOANTIGEN REACTIVITY HAS

2265
01:23:21,563 --> 01:23:22,764
CLEARLY BEEN ASSOCIATED WITH THE

2266
01:23:22,764 --> 01:23:25,367
RESPONSE TO ADOPTIVE

2267
01:23:25,367 --> 01:23:25,801
IMMUNOTHERAPY.

2268
01:23:25,801 --> 01:23:27,669
IN THIS PAPER PUBLISHED FROM THE

2269
01:23:27,669 --> 01:23:29,204
DANISH GROUP, THE FREQUENCY OF

2270
01:23:29,204 --> 01:23:31,306
NEW ANTIGEN-REACTIVE T CELLS

2271
01:23:31,306 --> 01:23:35,911
HERE IDENTIFIED USING

2272
01:23:35,911 --> 01:23:36,912
BARCODED -- WAS CLEARLY

2273
01:23:36,912 --> 01:23:38,847
ASSOCIATED WITH THE RESPONSE TO

2274
01:23:38,847 --> 01:23:39,414
MELANOMA TIL.

2275
01:23:39,414 --> 01:23:42,150
AND THEN IN OUR STUDY, WHICH WAS

2276
01:23:42,150 --> 01:23:47,522
PUBLISHED THE SAME YEAR, LEVI IN

2277
01:23:47,522 --> 01:23:50,025
OUR GROUP LOOKED AT PD-1 NAIVE

2278
01:23:50,025 --> 01:23:51,627
AND REFRACTORY MELANOMA PATIENTS

2279
01:23:51,627 --> 01:23:53,695
WHO RECEIVED ADOPTIVE CELL

2280
01:23:53,695 --> 01:23:56,932
TRANSFER, AND AS YOU CAN SEE

2281
01:23:56,932 --> 01:23:58,600
HERE, THE COMPLETE RESPONSE RATE

2282
01:23:58,600 --> 01:23:59,768
DROPPED PRECIPITOUSLY WHEN WE

2283
01:23:59,768 --> 01:24:01,503
LOOKED AT THE PD-1 REFRACTORY

2284
01:24:01,503 --> 01:24:02,504
PATIENTS.

2285
01:24:02,504 --> 01:24:03,305
INTERESTINGLY ENOUGH, THE

2286
01:24:03,305 --> 01:24:05,040
PARTIAL RESPONSE RATE WAS

2287
01:24:05,040 --> 01:24:06,575
SIMILAR IN THESE GROUPS.

2288
01:24:06,575 --> 01:24:11,747
BUT WHAT WAS MOST STRIKING, AND

2289
01:24:11,747 --> 01:24:13,048
I BELIEVE YUTAKA -- THIS SLIDE

2290
01:24:13,048 --> 01:24:14,583
HAS ALREADY BEEN SHOWN OR A

2291
01:24:14,583 --> 01:24:15,617
SIMILAR ONE -- RESPONDERS IN

2292
01:24:15,617 --> 01:24:17,853
BOTH THE PD-1 NAIVE AND

2293
01:24:17,853 --> 01:24:19,288
REFRACTORY GROUPS HAD A HIGHER

2294
01:24:19,288 --> 01:24:20,322
TUMOR MUTATIONAL BURDEN.

2295
01:24:20,322 --> 01:24:22,491
YOU CAN SEE PARTICULARLY ON THE

2296
01:24:22,491 --> 01:24:24,426
LEFT SIDE WHERE THERE ARE

2297
01:24:24,426 --> 01:24:25,861
MELANOMA TUMORS THAT HAVE VERY

2298
01:24:25,861 --> 01:24:29,031
HIGH MUTATIONAL BURDENS THAT THE

2299
01:24:29,031 --> 01:24:29,932
RESPONSE RATE, COMPLETE RESPONSE

2300
01:24:29,932 --> 01:24:31,867
RATE SHOWN IN THE BLUE DOT, IS

2301
01:24:31,867 --> 01:24:36,605
VERY HIGH, ESSENTIALLY ALL THE

2302
01:24:36,605 --> 01:24:38,473
PATIENTS THAT HAVE HIGH

2303
01:24:38,473 --> 01:24:39,875
MUTATIONAL BURDENS ARE

2304
01:24:39,875 --> 01:24:44,913
RESPONDING TO THERAPY.

2305
01:24:44,913 --> 01:24:47,282
THIS WAS ALSO TRUE FOR THE PD-1

2306
01:24:47,282 --> 01:24:47,916
REFRACTORY PATIENTS.

2307
01:24:47,916 --> 01:24:49,084
EVEN THOUGH THERE ISN'T A

2308
01:24:49,084 --> 01:24:50,085
SIGNIFICANCE DIFFERENCE,

2309
01:24:50,085 --> 01:24:50,986
STATISTICALLY BETWEEN THE NUMBER

2310
01:24:50,986 --> 01:24:52,754
OF MUTATIONS, WHEN YOU LOOK AT

2311
01:24:52,754 --> 01:24:54,489
THE RESPONDERS IN BOTH GROUPS,

2312
01:24:54,489 --> 01:24:57,559
YOU CAN SEE THAT WHAT'S MISSING

2313
01:24:57,559 --> 01:24:59,194
FROM THE PD-1 REFRACTORY

2314
01:24:59,194 --> 01:25:02,497
PATIENTS WITH THE EXCEPTION OF

2315
01:25:02,497 --> 01:25:03,899
THAT ONE PATIENT, ONE PARTIAL

2316
01:25:03,899 --> 01:25:04,967
RESPONDER IS THE TUMORS THAT

2317
01:25:04,967 --> 01:25:06,635
HAVE HIGH MUTATIONAL BURDENS.

2318
01:25:06,635 --> 01:25:09,838
NOW THE NUMBER OF MUTATIONS, THE

2319
01:25:09,838 --> 01:25:12,174
NUMBER OF NEOANTIGENS IDENTIFIED

2320
01:25:12,174 --> 01:25:14,176
IN BOTH OF THESE GROUPS, THOUGH,

2321
01:25:14,176 --> 01:25:16,845
WAS SIGNIFICANTLY HIGHER IN THE

2322
01:25:16,845 --> 01:25:18,914
RESPONDERS THAN THE

2323
01:25:18,914 --> 01:25:20,849
NON-RESPONDERS.

2324
01:25:20,849 --> 01:25:22,417
BUT ONE THING TO MENTION IS THAT

2325
01:25:22,417 --> 01:25:26,822
WHEN YOU LOOK AT THE DURATION OF

2326
01:25:26,822 --> 01:25:27,889
RESPONSES, THIS IS PARTICULARLY

2327
01:25:27,889 --> 01:25:30,525
TRUE FOR THE PD-1 REFRACTORY

2328
01:25:30,525 --> 01:25:32,294
PATIENT, THE PRs AS

2329
01:25:32,294 --> 01:25:33,729
ESSENTIALLY ALL OF THEM WITH THE

2330
01:25:33,729 --> 01:25:35,797
EXCEPTION OF ONE PATIENT WERE

2331
01:25:35,797 --> 01:25:39,201
PARTIAL RESPONDERS, WAS LOWER

2332
01:25:39,201 --> 01:25:43,071
THAN IN THE PD-1 NAIVE GROUP.

2333
01:25:43,071 --> 01:25:45,540
56% IN THE NAIVE GROUP VERSUS

2334
01:25:45,540 --> 01:25:46,241
ONLY 18%.

2335
01:25:46,241 --> 01:25:50,812
SO THE RESPONSES THAT WE DID SEE

2336
01:25:50,812 --> 01:25:52,981
IN THE REFRACTORY GROUP WERE OF

2337
01:25:52,981 --> 01:25:55,550
MORE LIMITED DURATION.

2338
01:25:55,550 --> 01:25:57,986
SO I THINK THIS EMPHASIZES THE

2339
01:25:57,986 --> 01:25:59,388
POINT AND RAISES THE QUESTION OF

2340
01:25:59,388 --> 01:26:03,325
WHAT'S HAPPENING IN THOSE

2341
01:26:03,325 --> 01:26:03,592
PATIENTS.

2342
01:26:03,592 --> 01:26:05,293
THERE IS LOWER MUTATIONAL BURDEN

2343
01:26:05,293 --> 01:26:07,295
IN THE REFRACTORY PATIENTS.

2344
01:26:07,295 --> 01:26:08,497
THAT CONTRIBUTES, I THINK, TO

2345
01:26:08,497 --> 01:26:11,166
SOME EXTENT BUT THERE MAY BE

2346
01:26:11,166 --> 01:26:13,835
OTHER REASONS WHY REFRACTORY

2347
01:26:13,835 --> 01:26:15,137
PATIENTS RESPOND AT A LOWER

2348
01:26:15,137 --> 01:26:15,337
RATE.

2349
01:26:15,337 --> 01:26:16,371
AND I THINK THAT'S SOMETHING WE

2350
01:26:16,371 --> 01:26:18,373
NEED TO UNDERSTAND.

2351
01:26:18,373 --> 01:26:20,342
NOW RECENT ANALYSIS CARRIED OUT

2352
01:26:20,342 --> 01:26:22,210
IN GI CANCER PATIENTS RECEIVING

2353
01:26:22,210 --> 01:26:26,581
TIL ACT PLUS PD-1 HAVE SHOWN

2354
01:26:26,581 --> 01:26:30,285
OBJECTIVE RESPONSE RATE OF

2355
01:26:30,285 --> 01:26:31,953
ALMOST 24%.

2356
01:26:31,953 --> 01:26:33,889
IN A PREVIOUS STUDY CARRIED OUT

2357
01:26:33,889 --> 01:26:37,325
IN OUR GROUP, 83% OF TIL FROM

2358
01:26:37,325 --> 01:26:39,294
G.I. PATIENTS RECOGNIZED ONE OR

2359
01:26:39,294 --> 01:26:40,529
MORE NEOANTIGENS.

2360
01:26:40,529 --> 01:26:42,798
NOW, THESE TIL WERE SELECTED

2361
01:26:42,798 --> 01:26:46,501
PRIMARILY FOR NEOANTIGEN

2362
01:26:46,501 --> 01:26:49,137
REACTIVITY AND GIVEN

2363
01:26:49,137 --> 01:26:49,604
PEMBROLIZUMAB.

2364
01:26:49,604 --> 01:26:52,007
THE RESPONSES IN THIS COHORT OF

2365
01:26:52,007 --> 01:26:53,475
PATIENTS WAS ASSOCIATED WITH A

2366
01:26:53,475 --> 01:26:55,644
NUMBER OF NEOANTIGENS

2367
01:26:55,644 --> 01:26:57,279
RECOGNIZED, ALTHOUGH THE NUMBER

2368
01:26:57,279 --> 01:26:59,581
OF TARGETS IS LOW SO THESE

2369
01:26:59,581 --> 01:27:01,883
DIFFERENCES MAY NOT APPEAR VERY

2370
01:27:01,883 --> 01:27:03,452
IMPRESSIVE, BUT I THINK WHAT'S

2371
01:27:03,452 --> 01:27:04,686
MORE IMPRESSIVE IS THE GRAPH ON

2372
01:27:04,686 --> 01:27:06,822
THE RIGHT, WHERE YOU LOOK AT THE

2373
01:27:06,822 --> 01:27:08,924
TREND ANALYSIS, WHERE WHEN YOU

2374
01:27:08,924 --> 01:27:11,093
HAVE T CELLS THAT RECOGNIZE MORE

2375
01:27:11,093 --> 01:27:15,063
THAN ONE TARGET, YOUR LIKELIHOOD

2376
01:27:15,063 --> 01:27:16,264
OF RESPONDING INCREASES.

2377
01:27:16,264 --> 01:27:19,334
SO THIS WAS SIGNIFICANT BY A

2378
01:27:19,334 --> 01:27:20,001
TREND ANALYSIS.

2379
01:27:20,001 --> 01:27:22,337
NOW THIS IS UNPUBLISHED AND

2380
01:27:22,337 --> 01:27:24,372
DR. ROSENBERG WILL BE SHOWING

2381
01:27:24,372 --> 01:27:25,841
SOME MORE INFORMATION ABOUT THIS

2382
01:27:25,841 --> 01:27:26,675
TRIAL.

2383
01:27:26,675 --> 01:27:30,979
BUT ONE THING THAT I WAS CURIOUS

2384
01:27:30,979 --> 01:27:32,714
ABOUT WAS THE COMPARISON BETWEEN

2385
01:27:32,714 --> 01:27:34,916
GI AND MELANOMA.

2386
01:27:34,916 --> 01:27:36,485
BECAUSE OF COURSE MELANOMAS HAVE

2387
01:27:36,485 --> 01:27:39,221
A MUCH HIGHER TUMOR MUTATIONAL

2388
01:27:39,221 --> 01:27:40,655
BURDEN ON AVERAGE, BUT IF YOU

2389
01:27:40,655 --> 01:27:41,490
SIMPLY REMOVE THOSE PATIENTS

2390
01:27:41,490 --> 01:27:43,692
THAT HAVE A HIGHER MUTATIONAL

2391
01:27:43,692 --> 01:27:45,026
BURDEN, NOW ESSENTIALLY TRY TO

2392
01:27:45,026 --> 01:27:47,496
NORMALIZE THE NUMBER OF

2393
01:27:47,496 --> 01:27:49,397
MUTATIONS PRESENT ON THOSE

2394
01:27:49,397 --> 01:27:51,299
CANCERS, BECAUSE THERE IS A

2395
01:27:51,299 --> 01:27:53,135
LARGE OVERLAP BETWEEN GI AND

2396
01:27:53,135 --> 01:27:55,537
MELANOMA, IT'S JUST THAT THE GI

2397
01:27:55,537 --> 01:27:57,038
PATIENTS, THE MICRO SATELLITE

2398
01:27:57,038 --> 01:27:57,873
STABLE PATIENTS DON'T HAVE

2399
01:27:57,873 --> 01:28:00,175
TUMORS THAT HAVE SUCH A HIGH

2400
01:28:00,175 --> 01:28:01,710
BURDEN, YOU SEE THAT THE --

2401
01:28:01,710 --> 01:28:04,012
THERE'S A SIMILAR OBJECTIVE

2402
01:28:04,012 --> 01:28:05,580
RESPONSE RATE.

2403
01:28:05,580 --> 01:28:08,083
AGAIN, 24% IN G.I. AND 29% IN

2404
01:28:08,083 --> 01:28:09,651
MELANOMA.

2405
01:28:09,651 --> 01:28:11,453
BUT WHAT YOU CAN SEE IS THE

2406
01:28:11,453 --> 01:28:13,555
COMPLETE RESPONSE RATE IN THE

2407
01:28:13,555 --> 01:28:15,790
MELANOMA COHORT WAS 19%.

2408
01:28:15,790 --> 01:28:17,726
SO THIS IS ONLY SLIGHTLY LOWER

2409
01:28:17,726 --> 01:28:19,594
THAN THE COMPLETE RESPONSE RATE

2410
01:28:19,594 --> 01:28:21,763
OVERALL.

2411
01:28:21,763 --> 01:28:24,332
WHICH I THOUGHT WAS INTERESTING.

2412
01:28:24,332 --> 01:28:27,002
BUT THE MAJOR DIFFERENCE IS THAT

2413
01:28:27,002 --> 01:28:29,971
IN THE G.I. COHORT, WHILE THERE

2414
01:28:29,971 --> 01:28:32,274
WERE TWO RESPONDERS THAT HAD A

2415
01:28:32,274 --> 01:28:35,343
DURABLE RESPONSE OF 42 MONTHS

2416
01:28:35,343 --> 01:28:36,778
AND THEN ONGOING RESPONSE OF 17

2417
01:28:36,778 --> 01:28:37,913
MONTHS IN ANOTHER PATIENT, THERE

2418
01:28:37,913 --> 01:28:39,848
WERE NO CRs IN THIS GROUP.

2419
01:28:39,848 --> 01:28:41,883
THIS IS NOT DUE TO A DIFFERENCE

2420
01:28:41,883 --> 01:28:44,586
IN THE RATE OF NEOANTIGEN

2421
01:28:44,586 --> 01:28:45,787
RECOGNITION, BECAUSE IT'S JUST A

2422
01:28:45,787 --> 01:28:48,290
LITTLE UNDER 2%, IF YOU LOOK AT

2423
01:28:48,290 --> 01:28:49,691
THE NUMBER OF MUTATIONS VERSUS

2424
01:28:49,691 --> 01:28:51,226
THE NUMBER OF NEOANTIGENS WE

2425
01:28:51,226 --> 01:28:52,794
WERE ABLE TO IDENTIFY FOR BOTH

2426
01:28:52,794 --> 01:28:54,162
GROUPS.

2427
01:28:54,162 --> 01:28:55,864
SO THAT'S NOT RESPONSIBLE FOR

2428
01:28:55,864 --> 01:28:57,065
THIS DIFFERENCE.

2429
01:28:57,065 --> 01:28:58,633
SO WHAT POSSIBLE FACTORS MIGHT

2430
01:28:58,633 --> 01:29:02,003
AFFECT THIS?

2431
01:29:02,003 --> 01:29:03,104
CERTAINLY THE NUMBER OF

2432
01:29:03,104 --> 01:29:04,706
NON-SYNONYMOUS MUTATIONS HAS A

2433
01:29:04,706 --> 01:29:05,006
ROLE.

2434
01:29:05,006 --> 01:29:06,408
WE HAVE A LOWER NUMBER AND

2435
01:29:06,408 --> 01:29:09,711
THERE'S LESS LIKELIHOOD OF

2436
01:29:09,711 --> 01:29:10,612
GENERATING A NEOANTIGEN

2437
01:29:10,612 --> 01:29:12,681
RESPONSE, BUT CERTAINLY TUMOR

2438
01:29:12,681 --> 01:29:13,715
HETEROGENEITY IS ANOTHER FACTOR

2439
01:29:13,715 --> 01:29:15,717
THAT I THINK REALLY CLEARLY

2440
01:29:15,717 --> 01:29:16,685
DISTINGUISHES THESE IN THE FAR

2441
01:29:16,685 --> 01:29:20,789
RIGHT, YOU CAN SEE MELANOMA

2442
01:29:20,789 --> 01:29:22,324
PATIENTS, AND THIS TREE DIAGRAM

2443
01:29:22,324 --> 01:29:23,558
BASICALLY SHOWS YOU THE NUMBER

2444
01:29:23,558 --> 01:29:25,894
OF SHARED VARIANTS THAT ARE SEEN

2445
01:29:25,894 --> 01:29:28,563
WHEN YOU SEQUENCE MULTIPLE

2446
01:29:28,563 --> 01:29:30,365
TUMORS, AND THEN THE THIRD FROM

2447
01:29:30,365 --> 01:29:32,334
THE RIGHT, YOU CAN SEE

2448
01:29:32,334 --> 01:29:32,734
COLORECTAL CANCER.

2449
01:29:32,734 --> 01:29:33,969
YOU CAN SEE THIS BRANCH

2450
01:29:33,969 --> 01:29:35,070
STRUCTURE HERE WHERE YOU SEE

2451
01:29:35,070 --> 01:29:37,072
MANY MORE MUTATIONS THAT ARE

2452
01:29:37,072 --> 01:29:39,808
SUBCLONE OR THAT ARE NOT SHARED.

2453
01:29:39,808 --> 01:29:41,009
CERTAINLY DIFFERENCES IN TUMOR

2454
01:29:41,009 --> 01:29:42,444
CELL BIOLOGY COULD ALSO ACCOUNT

2455
01:29:42,444 --> 01:29:45,213
FOR THIS.

2456
01:29:45,213 --> 01:29:46,848
AND THE FACT THAT THE MAJORITY

2457
01:29:46,848 --> 01:29:49,484
OF GI CANCER PATIENTS RECEIVE

2458
01:29:49,484 --> 01:29:51,386
MULTIPLE LINES OF CHEMOTHERAPY

2459
01:29:51,386 --> 01:29:52,420
WHICH ARE NOT GENERALLY

2460
01:29:52,420 --> 01:29:53,622
ADMINISTERED TO MELANOMA

2461
01:29:53,622 --> 01:29:56,157
PATIENTS.

2462
01:29:56,157 --> 01:29:57,025
 THESE DAYS COULD ALSO

2463
01:29:57,025 --> 01:29:59,160
GIVE RISE TO THIS HETEROGENEITY.

2464
01:29:59,160 --> 01:30:02,030
SO I THINK THAT THIS IS GOING TO

2465
01:30:02,030 --> 01:30:05,934
BE A MAJOR CONTRIBUTOR TO THE

2466
01:30:05,934 --> 01:30:07,102
DIFFERENCES IN RESPONSES.

2467
01:30:07,102 --> 01:30:08,903
SO WHAT ARE SOME OF THE FUTURE

2468
01:30:08,903 --> 01:30:11,239
OPPORTUNITIES AND CHALLENGES?

2469
01:30:11,239 --> 01:30:13,408
I THINK WE NEED TO PRIORITIZE

2470
01:30:13,408 --> 01:30:14,643
TARGETS, AND I'M NOT GOING TO

2471
01:30:14,643 --> 01:30:25,720
TALK ABOUT IT ABOUT  ABOUT TCR ,

2472
01:30:25,720 --> 01:30:27,455
TARGETING NEOAT GENERALS USING

2473
01:30:27,455 --> 01:30:27,889
T-CELL RECEPTORS.

2474
01:30:27,889 --> 01:30:29,224
I ANY TIME WHATTED TO POINT OUT

2475
01:30:29,224 --> 01:30:31,192
THIS RECENT SITE, THE CAP SER

2476
01:30:31,192 --> 01:30:34,062
EPITOPE DATABASE AND ANALYSIS

2477
01:30:34,062 --> 01:30:37,666
RESOURCE OR SE DA CEDAR DEVELOPN

2478
01:30:37,666 --> 01:30:39,968
ASSOCIATION WITH THE IEDB WHICH

2479
01:30:39,968 --> 01:30:42,737
OF COURSE HAS A WEBSITE AS WELL

2480
01:30:42,737 --> 01:30:45,140
THAT CATEGORIZES ANTIGENS.

2481
01:30:45,140 --> 01:30:47,776
THIS SITE IS COMPLETELY FOCUSED

2482
01:30:47,776 --> 01:30:50,845
ON CANCER EPITOPES, AND THERE'S

2483
01:30:50,845 --> 01:30:52,580
OVER 6300 T-CELL EPITOPES THAT

2484
01:30:52,580 --> 01:30:53,515
HAVE BEEN IDENTIFIED.

2485
01:30:53,515 --> 01:30:55,950
SO WHEN WE'RE LOOKING FOR MORE

2486
01:30:55,950 --> 01:30:58,586
TARGETS, THERE ARE A LOT OF

2487
01:30:58,586 --> 01:30:59,421
TARGETS THAT HAVE BEEN

2488
01:30:59,421 --> 01:31:00,922
IDENTIFIED BUT HOW DO WE

2489
01:31:00,922 --> 01:31:01,656
PRIORITIZE THEM?

2490
01:31:01,656 --> 01:31:03,825
I THINK THAT'S GOING TO BE A KEY

2491
01:31:03,825 --> 01:31:05,226
QUESTION.

2492
01:31:05,226 --> 01:31:06,861
I THINK AN OBVIOUS SET OF

2493
01:31:06,861 --> 01:31:09,230
TARGETS, THOUGH, ARE THE DRIVER

2494
01:31:09,230 --> 01:31:10,031
MUTATIONS, OR THOSE EPITOPES

2495
01:31:10,031 --> 01:31:12,200
THAT ARE ENCODED BY DRIVER

2496
01:31:12,200 --> 01:31:13,835
MUTATIONS SINCE THOSE APPEAR TO

2497
01:31:13,835 --> 01:31:17,505
BE CRITICAL FOR THE FUNCTION OF

2498
01:31:17,505 --> 01:31:18,073
THE TUMOR.

2499
01:31:18,073 --> 01:31:19,708
SO HERE'S JUST A PARTIAL LIST OF

2500
01:31:19,708 --> 01:31:20,842
SOME OF THE T-CELL RECEPTORS

2501
01:31:20,842 --> 01:31:25,580
THAT HAVE BEEN IDENTIFIED

2502
01:31:25,580 --> 01:31:27,782
AGAINST MUTATIONS IN KRAS.

2503
01:31:27,782 --> 01:31:34,723
P53, PIC3CA, EGFR, BRAF, NRAS,

2504
01:31:34,723 --> 01:31:36,591
CDKN2A, AND ACTUALLY RECENTLY A

2505
01:31:36,591 --> 01:31:38,493
CLASS 2 EPITOPE HAS BEEN

2506
01:31:38,493 --> 01:31:39,327
IDENTIFIED WHICH ISN'T ON THIS

2507
01:31:39,327 --> 01:31:43,431
SLIDE FOR THE P114L MUTATION.

2508
01:31:43,431 --> 01:31:45,533
SO THIS SLIDE IS CONTINUALLY

2509
01:31:45,533 --> 01:31:48,903
BEING UPDATED AS WE IDENTIFY

2510
01:31:48,903 --> 01:31:49,371
MORE T CELLS.

2511
01:31:49,371 --> 01:31:50,872
IN SOME CASES WE IDENTIFY T

2512
01:31:50,872 --> 01:31:52,640
CELLS AS CLASS 1 AND A CLASS

2513
01:31:52,640 --> 01:31:54,075
2 RESTRICTED T-CELL AGAINST THE

2514
01:31:54,075 --> 01:31:54,409
SAME EPITOPE.

2515
01:31:54,409 --> 01:31:57,846
SO I THINK THIS EMPHASIZES THE

2516
01:31:57,846 --> 01:32:00,648
POINT THAT THERE ARE CERTAIN

2517
01:32:00,648 --> 01:32:02,650
REGIONS OF PROTEINS THAT MAY BE

2518
01:32:02,650 --> 01:32:04,285
PREFERENTIALLY PROCESS AND

2519
01:32:04,285 --> 01:32:05,920
PRESENTED AND RECOGNIZED BY THE

2520
01:32:05,920 --> 01:32:09,758
IMMUNE SYSTEM.

2521
01:32:09,758 --> 01:32:11,359
SO I WANT TO SORT OF END ON

2522
01:32:11,359 --> 01:32:18,233
COMING BACK TO THIS WILL THIS CF

2523
01:32:18,233 --> 01:32:22,170
DARK MATTER, WE HAVE SO-CALLED

2524
01:32:22,170 --> 01:32:24,039
ORPHAN TCRs, WE'VE NOW

2525
01:32:24,039 --> 01:32:26,708
IDENTIFIED OVER 50 TCRs FROM

2526
01:32:26,708 --> 01:32:28,676
13 PATIENTS THAT RECOGNIZE THE

2527
01:32:28,676 --> 01:32:29,544
AUTOLOGOUS TUMOR CELL LINE BUT

2528
01:32:29,544 --> 01:32:32,881
FAIL TO RECOGNIZE ANY OF THE

2529
01:32:32,881 --> 01:32:35,784
SCREENED NEOANTIGENS.

2530
01:32:35,784 --> 01:32:37,786
SO WHAT CATEGORY OF ANTIGEN DOES

2531
01:32:37,786 --> 01:32:39,454
THERE'S T CELLS BELONG TO?

2532
01:32:39,454 --> 01:32:40,955
THIS COULD BE NEOANTIGENS THAT

2533
01:32:40,955 --> 01:32:42,857
WE HAVEN'T IDENTIFIED BECAUSE OF

2534
01:32:42,857 --> 01:32:43,725
LIMITATIONS IN THE TUMOR

2535
01:32:43,725 --> 01:32:44,159
SEQUENCING.

2536
01:32:44,159 --> 01:32:45,293
WE ONLY SEQUENCE A SMALL REGION

2537
01:32:45,293 --> 01:32:47,228
OF THE TUMOR, SO PERHAPS WE

2538
01:32:47,228 --> 01:32:48,430
HAVEN'T CAPTURED ALL THE

2539
01:32:48,430 --> 01:32:50,131
MUTATIONS THAT ARE PRESENT IN

2540
01:32:50,131 --> 01:32:52,400
THAT TUMOR OR THERE MAY BE OTHER

2541
01:32:52,400 --> 01:32:54,202
REASONS DUE TO THE DEPTH OF

2542
01:32:54,202 --> 01:32:55,603
SEQUENCING BEING INADEQUATE FOR

2543
01:32:55,603 --> 01:32:59,474
SOME REGIONS OF THE EXOME.

2544
01:32:59,474 --> 01:33:01,543
THESE COULD REPRESENT CANCER

2545
01:33:01,543 --> 01:33:03,378
GERMLINE OR TISSUE-SPECIFIC

2546
01:33:03,378 --> 01:33:05,613
ANTIGENS, AND WE'RE BEGINNING TO

2547
01:33:05,613 --> 01:33:06,915
SCREEN, WE'VE ALREADY DONE SOME

2548
01:33:06,915 --> 01:33:09,651
SCREENS LOOKING AT THE

2549
01:33:09,651 --> 01:33:10,952
OVEREXPRESSED GENE PRODUCTS THAT

2550
01:33:10,952 --> 01:33:12,187
ARE PRESENT ON THOSE CELL LINES

2551
01:33:12,187 --> 01:33:15,490
BECAUSE WE HAVE THE

2552
01:33:15,490 --> 01:33:16,524
TRANSCRIPTOME DATA.

2553
01:33:16,524 --> 01:33:20,495
BUT WE SO FAR HAVEN'T IDENTIFIED

2554
01:33:20,495 --> 01:33:26,568
THE PRODUCTS.

2555
01:33:26,568 --> 01:33:27,902
 -- TO TRY TO IDENTIFY THESE

2556
01:33:27,902 --> 01:33:29,337
BECAUSE THAT'S AN AGNOSTIC

2557
01:33:29,337 --> 01:33:31,639
METHOD.

2558
01:33:31,639 --> 01:33:33,341
SO WE'LL HAVE TO WAIT AND SEE.

2559
01:33:33,341 --> 01:33:34,609
IT COULD BE THAT THIS IS MORE

2560
01:33:34,609 --> 01:33:35,477
DARK MATTER, THOUGH.

2561
01:33:35,477 --> 01:33:36,778
THESE ARE THINGS THAT ARE FROM

2562
01:33:36,778 --> 01:33:41,850
PARTS OF THE GENOME THAT ARE

2563
01:33:41,850 --> 01:33:43,318
CHARACTERIZED AS BEING

2564
01:33:43,318 --> 01:33:43,818
NON-TRANSCRIBED.

2565
01:33:43,818 --> 01:33:45,286
WE CERTAINLY KNOW THERE'S TRANS

2566
01:33:45,286 --> 01:33:46,855
POE SAL BIOELEMENTS.

2567
01:33:46,855 --> 01:33:47,822
THERE'S LOTS OF OTHER MATERIAL

2568
01:33:47,822 --> 01:33:50,625
OUT THERE THAT COULD GIVE RISE

2569
01:33:50,625 --> 01:33:54,662
TO THESE EPITOPES.

2570
01:33:54,662 --> 01:33:55,597
BUT I THINK THIS IS IMPORTANT

2571
01:33:55,597 --> 01:33:56,931
BECAUSE WE KNOW THOSE T CELLS

2572
01:33:56,931 --> 01:33:57,832
ACTUALLY RECOGNIZE THE CELL LINE

2573
01:33:57,832 --> 01:33:58,333
FROM THAT PATIENT.

2574
01:33:58,333 --> 01:33:59,801
SO WE WANT TO TARGET THOSE

2575
01:33:59,801 --> 01:34:03,304
ANTIGENS, RIGHT?

2576
01:34:03,304 --> 01:34:05,340
NOT EVERY NEOTOAP REACTIVE

2577
01:34:05,340 --> 01:34:06,841
T-CELL WILL RECOGNIZE AN

2578
01:34:06,841 --> 01:34:07,375
ORGANOID.

2579
01:34:07,375 --> 01:34:08,910
SO INTERESTINGLY, WE'RE LOOKING

2580
01:34:08,910 --> 01:34:10,745
AT TUMOR RESISTANCE MECHANISMS

2581
01:34:10,745 --> 01:34:14,082
IN THOSE CELL LINES BECAUSE WE

2582
01:34:14,082 --> 01:34:15,550
DON'T KNOW IN MANY CASES WHAT'S

2583
01:34:15,550 --> 01:34:16,851
RESPONSIBLE FOR THE LACK OF

2584
01:34:16,851 --> 01:34:21,122
RECOGNITION.

2585
01:34:21,122 --> 01:34:22,557
THEN FINALLY I THINK WE NEED TO

2586
01:34:22,557 --> 01:34:24,425
USE MACHINE LEARNING APPROACHES.

2587
01:34:24,425 --> 01:34:28,396
WE NEED TO UNDERSTAND SOMETHING

2588
01:34:28,396 --> 01:34:30,298
ABOUT THESE ANTIGENS, WHY THEY

2589
01:34:30,298 --> 01:34:31,799
ARE PROCESSED AND PRESENTED.

2590
01:34:31,799 --> 01:34:33,868
THE RANDOM FOREST MODEL THAT WE

2591
01:34:33,868 --> 01:34:37,071
DEVELOPED BASED ON 147 KNOWN

2592
01:34:37,071 --> 01:34:38,840
CLASS I NEOEPITOPES REVEALS

2593
01:34:38,840 --> 01:34:40,975
FEATURES THAT ARE ASSOCIATED

2594
01:34:40,975 --> 01:34:41,943
WITH NEOANTIGEN RECOGNITION.

2595
01:34:41,943 --> 01:34:43,578
SO AS YOU GO TO THE LEFT OF THIS

2596
01:34:43,578 --> 01:34:45,313
GRAPH, THOSE ARE THE HIGHEST

2597
01:34:45,313 --> 01:34:47,448
AFFINITY PEPTIDES, AND THEN

2598
01:34:47,448 --> 01:34:49,984
GOING UP THE Y AXIS, THAT'S THE

2599
01:34:49,984 --> 01:34:51,519
MOST HIGHLY EXPRESSED ANTIGENS.

2600
01:34:51,519 --> 01:34:54,155
YOU CAN SEE ON THE UPPER

2601
01:34:54,155 --> 01:34:56,758
LEFT-HAND CORNER THERE'S AN

2602
01:34:56,758 --> 01:35:01,029
ENRICHMENT OF REACTIVITY AGAINST

2603
01:35:01,029 --> 01:35:02,931
PEPTIDES, THIS IS CLASS I

2604
01:35:02,931 --> 01:35:04,032
PEPTIDES THAT HAVE HIGH

2605
01:35:04,032 --> 01:35:07,235
EXPRESSION AND ARE VERY STRONG

2606
01:35:07,235 --> 01:35:07,468
BINDERS.

2607
01:35:07,468 --> 01:35:10,405
THIS WAS PRESENTED IN THE 2021

2608
01:35:10,405 --> 01:35:13,207
NATURE CANCER PAPER FROM OUR

2609
01:35:13,207 --> 01:35:13,741
GROUP.

2610
01:35:13,741 --> 01:35:16,444
CURRENTLY WE HAVE OVER 700

2611
01:35:16,444 --> 01:35:17,445
NEOANTIGENS THAT HAVE BEEN

2612
01:35:17,445 --> 01:35:20,982
IDENTIFIED AND OVER 300 CLASS I

2613
01:35:20,982 --> 01:35:21,950
NEOEPITOPES SO WE'VE MORE THAN

2614
01:35:21,950 --> 01:35:25,453
DOUBLED THE NUMBER OF TARGETS

2615
01:35:25,453 --> 01:35:25,787
HERE.

2616
01:35:25,787 --> 01:35:28,823
SO WE'RE HOPING TO UPDATE THIS

2617
01:35:28,823 --> 01:35:29,223
SOON.

2618
01:35:29,223 --> 01:35:32,493
USE SOME OTHER TOOLS, SUCH AS

2619
01:35:32,493 --> 01:35:35,463
THE MATCHING ALGORITHM THAT WAS

2620
01:35:35,463 --> 01:35:39,634
DEVELOPED BY STERNBERG AND HER

2621
01:35:39,634 --> 01:35:43,471
GROUP AND PUBLISHED IN A PAPER

2622
01:35:43,471 --> 01:35:44,772
IN IMMUNITY IN 2023.

2623
01:35:44,772 --> 01:35:46,808
SO WE'RE GOING TO RE-RUN THE

2624
01:35:46,808 --> 01:35:47,976
SYSTEM, RE-RUN THE MODEL AND TRY

2625
01:35:47,976 --> 01:35:50,078
TO SEE IF WE CAN IMPROVE OUR

2626
01:35:50,078 --> 01:35:54,749
ABILITY TO IDENTIFY THESE

2627
01:35:54,749 --> 01:35:55,817
TARGETS BECAUSE I THINK WHEN

2628
01:35:55,817 --> 01:35:57,652
YOU'RE TALKING ABOUT MINIMAL PEP

2629
01:35:57,652 --> 01:36:00,421
TIE, THERE'S A LARGE UNIVERSE OF

2630
01:36:00,421 --> 01:36:02,624
PEPTIDES, ANY ONE MUTATION CAN

2631
01:36:02,624 --> 01:36:05,893
GIVE RISE TO OVER 50 -- WE NEED

2632
01:36:05,893 --> 01:36:07,962
TO REALLY NARROW DOWN THE

2633
01:36:07,962 --> 01:36:08,830
CANDIDATES.

2634
01:36:08,830 --> 01:36:09,964
AND WE'RE ACTIVELY EXPLORING THE

2635
01:36:09,964 --> 01:36:13,368
USE OF THOSE MINIMAL PEPTIDES AS

2636
01:36:13,368 --> 01:36:16,004
METHODS TO IDENTIFY NEW

2637
01:36:16,004 --> 01:36:18,539
REACTIVITIES BY IN VITRO

2638
01:36:18,539 --> 01:36:21,142
SENSITIZATION OF TIL PERIPHERAL

2639
01:36:21,142 --> 01:36:23,344
BLOOD, SEE IF WE CAN INCREASE

2640
01:36:23,344 --> 01:36:24,812
THE UNIVERSE OF REACTIVITIES,

2641
01:36:24,812 --> 01:36:27,081
WHICH I THINK IS REALLY GOING TO

2642
01:36:27,081 --> 01:36:29,851
BE IMPORTANT FOR -- PARTICULARLY

2643
01:36:29,851 --> 01:36:40,561
FOR TREATING GI CANCER PATIENTS.

2644
01:36:40,561 --> 01:36:41,863
SO WHAT ARE SOME OF THE FUTURE

2645
01:36:41,863 --> 01:36:44,532
OPPORTUNITIES?

2646
01:36:44,532 --> 01:36:45,199
 TO DEVELOP MORE

2647
01:36:45,199 --> 01:36:46,100
EFFECTIVE TREATMENTS?

2648
01:36:46,100 --> 01:36:47,435
I THINK THE IDENTIFICATION OF

2649
01:36:47,435 --> 01:36:49,937
ADDITIONAL TARGETS FOR THERAPY

2650
01:36:49,937 --> 01:36:51,139
AS I SAID SEVERAL TIMES IS GOING

2651
01:36:51,139 --> 01:36:54,142
TO BE IMPORTANT PARTICULARLY FOR

2652
01:36:54,142 --> 01:36:57,311
THESE EPITHELIAL CANCERS.

2653
01:36:57,311 --> 01:36:59,414
CERTAINLY REACTIVITY AGAINST

2654
01:36:59,414 --> 01:37:01,382
SELF-ANTIGENS CAN CONTRIBUTE AND

2655
01:37:01,382 --> 01:37:04,886
ACT USING T CELLS ENGINEERED TO

2656
01:37:04,886 --> 01:37:14,095
RECOGNIZE NYESO1 LED TO -- RATE

2657
01:37:14,095 --> 01:37:15,630
OF MORE THAN 50% IN PATIENTS

2658
01:37:15,630 --> 01:37:18,700
WITH MELANOMA, SYNOVIAL CELL

2659
01:37:18,700 --> 01:37:19,000
SARCOMA.

2660
01:37:19,000 --> 01:37:21,769
I THINK THE COMBINED PROTEOMIC,

2661
01:37:21,769 --> 01:37:24,539
RNA SEQ AND DGE ANALYSIS REALLY

2662
01:37:24,539 --> 01:37:26,207
CAN FACILITATE IDENTIFICATION OF

2663
01:37:26,207 --> 01:37:27,508
ADDITIONAL TARGET ANTIGENS, BUT

2664
01:37:27,508 --> 01:37:28,543
PARTICULARLY WHEN YOU'RE TALKING

2665
01:37:28,543 --> 01:37:30,244
ABOUT THE DARK MATTER OUTSIDE OF

2666
01:37:30,244 --> 01:37:33,014
THE NORMAL EXOME BECOMES

2667
01:37:33,014 --> 01:37:34,949
COMPUTATIONALLY VERY INTENSIVE.

2668
01:37:34,949 --> 01:37:37,185
ONLY 2% OF THE GENOME ENCODES

2669
01:37:37,185 --> 01:37:38,553
KNOWN EX-ONICS SEQUENCES.

2670
01:37:38,553 --> 01:37:40,755
SO YOU'RE TALKING ABOUT THE 98%

2671
01:37:40,755 --> 01:37:43,124
OF THE 3 BILLION BASES OF THE

2672
01:37:43,124 --> 01:37:44,592
HUMAN GENOME, THE NEED TO BE

2673
01:37:44,592 --> 01:37:45,360
EXPLORED.

2674
01:37:45,360 --> 01:37:47,228
SO IT'S COMPUTATIONALLY

2675
01:37:47,228 --> 01:37:50,998
INTENSIVE, AND WE HAVE A

2676
01:37:50,998 --> 01:37:51,666
BIOINFORMATICS GROUP THAT WE

2677
01:37:51,666 --> 01:37:53,334
HOPE TO EXPAND TO REALLY ADDRESS

2678
01:37:53,334 --> 01:37:54,535
SOME OF THESE QUESTIONS BECAUSE

2679
01:37:54,535 --> 01:37:56,504
I THINK THAT'S REALLY GOING TO

2680
01:37:56,504 --> 01:37:57,905
BE IMPORTANT AS WE TRY TO

2681
01:37:57,905 --> 01:38:01,075
INTEGRATE ALL OF THESE

2682
01:38:01,075 --> 01:38:01,609
APPROACHES.

2683
01:38:01,609 --> 01:38:03,211
AND OF COURSE FINALLY, WE WANT

2684
01:38:03,211 --> 01:38:04,412
TO UNDERSTAND WHAT FACTORS ARE

2685
01:38:04,412 --> 01:38:08,649
ASSOCIATED WITH IMMUNE RESPONSE.

2686
01:38:08,649 --> 01:38:10,518
SO WHAT ARE THE ANTIGENS WE

2687
01:38:10,518 --> 01:38:12,120
SHOULD BE TARGETING, WHAT ARE

2688
01:38:12,120 --> 01:38:14,055
THE ONES MEDIATING THESE

2689
01:38:14,055 --> 01:38:14,756
EFFECTIVE IMMUNE RESPONSES?

2690
01:38:14,756 --> 01:38:16,991
IS IT THE EXPRESSION OR THE

2691
01:38:16,991 --> 01:38:18,693
CLOAALITY OF THOSE ANTIGENS

2692
01:38:18,693 --> 01:38:20,661
THAT'S KEY, THE ROLE OF THOSE

2693
01:38:20,661 --> 01:38:22,029
ANTIGENS OR POTENTIALLY OTHER

2694
01:38:22,029 --> 01:38:23,431
FACTORS THAT COULD INFLUENCE THE

2695
01:38:23,431 --> 01:38:26,367
ABILITY TO RESPOND.

2696
01:38:26,367 --> 01:38:27,702
 TO TREATMENT.

2697
01:38:27,702 --> 01:38:29,704
AND I'D JUST LIKE TO FINISH BY

2698
01:38:29,704 --> 01:38:31,572
ACKNOWLEDGING ALL THE SURGERY

2699
01:38:31,572 --> 01:38:32,507
BRANCH RESEARCH STAFF.

2700
01:38:32,507 --> 01:38:33,541
THERE'S TOO MANY PEOPLE TO PUT

2701
01:38:33,541 --> 01:38:36,310
ON THE SLIDE.

2702
01:38:36,310 --> 01:38:37,445
AND THE CLINICAL STAFF,

2703
01:38:37,445 --> 01:38:39,380
PATIENTS, AND OF COURSE

2704
01:38:39,380 --> 01:38:40,348
DR. ROSENBERG, WITHOUT WHOM THIS

2705
01:38:40,348 --> 01:38:41,282
WORK WOULD NOT BE POSSIBLE.

2706
01:38:41,282 --> 01:38:41,582
THANK YOU.

2707
01:38:41,582 --> 01:38:51,259
[APPLAUSE]

2708
01:38:51,259 --> 01:38:58,766
>> QUESTION FOR DR.
ROBBINS?

2709
01:38:58,766 --> 01:39:00,468
>> HI, PAUL.

2710
01:39:00,468 --> 01:39:01,836
 -- FROM TORONTO.

2711
01:39:01,836 --> 01:39:02,737
OLD FRIEND.

2712
01:39:02,737 --> 01:39:05,573
SO I AGREE WITH YOU ABOUT THE

2713
01:39:05,573 --> 01:39:06,574
NON-CODING RETRO TRANSPOSABLE

2714
01:39:06,574 --> 01:39:07,341
ELEMENTS.

2715
01:39:07,341 --> 01:39:09,710
I THINK THAT'S GOING TO BE A

2716
01:39:09,710 --> 01:39:10,011
HUGE AREA.

2717
01:39:10,011 --> 01:39:12,413
WE'VE BEEN LOOKING AT THAT IN

2718
01:39:12,413 --> 01:39:13,748
VARIOUS RARER CANCERS TOO AS

2719
01:39:13,748 --> 01:39:14,148
WELL.

2720
01:39:14,148 --> 01:39:15,450
THERE'S A HUGE AMOUNT OF

2721
01:39:15,450 --> 01:39:17,151
EXPRESSION AND PEPTIDES THAT ARE

2722
01:39:17,151 --> 01:39:18,786
PRESENTED, SO I WOULD DEFINITELY

2723
01:39:18,786 --> 01:39:19,887
BARK UP THAT TREE.

2724
01:39:19,887 --> 01:39:23,324
I HAD SENT A QUESTION, A LOT OF

2725
01:39:23,324 --> 01:39:27,094
THE FOCUS HAS BEEN ON CD8 IN

2726
01:39:27,094 --> 01:39:30,498
CLASS I, BUT WHAT ABOUT CLASS II

2727
01:39:30,498 --> 01:39:31,899
NEOANTIGENS, WHAT INRHODES ARE

2728
01:39:31,899 --> 01:39:33,334
BEING MADE?

2729
01:39:33,334 --> 01:39:35,236
ARE WE KIND OF BARKING UP THE

2730
01:39:35,236 --> 01:39:36,437
WRONG TREE BECAUSE A LOT OF

2731
01:39:36,437 --> 01:39:38,506
TUMORS DON'T EXPRESS A LOT OF

2732
01:39:38,506 --> 01:39:42,009
CLASS II BUT DENDRITIC CELLS

2733
01:39:42,009 --> 01:39:42,944
EXPRESS A LOT AND THEY'RE

2734
01:39:42,944 --> 01:39:44,345
NECESSARY FOR HELPING T CELLS.

2735
01:39:44,345 --> 01:39:46,547
SO SHOULD WE BE SCREENING MORE

2736
01:39:46,547 --> 01:39:48,182
NEOANTIGEN REACTIVE CD4 CELLS

2737
01:39:48,182 --> 01:39:49,317
THAT ARE ACTUALLY WHERE THE

2738
01:39:49,317 --> 01:39:53,521
PEPTIDES ARE BEING PRESENTED ON

2739
01:39:53,521 --> 01:39:54,989
DENDRITIC CELLS AND NOT NOT

2740
01:39:54,989 --> 01:39:55,556
NECESSARILY ON THE TUMOR.

2741
01:39:55,556 --> 01:39:56,357
>> WELL, WE ARE.

2742
01:39:56,357 --> 01:39:58,626
OUR SCREENING APPROACHES USE

2743
01:39:58,626 --> 01:40:00,695
LONG PEPTIDES, SO THOSE WE THINK

2744
01:40:00,695 --> 01:40:02,864
CAPTURE ESSENTIALLY ALL OF THE

2745
01:40:02,864 --> 01:40:03,231
CD4 REACTIVITY.

2746
01:40:03,231 --> 01:40:05,900
AND WE FIND IN GI CANCER

2747
01:40:05,900 --> 01:40:09,036
ACTUALLY A PREPONDERANCE OF

2748
01:40:09,036 --> 01:40:10,504
CD4 REACTIVITY, OR MAYBE IT'S

2749
01:40:10,504 --> 01:40:14,008
FAIRLY EQUAL IN TERMS OF THE CD.

2750
01:40:14,008 --> 01:40:17,979
SO WE ARE ADMINISTERING T CELLS,

2751
01:40:17,979 --> 01:40:19,513
CLASS II RESTRICTED T CELLS AND

2752
01:40:19,513 --> 01:40:21,382
IN SOME CASES WE'RE ACTUALLY

2753
01:40:21,382 --> 01:40:22,416
ADMINISTERING EXCLUSIVELY, AS

2754
01:40:22,416 --> 01:40:25,353
FAR AS WE KNOW, NEOANTIGEN

2755
01:40:25,353 --> 01:40:26,220
REACTIVE CD4 CELLS.

2756
01:40:26,220 --> 01:40:28,789
AND OF COURSE WE HAVE A

2757
01:40:28,789 --> 01:40:29,824
CHOLANGIOCARCINOMA PATIENT WHO

2758
01:40:29,824 --> 01:40:32,627
FAMOUSLY RESPONDED TO A CD4

2759
01:40:32,627 --> 01:40:33,160
REACTIVE T-CELL.

2760
01:40:33,160 --> 01:40:35,196
SO WE CERTAINLY DON'T WANT TO

2761
01:40:35,196 --> 01:40:36,831
DISCOUNT CD4 CELLS.

2762
01:40:36,831 --> 01:40:39,800
WE'RE ALSO EXPLORING THE USE OF

2763
01:40:39,800 --> 01:40:41,168
CLASS II RESTRICTED T-CELL

2764
01:40:41,168 --> 01:40:41,602
RECEPTORS.

2765
01:40:41,602 --> 01:40:42,803
WHETHER THOSE ALONE WILL BE

2766
01:40:42,803 --> 01:40:43,537
EFFECTIVE, WE DON'T KNOW.

2767
01:40:43,537 --> 01:40:45,206
WE'VE ONLY TREATED A FEW

2768
01:40:45,206 --> 01:40:47,541
PATIENTS SO IT'S STILL TOO

2769
01:40:47,541 --> 01:40:48,009
EARLY.

2770
01:40:48,009 --> 01:40:49,176
BUT PERHAPS THE COMBINATION OF

2771
01:40:49,176 --> 01:40:50,311
THE TWO WILL BE IMPORTANT.

2772
01:40:50,311 --> 01:40:52,313
WHICH AGAIN, WE JUST NEED TO

2773
01:40:52,313 --> 01:40:52,914
FIND MORE TARGETS BECAUSE YOU

2774
01:40:52,914 --> 01:40:55,950
NEED TO HAVE A PATIENT WHERE YOU

2775
01:40:55,950 --> 01:40:56,450
CAN MATCH BOTH.

2776
01:40:56,450 --> 01:40:58,486
AS I POINTED OUT WE HAVE KRAS

2777
01:40:58,486 --> 01:41:01,522
AND P53 CLASS I AND CLASS II

2778
01:41:01,522 --> 01:41:03,190
RESTRICTED T CELLS BUT THOSE ARE

2779
01:41:03,190 --> 01:41:04,392
NOT NECESSARILY IDENTIFIED IN

2780
01:41:04,392 --> 01:41:05,493
THE SAME PATIENT BECAUSE YOU

2781
01:41:05,493 --> 01:41:06,627
HAVE TO HAVE THE RIGHT

2782
01:41:06,627 --> 01:41:07,528
RESTRICTION ELEMENTS.

2783
01:41:07,528 --> 01:41:09,630
>> I GUESS WHAT I WAS
SAYING IS

2784
01:41:09,630 --> 01:41:11,532
LIKE NEOANTIGEN CLASS II

2785
01:41:11,532 --> 01:41:13,467
NEOANTIGEN HELPER EPITOPES AS

2786
01:41:13,467 --> 01:41:15,036
OPPOSED TO DIRECT -- ANYWAY, WE

2787
01:41:15,036 --> 01:41:16,237
CAN TALK ABOUT IT LATER.

2788
01:41:16,237 --> 01:41:17,772
>> OKAY, WE CAN TALK ABOUT
IT

2789
01:41:17,772 --> 01:41:17,972
LATER.

2790
01:41:17,972 --> 01:41:18,806
>> QUICK QUESTION.

2791
01:41:18,806 --> 01:41:22,710
SO PAUL, GREAT TALK.

2792
01:41:22,710 --> 01:41:25,613
THOSE T-CELL RECEPTORS YOU FIND

2793
01:41:25,613 --> 01:41:27,815
THAT ARE NOT NEOANTIGEN

2794
01:41:27,815 --> 01:41:28,816
RESTRICTIVE, HAVE YOU LOOKED AT

2795
01:41:28,816 --> 01:41:30,217
THOSE TO SEE HOW BROADLY THEY

2796
01:41:30,217 --> 01:41:32,086
REACT TO OTHER HLA MATCHED

2797
01:41:32,086 --> 01:41:32,486
TUMORS?

2798
01:41:32,486 --> 01:41:33,454
>> WE'RE JUST STARTING
THOSE

2799
01:41:33,454 --> 01:41:33,688
STUDIES.

2800
01:41:33,688 --> 01:41:36,590
SO I THINK WE DO IN A FEW CASES

2801
01:41:36,590 --> 01:41:37,658
HAVE EVIDENCE THAT THEY CAN

2802
01:41:37,658 --> 01:41:39,126
RECOGNIZE MORE THAN ONE, BUT WE

2803
01:41:39,126 --> 01:41:40,528
DON'T HAVE ENOUGH DATA TO SAY.

2804
01:41:40,528 --> 01:41:42,563
>> SO WE'LL PRESENT A
LITTLE BIT

2805
01:41:42,563 --> 01:41:47,835
OF DATA AT CTSI THAT APPEARS TO

2806
01:41:47,835 --> 01:41:50,972
BE HLA RESTRICTED IN A

2807
01:41:50,972 --> 01:41:51,672
B44 SUPERTYPE SO THERE ARE

2808
01:41:51,672 --> 01:41:52,540
THINGS THERE THAT ARE GOING TO

2809
01:41:52,540 --> 01:41:53,574
BE REALLY FASCINATING.

2810
01:41:53,574 --> 01:41:54,875
I THINK THEY'RE RELATED BACK TO

2811
01:41:54,875 --> 01:41:57,178
DARK MATTER.

2812
01:41:57,178 --> 01:41:58,713
>> SO WE'RE GOING TO MOVE
ON

2813
01:41:58,713 --> 01:42:01,282
WITH OUR NEXT SPEAKER, DR. JIM

2814
01:42:01,282 --> 01:42:03,284
YANG, WHO'S BEEN A MEMBER OF THE

2815
01:42:03,284 --> 01:42:04,652
SENIOR STAFF HERE FOR 40 YEARS.

2816
01:42:04,652 --> 01:42:06,454
SO I BELIEVE LIKE DR. ROSENBERG,

2817
01:42:06,454 --> 01:42:07,555
JIM, THIS HAS BEEN YOUR FIRST

2818
01:42:07,555 --> 01:42:08,522
AND ONLY JOB?

2819
01:42:08,522 --> 01:42:12,860
>> YES, FIRST AND ONLY
JOB.

2820
01:42:12,860 --> 01:42:13,828
[LAUGHTER]

2821
01:42:13,828 --> 01:42:19,133
I HOPE IT'S MY LAST.

2822
01:42:19,133 --> 01:42:20,401
I'D LIKE TO START OUT JUST BY

2823
01:42:20,401 --> 01:42:21,168
THANKING STEVE.

2824
01:42:21,168 --> 01:42:22,770
STEVE HAS CREATED A SCIENTIFIC

2825
01:42:22,770 --> 01:42:24,638
PARADISE HERE, AND HE HAS

2826
01:42:24,638 --> 01:42:29,010
ASSEMBLED A GROUP OF DEDICATED,

2827
01:42:29,010 --> 01:42:30,244
INTELLIGENT REALLY GOOD HEARTED

2828
01:42:30,244 --> 01:42:32,113
PEOPLE WHO UNDERSTAND THE

2829
01:42:32,113 --> 01:42:33,247
MESSAGE, AND MOST OF THEM ARE IN

2830
01:42:33,247 --> 01:42:34,015
THIS ROOM.

2831
01:42:34,015 --> 01:42:35,783
IT'S REALLY QUITE REMARKABLE,

2832
01:42:35,783 --> 01:42:37,618
AND HE SHARED WITH THEM THIS

2833
01:42:37,618 --> 01:42:40,287
UNIQUE EXPERIENCE OF USING YOUR

2834
01:42:40,287 --> 01:42:43,624
SKILLS TO TREAT A PATIENT WITH

2835
01:42:43,624 --> 01:42:44,592
INCURABLE CANCER AND RETURN THEM

2836
01:42:44,592 --> 01:42:46,360
TO A COMPLETELY NORMAL LIFE.

2837
01:42:46,360 --> 01:42:47,661
ONCE YOU'VE SEEN THAT, YOU NEVER

2838
01:42:47,661 --> 01:42:49,530
WANT TO DO ANYTHING ELSE.

2839
01:42:49,530 --> 01:42:51,932
SO THE NIH FACILITIES AND

2840
01:42:51,932 --> 01:42:52,833
STEVE'S LEADERSHIP HAS LED TO

2841
01:42:52,833 --> 01:42:54,101
THIS HAPPENING AGAIN AND AGAIN,

2842
01:42:54,101 --> 01:42:55,736
AND IT'S MADE MY LIFE A BLESSED

2843
01:42:55,736 --> 01:42:55,936
LIFE.

2844
01:42:55,936 --> 01:42:56,704
IT REALLY HAS.

2845
01:42:56,704 --> 01:43:01,042
SO I'D LIKE TO THANK YOU, STEVE.

2846
01:43:01,042 --> 01:43:03,878
SO I'M GOING TO BE TALKING ABOUT

2847
01:43:03,878 --> 01:43:05,046
TARGETING NEOANTIGEN WITH T

2848
01:43:05,046 --> 01:43:05,246
CELLS.

2849
01:43:05,246 --> 01:43:08,716
I'M GOING TO START OUT WITH,

2850
01:43:08,716 --> 01:43:13,788
LIKE JIM MULE,, THE PRETTIER THE

2851
01:43:13,788 --> 01:43:15,222
SLIDE, THE LESS COMPELLING THE

2852
01:43:15,222 --> 01:43:15,489
EVIDENCE.

2853
01:43:15,489 --> 01:43:16,724
SO WE ALWAYS JUST DID BLACK AND

2854
01:43:16,724 --> 01:43:17,425
WHITE SLIDES.

2855
01:43:17,425 --> 01:43:18,759
UNFORTUNATELY THERE ARE SOME

2856
01:43:18,759 --> 01:43:19,693
COLOR BACKGROUNDS THAT HAVE

2857
01:43:19,693 --> 01:43:20,828
SLIPPED IN, I'LL HAVE TO WORK ON

2858
01:43:20,828 --> 01:43:22,630
THAT.

2859
01:43:22,630 --> 01:43:25,166
IT'S TITLED STOCKING THE TCR

2860
01:43:25,166 --> 01:43:26,834
LIBRARY AGAINST DRIVER

2861
01:43:26,834 --> 01:43:28,736
MUTATIONS.

2862
01:43:28,736 --> 01:43:30,237
SO THE IDEA IS DISARMINGLY

2863
01:43:30,237 --> 01:43:32,139
SIMPLE OF ADOPTIVE T-CELL

2864
01:43:32,139 --> 01:43:34,008
TRANSFER, IS TO ADMINISTER TUMOR

2865
01:43:34,008 --> 01:43:35,643
REACTIVE T CELLS EXPANDED IN

2866
01:43:35,643 --> 01:43:37,445
VITRO TO CAUSE THE IMMUNOLOGIC

2867
01:43:37,445 --> 01:43:38,913
REJECTION OF METASTATIC CANCERS.

2868
01:43:38,913 --> 01:43:41,715
YOU CAN DO THIS WITH ORGANS,

2869
01:43:41,715 --> 01:43:43,751
SKIN GRAFTS AND SO FORTH, SO THE

2870
01:43:43,751 --> 01:43:44,952
QUESTION IS WHY NOT CANCER.

2871
01:43:44,952 --> 01:43:49,023
NOW THE THEORETICAL ADVANTAGES

2872
01:43:49,023 --> 01:43:50,257
FOR WHICH PROBABLY WE'RE THE

2873
01:43:50,257 --> 01:43:53,928
BEST KNOWN IS THAT YOU CAN

2874
01:43:53,928 --> 01:43:56,197
SELECT THE CLONE TYPES YOU CAN

2875
01:43:56,197 --> 01:43:57,231
ADMINISTER, YOU CAN USE REAGENTS

2876
01:43:57,231 --> 01:43:59,533
THAT ARE NOT TOLERATED IN VIVO,

2877
01:43:59,533 --> 01:44:00,901
CAN YOU ALSO PREPARE THE

2878
01:44:00,901 --> 01:44:04,038
RECIPIENT AND THE T-CELL INKNOCK

2879
01:44:04,038 --> 01:44:05,005
LANTS SEPARATELY BECAUSE THEY

2880
01:44:05,005 --> 01:44:06,207
OFTEN HAVE VERY CONFLICTING

2881
01:44:06,207 --> 01:44:08,242
NEEDS, AND YOU CAN MODIFY THE T

2882
01:44:08,242 --> 01:44:09,577
CELLS ADMINISTERED, SOMETHING

2883
01:44:09,577 --> 01:44:11,679
THAT STILL NEEDS TO BE EXPLORED

2884
01:44:11,679 --> 01:44:12,279
FURTHER THAT I'LL MENTION A

2885
01:44:12,279 --> 01:44:14,248
LITTLE BIT AT THE END.

2886
01:44:14,248 --> 01:44:16,450
SO YOU'VE HEARD FROM YUTAKA AND

2887
01:44:16,450 --> 01:44:19,553
PAUL ABOUT THE UNMUTATED SELF

2888
01:44:19,553 --> 01:44:23,824
ANTIGENS CHARACTER USED BY THE

2889
01:44:23,824 --> 01:44:25,326
MELANOCYTIC DIFFERENTIATION

2890
01:44:25,326 --> 01:44:27,161
PROTEINS AND YOU'VE ALSO HEARD

2891
01:44:27,161 --> 01:44:30,898
FROM PAUL DID -- IF YOU LOOK AT

2892
01:44:30,898 --> 01:44:32,533
THOSE TWO CATEGORIES WHAT YOU

2893
01:44:32,533 --> 01:44:35,169
SEE IS THAT THIS IS CONSTANT

2894
01:44:35,169 --> 01:44:36,003
BETWEEN PATIENTS.

2895
01:44:36,003 --> 01:44:37,004
THAT'S ITS REAL ATTRACTION.

2896
01:44:37,004 --> 01:44:38,172
PEOPLE LIKE IT BECAUSE YOU CAN

2897
01:44:38,172 --> 01:44:40,040
MAKE OFF THE SHELF REAGENTS.

2898
01:44:40,040 --> 01:44:41,675
BUT THE DOWNSIDE IS THERE'S A

2899
01:44:41,675 --> 01:44:43,344
POTENTIAL FOR AUTOIMMUNE

2900
01:44:43,344 --> 01:44:45,146
TOXICITY BECAUSE THESE ARE

2901
01:44:45,146 --> 01:44:47,715
NORMAL SELF PROTEINS AND THE

2902
01:44:47,715 --> 01:44:49,850
T-CELL REPERTOIRE CAN BE LIMITED

2903
01:44:49,850 --> 01:44:51,352
BY THYMIC EDITING.

2904
01:44:51,352 --> 01:44:53,721
NOW THE MUTATED NON-SELF

2905
01:44:53,721 --> 01:44:55,489
NEOANTIGENS ARE HIGHLY

2906
01:44:55,489 --> 01:44:55,923
PATIENT-SPECIFIC.

2907
01:44:55,923 --> 01:44:57,091
SO THAT'S VERY COMPLICATED.

2908
01:44:57,091 --> 01:44:59,360
BUT THEY HAVE VERY LOW POTENTIAL

2909
01:44:59,360 --> 01:45:01,262
FOR AUTOIMMUNITY, NO CENTRAL

2910
01:45:01,262 --> 01:45:03,697
THYMIC TOLERANCE, AND MOST

2911
01:45:03,697 --> 01:45:05,199
TUMORS AS PARKER AND OTHERS HAVE

2912
01:45:05,199 --> 01:45:07,701
SHOWN HAVE IMMUNOGENIC

2913
01:45:07,701 --> 01:45:09,803
NEOANTIGENS.

2914
01:45:09,803 --> 01:45:11,005
SO WHAT YOU'D REALLY LIKE IS

2915
01:45:11,005 --> 01:45:11,338
BOTH.

2916
01:45:11,338 --> 01:45:15,342
WHAT YOU'D LIKE TO TARGET THESE

2917
01:45:15,342 --> 01:45:16,343
UNIQUE NEOANTIGENS BUT ONES THAT

2918
01:45:16,343 --> 01:45:18,712
END UP BEING SHARED BETWEEN

2919
01:45:18,712 --> 01:45:19,813
DIFFERENT HUMAN CANCER, SO

2920
01:45:19,813 --> 01:45:20,781
THAT'S WHAT I'M GOING TO BE

2921
01:45:20,781 --> 01:45:22,850
TALKING ABOUT TODAY, IS

2922
01:45:22,850 --> 01:45:25,286
TARGETING RECURRENT ONCOGENIC

2923
01:45:25,286 --> 01:45:26,020
MUTATION.

2924
01:45:26,020 --> 01:45:27,755
WE KNOW THIS FROM THE PAPER

2925
01:45:27,755 --> 01:45:28,722
LOOKING AT A PATIENT TREATED

2926
01:45:28,722 --> 01:45:30,191
WITH TIL WHICH HAD REACTIVITY

2927
01:45:30,191 --> 01:45:34,895
AGAINST THE KRAS G12D MUTATION

2928
01:45:34,895 --> 01:45:38,432
PRESENTED BY H LACO802 AND SHE

2929
01:45:38,432 --> 01:45:41,202
HAD THIS REALLY GOOD RESPONSE OF

2930
01:45:41,202 --> 01:45:42,269
MULTIPLE LUNG METASTASES.

2931
01:45:42,269 --> 01:45:44,271
THIS WENT AWAY, THIS ONE WENT

2932
01:45:44,271 --> 01:45:45,873
AWAY, THIS ONE SHRUNK.

2933
01:45:45,873 --> 01:45:47,508
BUT THIS ONE IN THE THIRD ROW

2934
01:45:47,508 --> 01:45:51,011
GREW INITIALLY AND THEN --

2935
01:45:51,011 --> 01:45:52,146
SHRANK INITIALLY AND THEN GREW

2936
01:45:52,146 --> 01:45:52,413
BACK.

2937
01:45:52,413 --> 01:45:54,048
SO THIS SHOWS, THOUGH, THAT YOU

2938
01:45:54,048 --> 01:45:55,449
COULD INDEED TARGET THESE

2939
01:45:55,449 --> 01:45:57,017
EFFECTIVELY IN THIS CASE WITH

2940
01:45:57,017 --> 01:45:57,318
TIL.

2941
01:45:57,318 --> 01:45:58,586
SO WHAT I'M GOING TO BE TALKING

2942
01:45:58,586 --> 01:46:00,654
ABOUT IS GENERATING TCRs THAT

2943
01:46:00,654 --> 01:46:02,790
ARE OFF THE SHELF REAGENTS

2944
01:46:02,790 --> 01:46:03,991
AGAINST DRIVER MUTATIONS AND WE

2945
01:46:03,991 --> 01:46:05,993
USE HLA TRANSGENIC MICE FOR

2946
01:46:05,993 --> 01:46:06,393
THIS.

2947
01:46:06,393 --> 01:46:10,564
THE FIRST PAPER WE PUBLISHED WAS

2948
01:46:10,564 --> 01:46:11,532
AT THE SAME TIME THE CLINICAL

2949
01:46:11,532 --> 01:46:15,436
TIL PATIENT WAS PUBLISHED IN

2950
01:46:15,436 --> 01:46:15,669
2016.

2951
01:46:15,669 --> 01:46:17,972
THEY LOOKED AT IDENTIFYING THEM

2952
01:46:17,972 --> 01:46:21,408
USING TRANSGENIC MICE.

2953
01:46:21,408 --> 01:46:23,444
TRANSGENIC MICE HAVE HUMAN HLA

2954
01:46:23,444 --> 01:46:24,878
AND WE HAVE AT LEAST THREE

2955
01:46:24,878 --> 01:46:28,682
STRAINS THAT EXPRESS HLA0201,

2956
01:46:28,682 --> 01:46:33,520
A1101 AND WE MADE THE HL

2957
01:46:33,520 --> 01:46:36,423
HLA0301 MOUSE STRAIN.

2958
01:46:36,423 --> 01:46:38,058
THEY'RE IMMUNIZED AND YOU

2959
01:46:38,058 --> 01:46:39,260
HARVEST THEIR SPLEENS AND

2960
01:46:39,260 --> 01:46:40,561
DRAINING LYMPH NODES AND

2961
01:46:40,561 --> 01:46:43,397
STIMULATE THEM INVIE TROA.

2962
01:46:43,397 --> 01:46:46,233
 IN VITRO.

2963
01:46:46,233 --> 01:46:48,969
YOU CAN ISOLATE THEM AND THEN

2964
01:46:48,969 --> 01:46:52,106
YOU CLONE THE T-CELL RECEPTORS

2965
01:46:52,106 --> 01:46:54,041
AND REEXPRESS THEM IN HUMAN PBL

2966
01:46:54,041 --> 01:46:54,708
AND TEST THEM.

2967
01:46:54,708 --> 01:46:58,145
WHEN SHE DID THIS FOR HER FIRST

2968
01:46:58,145 --> 01:46:59,680
TWO KRAS SPECIFICALLY AL11

2969
01:46:59,680 --> 01:47:00,814
RESTRICTED TCRs, SHE FOUND

2970
01:47:00,814 --> 01:47:02,316
THAT THEY DID WORK IN MOUSE

2971
01:47:02,316 --> 01:47:03,584
MODELS, WHERE THIS IS A MOUSE

2972
01:47:03,584 --> 01:47:04,985
MODEL WHERE A TUMOR IS

2973
01:47:04,985 --> 01:47:10,491
EXPRESSING THE G12V MUTATION IN

2974
01:47:10,491 --> 01:47:11,959
HLA-A11 TRANSFECTED TUMOR SO

2975
01:47:11,959 --> 01:47:13,827
THAT WHAT YOU SEE IS THAT

2976
01:47:13,827 --> 01:47:20,200
STARTING WITH PALPABLE

2977
01:47:20,200 --> 01:47:21,568
MACROSCOPIC TUMORS THAT YOU

2978
01:47:21,568 --> 01:47:23,203
COULD GIVE THESE CELLS AND CAUSE

2979
01:47:23,203 --> 01:47:24,071
REGRESSION ON THE BOTTOM LINE

2980
01:47:24,071 --> 01:47:26,340
THAT DID NOT OCCUR WITH NO

2981
01:47:26,340 --> 01:47:27,441
TREATMENT UNTRANSDUCED CELLS OR

2982
01:47:27,441 --> 01:47:28,309
MOCK TRANSDUCED CELLS.

2983
01:47:28,309 --> 01:47:30,144
SO THEY WERE EFFECTIVE IN THE

2984
01:47:30,144 --> 01:47:35,749
XENOGRAPH MODELS.

2985
01:47:35,749 --> 01:47:37,618
NOW WHY ARE WE LOOKING AT MOUSE

2986
01:47:37,618 --> 01:47:37,885
RECEPTORS?

2987
01:47:37,885 --> 01:47:39,320
WE KNOW FROM OUR OWN RECEPTORS

2988
01:47:39,320 --> 01:47:41,588
THAT THEY WORK IN HUMAN PBLs.

2989
01:47:41,588 --> 01:47:43,991
YOU CAN PUT THEM IN WITH NO

2990
01:47:43,991 --> 01:47:45,292
MODIFICATION, GIVE TO THAT

2991
01:47:45,292 --> 01:47:47,161
PATIENT AND THEY WILL WORK.

2992
01:47:47,161 --> 01:47:48,495
THESE ARE THREE SETS OF

2993
01:47:48,495 --> 01:47:50,497
PROTOCOLS WE PUBLISHED USING

2994
01:47:50,497 --> 01:47:53,334
MURINE RECEPTORS AGAINST

2995
01:47:53,334 --> 01:47:56,804
DIFFERENTIATION ANTIGENS,

2996
01:47:56,804 --> 01:48:00,307
AGAINST NORMAL -- IN ALL OF

2997
01:48:00,307 --> 01:48:04,778
THESE WE DID SEE -- WE ALSO SAW

2998
01:48:04,778 --> 01:48:06,380
AUTOIMMUAUTOIMMUNE TOXICITIES.

2999
01:48:06,380 --> 01:48:07,915
THIS IS THE DANGER OF COURSE OF

3000
01:48:07,915 --> 01:48:09,683
TARGETING NON-MUTATED SELF

3001
01:48:09,683 --> 01:48:10,651
ANTIGENS.

3002
01:48:10,651 --> 01:48:12,519
SO OUR APPROACH WAS TO LOOK AT

3003
01:48:12,519 --> 01:48:13,253
MUTATED NEOANTIGENS THAT WERE

3004
01:48:13,253 --> 01:48:13,487
SHARED.

3005
01:48:13,487 --> 01:48:15,956
SO THIS IS A STUDY THAT WAS DONE

3006
01:48:15,956 --> 01:48:20,861
BY CATHERINE AEDE LOOKING AT

3007
01:48:20,861 --> 01:48:22,162
SYSTEMATIC IDENTIFICATION BY

3008
01:48:22,162 --> 01:48:22,763
MASS SPEC.

3009
01:48:22,763 --> 01:48:24,832
THE APPROACH WAS TO TRANSFECT

3010
01:48:24,832 --> 01:48:26,533
CELL LINES WITH MUTATED MINI

3011
01:48:26,533 --> 01:48:30,871
GENES EXPRESSING THE TARGET AND

3012
01:48:30,871 --> 01:48:32,206
THE ALLELE OF INTEREST.

3013
01:48:32,206 --> 01:48:35,642
THESE WERE MHC NULL LIELS TO

3014
01:48:35,642 --> 01:48:36,477
SIMPLIFY THE ELUSION OF

3015
01:48:36,477 --> 01:48:37,511
PEPTIDES.

3016
01:48:37,511 --> 01:48:39,279
WE USE LINES WITH BOTH THE

3017
01:48:39,279 --> 01:48:41,482
STANDARD PROTEOSOME AND THE

3018
01:48:41,482 --> 01:48:42,349
IMMUNOPROTEOSOME AND TYPICALLY

3019
01:48:42,349 --> 01:48:44,818
DIDN'T FIND MUCH DIFFERENCE BUT

3020
01:48:44,818 --> 01:48:47,788
OCCASIONALLY SEE IT, AND WE THEN

3021
01:48:47,788 --> 01:48:50,391
IMMUNOPRECIPITATE THE HLA AND EE

3022
01:48:50,391 --> 01:48:51,792
LUTE THE PEPTIDES AND ANALYZE

3023
01:48:51,792 --> 01:48:52,659
THEM BY MASS SPEC.

3024
01:48:52,659 --> 01:48:54,061
WE PICK THESE RECURRING

3025
01:48:54,061 --> 01:48:55,262
MUTATIONS BECAUSE THEY'RE THE

3026
01:48:55,262 --> 01:48:56,597
MOST COMMON ONES IN HUMAN

3027
01:48:56,597 --> 01:48:58,399
CANCERS WITH VERY SPECIFIC

3028
01:48:58,399 --> 01:48:59,199
RECURRING AMINO ACID

3029
01:48:59,199 --> 01:49:00,667
SUBSTITUTIONS.

3030
01:49:00,667 --> 01:49:05,406
IN RAS, EGFR -- YOU CAN SEE THE

3031
01:49:05,406 --> 01:49:07,708
VARIOUS MUTATIONS LISTED HERE

3032
01:49:07,708 --> 01:49:09,643
AND WHICH CANCERS THEY OCCUR IN.

3033
01:49:09,643 --> 01:49:11,812
WE THEN PICK THE DOZEN MOST

3034
01:49:11,812 --> 01:49:13,680
COMMON CLASS I ALLELES IN THE

3035
01:49:13,680 --> 01:49:15,215
U.S. POPULATION.

3036
01:49:15,215 --> 01:49:17,184
AND WANTED TO INVESTIGATE THOSE.

3037
01:49:17,184 --> 01:49:18,919
BUT THAT RESULTS IN HUNDREDS OF

3038
01:49:18,919 --> 01:49:20,754
COMBINATIONS OF MUTATIONS AND

3039
01:49:20,754 --> 01:49:22,222
ALLELES SO WE NEEDED A METHOD TO

3040
01:49:22,222 --> 01:49:23,557
FIGURE OUT WHICH ONES WERE

3041
01:49:23,557 --> 01:49:24,691
WORTHY OF INVESTIGATIONS AND

3042
01:49:24,691 --> 01:49:25,692
WHICH ONES WERE NOT.

3043
01:49:25,692 --> 01:49:27,394
SO THIS IS AN EXAMPLE OF HOW IT

3044
01:49:27,394 --> 01:49:29,563
LOOKED.

3045
01:49:29,563 --> 01:49:30,764
THIS IS -- ACROSS THE TOP IS

3046
01:49:30,764 --> 01:49:34,368
LOOKING AT THE E545K MUTATION IN

3047
01:49:34,368 --> 01:49:35,135
PIC3CA.

3048
01:49:35,135 --> 01:49:36,303
WE PUT IT INTO THE TWO LINES,

3049
01:49:36,303 --> 01:49:38,372
THE TOP ONE BEING THE

3050
01:49:38,372 --> 01:49:39,072
IMMUNOPROTEOSOME LINE, THE

3051
01:49:39,072 --> 01:49:41,375
BOTTOM BEING THE STANDARD

3052
01:49:41,375 --> 01:49:42,009
PROTEOSOME LINE.

3053
01:49:42,009 --> 01:49:44,812
THE PEPTIDE, MUTATED PEPTIDE IS

3054
01:49:44,812 --> 01:49:46,013
SHOWN IN THE THIRD COLUMN, AND

3055
01:49:46,013 --> 01:49:49,883
THEN THE GREEN BOX TO THE RIGHT

3056
01:49:49,883 --> 01:49:51,652
REPRESENT INDIVIDUAL REPLICATES,

3057
01:49:51,652 --> 01:49:53,053
BIOLOGICAL REPLICATES OF THESE

3058
01:49:53,053 --> 01:49:53,353
EXPERIMENTS.

3059
01:49:53,353 --> 01:49:54,288
SO CATHERINE DID EVERY ONE OF

3060
01:49:54,288 --> 01:49:55,355
THESE UP TO EIGHT TIMES, AND

3061
01:49:55,355 --> 01:49:56,890
WHAT YOU SEE, IF IT'S DARK

3062
01:49:56,890 --> 01:50:00,227
GREEP, I GREEN, IT MEANS THE

3063
01:50:00,227 --> 01:50:01,762
MUTATED PEPTIDE WAS RECOVERED

3064
01:50:01,762 --> 01:50:03,163
ABUNDANTLY AND CONSISTENTLY.

3065
01:50:03,163 --> 01:50:04,164
LIGHT GREEN MEANS IT WAS A

3066
01:50:04,164 --> 01:50:05,899
LITTLE LESS CONSISTENT OR

3067
01:50:05,899 --> 01:50:06,867
ABUNDANT.

3068
01:50:06,867 --> 01:50:08,502
RED MEANS NO CANDIDATE MUTATED

3069
01:50:08,502 --> 01:50:10,137
PEPTIDES WERE RECOVERED AND

3070
01:50:10,137 --> 01:50:11,205
WHITE MEANS IT HASN'T BEEN DONE

3071
01:50:11,205 --> 01:50:11,572
YET.

3072
01:50:11,572 --> 01:50:14,475
AND WE DID ALSO FRACTIONATION

3073
01:50:14,475 --> 01:50:15,843
THAT SHOWS BELOW THE PEPTIDE WE

3074
01:50:15,843 --> 01:50:17,444
EE LUTE AND IDENTIFY IS INDEED

3075
01:50:17,444 --> 01:50:19,146
THE PEPTIDE WE THINK IT IS.

3076
01:50:19,146 --> 01:50:23,150
SO THIS IS A SUMMARY OF THE HLA

3077
01:50:23,150 --> 01:50:24,284
A11 PEPTIDES FROM FOUR OF THE

3078
01:50:24,284 --> 01:50:27,921
COMMON MUTATED DRIVER GENES.

3079
01:50:27,921 --> 01:50:28,822
YOU CAN SEE MANY OF THEM ARE

3080
01:50:28,822 --> 01:50:30,891
WELL PROCESSED AND PRESENTED BY

3081
01:50:30,891 --> 01:50:32,860
BOTH OF THE LINES SHOWN HERE.

3082
01:50:32,860 --> 01:50:33,694
OCCASIONALLY YOU'LL SEE SOME

3083
01:50:33,694 --> 01:50:34,795
THAT ARE NOT.

3084
01:50:34,795 --> 01:50:41,068
THE BRAF -- WAS POORLY PRESENTED

3085
01:50:41,068 --> 01:50:42,903
BUT THE OTHERS WERE WELL

3086
01:50:42,903 --> 01:50:44,972
PRESENTED.

3087
01:50:44,972 --> 01:50:47,207
HLA A3 ALSO VERY GOOD PRESENTER

3088
01:50:47,207 --> 01:50:49,576
OF MANY OF THESE AND

3089
01:50:49,576 --> 01:50:51,712
OCCASIONALLY SOME LIKE YOUR G12D

3090
01:50:51,712 --> 01:50:53,847
PRESENTED BY A3 WAS POORLY

3091
01:50:53,847 --> 01:50:55,215
PRESENTED AND AGAIN, ONE WE DID

3092
01:50:55,215 --> 01:50:55,749
NOT PURSUE.

3093
01:50:55,749 --> 01:50:57,718
SO THIS ALLOWED US TO FOCUS ON

3094
01:50:57,718 --> 01:50:58,819
WHICH ONES WERE WORTHY OF

3095
01:50:58,819 --> 01:50:59,219
EFFORT.

3096
01:50:59,219 --> 01:51:01,488
THEY WEREN'T ALL POSITIVE.

3097
01:51:01,488 --> 01:51:04,791
HLA A11 DID NOT PRESENT THESE

3098
01:51:04,791 --> 01:51:07,294
TWO EPITOPES AND HLA A3 DIDN'T

3099
01:51:07,294 --> 01:51:08,595
PRESENT THE THREE BELOW.

3100
01:51:08,595 --> 01:51:09,897
THE OTHER THING THAT WAS

3101
01:51:09,897 --> 01:51:11,632
INTERESTING WAS THE A2 PRESENTED

3102
01:51:11,632 --> 01:51:12,833
EPITOPES WERE NOT VERY GOOD.

3103
01:51:12,833 --> 01:51:14,701
WE RARELY FOUND THESE PRESENTED

3104
01:51:14,701 --> 01:51:21,708
BY A2 SO WE FOCUSED MIME PRIMARN

3105
01:51:21,708 --> 01:51:22,042
A3 AND -- 11.

3106
01:51:22,042 --> 01:51:23,410
YOU DO THE VACCINATION, YOU

3107
01:51:23,410 --> 01:51:24,511
HARVEST THE SPLEENS AND LYMPH

3108
01:51:24,511 --> 01:51:26,446
NODES OF THESE HLA TRANSGENIC

3109
01:51:26,446 --> 01:51:28,015
MICE AND THEN YOU TRY AND SELECT

3110
01:51:28,015 --> 01:51:29,850
THE REACTIVE CELLS AND WE USED A

3111
01:51:29,850 --> 01:51:31,051
VARIETY OF TECHNIQUES, BUT ONE

3112
01:51:31,051 --> 01:51:33,554
THAT WAS VERY HELPFUL WAS USING

3113
01:51:33,554 --> 01:51:33,820
TETRAMERS.

3114
01:51:33,820 --> 01:51:41,628
WHAT I SHOW HERE IS THE TWO

3115
01:51:41,628 --> 01:51:42,496
DIFFERENT COLOR TETRAMERS ON THE

3116
01:51:42,496 --> 01:51:43,497
X AND Y AXIS.

3117
01:51:43,497 --> 01:51:44,631
THIS IS UNSTAINED.

3118
01:51:44,631 --> 01:51:46,133
OVER HERE IS THE TETRAMER

3119
01:51:46,133 --> 01:51:46,633
STAINING.

3120
01:51:46,633 --> 01:51:49,703
YOU CAN SEE THERE'S DOUBLE

3121
01:51:49,703 --> 01:51:50,904
POSITIVE TETRAMER EXPRESSING

3122
01:51:50,904 --> 01:51:51,104
CELLS.

3123
01:51:51,104 --> 01:51:52,306
YOU SORT FOR THESE, YOU THEN

3124
01:51:52,306 --> 01:51:53,840
CLONE THEIR T-CELL RECEPTORS AND

3125
01:51:53,840 --> 01:51:55,909
YOU GET THESE T-CELL RECEPTOR

3126
01:51:55,909 --> 01:51:57,711
ALPHA BETA PAIRS OVER HERE, YOU

3127
01:51:57,711 --> 01:51:59,179
RECONSTRUCT THEM IN PBL AND THEN

3128
01:51:59,179 --> 01:51:59,947
YOU TEST THEM.

3129
01:51:59,947 --> 01:52:01,415
WHEN YOU DO THAT, YOU SEE HERE

3130
01:52:01,415 --> 01:52:03,850
THE MUTANT PEPTIDE TITRATIONS OF

3131
01:52:03,850 --> 01:52:06,019
ONE, THIS IS THE HLA A11

3132
01:52:06,019 --> 01:52:09,556
RESTRICTED EGFRL858R MUTATION

3133
01:52:09,556 --> 01:52:10,591
AND WHEN YOU DO THAT, YOU CAN

3134
01:52:10,591 --> 01:52:12,359
SEE THAT THESE THREE RECEPTORS

3135
01:52:12,359 --> 01:52:13,961
WE ISOLATED WERE ALL SPECIFIC

3136
01:52:13,961 --> 01:52:15,929
FOR THE MUTANT PEPTIDE WITH

3137
01:52:15,929 --> 01:52:18,198
LITTLE TO NO RECOGNITION OF WILD

3138
01:52:18,198 --> 01:52:18,732
TYPE.

3139
01:52:18,732 --> 01:52:20,701
AND WHEN YOU DO THIS IN A

3140
01:52:20,701 --> 01:52:23,570
TRANSFECTED K562A11 EXPRESSING

3141
01:52:23,570 --> 01:52:24,705
CELL, YOU CAN SEE THAT PUTTING

3142
01:52:24,705 --> 01:52:26,273
IN THE TARGET AND ALLOWING TO BE

3143
01:52:26,273 --> 01:52:27,441
NATURALLY PROCESSED ALSO RESULTS

3144
01:52:27,441 --> 01:52:29,376
IN RECOGNITION WITH NO

3145
01:52:29,376 --> 01:52:32,446
RECOGNITION OF JUST HLA POS HIF

3146
01:52:32,446 --> 01:52:34,748
TARGETS WITHOUT THE ANTIGEN.

3147
01:52:34,748 --> 01:52:36,583
NOW, WHEN WE DID THAT, THIS IS

3148
01:52:36,583 --> 01:52:38,418
ANOTHER RECEPTOR, AGAIN TOTALLY

3149
01:52:38,418 --> 01:52:40,053
SPECIFIC FOR A MUTATED EPITOPE,

3150
01:52:40,053 --> 01:52:41,722
NO WILD TYPE REACTIVITY.

3151
01:52:41,722 --> 01:52:43,790
BUT WHEN WE TEST IT A PANEL OF

3152
01:52:43,790 --> 01:52:44,891
TUMORS THAT ARE NATURALLY

3153
01:52:44,891 --> 01:52:49,029
EXPRESSING THIS, THESE THREE

3154
01:52:49,029 --> 01:52:52,633
TUMORS EXPRESS HLA AND THE G12B

3155
01:52:52,633 --> 01:52:55,302
KRAS MUTATION.

3156
01:52:55,302 --> 01:52:56,970
ALL THREE SHOW SOME REACTIVITY.

3157
01:52:56,970 --> 01:52:57,971
THE TWO NEGATIVE CONTROLS FOR

3158
01:52:57,971 --> 01:52:59,940
HLA AND THE ANTIGEN ARE

3159
01:52:59,940 --> 01:53:01,108
NEGATIVE, BUT YOU CAN SEE THESE

3160
01:53:01,108 --> 01:53:02,409
ARE NOT VERY POTENT.

3161
01:53:02,409 --> 01:53:05,379
THIS AMOUNT OF INTERFERON GAMMA

3162
01:53:05,379 --> 01:53:07,748
ELABORATION IS VERY LOW FOR OUR

3163
01:53:07,748 --> 01:53:11,018
TYPICAL TUMOR REACTIVE T-CELL.

3164
01:53:11,018 --> 01:53:15,322
THE SAME WAS THROUGH FOR ANOTHER

3165
01:53:15,322 --> 01:53:16,657
ONE, A3 PRESENTED EPITOPE.

3166
01:53:16,657 --> 01:53:18,759
AGAIN WE HAD THREE TCRs, ALL

3167
01:53:18,759 --> 01:53:20,727
OF THEM WERE HIGHLY RECOGNIZING

3168
01:53:20,727 --> 01:53:23,430
THE MUTANT EPITOPE, BUT TWO OF

3169
01:53:23,430 --> 01:53:25,832
THEM HAD SOME WILD TYPE

3170
01:53:25,832 --> 01:53:27,367
REACTIVITY, TCR 4 HAD NONE.

3171
01:53:27,367 --> 01:53:29,336
WHEN YOU TAKE TCR 4 AND TEST IT

3172
01:53:29,336 --> 01:53:31,071
AGAINST THIS PANEL OF TARGETS,

3173
01:53:31,071 --> 01:53:33,140
AGAIN, THE SPECIFIC CORRECT

3174
01:53:33,140 --> 01:53:35,142
TUMORS ALL RELEASE SOME

3175
01:53:35,142 --> 01:53:35,976
INTERFERON, THE TWO NEGATIVE

3176
01:53:35,976 --> 01:53:36,376
CONTROLS DO NOT.

3177
01:53:36,376 --> 01:53:38,378
BUT AGAIN, VERY LOW LEVELS OF

3178
01:53:38,378 --> 01:53:40,180
INTERFERON.

3179
01:53:40,180 --> 01:53:41,615
AND SO AND THIS WAS TRUE FOR

3180
01:53:41,615 --> 01:53:44,117
MOST OF OUR TCRs WE FOUND.

3181
01:53:44,117 --> 01:53:45,919
THIS IS THE SET OF FOUR OF THEM

3182
01:53:45,919 --> 01:53:48,689
FOR HLA A11 AND I LIST THESE

3183
01:53:48,689 --> 01:53:50,557
FOUR BECAUSE WE HAVE NO HUMAN

3184
01:53:50,557 --> 01:53:51,525
HOMOLOGUE FOR THESE.

3185
01:53:51,525 --> 01:53:52,859
WE'VE NEVER FOUND THESE

3186
01:53:52,859 --> 01:53:54,061
REACTIVITIES IN HUMAN TIL.

3187
01:53:54,061 --> 01:53:58,598
SO WHEN WE WANT TO DO A T-CELL

3188
01:53:58,598 --> 01:54:00,100
RECEPTOR PROTOCOL, WE'VE BEEN

3189
01:54:00,100 --> 01:54:01,968
USING HUMAN TCRs BUT WE DO NOT

3190
01:54:01,968 --> 01:54:03,470
HAVE THEIR EQUIVALENT FOR THESE

3191
01:54:03,470 --> 01:54:04,805
IN HUMAN TCRs.

3192
01:54:04,805 --> 01:54:06,406
SO AGAIN, YOU CAN SEE THEY'RE

3193
01:54:06,406 --> 01:54:07,441
EXTREMELY ECK QIS ITALY SPECIFIC

3194
01:54:07,441 --> 01:54:09,443
FOR THE MUTANT ALLELE BUT NOT

3195
01:54:09,443 --> 01:54:09,976
FOR THE WILD TYPE.

3196
01:54:09,976 --> 01:54:11,411
THIS IS THE A3.

3197
01:54:11,411 --> 01:54:13,146
AGAIN, ALL OF THESE WERE VERY

3198
01:54:13,146 --> 01:54:14,681
SPECIFIC EXCEPT FOR THE ONE I

3199
01:54:14,681 --> 01:54:17,484
SHOWED YOU AGAINST BRAF -- TWO

3200
01:54:17,484 --> 01:54:20,153
OF THEM HAD WILD TYPE REACTIVITY

3201
01:54:20,153 --> 01:54:24,224
BUT RECEPTOR 4 DID NOT.

3202
01:54:24,224 --> 01:54:25,392
SO THE QUESTION IS CAN WE DO

3203
01:54:25,392 --> 01:54:26,159
SOMETHING ABOUT THIS.

3204
01:54:26,159 --> 01:54:27,928
CAN WE ENHANCE THE REACTIVITY OF

3205
01:54:27,928 --> 01:54:29,563
THESE TCRs TO FILL THESE

3206
01:54:29,563 --> 01:54:31,531
VACANCIES IN OUR DRIVER

3207
01:54:31,531 --> 01:54:32,833
NEOANTIGEN TCR LIBRARY.

3208
01:54:32,833 --> 01:54:36,737
SO WE TRIED MODIFYING CDR3s AS

3209
01:54:36,737 --> 01:54:38,038
PAUL HAS DONE PREVIOUSLY

3210
01:54:38,038 --> 01:54:38,371
SUCCESSFULLY.

3211
01:54:38,371 --> 01:54:40,474
WE ADDED CHIMERIC CORECEPTORS TO

3212
01:54:40,474 --> 01:54:41,208
THE TCRs.

3213
01:54:41,208 --> 01:54:43,744
WE MODIFIED THE SIGNALING IN

3214
01:54:43,744 --> 01:54:45,112
THESE T CELLS AND NONE OF THESE

3215
01:54:45,112 --> 01:54:46,446
INTERVENTIONS HAD CONSISTENT OR

3216
01:54:46,446 --> 01:54:47,314
SIGNIFICANT BENEFIT.

3217
01:54:47,314 --> 01:54:49,716
SO FINALLY WE TURNED TO THE IDEA

3218
01:54:49,716 --> 01:54:52,119
OF ADDING IL12 TO THE TUMOR

3219
01:54:52,119 --> 01:54:52,519
MICROENVIRONMENT.

3220
01:54:52,519 --> 01:54:54,187
WE DID THIS BECAUSE WE HAD A

3221
01:54:54,187 --> 01:54:55,122
PREVIOUS EXPERIENCE IN THE

3222
01:54:55,122 --> 01:54:58,859
BRANCH USING AN N FAD DRIVEN

3223
01:54:58,859 --> 01:55:00,727
PROMOTER TO CREATE A SINGLE

3224
01:55:00,727 --> 01:55:02,062
CHAIN IL2 MOLECULE.

3225
01:55:02,062 --> 01:55:04,498
THIS IS WITH LING SANG AND RICK

3226
01:55:04,498 --> 01:55:05,599
MORGAN AND THEY REPORTED THAT

3227
01:55:05,599 --> 01:55:09,903
THERE ARE 33 PATIENTS WITH MEL

3228
01:55:09,903 --> 01:55:12,172
MELANOMA ENROLLED.

3229
01:55:12,172 --> 01:55:14,474
ONE PERSON HAD A TRIVIAL CELL

3230
01:55:14,474 --> 01:55:16,643
DOAN'S, 30 MILLION TIL, HAD A

3231
01:55:16,643 --> 01:55:17,778
COMPLETE DURABLE AND COMPLETE

3232
01:55:17,778 --> 01:55:18,845
RESPONSE AND THE OVERALL

3233
01:55:18,845 --> 01:55:22,783
RESPONSE RATE WAS 6  63% WITH AG

3234
01:55:22,783 --> 01:55:24,084
LESS CELLS IN MANY CASES THAN WE

3235
01:55:24,084 --> 01:55:24,618
TYPICALLY GIVE.

3236
01:55:24,618 --> 01:55:27,320
SO THIS WAS VERY ENCOURAGING

3237
01:55:27,320 --> 01:55:29,389
INITIALLY BUT AT HIGHER DOSES

3238
01:55:29,389 --> 01:55:31,158
PATIENTS EXPERIENCED CYTOKINE

3239
01:55:31,158 --> 01:55:33,560
STORM AND HEPATOTOXICITY THAT

3240
01:55:33,560 --> 01:55:34,427
LIMITED OUR ABILITY TO GIVE

3241
01:55:34,427 --> 01:55:35,095
THOSE CELLS.

3242
01:55:35,095 --> 01:55:36,496
THIS IS THE PATIENT I MENTIONED,

3243
01:55:36,496 --> 01:55:38,665
QUITE A REMARKABLE PATIENT

3244
01:55:38,665 --> 01:55:40,300
BECAUSE SHE HAD BEEN TREATED

3245
01:55:40,300 --> 01:55:42,736
WITH CONVENTIONAL TIL AND IL-2.

3246
01:55:42,736 --> 01:55:44,771
SHE GOT 30 BILLION CELLS WITH

3247
01:55:44,771 --> 01:55:46,239
SEVERAL DOSES OF IL-2, YOU CAN

3248
01:55:46,239 --> 01:55:47,641
SEE HER TUMOR GREW RIGHT THROUGH

3249
01:55:47,641 --> 01:55:47,941
THAT.

3250
01:55:47,941 --> 01:55:51,144
WE THEN USED THE EXACT SAME TIL

3251
01:55:51,144 --> 01:55:56,016
USING THE -- IL12 AND SHE ONLY

3252
01:55:56,016 --> 01:55:57,350
GOT -- SHE HAD THIS VERY

3253
01:55:57,350 --> 01:55:57,984
DRAMATIC RESPONSE.

3254
01:55:57,984 --> 01:56:00,053
SO WE WERE VERY ENCOURAGED BY

3255
01:56:00,053 --> 01:56:01,121
THAT BUT WE WERE WORRIED ABOUT

3256
01:56:01,121 --> 01:56:01,421
THE SAFETY.

3257
01:56:01,421 --> 01:56:02,889
SO WE'RE LOOKING AT TRYING TO

3258
01:56:02,889 --> 01:56:10,730
ADD IL-2 TO CELLS SAFELY, AND

3259
01:56:10,730 --> 01:56:14,668
INITIALLY LYNN ZANG SHOWED THERE

3260
01:56:14,668 --> 01:56:16,102
WAS INCREASED SAFETY IF YOU

3261
01:56:16,102 --> 01:56:19,072
MEMBRANE TETHERED THE -- MICE

3262
01:56:19,072 --> 01:56:20,774
DID NOT GET SICK WITH THAT.

3263
01:56:20,774 --> 01:56:27,347
PETER THEN DEVELOPED AN NFAT

3264
01:56:27,347 --> 01:56:29,282
DRIVEN MEMBRANE TETHERED IL-12

3265
01:56:29,282 --> 01:56:33,486
INCORPORATING A DEGRON DOMAIN,

3266
01:56:33,486 --> 01:56:35,288
SO THIS IS YET AN ADDITIONAL

3267
01:56:35,288 --> 01:56:36,256
SAFETY MEASURE THAT YOU CAN USE

3268
01:56:36,256 --> 01:56:36,790
IN THIS CASE.

3269
01:56:36,790 --> 01:56:42,429
AND WE TRIED THIS THEN IN OUR

3270
01:56:42,429 --> 01:56:44,030
MURINE TIL PBL.

3271
01:56:44,030 --> 01:56:45,565
SO IL-12 CAN ENHANCE THE IN

3272
01:56:45,565 --> 01:56:47,767
VITRO FUNCTION OF TUMOR-REACTIVE

3273
01:56:47,767 --> 01:56:49,603
CELLS BOTH IN MICE AND

3274
01:56:49,603 --> 01:56:50,937
APPARENTLY IN HUMANS AS WELL.

3275
01:56:50,937 --> 01:56:52,572
THE DOMINANT KNOWN MECHANISM IS

3276
01:56:52,572 --> 01:56:53,874
THROUGH INTERFERON GAMMA.

3277
01:56:53,874 --> 01:56:56,476
IT AUGMENTS INTERFERON GAMMA, IT

3278
01:56:56,476 --> 01:57:01,748
BIASES CELLS TO A TH1

3279
01:57:01,748 --> 01:57:02,682
TC1 PHENOTYPE BUT LITTLE IS

3280
01:57:02,682 --> 01:57:04,784
KNOWN BEYOND THAT WHAT IT DOES

3281
01:57:04,784 --> 01:57:06,720
TO OTHER FUNCTIONS.

3282
01:57:06,720 --> 01:57:08,388
 -- OR ONE THAT IS REACTING

3283
01:57:08,388 --> 01:57:09,789
AGAINST A VERY SPARSE ANTIGEN.

3284
01:57:09,789 --> 01:57:10,824
IT'S ALSO NOT CLEAR WHAT IT

3285
01:57:10,824 --> 01:57:13,059
WOULD DO TO OTHER EFFECTOR

3286
01:57:13,059 --> 01:57:16,129
FUNCTIONS SUCH AS CYTOTOXICITY.

3287
01:57:16,129 --> 01:57:18,398
SO WE ADDED IT, CATHERINE AND

3288
01:57:18,398 --> 01:57:19,900
PETER TOGETHER ADDED THIS

3289
01:57:19,900 --> 01:57:23,003
CONSTRUCT TO THE PBL EXPRESSING.

3290
01:57:23,003 --> 01:57:25,405
IN THIS CASE THE MURINE TIL

3291
01:57:25,405 --> 01:57:28,575
AGAINST THE G TELL VA3 REA

3292
01:57:28,575 --> 01:57:29,409
STRICTED RECEPTOR FOR WHICH WE

3293
01:57:29,409 --> 01:57:31,144
DO NOT HAVE A HUMAN EQUIVALENT.

3294
01:57:31,144 --> 01:57:31,778
WHAT YOU SEE HERE IS THAT THIS

3295
01:57:31,778 --> 01:57:33,480
IS THE RECEPTOR BY ITSELF.

3296
01:57:33,480 --> 01:57:35,348
AGAIN, A FEW HUNDRED DOLLARS

3297
01:57:35,348 --> 01:57:37,517
PICOGRAMS OF INTERFERON GAMMA

3298
01:57:37,517 --> 01:57:38,919
ELABORATED AGAINST THE MUTANT

3299
01:57:38,919 --> 01:57:41,655
ALLELE, BUT WHEN YOU ADD THE

3300
01:57:41,655 --> 01:57:44,157
DEGRON DOMAIN AGAINST THIS

3301
01:57:44,157 --> 01:57:45,825
TUMOR, YOU GET A HUGE

3302
01:57:45,825 --> 01:57:47,027
AUGMENTATION OF THE INTERFERON

3303
01:57:47,027 --> 01:57:47,427
GAMMA SECRETION.

3304
01:57:47,427 --> 01:57:49,129
AND THIS IS TRUE FOR, AGAIN,

3305
01:57:49,129 --> 01:57:51,831
THIS TUMOR LINE AGAIN POSITIVE

3306
01:57:51,831 --> 01:57:54,234
FOR THE ANTIGEN AND THE MHC AND

3307
01:57:54,234 --> 01:57:55,535
THIS TUMOR LINE INTO THE

3308
01:57:55,535 --> 01:57:56,937
THOUSANDS INSTEAD OF HUNDREDS OF

3309
01:57:56,937 --> 01:57:58,238
PICOGRAMS OF INTERFERON.

3310
01:57:58,238 --> 01:58:00,106
AND WITHOUT LOSS OF SPECIFICITY.

3311
01:58:00,106 --> 01:58:01,741
THESE ARE THE SPECIFICITY

3312
01:58:01,741 --> 01:58:03,443
RESULTS FOR THE HLA AND THE

3313
01:58:03,443 --> 01:58:03,944
ANTIGEN.

3314
01:58:03,944 --> 01:58:10,550
SO THIS WAS A ENCOURAGING

3315
01:58:10,550 --> 01:58:11,584
AUGMENTATION WITHOUT LOSS OF

3316
01:58:11,584 --> 01:58:11,885
SPECIFICITY.

3317
01:58:11,885 --> 01:58:13,853
IF YOU THEN ADD THIS ALSO TO A

3318
01:58:13,853 --> 01:58:16,723
DIFFERENT RECEPTOR, THE TCR

3319
01:58:16,723 --> 01:58:17,824
4V600E RECEPTOR, I SHOWED YOU

3320
01:58:17,824 --> 01:58:19,659
THE SAME THING, AGAIN, THIS IS

3321
01:58:19,659 --> 01:58:21,161
VERY LOW REACTIVITY WE SAW

3322
01:58:21,161 --> 01:58:22,362
INITIALLY, THIS IS THE HIGHLY

3323
01:58:22,362 --> 01:58:23,430
AUGMENTED SECRETION OF

3324
01:58:23,430 --> 01:58:25,065
INTERFERON GAMMA, AND THE

3325
01:58:25,065 --> 01:58:26,533
SPECIFICITY REMAINED VERY GOOD

3326
01:58:26,533 --> 01:58:28,501
AGAINST THE WILD TYPE ALLELE.

3327
01:58:28,501 --> 01:58:31,071
SO THE QUESTION -- SO THIS IS

3328
01:58:31,071 --> 01:58:31,371
ENCOURAGING.

3329
01:58:31,371 --> 01:58:33,473
THE QUESTION IS WHAT DOES DO TO

3330
01:58:33,473 --> 01:58:34,641
OTHER EFFECTOR FUNCTIONS?  IF

3331
01:58:34,641 --> 01:58:38,044
YOU LOOK AT CYTOTOXICITY, THIS

3332
01:58:38,044 --> 01:58:41,881
IS THE FIRST KRAS REACTIVE

3333
01:58:41,881 --> 01:58:47,754
RECEPTOR, THIS IS THE DRK I'M

3334
01:58:47,754 --> 01:58:49,189
SORRY BRAF AND THIS IS THE K

3335
01:58:49,189 --> 01:58:49,656
RAF.

3336
01:58:49,656 --> 01:58:51,691
THE TCR ALONE SHOWS THIS BLUE

3337
01:58:51,691 --> 01:58:53,760
LINE REACTIVITY AND THE TUMOR

3338
01:58:53,760 --> 01:58:55,295
CELLS GROW OUT PROGRESSIVELY

3339
01:58:55,295 --> 01:58:56,196
WITH VERY LITTLE DIFFERENCE

3340
01:58:56,196 --> 01:58:56,963
BETWEEN THE CONTROLS SHOWING THE

3341
01:58:56,963 --> 01:58:57,731
AMOUNT OF KILLING HERE.

3342
01:58:57,731 --> 01:59:00,100
BUT WHEN YOU PUT IN THE IL12

3343
01:59:00,100 --> 01:59:01,801
DOMAIN, IT ACTUALLY TURNS INTO

3344
01:59:01,801 --> 01:59:03,837
AN EXCELLENT KILLER.

3345
01:59:03,837 --> 01:59:05,772
SAY TOE TOXICITY COMPARABLE TO

3346
01:59:05,772 --> 01:59:07,307
OTHER RECEPTORS THAT ARE

3347
01:59:07,307 --> 01:59:07,640
SUCCESSFUL.

3348
01:59:07,640 --> 01:59:09,876
AGAINST THE KRAS EPITOPE, AGAIN,

3349
01:59:09,876 --> 01:59:11,745
THERE WAS REALLY NO CYTOTOXICITY

3350
01:59:11,745 --> 01:59:13,413
OF THE RECEPTOR BY ITSELF, BUT

3351
01:59:13,413 --> 01:59:15,181
WITH THE DEGRON DOMAIN, THERE

3352
01:59:15,181 --> 01:59:16,650
CLEARLY IS CYTOTOXICITY.

3353
01:59:16,650 --> 01:59:19,119
IT WASN'T QUITE AS GOOD AS THIS

3354
01:59:19,119 --> 01:59:20,253
AUTOLOGOUS EFFECTOR CLONE FROM

3355
01:59:20,253 --> 01:59:22,489
THE SAME PATIENT AND FROM THE

3356
01:59:22,489 --> 01:59:25,258
PATIENT WHO PRODUCED THIS CELL

3357
01:59:25,258 --> 01:59:26,993
LINE, BUT IT CLEARLY IS

3358
01:59:26,993 --> 01:59:28,161
CYTOTOXICITY THAT WASN'T PRESENT

3359
01:59:28,161 --> 01:59:28,395
BEFORE.

3360
01:59:28,395 --> 01:59:31,765
SO THIS IS VERY ENCOURAGING THAT

3361
01:59:31,765 --> 01:59:33,433
IT IS AUGMENTING OTHER FUNCTIONS

3362
01:59:33,433 --> 01:59:34,634
BESIDES INTERFERON GAMMA.

3363
01:59:34,634 --> 01:59:35,769
SOME PEOPLE ASK WHY ARE YOU

3364
01:59:35,769 --> 01:59:40,607
TRYING TO RESCUE WEAK TCRs?

3365
01:59:40,607 --> 01:59:42,642
THE ANSWER TO THAT IS STRONG

3366
01:59:42,642 --> 01:59:44,044
ANTITUMOR RESPONSES CAN GENERATE

3367
01:59:44,044 --> 01:59:46,246
PRIMARY RESISTANCE THROUGH TUMOR

3368
01:59:46,246 --> 01:59:47,981
EDITINGMENT SOME OF THESE ESCAPE

3369
01:59:47,981 --> 01:59:50,617
MECHANISMS SUCH AS ANTIPD-1 ARE

3370
01:59:50,617 --> 01:59:51,484
REVERSIBLE.

3371
01:59:51,484 --> 01:59:54,087
IF A T-CELL EXPRESSES PD-1, IT

3372
01:59:54,087 --> 01:59:56,890
CAN BE BLOCKED BY ANTIPD-1, BUT

3373
01:59:56,890 --> 01:59:57,490
OTHERS ARE NOT.

3374
01:59:57,490 --> 01:59:58,925
YOU'VE HEARD A LOT IN THE

3375
01:59:58,925 --> 02:00:00,126
CLASS I SYSTEM FOR LOSS OF THE

3376
02:00:00,126 --> 02:00:01,327
PRESENTING ALLELE FOR THE TUMOR

3377
02:00:01,327 --> 02:00:01,728
ANTIGEN.

3378
02:00:01,728 --> 02:00:06,332
AND FOR CLASS I CELL THERAPY,

3379
02:00:06,332 --> 02:00:07,500
THAT'S THE KISS OF DEATH, THAT

3380
02:00:07,500 --> 02:00:08,635
NO LONGER WORKS.

3381
02:00:08,635 --> 02:00:10,670
SO THAT LED ME TO MY FINAL POINT

3382
02:00:10,670 --> 02:00:12,272
WHICH IS TALKING ABOUT THIS

3383
02:00:12,272 --> 02:00:14,107
SURPRISE ATTACK HYPOTHESIS.

3384
02:00:14,107 --> 02:00:15,208
THIS ORIGINALLY CAME UP BECAUSE

3385
02:00:15,208 --> 02:00:18,144
I WONDERED WHY DO CAR-T CELLS

3386
02:00:18,144 --> 02:00:20,747
AGAINST B CELL AND PLASMA CELL

3387
02:00:20,747 --> 02:00:21,614
MALIGNANCIES WORK SO WELL WITH

3388
02:00:21,614 --> 02:00:23,616
ONLY A FEW MILLION CELLS?

3389
02:00:23,616 --> 02:00:26,319
THAT'S A TYPICAL WHOLE BODY DOSE

3390
02:00:26,319 --> 02:00:29,789
WE GIVE TO PATIENT WITH THOSE

3391
02:00:29,789 --> 02:00:30,924
CARS.

3392
02:00:30,924 --> 02:00:32,025
THAT'S A THOUSAND FOLD FEWER WE

3393
02:00:32,025 --> 02:00:33,993
GIVE WITH TILL USING NORMAL

3394
02:00:33,993 --> 02:00:35,628
T-CELL RECEPTORS AGAINST A SOLID

3395
02:00:35,628 --> 02:00:36,396
TUMOR ANTIGENS.

3396
02:00:36,396 --> 02:00:38,465
AND THE ANSWER I ALWAYS GET WAS,

3397
02:00:38,465 --> 02:00:40,333
WELL, THE CARs ARE TREATING

3398
02:00:40,333 --> 02:00:42,969
LIQUID TUMORS, MORE ACCESSIBLE

3399
02:00:42,969 --> 02:00:45,038
TO T CELLS, OR THAT THE TARGET

3400
02:00:45,038 --> 02:00:46,339
TUMORS ARE HEMATOPOIETIC CANCERS

3401
02:00:46,339 --> 02:00:48,041
AND THEY STIMULATE OR

3402
02:00:48,041 --> 02:00:48,641
CO-STIMULATE T CELLS.

3403
02:00:48,641 --> 02:00:50,176
SO LOOKING AT THAT, THESE ARE --

3404
02:00:50,176 --> 02:00:54,047
THIS IS THE PARADOX.

3405
02:00:54,047 --> 02:00:56,015
THIS IS THE TIL AT THE TOP WHERE

3406
02:00:56,015 --> 02:00:58,384
WE GIVE 30 TO 150 BILLION CELLS,

3407
02:00:58,384 --> 02:00:59,486
WE GET VERY GOOD RESPONSE RATES

3408
02:00:59,486 --> 02:01:00,253
IN MELANOMA.

3409
02:01:00,253 --> 02:01:03,957
IF YOU LOOK AT THE TWO CAR CD19

3410
02:01:03,957 --> 02:01:05,825
AND BCMA, YOU'RE GIVING TWO TO

3411
02:01:05,825 --> 02:01:07,260
THREE LOGS LESS CELLS TO GET

3412
02:01:07,260 --> 02:01:08,161
THOSE RESPONSE RATES.

3413
02:01:08,161 --> 02:01:09,996
AND THE ANSWER WAS ALWAYS, OH,

3414
02:01:09,996 --> 02:01:11,097
JUST A LIQUID TUMOR.

3415
02:01:11,097 --> 02:01:14,734
BUT THEN THERE ARE NOW A COUPLE

3416
02:01:14,734 --> 02:01:17,604
OF CAR THERAPIES AGAINST SOLID

3417
02:01:17,604 --> 02:01:20,874
TUMORS THAT ARE STARTING TO SHOW

3418
02:01:20,874 --> 02:01:21,307
ACTIVITY.

3419
02:01:21,307 --> 02:01:24,144
NOTICE THE CELL DOSES ARE AGAIN

3420
02:01:24,144 --> 02:01:25,445
MICROSCOPIC, 2 TO 3 LOGS LESS,

3421
02:01:25,445 --> 02:01:27,514
AND COMPARABLE TO THE CARS FOR

3422
02:01:27,514 --> 02:01:28,715
LIQUID TUMORS.

3423
02:01:28,715 --> 02:01:31,117
I REMIND YOU ALSO THAT WE HAD A

3424
02:01:31,117 --> 02:01:34,420
T-CELL RECEPTOR AGAINST ANOTHER

3425
02:01:34,420 --> 02:01:37,390
ANTIGEN, CEA, AGAIN SOLID TUMOR,

3426
02:01:37,390 --> 02:01:39,792
CLASSIC T-CELL RECEPTOR, AND

3427
02:01:39,792 --> 02:01:43,730
AGAIN, THE DOSE THAT LED TO THIS

3428
02:01:43,730 --> 02:01:45,165
TUMOR REGRESSION, WE ONLY

3429
02:01:45,165 --> 02:01:45,932
TREATED THREE PATIENTS.

3430
02:01:45,932 --> 02:01:53,039
THIS TUMOR REGRESSION, AN AND

3431
02:01:53,039 --> 02:01:54,374
FEROCIOUS COLITIS, THAT WAS ALSO

3432
02:01:54,374 --> 02:01:57,510
WITH VERY, VERY SMALL NUMBERS OF

3433
02:01:57,510 --> 02:01:57,944
CELLS.

3434
02:01:57,944 --> 02:01:59,479
THEN FINALLY ARE THE THREE

3435
02:01:59,479 --> 02:02:01,781
NEWEST PROTOCOLS LOOKING AT

3436
02:02:01,781 --> 02:02:04,150
THESE OTHER SELF-ANTIGENS IN

3437
02:02:04,150 --> 02:02:04,751
SOLID TUMORS.

3438
02:02:04,751 --> 02:02:06,486
THESE ARE MIXED.

3439
02:02:06,486 --> 02:02:09,055
THESE ARE ANTIGENS THAT HAVE

3440
02:02:09,055 --> 02:02:11,257
SOME ENDOGENOUS IMMUNE RESPONSES

3441
02:02:11,257 --> 02:02:12,058
BUT OFTEN VERY WEAK.

3442
02:02:12,058 --> 02:02:13,726
IF YOU CLONE THEM AND AUGMENT

3443
02:02:13,726 --> 02:02:15,461
THEIR AFFINITY AND GIVE THEM,

3444
02:02:15,461 --> 02:02:19,399
AGAIN, IN SOME CASES, VERY LOW

3445
02:02:19,399 --> 02:02:20,833
NUMBERS OF CELLS GIVEN CAN

3446
02:02:20,833 --> 02:02:22,068
RESULT IN GOOD CLINICAL

3447
02:02:22,068 --> 02:02:22,802
RESPONSES.

3448
02:02:22,802 --> 02:02:26,506
SO THE ATTACK -- AND IF YOU'LL

3449
02:02:26,506 --> 02:02:27,840
NOTICE, THESE ALL REQUIRED

3450
02:02:27,840 --> 02:02:29,142
AFFINITY ENHANCEMENT HERE TO

3451
02:02:29,142 --> 02:02:33,179
CAUSE CLINICAL RESPONSES.

3452
02:02:33,179 --> 02:02:34,948
SO THE ATTACK HYPOTHESIS.

3453
02:02:34,948 --> 02:02:38,218
I SAID STRONG TUMOR NEOANTIGENS

3454
02:02:38,218 --> 02:02:39,419
WILL GENERATE PRIMARY

3455
02:02:39,419 --> 02:02:42,155
RESISTANCE, NONE OF WIS IS

3456
02:02:42,155 --> 02:02:42,522
REVERSIBLE.

3457
02:02:42,522 --> 02:02:43,856
THIS STUDY SHOWS IF YOU LOOK AT

3458
02:02:43,856 --> 02:02:48,261
ALL KRAS MUTATED PATIENTS IN OUR

3459
02:02:48,261 --> 02:02:51,631
DATABASE, YOU INCLUDE HLA A2 --

3460
02:02:51,631 --> 02:02:54,467
IT THE MOST COMMON HLA CLASS I

3461
02:02:54,467 --> 02:02:55,702
ALLELE AND THESE ARE FOUR

3462
02:02:55,702 --> 02:02:57,704
PRESENTING ALLELES THAT DO

3463
02:02:57,704 --> 02:02:59,105
PRESENT KRAS MUTATED EPITOPES.

3464
02:02:59,105 --> 02:03:03,977
IF YOU LACK AT THE G12D ONE,

3465
02:03:03,977 --> 02:03:05,411
THIS IS A NUMBER OF TUMORS IN

3466
02:03:05,411 --> 02:03:07,146
RED THAT HAVE LOST THEIR

3467
02:03:07,146 --> 02:03:07,547
PRESENTING ALLELE.

3468
02:03:07,547 --> 02:03:09,482
YOU CAN SEE THAT IN SOME CASES,

3469
02:03:09,482 --> 02:03:10,483
NONE OF THEM LOST IT.

3470
02:03:10,483 --> 02:03:12,518
BUT IN OTHER CASES, THERE IS

3471
02:03:12,518 --> 02:03:13,052
GROWING LOSS.

3472
02:03:13,052 --> 02:03:16,456
THIS IS THE G12V EPITOPE.

3473
02:03:16,456 --> 02:03:18,524
YOU SHOULD KNOW THAT THAT IS THE

3474
02:03:18,524 --> 02:03:19,993
MOST IMMUNOGENIC KRAS EPITOPE.

3475
02:03:19,993 --> 02:03:23,363
WHEN WE WERE VACCINATING OUR

3476
02:03:23,363 --> 02:03:24,230
MICE, THAT WAS OUR POSITIVE

3477
02:03:24,230 --> 02:03:25,365
CONTROL FOR VACCINATION, BECAUSE

3478
02:03:25,365 --> 02:03:29,502
WE ALWAYS GENERATED A GOOD G12V

3479
02:03:29,502 --> 02:03:32,905
ANTIEPITOPE RESPONSE.

3480
02:03:32,905 --> 02:03:34,407
SO IF YOU LOOK AT THAT, THE MOST

3481
02:03:34,407 --> 02:03:36,709
POTENT PRESENTER WITH THE MOST

3482
02:03:36,709 --> 02:03:43,683
ABUNDANT PEPTIDE PRESENTATION

3483
02:03:43,683 --> 02:03:44,851
WAS THE A11 EPITOPE.

3484
02:03:44,851 --> 02:03:47,387
YOU CAN SEE HERE THAT A11 HERE,

3485
02:03:47,387 --> 02:03:48,721
HALF OF THE PATIENTS THAT HAVE

3486
02:03:48,721 --> 02:03:50,790
THIS COMBINATION OF THIS HIGHLY

3487
02:03:50,790 --> 02:03:53,092
IMMUNOGENIC EPITOPE AND THE

3488
02:03:53,092 --> 02:03:57,897
MOST -- AND THE BEST PRESENTING

3489
02:03:57,897 --> 02:03:59,532
ALLELE HAVE CLASS I LOSS OF A11.

3490
02:03:59,532 --> 02:04:00,933
I ALSO SHOW YOU AT THE TOP WITH

3491
02:04:00,933 --> 02:04:04,037
THE ASTERISK, THESE ARE THE

3492
02:04:04,037 --> 02:04:05,438
EPITOPES AND HLA COMBINATIONS

3493
02:04:05,438 --> 02:04:07,173
FOR WHICH WE HAVE HUMAN TCRs

3494
02:04:07,173 --> 02:04:08,374
BECAUSE WE FOUND THAT REACTIVITY

3495
02:04:08,374 --> 02:04:09,809
IN TIL.

3496
02:04:09,809 --> 02:04:11,311
YOU CAN SEE THOSE ARE THE FOUR

3497
02:04:11,311 --> 02:04:15,181
WITH THE GREATEST CLASS I LOSS.

3498
02:04:15,181 --> 02:04:18,217
SO THIS IS A CLASS I SELECTION

3499
02:04:18,217 --> 02:04:21,621
PROBLEM THAT IS NOT REVERSIBLE.

3500
02:04:21,621 --> 02:04:23,656
SO THE ATTACK HYPOTHESIS STARTS

3501
02:04:23,656 --> 02:04:26,426
WITH THAT, AND THAT CARS AND

3502
02:04:26,426 --> 02:04:28,828
SOME TCRs AGAINST NORMAL SELF

3503
02:04:28,828 --> 02:04:30,296
ANTIGENS HAVE BEEN EFFECTIVE AT

3504
02:04:30,296 --> 02:04:31,798
LOW CELL DOSES BECAUSE THOSE

3505
02:04:31,798 --> 02:04:33,633
ATTACK TARGETS HAVE NEVER

3506
02:04:33,633 --> 02:04:34,300
ENCOUNTERED IMMUNE ATTACK

3507
02:04:34,300 --> 02:04:34,834
BEFORE.

3508
02:04:34,834 --> 02:04:38,905
THE P CELLS HA HAVE NOT BEEN

3509
02:04:38,905 --> 02:04:40,873
ATTACKED BECAUSE OF CD4 EVER IN

3510
02:04:40,873 --> 02:04:44,243
THEIR LIFE AND WEAK -- HAVE THIS

3511
02:04:44,243 --> 02:04:45,345
ADVANTAGE AS WELL BUT THEY CAN

3512
02:04:45,345 --> 02:04:47,447
BE MADE CLINICALLY EFFECTIVE

3513
02:04:47,447 --> 02:04:49,716
WITH PCR ENHANCEMENT.

3514
02:04:49,716 --> 02:04:51,818
ALBEIT WITH POTENTIAL HAZARD.

3515
02:04:51,818 --> 02:04:56,055
SO -- TO TRY AND ENHANCE THEIR

3516
02:04:56,055 --> 02:04:57,724
REACTIVITY BY -- DISPLAY,

3517
02:04:57,724 --> 02:04:58,591
PROTEIN PREDICTION STRUCTURAL

3518
02:04:58,591 --> 02:05:01,861
STUDIES, THEN TO PRODUCE THIS

3519
02:05:01,861 --> 02:05:05,031
ARRAY WITH THE MEMBRANE IL12

3520
02:05:05,031 --> 02:05:06,799
DEGRON CONSTRUCT AND IF THEY

3521
02:05:06,799 --> 02:05:09,769
SHOW ACTIVITY IN XENOGRAPH

3522
02:05:09,769 --> 02:05:11,270
MODELS AND DO NOT SHOW OFF

3523
02:05:11,270 --> 02:05:13,573
TARGET CROSS REACTIVITY, THEN WE

3524
02:05:13,573 --> 02:05:14,574
WOULD PROCEED TO CLINICAL TRIALS

3525
02:05:14,574 --> 02:05:15,141
WITH THOSE.

3526
02:05:15,141 --> 02:05:16,109
AND THESE ARE THE PEOPLE

3527
02:05:16,109 --> 02:05:16,376
INVOLVED.

3528
02:05:16,376 --> 02:05:16,876
THANK YOU.

3529
02:05:16,876 --> 02:05:27,053
[APPLAUSE]

3530
02:05:29,088 --> 02:05:32,925
>> THANKS, JIM.

3531
02:05:32,925 --> 02:05:36,863
OUR NEXT SPEAKER IS DR. ALENA

3532
02:05:36,863 --> 02:05:38,631
GROS FROM THE VAIL D'HEBON

3533
02:05:38,631 --> 02:05:40,466
INSTITUTE OF ONCOLOGY IN

3534
02:05:40,466 --> 02:05:45,838
BARCELONA, ALSO FORMER FELLOW.

3535
02:05:45,838 --> 02:05:47,140
>> GOOD MORNING, EVERYONE.

3536
02:05:47,140 --> 02:05:48,241
I'M THRILLED TO BE HERE.

3537
02:05:48,241 --> 02:05:49,675
THERE ARE TWO WORDS THAT REMIND

3538
02:05:49,675 --> 02:05:51,511
ME OF STEVEN ROSENBERG AND

3539
02:05:51,511 --> 02:05:54,580
AUTOMATICALLY MAKE ME SMILE.

3540
02:05:54,580 --> 02:05:56,449
LASER FOCUS.

3541
02:05:56,449 --> 02:05:58,551
HE'S REALLY, REALLY ABLE TO

3542
02:05:58,551 --> 02:06:00,620
FOCUS ON HIS SCIENTIFIC GOALS

3543
02:06:00,620 --> 02:06:05,658
WITH AN INTENSITY UNLIKE

3544
02:06:05,658 --> 02:06:06,959
ANYTHING I'VE SEEN, AND I THINK

3545
02:06:06,959 --> 02:06:08,861
IT'S PROBABLY ONE OF HIS SECRET

3546
02:06:08,861 --> 02:06:09,962
WEAPONS TO HIS SUCCESSFUL

3547
02:06:09,962 --> 02:06:10,563
CAREER.

3548
02:06:10,563 --> 02:06:11,464
I REMEMBER MEETING WITH HIM AND

3549
02:06:11,464 --> 02:06:13,199
SHOWING HIM SOME DATA AND HIM

3550
02:06:13,199 --> 02:06:15,401
SMILING AT ME WITH HIS BLUE EYES

3551
02:06:15,401 --> 02:06:17,670
AND SAYING, ALENA, I NEED TO

3552
02:06:17,670 --> 02:06:18,438
LASER-FOCUS ON THIS.

3553
02:06:18,438 --> 02:06:21,174
NOW MANY YEARS AFTER THAT, I

3554
02:06:21,174 --> 02:06:23,276
TELL THIS TO MYSELF PRETTY

3555
02:06:23,276 --> 02:06:27,780
FROACTLY, I MUST FREQUENTLY, I .

3556
02:06:27,780 --> 02:06:29,282
I'M THRILLED TO BE HERE AND I

3557
02:06:29,282 --> 02:06:32,552
CAN'T IMAGINE A BETTER WAY OF

3558
02:06:32,552 --> 02:06:33,553
CELEBRATING YOUR CAREER THAN

3559
02:06:33,553 --> 02:06:36,956
SHOWING YOU SOME DATA GENERATED

3560
02:06:36,956 --> 02:06:39,325
IN MY LAB, SO I'LL BE TALKING

3561
02:06:39,325 --> 02:06:43,529
ABOUT THE POSSIBILITY OF EXPL 

3562
02:06:43,529 --> 02:06:45,264
EXPLORING THE IMMUNOGENICITY OF

3563
02:06:45,264 --> 02:06:48,234
NOVEL SOURCES OR TUMOR ANTIGENS.

3564
02:06:48,234 --> 02:06:49,202
UNDERSTANDING WHAT TUMOR

3565
02:06:49,202 --> 02:06:51,170
ANTIGENS ARE LISTED ANTITUMOR

3566
02:06:51,170 --> 02:06:54,440
T-CELL RESPONSES IS CENTRAL TO

3567
02:06:54,440 --> 02:06:56,442
CANCER I KNEW KNOW THERAPY

3568
02:06:56,442 --> 02:06:57,944
BECAUSE MAINLY UNDERSTANDING

3569
02:06:57,944 --> 02:06:59,745
WHICH WILL ENABLE AND HAS

3570
02:06:59,745 --> 02:07:01,113
ENABLED THE DEVELOPMENT OF MORE

3571
02:07:01,113 --> 02:07:02,548
SAFE AND EFFECTIVE T-CELL

3572
02:07:02,548 --> 02:07:05,051
THERAPIES ON VACCINES BUT ALSO

3573
02:07:05,051 --> 02:07:06,919
TO UNDERSTAND AND PERSONALIZE

3574
02:07:06,919 --> 02:07:08,354
IMMUNE CHECKPOINT INHIBITOR

3575
02:07:08,354 --> 02:07:09,555
THERAPIES AND OTHER

3576
02:07:09,555 --> 02:07:15,495
IMMUNOTHERAPIES.

3577
02:07:15,495 --> 02:07:16,429
CERTAINLY NEOANTIGENS HAVE

3578
02:07:16,429 --> 02:07:20,333
EMERGED AS POTENT TARGETS FOR

3579
02:07:20,333 --> 02:07:22,268
CANCER IMMUNOTHERAPY, AND WE'VE

3580
02:07:22,268 --> 02:07:23,402
HEARD FROM PAUL ROBBINS SOME OF

3581
02:07:23,402 --> 02:07:24,737
THE BENEFITS OF TARGETING THESE.

3582
02:07:24,737 --> 02:07:26,839
THESE ARE MORE SAFE BECAUSE

3583
02:07:26,839 --> 02:07:28,040
THEY'RE EXQUISITELY

3584
02:07:28,040 --> 02:07:28,708
TUMOR-SPECIFIC AND THEY'RE NOT

3585
02:07:28,708 --> 02:07:30,142
SUBJECT TO CENTRAL TOLERANCE.

3586
02:07:30,142 --> 02:07:32,745
THERE IS REPRODUCIBLE DATA

3587
02:07:32,745 --> 02:07:35,915
SHOWING THAT THERE'S A

3588
02:07:35,915 --> 02:07:36,349
CORRELATION BETWEEN

3589
02:07:36,349 --> 02:07:37,250
ADMINISTERING HIGHER FREQUENCY

3590
02:07:37,250 --> 02:07:40,520
OF NEOANTIGEN REACTIVE TIL AND

3591
02:07:40,520 --> 02:07:44,357
HAVING A MORE LIKELY BETTER

3592
02:07:44,357 --> 02:07:46,025
RESPONSE TO TIL THERAPY AND ALSO

3593
02:07:46,025 --> 02:07:47,960
MORE LIKELY RESPONSE TO IMMUNE

3594
02:07:47,960 --> 02:07:49,295
CHECKPOINT BLOCKADE.

3595
02:07:49,295 --> 02:07:50,963
IMPORTANTLY, A VAST MAJORITY OF

3596
02:07:50,963 --> 02:07:52,698
PATIENTS WILL PRESENT

3597
02:07:52,698 --> 02:07:53,799
NEOANTIGEN-SPECIFIC TIL SO BY

3598
02:07:53,799 --> 02:07:55,334
TARGETING THESE NEOANTIGENS,

3599
02:07:55,334 --> 02:07:57,303
WHAT COULD POTENTIALLY GENERATE

3600
02:07:57,303 --> 02:07:59,505
A THERAPY TARGETING A BROAD

3601
02:07:59,505 --> 02:08:01,140
PATIENT POPULATION, AND THERE IS

3602
02:08:01,140 --> 02:08:05,545
INCREASING AMOUNT OF EVIDENCE OF

3603
02:08:05,545 --> 02:08:07,346
NEED OWE ANTIGEN SPECIFIC TO

3604
02:08:07,346 --> 02:08:09,148
INDUCING ANTITUMOR RESPONSES IN

3605
02:08:09,148 --> 02:08:09,682
SELECTED CANCER PATIENTS.

3606
02:08:09,682 --> 02:08:12,084
AND MANY OF THESE, MUCH OF THIS

3607
02:08:12,084 --> 02:08:13,386
WORK WAS BEING DONE IN THE

3608
02:08:13,386 --> 02:08:17,423
SURGERY BRANCH WHILE HE WAS A

3609
02:08:17,423 --> 02:08:19,859
POSTDOC.

3610
02:08:19,859 --> 02:08:21,527
SO WHEN I WENT BACK TO BARCELONA

3611
02:08:21,527 --> 02:08:23,195
TO START MY GROUP I DECIDED FOR

3612
02:08:23,195 --> 02:08:27,600
ONE OF MY MAIN FOCUSES TO START

3613
02:08:27,600 --> 02:08:30,369
A CLINICAL TRIAL WITH NEOANTIGEN

3614
02:08:30,369 --> 02:08:31,604
SELECTED TIL VERY MUCH INSPIRED

3615
02:08:31,604 --> 02:08:32,972
BY THE WORK I SAW HERE IN THE

3616
02:08:32,972 --> 02:08:33,639
SURGERY BRANCH.

3617
02:08:33,639 --> 02:08:38,110
SO ON ONE SIDE, WHAT WE DO, WE

3618
02:08:38,110 --> 02:08:39,378
RECENTLY STARTED THIS CLINICAL

3619
02:08:39,378 --> 02:08:49,922
TRIAL AND ON ONE SIDE, WE EXPAND

3620
02:08:50,222 --> 02:08:51,824
THE TIL FROM FRAGMENTS, WE THEN

3621
02:08:51,824 --> 02:08:54,427
SEQUENCE THE TUMOR, IDENTIFY

3622
02:08:54,427 --> 02:08:55,628
CANDIDATE MUTATIONS, WE EITHER

3623
02:08:55,628 --> 02:08:57,363
CLONE THESE IN THE FORM OF

3624
02:08:57,363 --> 02:09:00,132
TANDEM MINI GENES OR WE SIPT

3625
02:09:00,132 --> 02:09:02,735
SIZE LONG PEPTIDES AND WE USE

3626
02:09:02,735 --> 02:09:05,805
EITHER THESE RNA ENCODING FOR

3627
02:09:05,805 --> 02:09:07,006
TANDEM GENES OR PEPTIDES TO

3628
02:09:07,006 --> 02:09:09,675
PULSE OR EXPRESS THESE CANDIDATE

3629
02:09:09,675 --> 02:09:12,378
NEOANTIGENS IN AUTOLOGOUS

3630
02:09:12,378 --> 02:09:14,914
PRESENTING CELLS WHICH ARE USED

3631
02:09:14,914 --> 02:09:16,515
AS TARGETS, AND IF AND WHEN WE

3632
02:09:16,515 --> 02:09:18,584
FIND THESE NEOANTIGEN REACTIVE

3633
02:09:18,584 --> 02:09:19,619
TIL, WE SELECT THE TIL

3634
02:09:19,619 --> 02:09:21,053
CONTAINING THE REACTIVITY AND

3635
02:09:21,053 --> 02:09:22,121
FURTHER EXPAND FOR PATIENT

3636
02:09:22,121 --> 02:09:23,556
TREATMENT.

3637
02:09:23,556 --> 02:09:27,593
NOW IT BEEN  A VERY STEEP

3638
02:09:27,593 --> 02:09:28,494
LEARNING CURVE, I'M NOT A

3639
02:09:28,494 --> 02:09:29,695
CLINICIAN AND THERE STILL IS

3640
02:09:29,695 --> 02:09:31,230
SOME CHALLENGES BUT I'M REALLY

3641
02:09:31,230 --> 02:09:35,301
EXCITED TO SEE THIS HAPPENING IN

3642
02:09:35,301 --> 02:09:35,568
BARCELONA.

3643
02:09:35,568 --> 02:09:36,936
THANKS FOR THE ENORMOUS TEAM OF

3644
02:09:36,936 --> 02:09:40,406
PEOPLE AND A LOT OF

3645
02:09:40,406 --> 02:09:42,842
COLLABORATIONS.

3646
02:09:42,842 --> 02:09:45,344
NA TO THESE SELECTED TIL, WE'RE

3647
02:09:45,344 --> 02:09:47,246
ALSO EXPLORING THE USE OF

3648
02:09:47,246 --> 02:09:49,181
NON-SELECTED TIL AND T CELLS

3649
02:09:49,181 --> 02:09:50,282
FROM PERIPHERAL BLOOD.

3650
02:09:50,282 --> 02:09:51,283
BUT TODAY I'M REALLY EXCITED TO

3651
02:09:51,283 --> 02:09:52,985
TELL BUT SLIGHTLY MORE BASIC

3652
02:09:52,985 --> 02:09:57,490
QUESTION THAT WE'RE TRYING TO

3653
02:09:57,490 --> 02:09:58,124
ADDRESS.

3654
02:09:58,124 --> 02:09:58,924
WE HAVE ESTABLISHED SEVERAL

3655
02:09:58,924 --> 02:10:03,629
METHODS THAT WE USE, THEY'RE

3656
02:10:03,629 --> 02:10:04,697
COMPLIMENTARY APPROACHES WE USE

3657
02:10:04,697 --> 02:10:06,065
IN PARALLEL TO INVESTIGATE THE

3658
02:10:06,065 --> 02:10:07,233
SPECIFIC TUMOR ANTIGENS THAT ARE

3659
02:10:07,233 --> 02:10:08,300
TARGETED BY TIL.

3660
02:10:08,300 --> 02:10:14,473
WE ROUTINELY GET TUMOR AND

3661
02:10:14,473 --> 02:10:15,441
MATCHED PERIPHERAL BLOOD WITH

3662
02:10:15,441 --> 02:10:16,175
PATIENTS, DIFFERENT CANCER

3663
02:10:16,175 --> 02:10:17,843
TYPES, AND WE ATTEMPT TO

3664
02:10:17,843 --> 02:10:19,679
GENERATE AN AUTOLOGOUS TUMOR

3665
02:10:19,679 --> 02:10:24,650
CELL LINE OR AN ORGANOID, AND IN

3666
02:10:24,650 --> 02:10:27,053
PARALLEL WE EXPAND TILES BUT WE

3667
02:10:27,053 --> 02:10:29,088
ALSO ISOLATE A SPECIFIC -- WHICH

3668
02:10:29,088 --> 02:10:30,656
WE KNOW ARE ENRICHED IN TUMOR

3669
02:10:30,656 --> 02:10:30,990
REACTIVITY.

3670
02:10:30,990 --> 02:10:34,493
IN ORDER TO IDENTIFY WHAT THESE

3671
02:10:34,493 --> 02:10:35,661
TIL RECOGNIZE, WE OF COURSE WANT

3672
02:10:35,661 --> 02:10:38,831
TO INCLUDE THE NEOANTIGENS AND

3673
02:10:38,831 --> 02:10:40,533
CANDIDATE ANTIGENS SO WE PERFORM

3674
02:10:40,533 --> 02:10:44,904
NORMAL DNA BUT ALSO TUMOR DNA

3675
02:10:44,904 --> 02:10:48,107
SEQUENCING TO IDENTIFY THESE

3676
02:10:48,107 --> 02:10:49,175
MUTATIONS, WE USE THIS

3677
02:10:49,175 --> 02:10:50,276
PERSONALIZED SCREENING APPROACH

3678
02:10:50,276 --> 02:10:51,377
WHICH I ALLUDED TO IN THE

3679
02:10:51,377 --> 02:10:52,378
PREVIOUS SLIDE, BUT IN ADDITION

3680
02:10:52,378 --> 02:10:55,881
TO INCLUDING THE NEOANTIGENS, WE

3681
02:10:55,881 --> 02:10:57,516
FREQUENTLY ALSO CLONE CANCER

3682
02:10:57,516 --> 02:10:59,952
GERMLINE ANTIGENS WHICH WE FIND

3683
02:10:59,952 --> 02:11:00,986
ARE EXPRESSED AT RNA LEVEL IN

3684
02:11:00,986 --> 02:11:04,090
THE TUMOR BIOPSIES BUT ALSO

3685
02:11:04,090 --> 02:11:05,024
TISSUE DIFFERENTIATION ANTIGEN

3686
02:11:05,024 --> 02:11:06,726
SO WE'RE NOT LIMITING OURSELVES

3687
02:11:06,726 --> 02:11:08,794
TO NEOANTIGENS ONLY IN THIS MORE

3688
02:11:08,794 --> 02:11:09,595
EXPLORATORY WORK.

3689
02:11:09,595 --> 02:11:11,130
WE FREQUENTLY USE HL.

3690
02:11:11,130 --> 02:11:13,099
A BINDING PREDICTION

3691
02:11:13,099 --> 02:11:14,734
SPECIFICALLY WHEN PATIENTS HAVE

3692
02:11:14,734 --> 02:11:18,437
A VERY LARGE NUMBER OF SOMATIC

3693
02:11:18,437 --> 02:11:19,505
MUTATIONS AND WE HAVE ALSO

3694
02:11:19,505 --> 02:11:21,540
ESTABLISHED OUR OWN

3695
02:11:21,540 --> 02:11:23,075
IMMUNOPEPTIDE OMICS PLATFORM

3696
02:11:23,075 --> 02:11:28,047
WHICH ENABLES US TO I MAW KNOW

3697
02:11:28,047 --> 02:11:29,448
PRECIPITATE THE -- ON CANCER

3698
02:11:29,448 --> 02:11:30,783
CELL LINES THAT WE GENERATE, AND

3699
02:11:30,783 --> 02:11:32,318
TO IDENTIFY THE SPECIFIC

3700
02:11:32,318 --> 02:11:33,853
PEPTIDES EITHER CONTAINING

3701
02:11:33,853 --> 02:11:35,621
MUTATIONS OR DERIVED FROM CANCER

3702
02:11:35,621 --> 02:11:37,723
GERMLINE ANTIGENS OR TISSUE

3703
02:11:37,723 --> 02:11:38,624
DIFFERENTIATION ANTIGENS.

3704
02:11:38,624 --> 02:11:40,426
SO THESE APPROACHES ARE

3705
02:11:40,426 --> 02:11:42,728
COMPLEMENTARY.

3706
02:11:42,728 --> 02:11:45,898
AND WE USE THEM ALL IN PARALLEL.

3707
02:11:45,898 --> 02:11:48,334
WE EITHER -- RNA ENCODING FOR

3708
02:11:48,334 --> 02:11:53,472
THESE OR WE SYNTHESIZE THE

3709
02:11:53,472 --> 02:11:57,743
PEPTIDES, FINALLY, TO SCREEN AND

3710
02:11:57,743 --> 02:11:59,945
TEST WHETHER THESE TILES THAT

3711
02:11:59,945 --> 02:12:02,948
WERE EXPANDED OR T CELLS FROM

3712
02:12:02,948 --> 02:12:04,550
BLOOD THAT CAN RECOGNIZE ANY OF

3713
02:12:04,550 --> 02:12:04,984
THESE ANTIGENS.

3714
02:12:04,984 --> 02:12:06,485
I'M GOING TO SHOW YOU DATA FROM

3715
02:12:06,485 --> 02:12:08,587
THREE PATIENTS WE SCREENED USING

3716
02:12:08,587 --> 02:12:09,822
THESE THREE PARALLEL APPROACHES.

3717
02:12:09,822 --> 02:12:14,426
THIS IS THE REACTIVITY TO THE

3718
02:12:14,426 --> 02:12:15,628
AUTOLOGOUS CELL LINE OF SEVERAL

3719
02:12:15,628 --> 02:12:18,798
TIL THAT WERE EXPANDED FROM A

3720
02:12:18,798 --> 02:12:22,968
METASTATIC MELANOMA PATIENT.

3721
02:12:22,968 --> 02:12:24,370
WE CAN SEE THERE'S VARIABLE

3722
02:12:24,370 --> 02:12:25,805
FREQUENCY OF TUMOR RECOGNITION

3723
02:12:25,805 --> 02:12:27,439
BASED ON 41BB EXPRESSION AND

3724
02:12:27,439 --> 02:12:29,308
THIS IS ONLY LIMITED TO

3725
02:12:29,308 --> 02:12:33,145
CD8 RESPONSES FOR THE MOMENT.

3726
02:12:33,145 --> 02:12:34,613
SO WE TOOK THESE TILES AND

3727
02:12:34,613 --> 02:12:37,983
SCREENED FOR ALL THESE

3728
02:12:37,983 --> 02:12:40,419
NEOANTIGENS AND ALSO

3729
02:12:40,419 --> 02:12:40,920
TUMOR-ASSOCIATED ANTIGEN

3730
02:12:40,920 --> 02:12:41,220
RECOGNITION.

3731
02:12:41,220 --> 02:12:45,191
WHAT WE FOUND IS THAT WE COULD

3732
02:12:45,191 --> 02:12:46,458
EXPLAIN, FOR EXAMPLE, A VERY

3733
02:12:46,458 --> 02:12:48,527
DOMINANT T-CELL RESPONSE WAS

3734
02:12:48,527 --> 02:12:50,729
PRESENCE IN THIS TIL FRAGMENT

3735
02:12:50,729 --> 02:12:51,096
THREE.

3736
02:12:51,096 --> 02:12:53,866
ALSO SOME NEOANTIGEN REACTIVITY

3737
02:12:53,866 --> 02:12:56,468
IN TIL 5 AND NOT VERY DOMINANT.

3738
02:12:56,468 --> 02:13:01,841
AND A FAIRLY DOMINANT POPULATION

3739
02:13:01,841 --> 02:13:02,374
TARGETING -- 5.

3740
02:13:02,374 --> 02:13:03,809
BUT WHAT WE ALSO OBSERVED, IN

3741
02:13:03,809 --> 02:13:05,578
FACT, IS THAT MANY OF THESE

3742
02:13:05,578 --> 02:13:06,679
TILs, DESPITE ALL THIS

3743
02:13:06,679 --> 02:13:07,646
EXTENSIVE SCREENING, WE STILL

3744
02:13:07,646 --> 02:13:09,348
DIDN'T KNOW WHAT TUMOR ANTIGENS

3745
02:13:09,348 --> 02:13:10,082
THEY RECOGNIZE.

3746
02:13:10,082 --> 02:13:13,152
THEY CLEARLY RECOGNIZED THE

3747
02:13:13,152 --> 02:13:15,988
CANCER CELLS, NOT NON-MATCHED

3748
02:13:15,988 --> 02:13:16,989
MELANOMA CELL LINES, BUT WE

3749
02:13:16,989 --> 02:13:17,957
COULDN'T STILL KNOW WHAT THEY

3750
02:13:17,957 --> 02:13:21,794
WERE RECOGNIZING.

3751
02:13:21,794 --> 02:13:23,796
AND THIS HAS BEEN THE

3752
02:13:23,796 --> 02:13:24,697
OBSERVATION OVER MANY PATIENTS.

3753
02:13:24,697 --> 02:13:26,432
SO THESE ARE TWO OTHER PATIENTS

3754
02:13:26,432 --> 02:13:27,633
WITH HEAD AND NECK CANCER.

3755
02:13:27,633 --> 02:13:29,501
HE WITH EXPANDED TIL, MANY OF

3756
02:13:29,501 --> 02:13:30,836
THEM CAN RECOGNIZE TUMOR TO A

3757
02:13:30,836 --> 02:13:31,604
DIFFERENT EXTENT.

3758
02:13:31,604 --> 02:13:33,339
WE SCREEN FOR NEOANTIGEN

3759
02:13:33,339 --> 02:13:33,906
RECOGNITION.

3760
02:13:33,906 --> 02:13:35,274
WE CAN CERTAINLY FIND THESE.

3761
02:13:35,274 --> 02:13:36,976
THIS IS WHAT MAKES IT ROW U.P.S.

3762
02:13:36,976 --> 02:13:38,711
AND WE CAN NOW POTENTIALLY

3763
02:13:38,711 --> 02:13:40,246
EXPLORE THIS TOOL TO TREAT

3764
02:13:40,246 --> 02:13:41,046
PATIENTS.

3765
02:13:41,046 --> 02:13:43,649
HOWEVER, AGAIN, MANY OF THESE

3766
02:13:43,649 --> 02:13:45,084
TIL RECOGNIZE CANCER AS WE STILL

3767
02:13:45,084 --> 02:13:47,519
DON'T KNOW WHAT THEY RECOGNIZE.

3768
02:13:47,519 --> 02:13:48,654
SO THIS BRINGS US BACK TO THE

3769
02:13:48,654 --> 02:13:50,990
QUESTION, WHAT ADDITIONAL

3770
02:13:50,990 --> 02:13:57,897
ANTIGENS CAN' LIS CAN ELICIT REN

3771
02:13:57,897 --> 02:13:59,098
CANCER PATIENTS?

3772
02:13:59,098 --> 02:14:01,934
WHEN WE MADE THIS O OBSERVATION

3773
02:14:01,934 --> 02:14:03,302
THERE WERE A GROWING NUMBER OF

3774
02:14:03,302 --> 02:14:05,471
ARTICLES POINTING TOWARDS

3775
02:14:05,471 --> 02:14:08,540
NON-CANONICAL ANTIGENS, ALSO

3776
02:14:08,540 --> 02:14:11,410
KNOWN AS CRYPTIC ANTIGENS OR

3777
02:14:11,410 --> 02:14:12,378
ANTIGENS DERIVED FROM DARK

3778
02:14:12,378 --> 02:14:12,945
MATTER.

3779
02:14:12,945 --> 02:14:16,682
THE FACT IS THAT MOST OF THE

3780
02:14:16,682 --> 02:14:18,417
CURRENT EFFORTS OF TUMOR ANTIGEN

3781
02:14:18,417 --> 02:14:22,288
DISCOVERY FOCUS ON TESTING THE

3782
02:14:22,288 --> 02:14:23,555
IMMUNOGENICITY OF ANNOTATED

3783
02:14:23,555 --> 02:14:25,524
PROTEINS WHICH REPRESENT

3784
02:14:25,524 --> 02:14:27,293
APPROXIMATELY 2% OF THE ENTIRE

3785
02:14:27,293 --> 02:14:28,127
GENOME.

3786
02:14:28,127 --> 02:14:31,163
HOWEVER, IT IS NOW KNOWN THAT

3787
02:14:31,163 --> 02:14:33,465
UNDER CERTAIN CIRCUMSTANCES, UP

3788
02:14:33,465 --> 02:14:35,534
TO 75% OF THE GENOME CAN BE

3789
02:14:35,534 --> 02:14:37,102
TRANSCRIBED AND POTENTIALLY

3790
02:14:37,102 --> 02:14:38,737
TRANSLATED.

3791
02:14:38,737 --> 02:14:42,975
AND THERE IS EVIDENCE OF SOME

3792
02:14:42,975 --> 02:14:44,543
LITERATURE OF T-CELL RESPONSES

3793
02:14:44,543 --> 02:14:45,844
TARGETING DIFFERENT TYPES OF

3794
02:14:45,844 --> 02:14:47,146
EPITOPES DERIVED FROM DARK

3795
02:14:47,146 --> 02:14:49,548
MATTER SUCH AS TRANSPOSABLE

3796
02:14:49,548 --> 02:14:52,017
ELEMENTS, ALTERNATIVE RNA

3797
02:14:52,017 --> 02:14:54,153
SPLICING, RNA TRANSLATION AND

3798
02:14:54,153 --> 02:14:54,820
PEPTIDE SPLICING.

3799
02:14:54,820 --> 02:14:57,022
MUCH OF THIS EVIDENCE WAS

3800
02:14:57,022 --> 02:14:59,024
GENERATED IN THE 1990s, USING

3801
02:14:59,024 --> 02:15:01,093
THE CDNA TUMOR LIBRARIES.

3802
02:15:01,093 --> 02:15:03,062
BUT THERE WAS EMERGING DATA

3803
02:15:03,062 --> 02:15:05,497
SUPPORTING THAT HLA ANALYSIS

3804
02:15:05,497 --> 02:15:07,700
COULD LEAD TO THE MORE

3805
02:15:07,700 --> 02:15:08,600
SYSTEMATIC IDENTIFICATION OF

3806
02:15:08,600 --> 02:15:11,737
THESE CRYPTIC EPITOPES IN A MORE

3807
02:15:11,737 --> 02:15:13,072
OR LESS PERSONALIZED FASHION

3808
02:15:13,072 --> 02:15:14,573
EITHER USING BIOPSIES OR CANCER

3809
02:15:14,573 --> 02:15:18,811
CELL LINES.

3810
02:15:18,811 --> 02:15:21,580
SO WE REASONED THAT IF ABERRANT

3811
02:15:21,580 --> 02:15:24,316
TRANSLATION HAPPENS EXCLUSIVELY

3812
02:15:24,316 --> 02:15:25,050
IN CANCER CELLS, THIS COULD LEAD

3813
02:15:25,050 --> 02:15:26,418
TO THE PRESENTATION OF

3814
02:15:26,418 --> 02:15:27,786
IMMUNOGENIC PEPTIDES THAT COULD

3815
02:15:27,786 --> 02:15:28,921
POTENTIALLY EXPAND THE LANDSCAPE

3816
02:15:28,921 --> 02:15:30,889
OF TARGETABLE ANTIGENS FOR

3817
02:15:30,889 --> 02:15:31,757
CANCER IMMUNOTHERAPY.

3818
02:15:31,757 --> 02:15:39,264
AND THIS BECAME THE QUESTION OF

3819
02:15:39,264 --> 02:15:41,200
A VERY TALENTED GRADUATE STUDENT

3820
02:15:41,200 --> 02:15:43,168
THAT I HAD IN MY LAB, SHE'S NOW

3821
02:15:43,168 --> 02:15:47,006
A POSTDOC, AND SO WHAT SHE DID

3822
02:15:47,006 --> 02:15:50,542
IS SHE PERFORMED IMMUNOPEPTIDE

3823
02:15:50,542 --> 02:15:52,011
OMICS OF CELL LINES OF DIFFERENT

3824
02:15:52,011 --> 02:15:52,244
ORIGIN.

3825
02:15:52,244 --> 02:15:56,749
I WILL EXPLAIN LATER THE ORIGIN.

3826
02:15:56,749 --> 02:15:59,752
FOLLOWING THIS AND IN

3827
02:15:59,752 --> 02:16:02,721
COLLABORATION, WE DECIDED TO USE

3828
02:16:02,721 --> 02:16:06,392
HIS PIPELINE PEPTIDE PRISSMM,

3829
02:16:06,392 --> 02:16:08,527
IT'S A PROTEOGENOMICS PIPELINE

3830
02:16:08,527 --> 02:16:13,399
WHICH ENABLE US ON ONE HAND TO

3831
02:16:13,399 --> 02:16:14,533
IDENTIFY PEPTIDES THAT MAP TO

3832
02:16:14,533 --> 02:16:16,368
THE ANNOTATED PROTEINS IN THE

3833
02:16:16,368 --> 02:16:19,571
GENOME, BUT IT CAN ALSO MAP

3834
02:16:19,571 --> 02:16:22,541
PEPTIDES TO THE THREE FRAME

3835
02:16:22,541 --> 02:16:23,642
TRANSCRIPTOME, SIX FRAME GENOME,

3836
02:16:23,642 --> 02:16:26,478
AND ALSO INCLUDING MUTATIONS

3837
02:16:26,478 --> 02:16:27,780
IDENTIFIED THROUGH WHOLE EXOME

3838
02:16:27,780 --> 02:16:28,080
SEQUENCING.

3839
02:16:28,080 --> 02:16:30,115
SO USING THIS APPROACH, ONE CAN

3840
02:16:30,115 --> 02:16:32,985
IDENTIFY PEPTIDES THAT ARE

3841
02:16:32,985 --> 02:16:35,020
MAPPING TO FIVE PRIME UTRs,

3842
02:16:35,020 --> 02:16:38,957
THREE PRIME UTRs, OFF-FRAME,

3843
02:16:38,957 --> 02:16:41,894
INTRONIC REGIONS, INTERGENIC AND

3844
02:16:41,894 --> 02:16:43,128
ALSO POTENTIALLY NON-CONTAINING

3845
02:16:43,128 --> 02:16:43,696
MUTATIONS.

3846
02:16:43,696 --> 02:16:45,264
SO SUFFICE TO SAY WE USED THIS

3847
02:16:45,264 --> 02:16:47,299
APPROACH TO IDENTIFY THE

3848
02:16:47,299 --> 02:16:49,968
CANONICAL PEPTIDES, WHICH WERE

3849
02:16:49,968 --> 02:16:51,704
EITHER CONTAINING MUTATIONS,

3850
02:16:51,704 --> 02:16:54,173
CANCER GERMLINE ANTIGENS OR

3851
02:16:54,173 --> 02:16:57,576
TUMOR-ASSOCIATED ANTIGENS, BUT

3852
02:16:57,576 --> 02:16:59,111
ALSO THESE NON-CANONICAL

3853
02:16:59,111 --> 02:16:59,445
ANTIGENS.

3854
02:16:59,445 --> 02:17:01,413
BECAUSE SOME OF THESE

3855
02:17:01,413 --> 02:17:03,115
NON-CANONICAL ANTIGENS CAN BE

3856
02:17:03,115 --> 02:17:04,850
POTENTIALLY TRANSLATED IN ALSO

3857
02:17:04,850 --> 02:17:07,286
HEALTHY TISSUE, WE USE THIS HLA

3858
02:17:07,286 --> 02:17:10,489
LIGAND ATLAS TO FILTER OUT

3859
02:17:10,489 --> 02:17:11,657
WHATEVER PEPTIDES THAT COULD

3860
02:17:11,657 --> 02:17:14,493
POTENTIALLY BE ALSO FOUND IN

3861
02:17:14,493 --> 02:17:17,729
THESE LIGAND -- 2, FINALLY GET A

3862
02:17:17,729 --> 02:17:19,798
LIST OF MORE TUMOR PREFERENTIAL

3863
02:17:19,798 --> 02:17:21,333
NON-CANNON CAN ANTIGENS

3864
02:17:21,333 --> 02:17:22,134
PREFERENTIALLY PRESENTED IN

3865
02:17:22,134 --> 02:17:23,135
CANCER CELLS.

3866
02:17:23,135 --> 02:17:24,470
SO VERY BRIEFLY, I WANT TO SHOW

3867
02:17:24,470 --> 02:17:27,840
YOU THE DATA.

3868
02:17:27,840 --> 02:17:28,807
SO ACROSS NINE DIFFERENT CANCER

3869
02:17:28,807 --> 02:17:31,477
CELL LINES, YOU CAN SEE WE HAVE

3870
02:17:31,477 --> 02:17:34,446
FOUR TUMORS, TWO HEAD AND NECK,

3871
02:17:34,446 --> 02:17:35,848
THREE MELANOMAS, WE WERE ABLE TO

3872
02:17:35,848 --> 02:17:37,683
IDENTIFY NON-CANONICAL PEPTIDES

3873
02:17:37,683 --> 02:17:39,284
IN ALL NINE CANCER CELL LINES.

3874
02:17:39,284 --> 02:17:41,053
AND THEY REPRESENTED A

3875
02:17:41,053 --> 02:17:42,187
RELATIVELY SMALL FRACTION OF ALL

3876
02:17:42,187 --> 02:17:44,223
THE PEPTIDES THAT WE WERE EABL

3877
02:17:44,223 --> 02:17:48,627
TO ELUTE FROM THESE CELL LINES.

3878
02:17:48,627 --> 02:17:50,028
USING THIS FILTER, FILTERING OUT

3879
02:17:50,028 --> 02:17:52,764
ALL THE PEPTIDES NON-CANONICAL

3880
02:17:52,764 --> 02:17:54,700
PEPTIDES THAT COULD BE DETECTED

3881
02:17:54,700 --> 02:17:57,035
IN THIS HLA LIGAND ATLAS OF

3882
02:17:57,035 --> 02:18:01,306
HEALTHY TISSUES, WE THEN

3883
02:18:01,306 --> 02:18:03,642
OBTAINED A MORE NARROW LIST OF

3884
02:18:03,642 --> 02:18:04,643
NON-CANONICAL TUMOR LIGANDS.

3885
02:18:04,643 --> 02:18:06,612
THESE ARE POTENTIALLY

3886
02:18:06,612 --> 02:18:07,513
PREFERENTIALLY PRESENTED BY

3887
02:18:07,513 --> 02:18:10,215
CANCER CELLS.

3888
02:18:10,215 --> 02:18:11,717
SO WE DECIDED TO STUDY THIS IN

3889
02:18:11,717 --> 02:18:14,319
MORE DETAIL.

3890
02:18:14,319 --> 02:18:16,822
WHEN WE LOOKED AT WHAT TYPE OF

3891
02:18:16,822 --> 02:18:17,956
NON-CANONICAL ANTIGENS THESE

3892
02:18:17,956 --> 02:18:19,892
DERIVE FROM, WHAT WE FOUND IS

3893
02:18:19,892 --> 02:18:21,927
THAT THEY MAINLY DERIVE FROM

3894
02:18:21,927 --> 02:18:24,463
FIVE-TIME UTR OR ALSO

3895
02:18:24,463 --> 02:18:25,898
ALTERNATIVE OPEN READING FRAMES,

3896
02:18:25,898 --> 02:18:27,466
NON-CODING RNA, AND LESS

3897
02:18:27,466 --> 02:18:29,668
FREQUENTLY TO THREE PRIME

3898
02:18:29,668 --> 02:18:31,537
UTRs, INTRONIC OR INTERGENIC

3899
02:18:31,537 --> 02:18:31,837
REGION.

3900
02:18:31,837 --> 02:18:33,805
AND WE WERE ONLY ABLE TO

3901
02:18:33,805 --> 02:18:36,575
IDENTIFY ONE SINGLE PEPTIDE THAT

3902
02:18:36,575 --> 02:18:38,277
WAS CRYPTIC AND CONTAINED A

3903
02:18:38,277 --> 02:18:38,544
MUTATION.

3904
02:18:38,544 --> 02:18:39,444
WE THOUGHT POTENTIALLY THIS ONE

3905
02:18:39,444 --> 02:18:42,948
COULD BE REALLY INTERESTING TO

3906
02:18:42,948 --> 02:18:43,749
TEST.

3907
02:18:43,749 --> 02:18:46,718
ON THE RIGHT WHAT YOU CAN SEE IS

3908
02:18:46,718 --> 02:18:47,586
THE COMPARISON IN TERMS OF THE

3909
02:18:47,586 --> 02:18:49,488
NUMBER OF PEPTIDES THAT WE

3910
02:18:49,488 --> 02:18:52,191
IDENTIFIED FROM EACH OF THE --

3911
02:18:52,191 --> 02:18:56,261
WE HAVE MUTATED PEPTIDES ON THE

3912
02:18:56,261 --> 02:18:58,630
TOP, CANCER GERMLINE MELANOMA

3913
02:18:58,630 --> 02:19:03,635
ASSOCIATED AND THE NON-CANONICAL

3914
02:19:03,635 --> 02:19:04,836
TUMOR LIGANDS.

3915
02:19:04,836 --> 02:19:06,138
AS YOU CAN SEE WHAT WE FOUND IS

3916
02:19:06,138 --> 02:19:08,340
THAT INDEED THESE NON-CANONICAL

3917
02:19:08,340 --> 02:19:09,608
TUMOR LIGANDS APPEARED TO BE

3918
02:19:09,608 --> 02:19:13,312
QUITE AN ABUNDANT SOURCE OF

3919
02:19:13,312 --> 02:19:14,780
ANTIGENS.

3920
02:19:14,780 --> 02:19:15,948
BUT YET WE NEEDED TO TEST

3921
02:19:15,948 --> 02:19:17,216
WHETHER THEY WERE IMMUNOGENIC.

3922
02:19:17,216 --> 02:19:18,217
THIS WAS THE MAIN QUESTION THAT

3923
02:19:18,217 --> 02:19:21,720
WE INITIALLY SET TO RESPOND.

3924
02:19:21,720 --> 02:19:23,856
SO TO ADDRESS THIS, WHAT WE DID

3925
02:19:23,856 --> 02:19:25,591
IS WE SYNTHESIZED ALL THE

3926
02:19:25,591 --> 02:19:27,759
PEPTIDES SHOWN HERE IN THIS

3927
02:19:27,759 --> 02:19:31,430
GRAVEL ONGRAPH ON THE RIGHT.

3928
02:19:31,430 --> 02:19:32,731
WHAT WE AIMED TO DO IS TEST THIS

3929
02:19:32,731 --> 02:19:34,333
IN A PERSONALIZED FASHION.

3930
02:19:34,333 --> 02:19:40,005
SO FOR EXAMPLE THE PEPTIDES FROM

3931
02:19:40,005 --> 02:19:40,973
MEL 3 WOULD ONLY BE TESTED FOR

3932
02:19:40,973 --> 02:19:41,540
THAT PATIENT.

3933
02:19:41,540 --> 02:19:43,976
SO THE TILES WHICH WE HAD TILs

3934
02:19:43,976 --> 02:19:46,612
WERE RECOGNIZING THE AUTOLOGOUS

3935
02:19:46,612 --> 02:19:48,080
SELL LINE WERE CO-CULTURED WITH

3936
02:19:48,080 --> 02:19:51,617
THE CELL LINES DERIVED FROM THIS

3937
02:19:51,617 --> 02:19:52,351
MELANOMA CELL LINE.

3938
02:19:52,351 --> 02:19:56,455
AND THE FINDINGS IN FACT WERE

3939
02:19:56,455 --> 02:19:57,589
QUITE INTRIGUING I MUST SAY.

3940
02:19:57,589 --> 02:19:59,124
SO I'M GOING TO FOCUS, AND I

3941
02:19:59,124 --> 02:20:09,601
WISH I COULD HAVE A POINTER?

3942
02:20:12,838 --> 02:20:14,006
SO FOCUSING HERE ON ONE OF THE

3943
02:20:14,006 --> 02:20:15,507
PATIENTS WE STUDIED IN DETAIL,

3944
02:20:15,507 --> 02:20:17,175
YOU CAN SEE THAT FOR THIS

3945
02:20:17,175 --> 02:20:21,280
PATIENT, WE SCREENED SEVERAL TIL

3946
02:20:21,280 --> 02:20:23,115
POPULATIONS THAT WE HAD THAT WE

3947
02:20:23,115 --> 02:20:26,351
KNEW RECOGNIZED THE AUTOLOGOUS

3948
02:20:26,351 --> 02:20:27,319
TUMOR CELL LINE.

3949
02:20:27,319 --> 02:20:29,121
PARTICULARLY IN THIS PATIENT WE

3950
02:20:29,121 --> 02:20:30,555
IDENTIFIED 215 NON-CANONICAL

3951
02:20:30,555 --> 02:20:32,958
TUMOR LIGANDS, SEVERAL TUMOR

3952
02:20:32,958 --> 02:20:35,027
ASSOCIATED CANCER GERMLINE AND

3953
02:20:35,027 --> 02:20:35,827
THREE MUTATED PEPTIDES.

3954
02:20:35,827 --> 02:20:37,729
AND AS YOU CAN SEE, WE FOUND

3955
02:20:37,729 --> 02:20:38,697
THAT TWO OUT OF THE THREE

3956
02:20:38,697 --> 02:20:40,899
MUTATED PEPTIDES WERE

3957
02:20:40,899 --> 02:20:41,333
IMMUNOGENIC.

3958
02:20:41,333 --> 02:20:46,438
TWO OUT OF THE 22 TUMOR

3959
02:20:46,438 --> 02:20:48,173
ASSOCIATED ANTIGENS WERE

3960
02:20:48,173 --> 02:20:50,909
IMMUNOGENIC BUT NON-OF THE 215

3961
02:20:50,909 --> 02:20:52,110
NON-CANONICAL TUMOR LIGANDS WE

3962
02:20:52,110 --> 02:20:54,079
IDENTIFIED WERE IMMUNOGENIC,

3963
02:20:54,079 --> 02:20:54,479
UNFORTUNATELY.

3964
02:20:54,479 --> 02:20:56,615
AND IN FACT, GLOBALLY, WE DID --

3965
02:20:56,615 --> 02:21:00,552
WE WERE NOT ABLE TO DETECT ANY

3966
02:21:00,552 --> 02:21:02,387
REACTIVITY TO ANY OF THE

3967
02:21:02,387 --> 02:21:04,690
NON-CANONICAL TUMOR LIGANDS

3968
02:21:04,690 --> 02:21:05,257
IDENTIFIED.

3969
02:21:05,257 --> 02:21:08,160
I MUST SAY THAT THIS WAS QUITE

3970
02:21:08,160 --> 02:21:08,694
SURPRISING.

3971
02:21:08,694 --> 02:21:10,896
WE HAD IN FACT VALIDATED THIS

3972
02:21:10,896 --> 02:21:12,397
PEPTIDE SO WE'RE PRETTY

3973
02:21:12,397 --> 02:21:13,231
CONFIDENT THAT THESE ARE

3974
02:21:13,231 --> 02:21:14,366
ACTUALLY PRESENTED ON THE CELL

3975
02:21:14,366 --> 02:21:16,968
SURFACE OF THE CANCER -- WE WERE

3976
02:21:16,968 --> 02:21:18,070
QUITE STRUCK EVEN THOUGH THE

3977
02:21:18,070 --> 02:21:20,205
LITERATURE POINTING TOWARDS

3978
02:21:20,205 --> 02:21:21,573
THESE ANDROGENS.

3979
02:21:21,573 --> 02:21:24,042
AND YET WE STILL WANTED TO KNOW,

3980
02:21:24,042 --> 02:21:28,814
WELL, YOU KNOW, POTENTIALLY THEY

3981
02:21:28,814 --> 02:21:31,650
ARE NOT BEING RECOGNIZED IN

3982
02:21:31,650 --> 02:21:32,918
CANCER PATIENTS NAYTIVELY, BUT

3983
02:21:32,918 --> 02:21:37,189
COULD WE IDENTIFY T CELLS AND

3984
02:21:37,189 --> 02:21:39,925
TCRs TARGETING NON-CANONICAL

3985
02:21:39,925 --> 02:21:42,427
TUMOR LIGANDS.

3986
02:21:42,427 --> 02:21:44,262
SO -- WITH A LIST OF

3987
02:21:44,262 --> 02:21:45,230
NON-CANONICAL TUMOR LIGANDS THAT

3988
02:21:45,230 --> 02:21:49,301
WERE IDENTIFIED AND ELUTED FROM

3989
02:21:49,301 --> 02:21:51,203
HLA A1101.

3990
02:21:51,203 --> 02:21:53,872
FOLLOWING THIS DESENSITIZATION,

3991
02:21:53,872 --> 02:21:58,243
DESENSITIZATION -- TARGETING

3992
02:21:58,243 --> 02:22:00,112
THREE DISTINCT NON-CANONICAL

3993
02:22:00,112 --> 02:22:01,413
TUMOR LIGANDS SHOWN HERE, ONE

3994
02:22:01,413 --> 02:22:03,982
DERIVING FROM FIVE PRIME UTR --

3995
02:22:03,982 --> 02:22:07,886
13, ONE FROM A NON-CODING RNA

3996
02:22:07,886 --> 02:22:10,021
AND ANOTHER ONE FROM A SECOND

3997
02:22:10,021 --> 02:22:11,323
FIVE PRIME UTR.

3998
02:22:11,323 --> 02:22:14,226
AND AS SHOWN ON THE RIGHT, THE

3999
02:22:14,226 --> 02:22:16,795
HLA RESTRICTION OF THESE

4000
02:22:16,795 --> 02:22:19,030
PEPTIDES WAS PROVEN TO BE FOR

4001
02:22:19,030 --> 02:22:23,001
TWO OF THEM HLA11 RESTRICT AND

4002
02:22:23,001 --> 02:22:25,370
FOR ONE OF THEM, HLA6801.

4003
02:22:25,370 --> 02:22:27,806
THE MAIN QUESTION WE HAD AFTER

4004
02:22:27,806 --> 02:22:29,741
SEEING THESE REACTIVITIES WAS

4005
02:22:29,741 --> 02:22:31,443
WHETHER THESE T-CELL POPULATIONS

4006
02:22:31,443 --> 02:22:34,079
WERE CAPABLE OF RECOGNIZING

4007
02:22:34,079 --> 02:22:35,647
THESE PEPTIDES NATURALLY

4008
02:22:35,647 --> 02:22:36,815
EXPRESSED AND PRESENTED BY

4009
02:22:36,815 --> 02:22:38,083
CANCER CELLS WHERE THEY WERE

4010
02:22:38,083 --> 02:22:39,818
INITIALLY IDENTIFIED.

4011
02:22:39,818 --> 02:22:41,686
AND SO WE PERFORMED THE

4012
02:22:41,686 --> 02:22:43,422
EXPERIMENTS, AND THE FINDINGS

4013
02:22:43,422 --> 02:22:47,426
WERE REALLY INTERESTING.

4014
02:22:47,426 --> 02:22:51,496
INDEED ONE -- THE CORRECT HLA

4015
02:22:51,496 --> 02:22:52,330
RESTRICTION ELEMENTS, YOU CAN

4016
02:22:52,330 --> 02:22:53,832
SEE THAT THESE T CELLS RESPOND

4017
02:22:53,832 --> 02:22:55,267
TO THE PEPTIDE WELL.

4018
02:22:55,267 --> 02:22:58,136
THEY DO NOT RESPOND TO MELANOMA

4019
02:22:58,136 --> 02:22:59,971
CELL LINE WHERE THESE ANTIGENS

4020
02:22:59,971 --> 02:23:01,373
WERE NOT IDENTIFIED.

4021
02:23:01,373 --> 02:23:05,577
EVEN WHEN YOU TRANSFECT HLA A11

4022
02:23:05,577 --> 02:23:06,845
OR A6801.

4023
02:23:06,845 --> 02:23:10,849
BUT THEY DO NATURALLY PRESENT

4024
02:23:10,849 --> 02:23:13,819
AND NATURALLY RECOGNIZE MEL 3.

4025
02:23:13,819 --> 02:23:16,888
SO LONG AS THE HLA RESTRICTION

4026
02:23:16,888 --> 02:23:18,390
ELEMENT IS ALSO PRESENT.

4027
02:23:18,390 --> 02:23:21,860
AND THIS CELL LINE IS NAYTIVELY

4028
02:23:21,860 --> 02:23:24,529
A1101 POSITIVE.

4029
02:23:24,529 --> 02:23:26,832
SO WE NEXT WANTED TO KNOW ONE OF

4030
02:23:26,832 --> 02:23:28,200
THE ADVANTAGES POTENTIALLY OF

4031
02:23:28,200 --> 02:23:31,169
TARGETING THESE NON-CANONICAL

4032
02:23:31,169 --> 02:23:32,571
CRYPTIC PEPTIDES THESE ARE NOT

4033
02:23:32,571 --> 02:23:35,006
PRIVATE SO POTENTIALLY BY

4034
02:23:35,006 --> 02:23:36,875
TARGETING THIS ONE COULD TREAT A

4035
02:23:36,875 --> 02:23:37,943
LARGER PATIENT POPULATION SO

4036
02:23:37,943 --> 02:23:40,612
LONG AS THIS IS PROCESSED,

4037
02:23:40,612 --> 02:23:42,514
PRESENTED AND RECOGNIZED BY THE

4038
02:23:42,514 --> 02:23:45,450
T CELLS.

4039
02:23:45,450 --> 02:23:46,551
AND ON DIFFERENT CELL LINES.

4040
02:23:46,551 --> 02:23:48,787
SO WHAT WE DID IS WE CLONED THE

4041
02:23:48,787 --> 02:23:51,089
TCR GENERATED TCR TRANSDUCED T

4042
02:23:51,089 --> 02:23:52,524
CELLS TARGETING -- JUST SHOWING

4043
02:23:52,524 --> 02:23:55,460
THE RESULTS FOR ONE OF THEM,

4044
02:23:55,460 --> 02:23:59,931
TARGETING 5 PRIME UTR OF HOC13.

4045
02:23:59,931 --> 02:24:02,367
AS YOU CAN SEE WE CO-CULTURED

4046
02:24:02,367 --> 02:24:04,169
THESE CELLS WITH A GOOD NUMBER

4047
02:24:04,169 --> 02:24:05,770
OF CANCER CELL LINES THAT WE

4048
02:24:05,770 --> 02:24:07,239
GENERATED OVER THE YEARS FROM

4049
02:24:07,239 --> 02:24:08,840
DIFFERENT ORIGIN GYNECOLOGICAL

4050
02:24:08,840 --> 02:24:11,243
HEAD AND NECK MELANOMA GI AND

4051
02:24:11,243 --> 02:24:16,982
RENAL AND LUNG, AND OBSERVED IN

4052
02:24:16,982 --> 02:24:20,852
THE -- WHAT WE OBSERVED WAS THEY

4053
02:24:20,852 --> 02:24:22,454
WERE ABLE TO RECOGNIZE ONLY THE

4054
02:24:22,454 --> 02:24:23,755
MELANOMA CELL LINES THAT WEREN'T

4055
02:24:23,755 --> 02:24:26,258
NATURALLY EXPRESSING HLA A1101

4056
02:24:26,258 --> 02:24:27,425
WHICH WAS THE RESTRICTION

4057
02:24:27,425 --> 02:24:30,595
ELEMENT FOR THE TCR.

4058
02:24:30,595 --> 02:24:32,430
NONETHELESS WHEN WE INTRODUCED

4059
02:24:32,430 --> 02:24:34,799
HLA SN 1101 INTO ALL THE REST OF

4060
02:24:34,799 --> 02:24:35,600
THE CANCER CELL LINES, WE BEGAN

4061
02:24:35,600 --> 02:24:40,505
TO SEE SOME RECOGNITION OF GI

4062
02:24:40,505 --> 02:24:42,674
CANCER OR GYNECOLOGICAL CANCER,

4063
02:24:42,674 --> 02:24:43,542
AGAIN POTENTIALLY SUGGESTING

4064
02:24:43,542 --> 02:24:45,410
THAT THESE CRYPTIC PEPTIDES

4065
02:24:45,410 --> 02:24:48,513
COULD BE TARGETABLE IN OTHER

4066
02:24:48,513 --> 02:24:50,715
CANCER TYPES.

4067
02:24:50,715 --> 02:24:52,551
AND NOT WITH A6801.

4068
02:24:52,551 --> 02:24:54,219
THIS WAS REALLY INTERESTING, WE

4069
02:24:54,219 --> 02:24:57,222
WERE STILL SLIGHTLY WORRIED THAT

4070
02:24:57,222 --> 02:24:59,724
WE DIDN'T KNOW HOW

4071
02:24:59,724 --> 02:25:01,259
TUMOR-SPECIFIC THESE ANTIGENS

4072
02:25:01,259 --> 02:25:02,427
WERE.

4073
02:25:02,427 --> 02:25:03,828
TO ADDRESS THIS -- ADDRESSING

4074
02:25:03,828 --> 02:25:06,665
THIS IS NOT THAT SIMPLE BECAUSE

4075
02:25:06,665 --> 02:25:08,500
THIS ABERRANT TRANSLATION CANNOT

4076
02:25:08,500 --> 02:25:10,402
BE DETECTED AT RNA SEQ LEVELS SO

4077
02:25:10,402 --> 02:25:12,704
WE CANNOT USE RNA SEQ TO SEE

4078
02:25:12,704 --> 02:25:13,738
WHETHER CELL LINES ARE POSITIVE

4079
02:25:13,738 --> 02:25:15,941
OR NEGATIVE FOR OUR TARGETS.

4080
02:25:15,941 --> 02:25:17,275
SO WE USED A SLIGHTLY DIFFERENT

4081
02:25:17,275 --> 02:25:18,076
APPROACH.

4082
02:25:18,076 --> 02:25:20,045
WE PURCHASED HEALTHY CELLS.

4083
02:25:20,045 --> 02:25:22,781
THESE ARE RENAL FIBROBLASTS,

4084
02:25:22,781 --> 02:25:25,483
EPITHELIAL CELLS, CARDIAC

4085
02:25:25,483 --> 02:25:35,894
MYOCYTES OR MELANOCYTES.

4086
02:25:38,196 --> 02:25:42,701
WHAT WE SEE IS THAT, IN FACT,

4087
02:25:42,701 --> 02:25:45,103
THESE TCR TRANSDUCED T CELLS CAN

4088
02:25:45,103 --> 02:25:46,271
RECOGNIZE THESE CELL LINES SO

4089
02:25:46,271 --> 02:25:48,240
LONG AS THE HLA RESTRICTION

4090
02:25:48,240 --> 02:25:50,275
ELEMENT IS THERE, IT CAN EVEN

4091
02:25:50,275 --> 02:25:52,110
INCREASE WHEN YOU FURTHER

4092
02:25:52,110 --> 02:25:53,745
ENHANCE THE EXPRESSION OF HLA

4093
02:25:53,745 --> 02:25:55,380
RESTRICTION ELEMENT, BUT IT DOES

4094
02:25:55,380 --> 02:25:57,215
NOT DISPLAY RECOGNITION OF ANY

4095
02:25:57,215 --> 02:26:02,520
OF THE HEALTHY CELLS.

4096
02:26:02,520 --> 02:26:03,722
NOW WE'RE ONLY TESTING A FEW

4097
02:26:03,722 --> 02:26:05,056
NUMBER OF NORMAL HEALTHY CELLS

4098
02:26:05,056 --> 02:26:06,224
AND THIS MAY BE A LIMITATION,

4099
02:26:06,224 --> 02:26:07,859
BUT WE DID HAVE A POSITIVE

4100
02:26:07,859 --> 02:26:09,728
CONTROL OF A TCR THAT WE KNOW

4101
02:26:09,728 --> 02:26:12,998
CAN LEAD TO AUTOIMMUNE TOXICITY

4102
02:26:12,998 --> 02:26:17,769
WHICH IS THE MART 1 CELLS AND

4103
02:26:17,769 --> 02:26:20,305
THESE ARE RESTRICTED -- NOT ONLY

4104
02:26:20,305 --> 02:26:21,940
THEY RECOGNIZE MELANOMA CELL

4105
02:26:21,940 --> 02:26:26,845
LINES THAT ARE TRANSDUCED WITH

4106
02:26:26,845 --> 02:26:28,146
HLA -- AND SURPRISINGLY TO A

4107
02:26:28,146 --> 02:26:30,649
LOWER EXTENT CARDIAC MYOCYTES.

4108
02:26:30,649 --> 02:26:35,553
SO I THINK THIS -- IN SUMMARY, I

4109
02:26:35,553 --> 02:26:37,522
FIND THAT THESE NON-CANONICAL

4110
02:26:37,522 --> 02:26:40,025
TUMOR LIGANDS CAN BE IMMUNOGENIC

4111
02:26:40,025 --> 02:26:41,726
AND SHARED ACROSS CANCER TYPES

4112
02:26:41,726 --> 02:26:43,261
AND APPEAR TO BE PREFERENTIALLY

4113
02:26:43,261 --> 02:26:44,295
PRESENTED BY CANCER CELLS.

4114
02:26:44,295 --> 02:26:46,665
I THINK AT THIS POINT WE STILL

4115
02:26:46,665 --> 02:26:48,933
HAVE TO EVALUATE HOW

4116
02:26:48,933 --> 02:26:49,701
TUMOR-SPECIFIC THEY ARE AND ALSO

4117
02:26:49,701 --> 02:26:52,671
WE HAVE TO FIND WAYS POTENTIALLY

4118
02:26:52,671 --> 02:26:54,606
HOW TO LOGISTICALLY SELECT THESE

4119
02:26:54,606 --> 02:26:56,207
PATIENTS IF WE WANT TO PUSH

4120
02:26:56,207 --> 02:26:59,511
FURTHER WITH THE TCR TRANSDUCED

4121
02:26:59,511 --> 02:27:01,346
APPROACH.

4122
02:27:01,346 --> 02:27:04,716
WE FOUND THAT ABERRANT

4123
02:27:04,716 --> 02:27:07,986
TRANSLATION DID NOT EXPLAIN THE

4124
02:27:07,986 --> 02:27:09,854
RESPONSES AND THIS BEGS THE

4125
02:27:09,854 --> 02:27:11,923
QUESTION WHY DIDN'T THESE

4126
02:27:11,923 --> 02:27:14,392
CRYPTIC PEPTIDES ELICIT A T-CELL

4127
02:27:14,392 --> 02:27:15,827
RESPONSE IN CANCER PATIENTS.

4128
02:27:15,827 --> 02:27:18,363
WE HAVE SOME POTENTIAL TECHNICAL

4129
02:27:18,363 --> 02:27:19,497
EXPLANATIONS WHICH WE HAVE MORE

4130
02:27:19,497 --> 02:27:21,132
OR LESS RULED OUT SINCE WE THINK

4131
02:27:21,132 --> 02:27:22,567
THOSE SHOULD AFFECT OTHER

4132
02:27:22,567 --> 02:27:24,102
NEOANTIGENS AND OTHER

4133
02:27:24,102 --> 02:27:25,170
TUMOR-ASSOCIATED ANTIGENS.

4134
02:27:25,170 --> 02:27:29,641
BUT WE FEEL THAT TWO PLAUSIBLE

4135
02:27:29,641 --> 02:27:30,975
HYPOTHESES FOR THAT IS THAT WE

4136
02:27:30,975 --> 02:27:32,243
BELIEVE THESE PEPTIDES ARE

4137
02:27:32,243 --> 02:27:35,246
POTENTIALLY VERY EFFECTIVELY

4138
02:27:35,246 --> 02:27:37,182
PRESENTED ON -- OF CANCER CELLS

4139
02:27:37,182 --> 02:27:39,784
BUT LESS EFFECTIVELY CROSS

4140
02:27:39,784 --> 02:27:40,752
PRESENTED POTENTIALLY LEADING TO

4141
02:27:40,752 --> 02:27:42,187
INEFFECTIVE PRIMING OF T-CELL

4142
02:27:42,187 --> 02:27:44,289
RESPONSES.

4143
02:27:44,289 --> 02:27:46,791
NOW THIS ALTHOUGH COULD BE A

4144
02:27:46,791 --> 02:27:47,358
DISADVANTAGE IN TERMS THAT

4145
02:27:47,358 --> 02:27:49,327
THEY'RE NOT NATURALLY

4146
02:27:49,327 --> 02:27:52,530
IMMUNOGENIC COULD BE AN

4147
02:27:52,530 --> 02:27:54,265
ADVANTAGE, AS THEY HAVE NOT BEEN

4148
02:27:54,265 --> 02:27:54,666
SO IMMUNOEDITED.

4149
02:27:54,666 --> 02:27:55,700
SO THIS IS SOMETHING THAT

4150
02:27:55,700 --> 02:27:56,768
POTENTIALLY WE NEED TO STUDY

4151
02:27:56,768 --> 02:27:59,704
MORE IN DEPTH.

4152
02:27:59,704 --> 02:28:01,473
THERE'S A SECOND HYPOTHESIS,

4153
02:28:01,473 --> 02:28:03,108
THOUGH, WHICH IS INDEED THESE

4154
02:28:03,108 --> 02:28:04,976
ARE NOT SO TUMOR-SPECIFIC,

4155
02:28:04,976 --> 02:28:07,846
POTENTIALLY THIS COULD BE

4156
02:28:07,846 --> 02:28:18,490
EXPRESSED AND PRESENT BID KIEEDY

4157
02:28:19,824 --> 02:28:20,759
THYMIC -- DURING THYMIC

4158
02:28:20,759 --> 02:28:21,159
DEVELOPMENT.

4159
02:28:21,159 --> 02:28:23,061
FINALLY WE ARE STILL MISSING A

4160
02:28:23,061 --> 02:28:24,763
CONSIDERABLE FRACTION OF

4161
02:28:24,763 --> 02:28:25,830
ANTIGENS TARGETED BY T CELLS IN

4162
02:28:25,830 --> 02:28:28,166
CANCER PATIENTS AND WE ARE STILL

4163
02:28:28,166 --> 02:28:30,101
DRIVEN TO CONTINUE TO ADDRESS

4164
02:28:30,101 --> 02:28:30,769
THIS QUESTION.

4165
02:28:30,769 --> 02:28:34,806
WE THINK FUSIONS, ALTERNATIVE

4166
02:28:34,806 --> 02:28:35,974
SPLICING, INTRON RETENTION,

4167
02:28:35,974 --> 02:28:37,542
STRUCTURAL VARIANTS AND

4168
02:28:37,542 --> 02:28:40,011
CERTAINLY TUMOR ASSOCIATED AND

4169
02:28:40,011 --> 02:28:42,180
TISSUE DIFFERENTIATION AND

4170
02:28:42,180 --> 02:28:43,414
CANCER GERMLINE ANTIGENS.

4171
02:28:43,414 --> 02:28:45,550
HOWEVER THIS LIST OF ANTIGENS IS

4172
02:28:45,550 --> 02:28:46,651
EVER-GROWING AND WE FEEL THAT

4173
02:28:46,651 --> 02:28:48,720
THIS PROTEOMICS APPROACH IS NOT

4174
02:28:48,720 --> 02:28:51,456
SENSITIVE ENOUGH, AND WE ARE IN

4175
02:28:51,456 --> 02:28:53,858
NEED OF MORE HIGH-THROUGHPUT

4176
02:28:53,858 --> 02:28:55,160
STRATEGIES TO -- SUCH A LONG

4177
02:28:55,160 --> 02:28:55,827
LIST OF PEPTIDES.

4178
02:28:55,827 --> 02:28:57,028
AND FOR THIS REASON, WE ARE

4179
02:28:57,028 --> 02:28:58,496
MOVING TOWARDS A MORE

4180
02:28:58,496 --> 02:29:02,233
HIGH-THROUGHPUT SCREENING OF

4181
02:29:02,233 --> 02:29:04,869
USING DNA BASED TUMOR LIBRARIES.

4182
02:29:04,869 --> 02:29:07,005
THIS IS SPEARHEADED BY A POSE

4183
02:29:07,005 --> 02:29:10,575
DPOSTDOCAND GRADUATE STUDENT INB

4184
02:29:10,575 --> 02:29:12,677
WHO HAVE COME UP WITH THIS TITLE

4185
02:29:12,677 --> 02:29:14,212
OF UNBIASED PERSONALIZED

4186
02:29:14,212 --> 02:29:18,616
SCREENING OF CANDIDATE ANTIGEN

4187
02:29:18,616 --> 02:29:21,052
LIBRARIES.

4188
02:29:21,052 --> 02:29:23,488
WHEREBY WE INTEND TO

4189
02:29:23,488 --> 02:29:25,557
IMMORTGAGIZE B CELLS AND EXPRESS

4190
02:29:25,557 --> 02:29:28,626
AN ANTIGEN LIBRARY WHERE EACH B

4191
02:29:28,626 --> 02:29:31,329
CELL IS EXPRESSING A DIFFERENT

4192
02:29:31,329 --> 02:29:32,163
CANDIDATE ANTIGEN AND YOU CAN

4193
02:29:32,163 --> 02:29:35,466
HAVE UP TO TENS OF THOUSANDS OF

4194
02:29:35,466 --> 02:29:36,968
ANTIGENS AND CO-CULTURE T CELLS

4195
02:29:36,968 --> 02:29:39,904
OR TCRs OR TCR LIBRARIES WITH

4196
02:29:39,904 --> 02:29:41,039
THESE CANDIDATE ANTIGENS,

4197
02:29:41,039 --> 02:29:42,340
ISOLATE THOSE THAT HAVE BEEN

4198
02:29:42,340 --> 02:29:47,212
RECOGNIZED BY T CELLS TO GZB

4199
02:29:47,212 --> 02:29:48,646
REPORTER AND FINALLY SEQUENCING

4200
02:29:48,646 --> 02:29:50,715
THE RECOGNIZED ANTIGENS TO

4201
02:29:50,715 --> 02:29:52,550
DISCOVER NOVEL PEPTIDES.

4202
02:29:52,550 --> 02:29:56,054
THIS IS ONGOING WORK, AND WITH

4203
02:29:56,054 --> 02:29:58,223
THAT, I WILL END WITH THE

4204
02:29:58,223 --> 02:29:58,656
ACKNOWLEDGMENTS.

4205
02:29:58,656 --> 02:30:00,291
I'D LIKE TO THANK THE PEOPLE

4206
02:30:00,291 --> 02:30:01,492
FROM MY GROUP THAT HAVE

4207
02:30:01,492 --> 02:30:03,228
CONTRIBUTED TO THIS WORK.

4208
02:30:03,228 --> 02:30:04,929
ALL THE COLLABORATORS, THE

4209
02:30:04,929 --> 02:30:07,665
FUNDING AI AGENCIES AND VERY

4210
02:30:07,665 --> 02:30:08,533
ESPECIALLY ALL PATIENTS THAT

4211
02:30:08,533 --> 02:30:08,833
CONTRIBUTED.

4212
02:30:08,833 --> 02:30:09,434
THANK YOU VERY MUCH.

4213
02:30:09,434 --> 02:30:19,611
[APPLAUSE]

4214
02:30:27,552 --> 02:30:28,753
>> THANK YOU, DR. GROS.

4215
02:30:28,753 --> 02:30:29,721
OUR FINAL SPEAKER FOR THIS

4216
02:30:29,721 --> 02:30:32,056
SESSION WILL BE DR. KEN-ICHI

4217
02:30:32,056 --> 02:30:33,892
HANADA, STAFF SCIENTIST FROM THE

4218
02:30:33,892 --> 02:30:36,995
SURGE ROW BRANCH.

4219
02:30:36,995 --> 02:30:37,695
SURGERY BRANCH.

4220
02:30:37,695 --> 02:30:42,100
>> SO MY -- I HAVE TO USE
MY

4221
02:30:42,100 --> 02:30:44,669
LAPTOP.

4222
02:30:44,669 --> 02:30:55,179
GIVE ME A SECOND TO SET IT UP.

4223
02:30:58,416 --> 02:30:59,484
SO WHILE WE'RE WAITING I'D LIKE

4224
02:30:59,484 --> 02:31:02,287
TO SHARE MY EXPERIENCE THROUGH

4225
02:31:02,287 --> 02:31:03,454
WHICH I CAME TO UNDERSTAND WHAT

4226
02:31:03,454 --> 02:31:10,595
THE SURGERY BRANCH IS ABOUT.

4227
02:31:10,595 --> 02:31:13,131
I WAS FORTUNATE ENOUGH TO

4228
02:31:13,131 --> 02:31:15,867
IDENTIFY POST TRANSLATIONALLY

4229
02:31:15,867 --> 02:31:16,434
SPLICED PEPTIDE.

4230
02:31:16,434 --> 02:31:18,102
IT TOOK ME MORE THAN THREE

4231
02:31:18,102 --> 02:31:21,439
YEARS, FOUR YEARS, AND FINALLY

4232
02:31:21,439 --> 02:31:25,677
FROM FOUND THE EPITOPE, I WAS FF

4233
02:31:25,677 --> 02:31:26,978
JOY.

4234
02:31:26,978 --> 02:31:29,380
AND THEN AT THE MEETING I

4235
02:31:29,380 --> 02:31:31,549
PRESENTED THE DATA TO

4236
02:31:31,549 --> 02:31:31,883
DR. ROSENBERG.

4237
02:31:31,883 --> 02:31:33,851
SO WHEN I WAS PRESENTING THE

4238
02:31:33,851 --> 02:31:35,820
DATA, I HAD THIS BURNING

4239
02:31:35,820 --> 02:31:37,121
QUESTION, OKAY, I FOUND THIS

4240
02:31:37,121 --> 02:31:38,289
EPITOPE, BUT HOW IS THIS

4241
02:31:38,289 --> 02:31:39,424
HAPPENING?

4242
02:31:39,424 --> 02:31:40,525
WHAT IS THE MECHANISM?

4243
02:31:40,525 --> 02:31:43,461
THAT WAS MY BURNING QUESTION

4244
02:31:43,461 --> 02:31:46,631
THAT GET ME AWAKE.

4245
02:31:46,631 --> 02:31:49,133
SO WHEN I PRESENTED THE DATA TO

4246
02:31:49,133 --> 02:31:51,302
DR. ROSENBERG, I EXPECTED AN

4247
02:31:51,302 --> 02:31:52,537
ENCOURAGING COMMENT LIKE, OKAY,

4248
02:31:52,537 --> 02:31:55,473
NOW YOU WANT TO FIND THE

4249
02:31:55,473 --> 02:31:57,108
MECHANISM, WHAT WILL BE YOUR

4250
02:31:57,108 --> 02:31:57,575
APPROACH?

4251
02:31:57,575 --> 02:31:58,843
THAT KIND OF COMMENT, I

4252
02:31:58,843 --> 02:31:59,944
EXPECTED.

4253
02:31:59,944 --> 02:32:01,279
BUT DR. ROSENBERG'S COMMENT WAS

4254
02:32:01,279 --> 02:32:02,213
VERY DIFFERENT.

4255
02:32:02,213 --> 02:32:07,385
HE WAS LIKE, OKAY, YOU MADE A

4256
02:32:07,385 --> 02:32:07,885
GREAT DISCOVERY.

4257
02:32:07,885 --> 02:32:09,988
IT'S VERY INTERESTING.

4258
02:32:09,988 --> 02:32:11,589
SO OTHER PEOPLE WILL WORK ON

4259
02:32:11,589 --> 02:32:11,956
THIS TOO.

4260
02:32:11,956 --> 02:32:16,094
SO YOU STOP IT.

4261
02:32:16,094 --> 02:32:18,496
SO YOU HAVE TO MOVE ON.

4262
02:32:18,496 --> 02:32:21,466
HE ALSO SAID THAT --

4263
02:32:21,466 --> 02:32:22,300
DR. ROSENBERG ALSO SAID WE HAVE

4264
02:32:22,300 --> 02:32:25,069
TO WORK ON THE QUESTIONS, WE

4265
02:32:25,069 --> 02:32:27,438
THINK IS IMPORTANT, BUT NO OTHER

4266
02:32:27,438 --> 02:32:28,673
PEOPLE FEEL SO IMPORTANT.

4267
02:32:28,673 --> 02:32:35,646
SO WE HAVE TO FOCUS OUR POWER,

4268
02:32:35,646 --> 02:32:36,514
RESEARCH POWER ON THAT KIND OF

4269
02:32:36,514 --> 02:32:36,781
QUESTION.

4270
02:32:36,781 --> 02:32:40,618
THAT WAS HIS COMMENT.

4271
02:32:40,618 --> 02:32:43,588
SO WHEN I HEARD THE COMMENT, AT

4272
02:32:43,588 --> 02:32:45,356
FIRST FOR A SECOND OR TWO, I WAS

4273
02:32:45,356 --> 02:32:49,827
LIKE, WHAT?

4274
02:32:49,827 --> 02:32:51,662
I WAS SO DISAPPOINTED FOR A

4275
02:32:51,662 --> 02:32:51,896
SECOND.

4276
02:32:51,896 --> 02:32:55,066
BUT YOU KNOW, IT DIDN'T TAKE

4277
02:32:55,066 --> 02:32:58,870
LONG TO REALLY UNDERSTAND, YEAH,

4278
02:32:58,870 --> 02:32:59,871
THAT'S -- YOU KNOW, THAT'S THE

4279
02:32:59,871 --> 02:33:05,076
REASON WHY -- OUR EXISTENCE, THE

4280
02:33:05,076 --> 02:33:06,377
BRANCH, THAT'S WHAT THE BRANCH

4281
02:33:06,377 --> 02:33:07,912
IS ABOUT, THAT'S WHAT

4282
02:33:07,912 --> 02:33:08,746
DR. ROSENBERG IS ABOUT.

4283
02:33:08,746 --> 02:33:12,450
HE HAS BEEN THE -- TO ME HE HAS

4284
02:33:12,450 --> 02:33:14,519
BEEN THE LIGHTHOUSE OR THE

4285
02:33:14,519 --> 02:33:17,355
BEACON FOR ALREADY 27 YEARS, AND

4286
02:33:17,355 --> 02:33:19,757
THEN EVERY DAY, I CAN COME IN

4287
02:33:19,757 --> 02:33:20,658
BEING EXCITED.

4288
02:33:20,658 --> 02:33:25,630
SO I FEEL IT A GIFT, AND

4289
02:33:25,630 --> 02:33:27,031
DIRECTLY THANK DR. ROSENBERG FOR

4290
02:33:27,031 --> 02:33:27,732
IT.

4291
02:33:27,732 --> 02:33:28,266
OKAY.

4292
02:33:28,266 --> 02:33:33,504
SO NOW, BY THE WAY, MY NAME IS

4293
02:33:33,504 --> 02:33:33,871
KEN-ICHI HANADA.

4294
02:33:33,871 --> 02:33:40,578
I'M A STAFF SCIENTIST AT

4295
02:33:40,578 --> 02:33:42,580
DR. JAMES YANG'S LABORATORY.

4296
02:33:42,580 --> 02:33:46,617
THTODAY'S TALK IS TITLED ANTITUR

4297
02:33:46,617 --> 02:33:50,788
MECHANISM MEDIATED BY CLASS II

4298
02:33:50,788 --> 02:34:00,698
MHC-RESTRICTED CD4 PLUS T CELLS.

4299
02:34:00,698 --> 02:34:02,233
NOW I'D LIKE TO START WITH AN

4300
02:34:02,233 --> 02:34:02,900
INTRODUCTION.

4301
02:34:02,900 --> 02:34:05,536
AS A SURGERY BRANCH, WE EMPLOY

4302
02:34:05,536 --> 02:34:07,105
THREE APPROACHES TO TREAT

4303
02:34:07,105 --> 02:34:12,710
PATIENTS USING -- CELL TRANSFER.

4304
02:34:12,710 --> 02:34:15,179
FIRST TUMOR INFILTRATING

4305
02:34:15,179 --> 02:34:19,016
LYMPHOSIGNS, TILs, WITH TUMOR

4306
02:34:19,016 --> 02:34:20,518
REACTIVITY.

4307
02:34:20,518 --> 02:34:25,857
SECOND APPROACH IS AUTOLOGOUS

4308
02:34:25,857 --> 02:34:28,159
LYMPHOCYTES ENGINEERS TO EXPRESS

4309
02:34:28,159 --> 02:34:29,026
PATIENT-SPECIFIC

4310
02:34:29,026 --> 02:34:30,895
NEOANTIGEN-REACTIVE T-CELL

4311
02:34:30,895 --> 02:34:33,631
RECEPTOR, SO-CALLED TCR

4312
02:34:33,631 --> 02:34:34,866
PROTOCOLS, AND THE THIRD WAY IS

4313
02:34:34,866 --> 02:34:37,068
OFF THE SHELF TCRs TARGETING

4314
02:34:37,068 --> 02:34:38,769
COMMON DRIVER MUTATION DERIVED

4315
02:34:38,769 --> 02:34:40,271
EPITOPES PRESENTED BY WIDELY

4316
02:34:40,271 --> 02:34:42,206
SHARED MHC MOLECULE.

4317
02:34:42,206 --> 02:34:44,142
DR. YANG PRESENTED THAT.

4318
02:34:44,142 --> 02:34:46,410
SO -- BUT IN CONDUCTING THESE

4319
02:34:46,410 --> 02:34:50,481
CLINICAL TRIALS, WE REALIZED

4320
02:34:50,481 --> 02:34:53,084
SOME PROBLEMS.

4321
02:34:53,084 --> 02:34:54,385
ONE PROBLEM IS A SIGNIFICANT

4322
02:34:54,385 --> 02:34:56,587
NUMBER OF PATIENTS HAVE

4323
02:34:56,587 --> 02:34:59,090
ALREADY -- HAVE ALREADY

4324
02:34:59,090 --> 02:35:00,525
EXPERIENCED MHC LOSS PRIOR TO

4325
02:35:00,525 --> 02:35:03,094
THE THERAPY AS A BRANCH.

4326
02:35:03,094 --> 02:35:07,365
SO THIS IS -- THESE PIE CHARTS

4327
02:35:07,365 --> 02:35:11,836
SHOW THE FREQUENCY OF -- LOSS AT

4328
02:35:11,836 --> 02:35:17,175
THE SURGERY BRANCH - BASED ON

4329
02:35:17,175 --> 02:35:18,342
WHOLE EXOME SEQUENCING.

4330
02:35:18,342 --> 02:35:20,811
THERE ARE SIX CANCER, AND

4331
02:35:20,811 --> 02:35:22,880
ROUGHLY -- SO THE RED PIE,

4332
02:35:22,880 --> 02:35:26,150
THAT'S A LOSS OF MHC LOSS.

4333
02:35:26,150 --> 02:35:31,589
BLUE IS INCONCLUSIVE, BECAUSE WE

4334
02:35:31,589 --> 02:35:35,793
ANALYZED THE -- USING TUMOR

4335
02:35:35,793 --> 02:35:37,261
TISSUE SO DEPENDING ON

4336
02:35:37,261 --> 02:35:39,230
CONTAMINATION OF THE -- CELLS,

4337
02:35:39,230 --> 02:35:43,234
MEASURING OR JUDGING JUDGMENT

4338
02:35:43,234 --> 02:35:44,602
LOH -- SO THERE ARE MANY

4339
02:35:44,602 --> 02:35:47,338
INCONCLUSIVE CASES.

4340
02:35:47,338 --> 02:35:49,507
BUT AFTER AT LEAST 20 TO 30%,

4341
02:35:49,507 --> 02:35:52,910
THIS IS A VERY -- BASED ON THE

4342
02:35:52,910 --> 02:35:56,080
VERY STRICT CRITERIA, SO 22, 30%

4343
02:35:56,080 --> 02:36:01,085
OF THE PATIENTS COME IN WITH MHC

4344
02:36:01,085 --> 02:36:01,519
LOSS.

4345
02:36:01,519 --> 02:36:03,588
SO THAT'S ONE BIG PROBLEM.

4346
02:36:03,588 --> 02:36:09,060
ON THE SECOND PROBLEM IS T-CELL

4347
02:36:09,060 --> 02:36:10,127
REACTIVITY CAN LEAD TO THE SLEK

4348
02:36:10,127 --> 02:36:13,931
THECOLLECTION OF TUMOR CELLS WIH

4349
02:36:13,931 --> 02:36:14,832
LOSS OF FUNCTION MUTATION --

4350
02:36:14,832 --> 02:36:17,468
LOSS OF FUNCTION MUTATIONS OR

4351
02:36:17,468 --> 02:36:19,837
LOSS OF MHC MOLECULES.

4352
02:36:19,837 --> 02:36:22,673
AND THEN THERE ARE EXAMPLES OF

4353
02:36:22,673 --> 02:36:26,944
THAT, SO IF I BRIEFLY MENTION

4354
02:36:26,944 --> 02:36:27,912
THESE EXAMPLES.

4355
02:36:27,912 --> 02:36:31,215
THE FIRST ONE WAS PUBLISHED BY

4356
02:36:31,215 --> 02:36:32,717
ERIC TRAN AND THEN THIS WAS A

4357
02:36:32,717 --> 02:36:36,887
CASE IN WHICH COLORECTAL CANCER

4358
02:36:36,887 --> 02:36:43,060
PATIENT WAS TREATED WITH KRAS --

4359
02:36:43,060 --> 02:36:44,462
AND THIS RESULTED IN THE

4360
02:36:44,462 --> 02:36:45,997
EMERGENCE OF RECURRENT TUMOR

4361
02:36:45,997 --> 02:36:51,135
WITH HLA-C0802 LOSS.

4362
02:36:51,135 --> 02:36:52,837
THE SECOND CASE IS A MORE RECENT

4363
02:36:52,837 --> 02:36:57,008
CASE, SO THIS PATIENT WAS

4364
02:36:57,008 --> 02:37:04,215
TREATED WITH AGAIN KRAS G12D

4365
02:37:04,215 --> 02:37:06,183
BUT -- RESTRICTED.

4366
02:37:06,183 --> 02:37:08,819
INITIALLY, SEVEN MONTHS, VERY

4367
02:37:08,819 --> 02:37:11,022
GOOD RESPONSE WAS SEEN.

4368
02:37:11,022 --> 02:37:12,523
BUT AFTER TWO MONTHS, THERE WAS

4369
02:37:12,523 --> 02:37:17,295
A SMALL RECURRENCE AND THIS

4370
02:37:17,295 --> 02:37:20,164
TUMOR HAD MUTATION IN THE

4371
02:37:20,164 --> 02:37:23,367
RESTRICTED MHC, LOSS OF

4372
02:37:23,367 --> 02:37:28,072
FUNCTION -- MUTATION MHC.

4373
02:37:28,072 --> 02:37:31,976
SO THIS, A BIG PROGRAM WITH

4374
02:37:31,976 --> 02:37:35,079
ATTACKING TUMOR WITH CD8 T

4375
02:37:35,079 --> 02:37:35,713
CELLS.

4376
02:37:35,713 --> 02:37:37,748
SO TODAY I'D LIKE TO TALK ABOUT

4377
02:37:37,748 --> 02:37:41,152
CD4 T CELLS AND THEN I'D LIKE TO

4378
02:37:41,152 --> 02:37:43,587
EXPLAIN WHY CD4 T CELLS CAN BE

4379
02:37:43,587 --> 02:37:45,423
IMPORTANT.

4380
02:37:45,423 --> 02:37:47,425
SO FIRST I'D LIKE TO EXPLAIN TO

4381
02:37:47,425 --> 02:37:51,095
YOU, DOES -- ANTITUMOR CD4

4382
02:37:51,095 --> 02:37:54,265
RESPONSE IS MORE COMPLICATED

4383
02:37:54,265 --> 02:37:55,466
THAN CD8 RESPONSE.

4384
02:37:55,466 --> 02:37:57,368
SO I WANT TO BRIEFLY EXPLAIN

4385
02:37:57,368 --> 02:38:02,139
ABOUT THAT.

4386
02:38:02,139 --> 02:38:04,542
THEN CD8 T CELLS, MOST OF THE

4387
02:38:04,542 --> 02:38:05,676
REACTIVITY IS BASED ON THE

4388
02:38:05,676 --> 02:38:09,547
DIRECT RECOGNITION OF TUMORS

4389
02:38:09,547 --> 02:38:11,716
THROUGH -- PRESENTING THE

4390
02:38:11,716 --> 02:38:12,416
EPITOPE.

4391
02:38:12,416 --> 02:38:14,352
VERY SIMILAR THING CAN HAPPEN

4392
02:38:14,352 --> 02:38:15,252
WITH CD4 TOO.

4393
02:38:15,252 --> 02:38:18,055
NOW IN THE CASE OF CD4, THE

4394
02:38:18,055 --> 02:38:20,124
ANTIGEN PROCESSING MECHANISM IS

4395
02:38:20,124 --> 02:38:20,858
SLIGHTLY DIFFERENT BUT AT THE

4396
02:38:20,858 --> 02:38:26,063
END OF THE DAY CD4 T CELLS CAN

4397
02:38:26,063 --> 02:38:28,666
REPRESENT AN EPITOPE PRESENT ON

4398
02:38:28,666 --> 02:38:31,001
THE SURFACE OF THE TUMOR, SO --

4399
02:38:31,001 --> 02:38:32,570
EXIST IN BOTH CASES.

4400
02:38:32,570 --> 02:38:35,339
THE MECHANISMS DOESN'T SEEM TO

4401
02:38:35,339 --> 02:38:41,312
EXIST ON CD8, CD4 UNIQUE

4402
02:38:41,312 --> 02:38:42,513
MECHANISM -- ANTITUMOR MECHANISM

4403
02:38:42,513 --> 02:38:43,748
BY CD4 T CELLS.

4404
02:38:43,748 --> 02:38:45,683
SO THIS HAS BEEN SHOWN MOUSE

4405
02:38:45,683 --> 02:38:47,651
MODEL.

4406
02:38:47,651 --> 02:38:51,055
THE CONCEPT CD4 T CELLS DON'T

4407
02:38:51,055 --> 02:38:53,557
NEED AN MHC EXPRESSION OF TUMOR

4408
02:38:53,557 --> 02:38:57,128
CELLS, IT'S NOT A NEW IDEA.

4409
02:38:57,128 --> 02:38:58,529
THERE WERE TWO MAJOR

4410
02:38:58,529 --> 02:39:02,133
PUBLICATIONS THAT SHOWED THAT

4411
02:39:02,133 --> 02:39:04,535
WORKED IN DEPTH ABOUT HOW THIS

4412
02:39:04,535 --> 02:39:07,171
ANTITUMOR MECHANISM BY CD4 IS

4413
02:39:07,171 --> 02:39:07,705
WORKING.

4414
02:39:07,705 --> 02:39:11,308
ACCORDING TO THEM, SO THE TUMOR

4415
02:39:11,308 --> 02:39:13,144
CELLS SECRETE ANTIGENS.

4416
02:39:13,144 --> 02:39:16,046
THE ANTIGEN IS TAKEN UP BY A PSM

4417
02:39:16,046 --> 02:39:17,982
C WHICH IS RECOGNIZED BY CD4.

4418
02:39:17,982 --> 02:39:20,484
THE CD4 T CELLS SECRETE

4419
02:39:20,484 --> 02:39:22,853
CYTOKINES SUCH AS INTERFERON KA

4420
02:39:22,853 --> 02:39:27,391
GAMMA -- MONOCYTES OR

4421
02:39:27,391 --> 02:39:30,528
NEUTROPHILS.

4422
02:39:30,528 --> 02:39:31,729
SO -- SECRETE EFFECTOR MOLECULES

4423
02:39:31,729 --> 02:39:34,231
SUCH ACINI TRICK OXIDE AND THAT

4424
02:39:34,231 --> 02:39:35,599
RESULTS IN KILLING OF THE TUMOR.

4425
02:39:35,599 --> 02:39:41,405
STILL, THEY DIDN'T HAVE A CLEAR

4426
02:39:41,405 --> 02:39:42,473
EXPLANATION ABOUT WHERE THE

4427
02:39:42,473 --> 02:39:43,707
TUMOR SPECIFICITY COMES FROM.

4428
02:39:43,707 --> 02:39:47,812
THEY DID NOT HAVE THAT KIND OF

4429
02:39:47,812 --> 02:39:51,415
EXPLANATION, OR BECAUSE OF THE

4430
02:39:51,415 --> 02:39:52,483
COMPLEXITY, WE STILL DON'T KNOW

4431
02:39:52,483 --> 02:39:57,121
IF THIS MECHANISM -- YOU CAN

4432
02:39:57,121 --> 02:39:58,656
POTENTIALLY TREAT -- TUMOR SO

4433
02:39:58,656 --> 02:40:00,357
IT'S A VERY -- BUT AT THIS POINT

4434
02:40:00,357 --> 02:40:03,561
WE DON'T KNOW IF IT CAN BE

4435
02:40:03,561 --> 02:40:08,699
TRANSLATABLE TO HUMAN.

4436
02:40:08,699 --> 02:40:11,235
SO I'M TRYING TO ANSWER THE

4437
02:40:11,235 --> 02:40:12,403
QUESTION IF IT IS TRANSLATABLE

4438
02:40:12,403 --> 02:40:13,170
TO HUMAN.

4439
02:40:13,170 --> 02:40:15,573
THAT'S ONE REASON WHY CD4 IS

4440
02:40:15,573 --> 02:40:16,373
IMPORTANT.

4441
02:40:16,373 --> 02:40:18,209
THE SECOND REASON CD4 CAN BE

4442
02:40:18,209 --> 02:40:24,715
IMPORTANT IS THAT THIS IS FROM

4443
02:40:24,715 --> 02:40:28,052
A -- BY MARIAH, SO IN THIS

4444
02:40:28,052 --> 02:40:29,987
STUDY, AS YOU MAY KNOW, IN THE

4445
02:40:29,987 --> 02:40:35,059
CASE OF MELANOMA, CD8 REACTIVITY

4446
02:40:35,059 --> 02:40:37,495
WAS OVERWHELMINGLY DOMINANT, BUT

4447
02:40:37,495 --> 02:40:39,230
IN THE CASE OF -- CANCER, IT'S

4448
02:40:39,230 --> 02:40:40,898
NOT THE CASE.

4449
02:40:40,898 --> 02:40:43,033
ACTUALLY CD4 IS MORE THAN CD8,

4450
02:40:43,033 --> 02:40:48,839
AND IN SOME CASES, I THINK ONLY

4451
02:40:48,839 --> 02:40:51,375
CD4 REACTIVITY, SO THAT MAKES --

4452
02:40:51,375 --> 02:40:52,276
DEPENDING ON THE CASE, IT

4453
02:40:52,276 --> 02:40:54,845
BECOMES AN IMPORTANT REACTIVITY.

4454
02:40:54,845 --> 02:41:00,651
AND THEN THIS IS IN THIS -- THIS

4455
02:41:00,651 --> 02:41:03,621
IS A CLINICAL TRIAL CONDUCTED AT

4456
02:41:03,621 --> 02:41:06,123
THE BRANCH RECENTLY.

4457
02:41:06,123 --> 02:41:07,525
IT'S A CLINICAL PROTOCOL THAT

4458
02:41:07,525 --> 02:41:09,493
TREATED THE GASTROINTESTINAL

4459
02:41:09,493 --> 02:41:15,533
CANCER USING TIL.

4460
02:41:15,533 --> 02:41:18,669
THEN FRANK LOWERY AND STEPHANIE

4461
02:41:18,669 --> 02:41:24,308
GOFF EXAMINED THE ASSOCIATION

4462
02:41:24,308 --> 02:41:27,311
BETWEEN CLINICAL RESPONSE AND

4463
02:41:27,311 --> 02:41:30,281
HIGHER CD4 T-CELL COUNTS.

4464
02:41:30,281 --> 02:41:34,151
IN THIS CASE, CD4 T-CELLS SHOWED

4465
02:41:34,151 --> 02:41:37,621
BETTER ASSOCIATION WITH PARTIAL

4466
02:41:37,621 --> 02:41:37,955
RESPONSE.

4467
02:41:37,955 --> 02:41:40,257
SO I GUESS WE STILL DON'T KNOW

4468
02:41:40,257 --> 02:41:41,892
THE EXACT MECHANISM, BUT IF THIS

4469
02:41:41,892 --> 02:41:47,031
IS THE CASE, AGAIN, CD4 T CELLS

4470
02:41:47,031 --> 02:41:53,170
MAY BE A -- AND THE LAST ONE IS

4471
02:41:53,170 --> 02:41:56,040
ACCUMULATING SUCCESSFUL --

4472
02:41:56,040 --> 02:41:57,975
CLINICAL RESPONSES FOUND WITH

4473
02:41:57,975 --> 02:41:59,310
CD4 T CELLS.

4474
02:41:59,310 --> 02:42:03,347
THE FIRST EXAMPLE IS THE PAPER

4475
02:42:03,347 --> 02:42:08,452
IN WHICH THEY TREATED -- USING

4476
02:42:08,452 --> 02:42:09,587
THE -- CD4 T CELLS.

4477
02:42:09,587 --> 02:42:13,090
IT WAS A SINK  SINGLE CASE BUT S

4478
02:42:13,090 --> 02:42:13,924
RESULTED IN THE COMPLETE

4479
02:42:13,924 --> 02:42:14,592
RESPONSE.

4480
02:42:14,592 --> 02:42:18,963
AND THEN THE SECOND EXAMPLE IS

4481
02:42:18,963 --> 02:42:20,297
AGAIN ERIC TRAN'S PUBLICATION,

4482
02:42:20,297 --> 02:42:27,705
IN THIS CASE -- REACTIVE TIL

4483
02:42:27,705 --> 02:42:31,408
RESULTED IN CLINICAL RESPONSES.

4484
02:42:31,408 --> 02:42:33,077
AND THEN THE THIRD EXAMPLE IS

4485
02:42:33,077 --> 02:42:39,183
THIS IS A TCR TRANSDUCTION STUDY

4486
02:42:39,183 --> 02:42:45,222
USING THE -- RECEPTOR -- AND IN

4487
02:42:45,222 --> 02:42:47,257
THIS CASE TWO COMPLETE RESPONSES

4488
02:42:47,257 --> 02:42:49,226
AGAINST CERVICAL CANCER AND --

4489
02:42:49,226 --> 02:42:52,963
CANCER AND THEN TWO PARTIAL

4490
02:42:52,963 --> 02:42:54,265
RESPONSES AGAINST ESOPHAGEAL

4491
02:42:54,265 --> 02:42:57,635
CANCER AND THEN OSTEOSARCOMA

4492
02:42:57,635 --> 02:42:58,802
AMONG 17 PATIENTS TREATED.

4493
02:42:58,802 --> 02:43:01,071
SO THIS IS AN EXAMPLE OF THE

4494
02:43:01,071 --> 02:43:05,309
COMPLETE RESPONSE WITH --

4495
02:43:05,309 --> 02:43:05,876
CANCER.

4496
02:43:05,876 --> 02:43:09,780
THE LEFT SIDE SCAN IS FROM

4497
02:43:09,780 --> 02:43:11,315
AUGUST TO -- AND THE RIGHT SIDE

4498
02:43:11,315 --> 02:43:12,516
IS FROM 2019.

4499
02:43:12,516 --> 02:43:17,321
YOU CAN SEE THE MULTIPLE

4500
02:43:17,321 --> 02:43:19,390
VISCERAL METASTASES DISAPPEARED

4501
02:43:19,390 --> 02:43:25,429
AFTER THIS THERAPY.

4502
02:43:25,429 --> 02:43:28,565
SO CD4 THERAPY CAN WORK.

4503
02:43:28,565 --> 02:43:30,801
SO BASED ON THESE FINDINGS, I

4504
02:43:30,801 --> 02:43:35,372
STARTED MY EXPERIMENTS.

4505
02:43:35,372 --> 02:43:36,573
SOME EXPERIMENTS I'M GOING TO

4506
02:43:36,573 --> 02:43:38,108
PRESENT ARE ALREADY PUBLISHED,

4507
02:43:38,108 --> 02:43:45,883
BUT I WANTED TO CONFIRM TO SEE

4508
02:43:45,883 --> 02:43:46,650
HOW IT GOES.

4509
02:43:46,650 --> 02:43:49,586
SO I USE THIS MOUSE MODEL, AND T

4510
02:43:49,586 --> 02:43:52,022
CELLS ARE -- REACTIVE CD4 T

4511
02:43:52,022 --> 02:44:00,664
CELLS RESTRICTED BY -- AND THEN

4512
02:44:00,664 --> 02:44:04,835
ISOLATED T CELLS FROM THE TCR

4513
02:44:04,835 --> 02:44:06,904
TRANSGENIC MICE OR USING

4514
02:44:06,904 --> 02:44:10,507
RETROVIRUS TRANSDUCE THE T-CELL

4515
02:44:10,507 --> 02:44:13,477
RECEPTOR TO CD4 SPLENOCYTES.

4516
02:44:13,477 --> 02:44:16,113
THIS TRANSDUCTION EXPERIMENT I

4517
02:44:16,113 --> 02:44:16,980
PERFORM IS BECAUSE THAT'S WHAT

4518
02:44:16,980 --> 02:44:19,149
WE DO WHEN WE DO THE CLINICAL

4519
02:44:19,149 --> 02:44:22,886
TREATMENT, WE TRANSDUCE TCR BY

4520
02:44:22,886 --> 02:44:24,955
RETROVIRUS, SO I WANTED TO MIMIC

4521
02:44:24,955 --> 02:44:26,023
THAT CLINICAL TRIAL SO I TOOK

4522
02:44:26,023 --> 02:44:26,890
THIS WAY.

4523
02:44:26,890 --> 02:44:31,228
FOR THE TUMOR, B16-F10 OR

4524
02:44:31,228 --> 02:44:35,032
B16-F10 WITH H -- LOSS BY

4525
02:44:35,032 --> 02:44:37,968
CRISPR.

4526
02:44:37,968 --> 02:44:40,371
SO B16-F10 RESULTING GAMMA

4527
02:44:40,371 --> 02:44:47,211
TREATMENT DOES NOT EXPRESS --

4528
02:44:47,211 --> 02:44:49,113
MHC BUT WITH INTERFERON

4529
02:44:49,113 --> 02:44:50,247
TREATMENT -- AND IT DOESN'T

4530
02:44:50,247 --> 02:44:52,616
HAPPEN IN THE CASE OF THE CRISPR

4531
02:44:52,616 --> 02:44:57,421
KNOCKED OUT B16 AND THEN ON THE

4532
02:44:57,421 --> 02:44:58,522
RIGHT SIDE I'M SHOWING DIRECT

4533
02:44:58,522 --> 02:45:00,290
RECOGNITION OF THE TUMOR BY THE

4534
02:45:00,290 --> 02:45:04,027
T-CELL, SO THIS T-CELL CAN'T

4535
02:45:04,027 --> 02:45:10,567
DIRECTLY RECOGNIZE THE -- THE

4536
02:45:10,567 --> 02:45:11,769
RESTRICTION ELEMENT AND WHICH

4537
02:45:11,769 --> 02:45:13,270
DOES NOT EXIST IN THE CASE OF

4538
02:45:13,270 --> 02:45:15,739
THE CRISPR KNOCKOUT.

4539
02:45:15,739 --> 02:45:18,375
SO USING THESE I PERFORM THE

4540
02:45:18,375 --> 02:45:19,576
FOLLOWING EXPERIMENT.

4541
02:45:19,576 --> 02:45:23,180
SO THE FIRST IN VIVO MODEL I

4542
02:45:23,180 --> 02:45:27,151
PERFORMED WAS FIRST I INJECTED

4543
02:45:27,151 --> 02:45:30,854
B16 OR H-2A -- KNOCKOUT B16 TO

4544
02:45:30,854 --> 02:45:32,689
MICE AND THEN WAITED FOR 10 OR

4545
02:45:32,689 --> 02:45:37,394
11 DAYS UNTIL TUMOR IS

4546
02:45:37,394 --> 02:45:42,566
ESTABLISHED.

4547
02:45:42,566 --> 02:45:45,836
WE DID A WHOLE BODY IRRADIATION

4548
02:45:45,836 --> 02:45:51,708
AND ON DAY ZERO, I GAVE TYRP1 T

4549
02:45:51,708 --> 02:45:55,045
CELLS IV IN CONJUNCTION WITH

4550
02:45:55,045 --> 02:45:55,612
ANTI-OX40 ANTIBODY.

4551
02:45:55,612 --> 02:46:06,089
SO THIS IS A MODEL BY HIRSCHO

4552
02:46:06,089 --> 02:46:06,857
RN'S GROUP.

4553
02:46:06,857 --> 02:46:10,894
THIS MODEL HAS A STRENGTH, THE

4554
02:46:10,894 --> 02:46:18,468
POTENTIAL FOR -- AGONIST

4555
02:46:18,468 --> 02:46:19,470
AVAILABLE USED IN CLINICAL

4556
02:46:19,470 --> 02:46:23,307
TRIALS AND HAVE SHOWN SAFETY.

4557
02:46:23,307 --> 02:46:27,644
AND THEN THIS METHOD DOES NOT

4558
02:46:27,644 --> 02:46:28,779
NEED VACCINATION.

4559
02:46:28,779 --> 02:46:31,081
SO VACCINATION CAN BE LIMITATION

4560
02:46:31,081 --> 02:46:33,784
IN THE CLINICAL SETTING BECAUSE

4561
02:46:33,784 --> 02:46:35,953
OFTENTIMES THE MUTATIONS ARE

4562
02:46:35,953 --> 02:46:36,887
SPECIFIC TO PATIENTS.

4563
02:46:36,887 --> 02:46:39,923
SO IF YOU HAVE TO PREPARE

4564
02:46:39,923 --> 02:46:43,093
PATIENT-SPECIFIC VACCINES, IT

4565
02:46:43,093 --> 02:46:46,597
BECOMES A HEAVY BURDEN TO OUR

4566
02:46:46,597 --> 02:46:46,797
SITE.

4567
02:46:46,797 --> 02:46:47,698
BUT IN THIS CASE, IT'S NOT

4568
02:46:47,698 --> 02:46:55,472
NEEDED.

4569
02:46:55,472 --> 02:47:04,414
SO THE TOP -- AND THEN THE -- IN

4570
02:47:04,414 --> 02:47:06,850
BOTH CASES, BOTH TUMORS GROW

4571
02:47:06,850 --> 02:47:10,053
RAPIDLY, AND THEN WE HAVE TO

4572
02:47:10,053 --> 02:47:13,357
EUTHANIZE THE MICE.

4573
02:47:13,357 --> 02:47:16,193
AND THEN IF YOU USE THE T-CELL

4574
02:47:16,193 --> 02:47:19,463
AND THEN ANTIOX40, IN BOTH

4575
02:47:19,463 --> 02:47:24,835
CASES, THIS CASE, THERE IS NO

4576
02:47:24,835 --> 02:47:27,871
RESTRICTIONAL ELEMENT -- SO IN

4577
02:47:27,871 --> 02:47:29,406
THIS CASE THIS RESPONSE SEEMS TO

4578
02:47:29,406 --> 02:47:35,612
BE HAPPENING RESULT OF DIRECT

4579
02:47:35,612 --> 02:47:35,946
CYTOTOXICITY.

4580
02:47:35,946 --> 02:47:37,080
FOR THIS KIND OF RESPONSE TO

4581
02:47:37,080 --> 02:47:38,715
HAPPEN, YOU NEED BOTH T CELLS

4582
02:47:38,715 --> 02:47:43,320
AND THE ANTIOX40 BECAUSE

4583
02:47:43,320 --> 02:47:44,021
ANTIOX40 ANTIBODY ALONE DOES NOT

4584
02:47:44,021 --> 02:47:49,893
DO IT OR TYRP1 T CELLS DOES NOT

4585
02:47:49,893 --> 02:47:50,561
DO THAT EITHER.

4586
02:47:50,561 --> 02:47:55,098
SO JUST A QUICK SLIDE SHOWING IT

4587
02:47:55,098 --> 02:47:58,969
IS NOT LINKED TO -- IN THIS CASE

4588
02:47:58,969 --> 02:48:02,139
I USE OVER TUMOR CELLS B16-F10

4589
02:48:02,139 --> 02:48:06,843
OR F10 WITH OVA AND THEN THESE

4590
02:48:06,843 --> 02:48:09,913
MICE WERE TREATED WITH OT-II T

4591
02:48:09,913 --> 02:48:12,382
CELLS IN THIS CASE AND IT WASN'T

4592
02:48:12,382 --> 02:48:15,719
AS STRONG AS TYRP BUT YOU SEE

4593
02:48:15,719 --> 02:48:20,524
OBVIOUS YOU CAN ACHIEVE COMPLETE

4594
02:48:20,524 --> 02:48:22,993
RESPONSE SO IT'S NOT LIMITED TO

4595
02:48:22,993 --> 02:48:24,294
TYRP1.

4596
02:48:24,294 --> 02:48:31,768
IN THIS EXPERIMENT, I EXAMINE

4597
02:48:31,768 --> 02:48:34,905
THIS RESPONSE DEPENDENCY ON

4598
02:48:34,905 --> 02:48:37,107
THOSE HOST T CELLS AND B CELLS

4599
02:48:37,107 --> 02:48:42,779
BY UTILIZING RAD KNOCKOUT MICE.

4600
02:48:42,779 --> 02:48:47,084
THE LEFT MOST IS B16-F10 SO THIS

4601
02:48:47,084 --> 02:48:52,522
IS B16-F10 GIVEN TO NORMAL MICE.

4602
02:48:52,522 --> 02:48:54,858
YOU SEE GOOD RESPONSE.

4603
02:48:54,858 --> 02:49:00,564
THEN SECOND ONE THIS IS A NORMAL

4604
02:49:00,564 --> 02:49:02,332
B6 MOUSE BUT THE TUMOR CELLS

4605
02:49:02,332 --> 02:49:06,436
DIDN'T EXPRESS THE RESTRICTIONAL

4606
02:49:06,436 --> 02:49:07,838
ELEMENT.

4607
02:49:07,838 --> 02:49:10,040
AS I SHOW IN THE PREVIOUS

4608
02:49:10,040 --> 02:49:10,707
EXPERIMENT.

4609
02:49:10,707 --> 02:49:13,343
THE THIRD GROUP IS THE RESULT

4610
02:49:13,343 --> 02:49:15,245
ENDOGENOUS T1B CELLS.

4611
02:49:15,245 --> 02:49:19,449
AGAIN YOU SEE THE RESPONSE.

4612
02:49:19,449 --> 02:49:20,317
THE FOURTH GROUP IS WHEN YOU

4613
02:49:20,317 --> 02:49:24,421
LOSE BOTH THE -- AND

4614
02:49:24,421 --> 02:49:28,091
RESTRICTIONAL ELEMENT, YOU START

4615
02:49:28,091 --> 02:49:32,095
SEEING -- TREATMENT BUT EVERY

4616
02:49:32,095 --> 02:49:35,966
CASE, IF YOU COMPARE BETWEEN THE

4617
02:49:35,966 --> 02:49:37,501
RADIATION CONTROL VERSUS TREATED

4618
02:49:37,501 --> 02:49:43,240
GROUP, YOU DO SEE SIGNIFICANT

4619
02:49:43,240 --> 02:49:47,344
IMPROVEMENT, THERAPEUTIC EFFECT.

4620
02:49:47,344 --> 02:49:49,346
SO THIS TREATMENT CAN'T HAPPEN

4621
02:49:49,346 --> 02:49:54,151
WITHOUT THE HELP OF THE

4622
02:49:54,151 --> 02:49:56,520
ENDOGENOUS B CELLS.

4623
02:49:56,520 --> 02:49:58,422
FOR THE NEXT EXPERIMENT, I

4624
02:49:58,422 --> 02:50:01,258
WANTED TO IDENTIFY THE

4625
02:50:01,258 --> 02:50:05,195
ENDOGENOUS -- WHEN YOU GIVE

4626
02:50:05,195 --> 02:50:06,296
TYRP1 T CELLS TO MICE, WHAT KIND

4627
02:50:06,296 --> 02:50:09,866
OF CELLS ARE BEING AFFECTED?

4628
02:50:09,866 --> 02:50:12,369
IS IT -- THE PUBLICATIONS, ONE

4629
02:50:12,369 --> 02:50:14,337
PUBLICATION SUGGESTS IT'S

4630
02:50:14,337 --> 02:50:16,039
MACROPHAGE, THE OTHER SUGGEST

4631
02:50:16,039 --> 02:50:17,140
NEUTROPHIL, AND THEN I WANTED TO

4632
02:50:17,140 --> 02:50:19,576
TEST IT BY MY HAND.

4633
02:50:19,576 --> 02:50:21,411
I STILL DON'T -- HONESTLY, I

4634
02:50:21,411 --> 02:50:25,382
STILL DON'T HAVE THE ANSWER, BUT

4635
02:50:25,382 --> 02:50:27,918
TO ANSWER THIS QUESTION, I

4636
02:50:27,918 --> 02:50:31,922
PERFORM THIS EXPERIMENT.

4637
02:50:31,922 --> 02:50:34,224
ACTUALLY STILL ONGOING BUT I'D

4638
02:50:34,224 --> 02:50:37,561
LIKE TO SHARE SOME RESULTS OF

4639
02:50:37,561 --> 02:50:37,994
THIS EXPERIMENT.

4640
02:50:37,994 --> 02:50:40,597
THERE WERE FOUR GROUPS.

4641
02:50:40,597 --> 02:50:42,933
THE FIRST TWO GROUPS RECEIVED

4642
02:50:42,933 --> 02:50:45,235
B16-F10 AND THE THIRD AND FOURTH

4643
02:50:45,235 --> 02:50:47,738
GROUP RECEIVED WITHOUT THE

4644
02:50:47,738 --> 02:50:48,705
RESTRICTIONAL ELEMENT.

4645
02:50:48,705 --> 02:50:53,710
AND THEN THE FIRST GROUP WAS THE

4646
02:50:53,710 --> 02:50:58,915
T-CELL WAS MOCK TRANSDUCED T

4647
02:50:58,915 --> 02:51:03,186
CELLS, PLUS ANTIOX 40.

4648
02:51:03,186 --> 02:51:13,163
THE SECOND ONE IS -- THE T CELLS

4649
02:51:13,163 --> 02:51:17,200
WAS THYS IS 1.1.

4650
02:51:17,200 --> 02:51:21,705
THIS IS RESULT FROM THE -- SO

4651
02:51:21,705 --> 02:51:25,075
AFTER THE TREATMENT, I FORGOT TO

4652
02:51:25,075 --> 02:51:27,711
MENTION THIS, AFTER TREATMENT ON

4653
02:51:27,711 --> 02:51:32,749
DAY FOUR, I ISOLATED CD45

4654
02:51:32,749 --> 02:51:35,585
POSITIVE CELLS FROM THE TUMOR,

4655
02:51:35,585 --> 02:51:46,129
AND THEN PERFORMED THE CITE-SEQ

4656
02:51:46,463 --> 02:51:47,197
ANALYSIS.

4657
02:51:47,197 --> 02:51:48,932
THE REASON BEING THIS IS A

4658
02:51:48,932 --> 02:51:50,267
POINT -- I START SEEING THE

4659
02:51:50,267 --> 02:51:52,068
DIFFERENCE IN THE TUMOR SIZE.

4660
02:51:52,068 --> 02:51:54,571
I START SEEING THE TUMOR SHRINK

4661
02:51:54,571 --> 02:51:56,773
AFNLGT SO I WANTED TO SEE WHAT

4662
02:51:56,773 --> 02:51:57,807
WAS THE FIRST THING THAT

4663
02:51:57,807 --> 02:52:00,644
HAPPENS.

4664
02:52:00,644 --> 02:52:06,349
AND THEN SO -- I AM RUNNING

4665
02:52:06,349 --> 02:52:06,883
OVER.

4666
02:52:06,883 --> 02:52:08,752
I'M SORRY.

4667
02:52:08,752 --> 02:52:15,425
SO THIS IS THE RESULT WITH THE

4668
02:52:15,425 --> 02:52:17,160
CD45 -- AS ANALYZED BY SINGLE

4669
02:52:17,160 --> 02:52:18,929
CELL ANALYSIS, AND THEN AS YOU

4670
02:52:18,929 --> 02:52:26,203
CAN SEE, THERE IS CD4 T CELLS --

4671
02:52:26,203 --> 02:52:27,904
AS YOU CAN SEE VERY MINOR

4672
02:52:27,904 --> 02:52:30,407
POPULATION WITHIN THIS CD 45

4673
02:52:30,407 --> 02:52:31,942
POSITIVE CELLS.

4674
02:52:31,942 --> 02:52:34,678
THERE ARE MACROPHAGE -- NSM K

4675
02:52:34,678 --> 02:52:39,849
C -- NK CELLSAND THEN NEUTROPHI.

4676
02:52:39,849 --> 02:52:42,152
I WANTED TO SHOW YOU THE BIG

4677
02:52:42,152 --> 02:52:43,920
PICTURE OF WHAT CHANGE IS

4678
02:52:43,920 --> 02:52:46,756
HAPPENING IN THESE DIFFERENT

4679
02:52:46,756 --> 02:52:49,459
CELLS AND THEN ROUGHLY SPEAKING,

4680
02:52:49,459 --> 02:52:52,762
I THINK YOU CAN SEE MAJOR GENE

4681
02:52:52,762 --> 02:53:01,738
EXPRESSION CHANGE ON THE -- WHEN

4682
02:53:01,738 --> 02:53:05,242
T -- GIVEN TO MICE CARRYING THE

4683
02:53:05,242 --> 02:53:06,209
B16-F10 WITHOUT THE

4684
02:53:06,209 --> 02:53:07,410
RESTRICTIONAL ELEMENT.

4685
02:53:07,410 --> 02:53:09,179
WHEN B16 DOES NOT HAVE THE

4686
02:53:09,179 --> 02:53:10,480
RESTRICTIONAL ELEMENT, YOU SEE A

4687
02:53:10,480 --> 02:53:16,519
STRONGER EFFECT ON THESE OTHER

4688
02:53:16,519 --> 02:53:17,053
CELLS.

4689
02:53:17,053 --> 02:53:22,993
SO IN TERMS OF -- IN THIS -- OF

4690
02:53:22,993 --> 02:53:26,196
DENDRITIC CELLS, THIS SEEMS TO

4691
02:53:26,196 --> 02:53:27,063
BE -- MUCH DIFFERENCE BETWEEN

4692
02:53:27,063 --> 02:53:31,334
THESE GROUPS, AND THEN IN TERMS

4693
02:53:31,334 --> 02:53:33,603
TERMS -- IN THE INTEREST OF

4694
02:53:33,603 --> 02:53:36,306
TIME, THERE IS SOME SIGN OF

4695
02:53:36,306 --> 02:53:37,440
INTERFERON RESPONSE, BUT NOT

4696
02:53:37,440 --> 02:53:40,944
MUCH DIFFERENCE.

4697
02:53:40,944 --> 02:53:43,680
I WANT TO SHOW YOU WHAT HAPPENED

4698
02:53:43,680 --> 02:53:47,217
TO THE CD8 T CELLS, DENDRITIC

4699
02:53:47,217 --> 02:53:48,952
CELLS IN TERMS OF THE NUMBER,

4700
02:53:48,952 --> 02:53:54,424
YOU SEE MORE CD8 T CELLS WHEN

4701
02:53:54,424 --> 02:53:56,826
TYRP1 T CELLS ARE GIVEN TO THE

4702
02:53:56,826 --> 02:53:58,261
RICE -- LOSS.

4703
02:53:58,261 --> 02:54:00,764
AND THEN ALL OF THESE CELLS,

4704
02:54:00,764 --> 02:54:04,034
THIS GRAPH SHOWS THE CD8 T CELLS

4705
02:54:04,034 --> 02:54:09,639
AND ALL THESE ARE -- ALL DERIVED

4706
02:54:09,639 --> 02:54:12,709
FROM -- THAT SURVIVED THE

4707
02:54:12,709 --> 02:54:14,244
OPERATION AND THEN PROLIFERATED

4708
02:54:14,244 --> 02:54:18,181
IN RESPONSE TO THE CD4 T CELLS

4709
02:54:18,181 --> 02:54:21,685
GIVEN TO THESE MICE.

4710
02:54:21,685 --> 02:54:23,553
AND THEN THIS IS SHOWING ON THE

4711
02:54:23,553 --> 02:54:27,290
LEFT SIDE, YOU SEE WHAT HAPPENED

4712
02:54:27,290 --> 02:54:32,429
TO CD8 T CELLS IN B16-F10 -- ON

4713
02:54:32,429 --> 02:54:39,002
THE RIGHT SIDE IS MHC LOSS --

4714
02:54:39,002 --> 02:54:42,505
CD8 T CELLS.

4715
02:54:42,505 --> 02:54:47,310
THE GREEN GENES OR -- PATHWAY

4716
02:54:47,310 --> 02:54:48,845
INVOLVE THE GENES.

4717
02:54:48,845 --> 02:54:51,881
SO IT SHOWS THAT METABOLISM OF T

4718
02:54:51,881 --> 02:54:54,351
CELLS HAVE CHANGED -- SHIFTED

4719
02:54:54,351 --> 02:54:57,187
FROM OX 4 TO -- PATHWAY, AND

4720
02:54:57,187 --> 02:55:01,157
THEN ALSO YOU SEE THE EFFECTOR

4721
02:55:01,157 --> 02:55:03,993
MOLECULE SUCH AS -- GRZ AND SO

4722
02:55:03,993 --> 02:55:06,296
ON, AND IN ADDITION, YOU SEE THE

4723
02:55:06,296 --> 02:55:11,000
GENES THAT ARE ASSOCIATED WITH

4724
02:55:11,000 --> 02:55:12,135
EFFECTOR DIFFERENTIATION.

4725
02:55:12,135 --> 02:55:14,738
YOU SEE THE DOWN REGULATION,

4726
02:55:14,738 --> 02:55:17,140
HERE YOU SEE THE DOWN REGULATION

4727
02:55:17,140 --> 02:55:23,480
OF KF2 OR -- THAT'S BACK TO AND

4728
02:55:23,480 --> 02:55:25,448
THEN -- SO ID2 IS HIGHLY

4729
02:55:25,448 --> 02:55:31,154
EXPRESSED SO THIS -- GIVING

4730
02:55:31,154 --> 02:55:33,690
TYRP1 T CELLS IN THE CONTEXT

4731
02:55:33,690 --> 02:55:35,091
OF -- RESTRICTIONAL ELEMENT

4732
02:55:35,091 --> 02:55:39,262
RESULTED IN THE FURTHER

4733
02:55:39,262 --> 02:55:42,232
DIFFERENTIATION OF ENDOGENOUS

4734
02:55:42,232 --> 02:55:42,899
CD8 T CELLS.

4735
02:55:42,899 --> 02:55:44,300
SO AT THIS POINT, THAT'S ALL I

4736
02:55:44,300 --> 02:55:47,036
HAVE, AND THEN IF I -- I DON'T

4737
02:55:47,036 --> 02:55:53,410
THINK I HAVE TIME TO SUMMARIZE

4738
02:55:53,410 --> 02:55:55,345
BUT -- I'M GOING TO READ THROUGH

4739
02:55:55,345 --> 02:55:56,346
VERY QUICKLY.

4740
02:55:56,346 --> 02:55:58,214
SO THE SIGNIFICANT FREQUENCY OF

4741
02:55:58,214 --> 02:56:01,484
LOSS OF NEOANTIGEN-SPECIFIC

4742
02:56:01,484 --> 02:56:03,186
CLASS I MHC ALLELE IN PATIENT

4743
02:56:03,186 --> 02:56:05,655
TUMORS THE HIGHER PREVALENCE OF

4744
02:56:05,655 --> 02:56:08,091
CD4 NEOANTIGEN REACTIVITIES IN

4745
02:56:08,091 --> 02:56:09,492
NON-MELANOMA EPITHELIAL CANCERS

4746
02:56:09,492 --> 02:56:13,196
AND SEVERAL EXAMPLES OF CD4 T

4747
02:56:13,196 --> 02:56:14,330
CELLS SUCCESSFULLY TREATING

4748
02:56:14,330 --> 02:56:18,368
TUMORS IN HUMANS HIGHLIGHT THE

4749
02:56:18,368 --> 02:56:21,037
GROWING UP IMPORTANCE OF CD4

4750
02:56:21,037 --> 02:56:23,106
T-CELL BASED THERAPIES.

4751
02:56:23,106 --> 02:56:26,075
AND THE CD4 T CELLS APPEAR TO

4752
02:56:26,075 --> 02:56:27,277
MEDIATE ANTITUMOR EFFECTS

4753
02:56:27,277 --> 02:56:28,511
THROUGH THREE KEY MECHANISMS.

4754
02:56:28,511 --> 02:56:30,580
ONE IS ACTIVATION OF HOST

4755
02:56:30,580 --> 02:56:32,749
MACROPHAGES AND THE NEUTROPHILS,

4756
02:56:32,749 --> 02:56:35,185
WHICH IS MHC INDEPENDENT AND

4757
02:56:35,185 --> 02:56:37,320
VERY ATTRACTIVE BUT MECHANISM

4758
02:56:37,320 --> 02:56:39,789
THAT WE DO NOT KNOW IF IT

4759
02:56:39,789 --> 02:56:40,790
TRANSLATES TO HUMAN.

4760
02:56:40,790 --> 02:56:43,226
AND THEN DIRECT RECOGNITION AND

4761
02:56:43,226 --> 02:56:45,161
ACTIVATION OF ENDOGENOUS CD8

4762
02:56:45,161 --> 02:56:46,162
T-CELL RESPONSES.

4763
02:56:46,162 --> 02:56:50,967
AND THEN THE FIRST MECHANISM

4764
02:56:50,967 --> 02:56:52,569
NEEDS FURTHER INVESTIGATION,

4765
02:56:52,569 --> 02:56:54,938
FURTHER STUDY ABOUT THE OTHER

4766
02:56:54,938 --> 02:56:57,040
IMMUNE COMPONENTS IN THE TUMOR

4767
02:56:57,040 --> 02:57:01,077
TO UNDERSTAND BETTER.

4768
02:57:01,077 --> 02:57:04,147
AND THEN -- SO THE LAST POINT IS

4769
02:57:04,147 --> 02:57:06,483
THE POINT THAT I JUST MADE, CD8

4770
02:57:06,483 --> 02:57:10,186
T CELLS ARE BETTER ACTIVATED

4771
02:57:10,186 --> 02:57:12,555
WHEN TUMOR CELLS DID NOT EXPRESS

4772
02:57:12,555 --> 02:57:14,123
THE PLUS 2 MHC.

4773
02:57:14,123 --> 02:57:15,225
OKAY.

4774
02:57:15,225 --> 02:57:16,392
FUTURE PLAN, I WILL SKIP THIS,

4775
02:57:16,392 --> 02:57:18,828
AND THEN THIS IS THE

4776
02:57:18,828 --> 02:57:20,463
ACKNOWLEDGMENT.

4777
02:57:20,463 --> 02:57:22,432
SO SORRY FOR RUNNING OVER.

4778
02:57:22,432 --> 02:57:24,100
I WOULD BE GLAD TO TAKE

4779
02:57:24,100 --> 02:57:24,434
QUESTIONS.

4780
02:57:24,434 --> 02:57:34,277
[APPLAUSE]

4781
02:57:34,277 --> 02:57:39,516
>> ONE QUICK QUESTION AND
THE

4782
02:57:39,516 --> 02:57:41,718
THEN A QUICK COMMENT.

4783
02:57:41,718 --> 02:57:45,522
KEN, YOU THAT FOR EMPHASIZING

4784
02:57:45,522 --> 02:57:47,290
THE IMPORTANCE OF CD4 CELL,

4785
02:57:47,290 --> 02:57:49,459
BECAUSE I WORK ON CD4 CELL FOR A

4786
02:57:49,459 --> 02:57:53,229
LONG TIME AND WITH DR. ROSENBERG

4787
02:57:53,229 --> 02:57:56,499
AND I HAVE -- BUT I WANT TO JUST

4788
02:57:56,499 --> 02:58:04,274
TELL YOU, WE -- IN HUMAN AND --

4789
02:58:04,274 --> 02:58:07,177
AND PARTICULARLY I WANT TO THANK

4790
02:58:07,177 --> 02:58:11,414
NCI FOR SUPPORTING OUR

4791
02:58:11,414 --> 02:58:12,482
PROGRAM -- AND TODAY HERE AND I

4792
02:58:12,482 --> 02:58:19,489
WANT TO TALK WITH YOU MORE.

4793
02:58:19,489 --> 02:58:23,560
THAT IS -- TCR.

4794
02:58:23,560 --> 02:58:25,595
SO WORK FAIRLY WELL IN THE LUNG

4795
02:58:25,595 --> 02:58:27,597
CANCER, BREAST CANCER, COMPLETE

4796
02:58:27,597 --> 02:58:30,066
ELIMINATE CANCER CELL.

4797
02:58:30,066 --> 02:58:31,768
BECAUSE -- FOR FIVE YEARS, I

4798
02:58:31,768 --> 02:58:35,538
NEVER ABLE TO ERADICATE THE

4799
02:58:35,538 --> 02:58:37,273
BREAST CANCER BUT WHEN I START

4800
02:58:37,273 --> 02:58:41,311
WORKING ON CD4 CELL, COMPLETELY

4801
02:58:41,311 --> 02:58:42,378
ERADICATE CANCER CELL.

4802
02:58:42,378 --> 02:58:44,547
IT'S AMAZING RESULT.

4803
02:58:44,547 --> 02:58:44,847
THANK YOU.

4804
02:58:44,847 --> 02:58:45,615
>> VERY INTERESTING.

4805
02:58:45,615 --> 02:58:46,816
I'D LIKE TO TALK ABOUT IT.

4806
02:58:46,816 --> 02:58:47,684
>> OKAY.

4807
02:58:47,684 --> 02:58:49,018
BEFORE WE ADJOURN, I JUST HAVE A

4808
02:58:49,018 --> 02:58:52,722
FEW REMARKS AND SOME

4809
02:58:52,722 --> 02:58:55,124
INSTRUCTIONS.

4810
02:58:55,124 --> 02:58:56,593
I'D LIKE TO JUST SAY HOW PROUD I

4811
02:58:56,593 --> 02:58:58,094
AM TO NOT ONLY HAVE BEEN A

4812
02:58:58,094 --> 02:59:00,396
SURGERY BRANCH ALUMNI, BUT HAVE

4813
02:59:00,396 --> 02:59:04,233
ALSO SPENT THAT COVETED ONE-YEAR

4814
02:59:04,233 --> 02:59:05,768
IMMUNOTHERAPY FELLOWSHIP UNDER

4815
02:59:05,768 --> 02:59:07,203
DR. ROSENBERG, AND I ECHO JIM'S

4816
02:59:07,203 --> 02:59:09,172
COMMENTS THAT THIS IS REALLY A

4817
02:59:09,172 --> 02:59:10,707
LIFE-CHANGING EXPERIENCE.

4818
02:59:10,707 --> 02:59:14,444
AND NOW I JOINED THE VERY

4819
02:59:14,444 --> 02:59:19,382
TALENTED TEAM AT IOVANCE WHO HAD

4820
02:59:19,382 --> 02:59:21,684
A REMARKABLE 2024 WITH THE FOOD

4821
02:59:21,684 --> 02:59:22,185
AND DRUG ADMINISTRATION

4822
02:59:22,185 --> 02:59:26,956
APPROVING THE FIRST

4823
02:59:26,956 --> 02:59:29,359
TUMOR-ACQUIRED AUTOLOGOUS T-CELL

4824
02:59:29,359 --> 02:59:30,927
THERAPY FOR PATIENTS WITH

4825
02:59:30,927 --> 02:59:32,962
REFRACTORY METASTATIC MELANOMA.

4826
02:59:32,962 --> 02:59:34,197
AND REALLY THIS IS THE TIP OF

4827
02:59:34,197 --> 02:59:35,832
THE ICEBERG.

4828
02:59:35,832 --> 02:59:38,034
WE ALSO HAVE AN EXPANDING

4829
02:59:38,034 --> 02:59:41,270
PIPELINE FOR EARLIER INDICATIONS

4830
02:59:41,270 --> 02:59:43,072
AS WELL AS BROADER INDICATIONS.

4831
02:59:43,072 --> 02:59:45,908
SO WE'RE VERY EXCITED ABOUT THE

4832
02:59:45,908 --> 02:59:48,645
WORK THAT WE'VE DONE, YET THAT

4833
02:59:48,645 --> 02:59:49,779
HAS BEEN 50 YEARS IN THE MAKING

4834
02:59:49,779 --> 02:59:51,614
AND NONE OF THAT WOULD BE

4835
02:59:51,614 --> 02:59:53,283
POSSIBLE WITHOUT THE WORK THAT

4836
02:59:53,283 --> 02:59:57,453
YOU HAVE DONE HERE AS A PIONEER,

4837
02:59:57,453 --> 02:59:57,787
DR. ROSENBERG.

4838
02:59:57,787 --> 02:59:59,088
YOUR CLINICAL STAFF, MANY WHOM

4839
02:59:59,088 --> 03:00:02,792
ARE IN THIS ROOM, THE STAFF OF

4840
03:00:02,792 --> 03:00:04,360
THREE NORTHWEST AGAIN, WE'RE SO

4841
03:00:04,360 --> 03:00:05,261
GRATEFUL FOR THAT, WE'RE

4842
03:00:05,261 --> 03:00:07,230
GRATEFUL FOR WHAT YOU'VE DONE

4843
03:00:07,230 --> 03:00:09,198
FOR US, FOR OUR PATIENT, SOME OF

4844
03:00:09,198 --> 03:00:12,001
WHOM ARE ACTUALLY IN THIS ROOM

4845
03:00:12,001 --> 03:00:14,170
TODAY.

4846
03:00:14,170 --> 03:00:16,439
SO THANK YOU FOR THAT, AND

4847
03:00:16,439 --> 03:00:18,307
IOVANCE IS PROUD TO BE A

4848
03:00:18,307 --> 03:00:19,609
SUPPORTER OF TODAY'S SYMPOSIUM.

4849
03:00:19,609 --> 03:00:23,446
SO WE ARE TO RECONVENE AT

4850
03:00:23,446 --> 03:00:25,314
1:20 SHARP, I'M TOLD, SO PLEASE

4851
03:00:25,314 --> 03:00:27,583
BE ON TIME, BUT WE WILL NOW

4852
03:00:27,583 --> 03:00:28,985
ADJOURN FOR THE POSTER AND

4853
03:00:28,985 --> 03:00:29,185
LUNCH.

4854
03:00:29,185 --> 03:00:33,122
THANK YOU.

4855
03:00:33,122 --> 03:00:34,791
THANK YOU FOR COMING, ANOTHER

4856
03:00:34,791 --> 03:00:36,659
THANK YOU FOR THE SPONSOR OF

4857
03:00:36,659 --> 03:00:39,028
LUNCH AND POSTER SESSIONS TODAY

4858
03:00:39,028 --> 03:00:41,431
AS WELL AS REFRESHMENTS AT THE

4859
03:00:41,431 --> 03:00:45,601
BREAKS.

4860
03:00:45,601 --> 03:00:48,971
IT IS MY HONOR TOLL START THE

4861
03:00:48,971 --> 03:00:50,606
ROUNDS OF INTRODUCTIONS BY

4862
03:00:50,606 --> 03:00:51,507
ASKING DR. MONICA BERTAGNOLLI TO

4863
03:00:51,507 --> 03:00:53,476
COME TO THE STAGE.

4864
03:00:53,476 --> 03:00:55,611
SHE'S THE 17th DIRECTOR OF THE

4865
03:00:55,611 --> 03:00:57,847
NIH, SHE IS THE FIRST SURGEON,

4866
03:00:57,847 --> 03:01:03,186
ONLY THE SECOND WOMAN TO EVER

4867
03:01:03,186 --> 03:01:03,653
HOLD THAT POSITION.

4868
03:01:03,653 --> 03:01:09,358
[APPLAUSE] 

4869
03:01:09,358 --> 03:01:11,394
SHE PREVIOUSLY SERVED AS 16th

4870
03:01:11,394 --> 03:01:13,363
DIRECTOR OF NCI, AND I GOT TO

4871
03:01:13,363 --> 03:01:16,032
KNOW HER WHEN SHE WAS RICHARD

4872
03:01:16,032 --> 03:01:18,000
WILSON PROFESSOR OF SURGERY AT

4873
03:01:18,000 --> 03:01:22,271
THE BRIGHAM.

4874
03:01:22,271 --> 03:01:24,140
WITHOUT FURTHER ADO, DR.

4875
03:01:24,140 --> 03:01:25,074
BERTAGNOLLI.

4876
03:01:25,074 --> 03:01:25,541
>> THANK YOU.

4877
03:01:25,541 --> 03:01:25,875
[APPLAUSE]

4878
03:01:25,875 --> 03:01:29,545
I GET THE BEST JOB OF THE DAY, I

4879
03:01:29,545 --> 03:01:34,417
GET TO INTRODUCE OUR DR. STEPHEN

4880
03:01:34,417 --> 03:01:34,684
ROSENBERG.

4881
03:01:34,684 --> 03:01:36,486
LET ME JUST SAY, STEVE HAS BEEN

4882
03:01:36,486 --> 03:01:39,288
ONE OF MY HEROES SINCE 1985.

4883
03:01:39,288 --> 03:01:42,925
THAT WAS THE YEAR I BECAME AN

4884
03:01:42,925 --> 03:01:44,627
INTERN IN SURGERY AT BRIGHAM AND

4885
03:01:44,627 --> 03:01:45,728
WOMEN'S HOSPITAL.

4886
03:01:45,728 --> 03:01:47,463
IN MEDICAL SCHOOL, I WANTED TO

4887
03:01:47,463 --> 03:01:50,266
BE AN IMMUNOLOGIST.

4888
03:01:50,266 --> 03:01:51,234
I LOVED IMMUNOLOGY.

4889
03:01:51,234 --> 03:01:53,035
BUT THE FIRST TIME I ENTERED AN

4890
03:01:53,035 --> 03:01:55,738
OPERATING ROOM I KNEW I HAD TO

4891
03:01:55,738 --> 03:01:57,173
BE A SURGEON.

4892
03:01:57,173 --> 03:02:00,042
IT HAPPENS TO SURGEONS.

4893
03:02:00,042 --> 03:02:01,444
AND I WAS ACTUALLY -- YOU KNOW,

4894
03:02:01,444 --> 03:02:03,346
THEN I THOUGHT, I HAVE TO MAKE A

4895
03:02:03,346 --> 03:02:05,515
DECISION, A CHOICE.

4896
03:02:05,515 --> 03:02:07,216
I'M EITHER GOING TO PURSUE

4897
03:02:07,216 --> 03:02:09,252
SURGERY OR BE AN IMMUNOLOGIST.

4898
03:02:09,252 --> 03:02:12,188
I DECIDED I WOULD DO A SURGERY

4899
03:02:12,188 --> 03:02:12,455
RESIDENCY.

4900
03:02:12,455 --> 03:02:14,690
IT JUST DIDN'T SEEM POSSIBLE TO

4901
03:02:14,690 --> 03:02:16,225
EXCEL IN BOTH FIELDS.

4902
03:02:16,225 --> 03:02:17,760
SO IMAGINE HOW THRILLED I WAS

4903
03:02:17,760 --> 03:02:20,096
WHEN I ENTERED MY INTERNSHIP,

4904
03:02:20,096 --> 03:02:22,932
FOUND OUT IT WAS NOT ONLY

4905
03:02:22,932 --> 03:02:25,034
POSSIBLE TO CONTINUE TO STUDY

4906
03:02:25,034 --> 03:02:27,036
TUMOR IMMUNOLOGY WHILE PURSUING

4907
03:02:27,036 --> 03:02:29,071
A CAREER IN SURGERY, IT WAS

4908
03:02:29,071 --> 03:02:31,340
ACTUALLY HIGHLY ENCOURAGED.

4909
03:02:31,340 --> 03:02:37,013
AND IN FACT, A WIDELY, WIDELY

4910
03:02:37,013 --> 03:02:38,548
ACCLAIMED SURGEON WHO TRAINED AT

4911
03:02:38,548 --> 03:02:41,350
BRIGHAM AND WOMEN'S WAS

4912
03:02:41,350 --> 03:02:42,351
TRANSFORMING THE FIELD OF

4913
03:02:42,351 --> 03:02:43,553
IMMUNOLOGY SHOWING HOW ANTITUMOR

4914
03:02:43,553 --> 03:02:45,121
RESPONSES COULD BE DRIVEN IN

4915
03:02:45,121 --> 03:02:46,322
REAL PEOPLE.

4916
03:02:46,322 --> 03:02:51,527
NOT JUST MICE.

4917
03:02:51,527 --> 03:02:54,163
USING EXOGENOUSLY ADMINISTERED

4918
03:02:54,163 --> 03:02:54,430
CYTOKINES.

4919
03:02:54,430 --> 03:02:55,164
AT BRIGHAM AND WOMEN'S, STEVE

4920
03:02:55,164 --> 03:02:56,232
WAS A VERY BIG DEAL.

4921
03:02:56,232 --> 03:02:59,235
I READ EVERY ONE OF HIS PAPERS,

4922
03:02:59,235 --> 03:03:01,504
HE WAS A ROLE MODEL CRITICAL TO

4923
03:03:01,504 --> 03:03:05,842
MY GROWTH AS A RESEARCHER AND A

4924
03:03:05,842 --> 03:03:06,075
SURGEON.

4925
03:03:06,075 --> 03:03:07,043
HE'S STILL MY HERO.

4926
03:03:07,043 --> 03:03:09,479
I LOVE EVERY MINUTE THAT I GET

4927
03:03:09,479 --> 03:03:10,913
TO SPEND ATTENDING ROSENBERG LAB

4928
03:03:10,913 --> 03:03:12,415
MEETINGS HERE AT NIH.

4929
03:03:12,415 --> 03:03:15,585
IT'S FAR TOO RARE THAT I GET TO

4930
03:03:15,585 --> 03:03:21,057
SPEND A WHOLE LAB MEETING, BUT

4931
03:03:21,057 --> 03:03:22,959
IT'S WONDERFUL.

4932
03:03:22,959 --> 03:03:26,062
STEVE IS ALSO A VERY BIG DEAL AT

4933
03:03:26,062 --> 03:03:26,996
BRIGHAM AND WOMEN'S HOSPITAL FOR

4934
03:03:26,996 --> 03:03:27,964
ANOTHER REASON.

4935
03:03:27,964 --> 03:03:32,335
HE WAS MARRIED TO ALICE

4936
03:03:32,335 --> 03:03:32,802
O'CONNELL.

4937
03:03:32,802 --> 03:03:34,503
THE ALICE O'CONNELL.

4938
03:03:34,503 --> 03:03:36,072
HEAD NURSE, OVERALL DIRECTOR OF

4939
03:03:36,072 --> 03:03:39,976
THE BRIGHAM AND WOMEN'S HOSPITAL

4940
03:03:39,976 --> 03:03:40,710
EMERGENCY ROOM.

4941
03:03:40,710 --> 03:03:43,179
AT THE BRIGHAM, ESPECIALLY IN

4942
03:03:43,179 --> 03:03:44,914
THOSE DAYS, EMERGENCY ROOM WAS

4943
03:03:44,914 --> 03:03:47,617
THE NERVE CENTER OF THE ENTIRE

4944
03:03:47,617 --> 03:03:50,519
HOSPITAL, AND, BOY, YOU WOULD BE

4945
03:03:50,519 --> 03:03:53,723
ABSOLUTELY INSANE TO MESS AROUND

4946
03:03:53,723 --> 03:03:54,891
WITH THE DIRECTOR.

4947
03:03:54,891 --> 03:03:55,157
[LAUGHTER]

4948
03:03:55,157 --> 03:03:56,592
SO I'M TOLD BY THOSE WHO WERE

4949
03:03:56,592 --> 03:03:58,594
THERE AT THE TIME THAT STEVE'S

4950
03:03:58,594 --> 03:03:59,729
RELATIONSHIP WITH ALICE WAS

4951
03:03:59,729 --> 03:04:04,300
ANOTHER THING THAT MADE HIM

4952
03:04:04,300 --> 03:04:04,767
INVINCIBLE.

4953
03:04:04,767 --> 03:04:05,234
[LAUGHTER]

4954
03:04:05,234 --> 03:04:06,702
AND OVER THE YEARS, AS I'VE HAD

4955
03:04:06,702 --> 03:04:08,771
THE PLEASURE OF KNOWING BOTH OF

4956
03:04:08,771 --> 03:04:11,741
THEM, IT'S CLEAR THAT THIS IS

4957
03:04:11,741 --> 03:04:13,709
STILL VERY TRUE TODAY.

4958
03:04:13,709 --> 03:04:14,944
SO, STEVE, WE ALL KNOW YOU'RE

4959
03:04:14,944 --> 03:04:16,445
NOT ONE TO SEEK GLORY FOR

4960
03:04:16,445 --> 03:04:18,347
YOURSELF AND EVENTS LIKE THIS

4961
03:04:18,347 --> 03:04:19,782
MAKE YOU VERY UNCONTRACTABLE.

4962
03:04:19,782 --> 03:04:21,017
WELL, TOO BAD, YOU'LL HAVE TO

4963
03:04:21,017 --> 03:04:24,020
SIT THERE AND TAKE IT, BECAUSE

4964
03:04:24,020 --> 03:04:25,955
WE'RE ALSO PROUD OF YOU AND SO

4965
03:04:25,955 --> 03:04:27,623
GRATEFUL FOR ALL YOU'VE GIVEN TO

4966
03:04:27,623 --> 03:04:29,659
US PERSONALLY AND TO THE ENTIRE

4967
03:04:29,659 --> 03:04:30,927
WORLD.

4968
03:04:30,927 --> 03:04:32,128
A FEW QUICK HIGHLIGHTS.

4969
03:04:32,128 --> 03:04:34,130
STEVE LEFT HIS RESIDENCY TO

4970
03:04:34,130 --> 03:04:40,670
PURSUE Ph.D. IN BIOPHYSICS AT

4971
03:04:40,670 --> 03:04:42,571
HARVARD.

4972
03:04:42,571 --> 03:04:44,206
HE THEN -- HE STUDIED CELL

4973
03:04:44,206 --> 03:04:46,409
MEMBRANES, STRUCTURE OF HUMAN

4974
03:04:46,409 --> 03:04:47,910
CELL MEMBRANES, HE THEN JOINED

4975
03:04:47,910 --> 03:04:50,546
THE PUBLIC HEALTH SERVICE, WAS

4976
03:04:50,546 --> 03:04:52,515
AN IMMUNOLOGY FELLOW AT NATIONAL

4977
03:04:52,515 --> 03:04:54,050
CANCER INSTITUTE, BECAME CHIEF

4978
03:04:54,050 --> 03:04:58,220
OF THE SURGICAL BRANCH HERE AT

4979
03:04:58,220 --> 03:05:01,157
NIH JULY 1, 1974, A POST HE

4980
03:05:01,157 --> 03:05:02,959
STILL HOLDS TODAY.

4981
03:05:02,959 --> 03:05:03,926
TWO HIGHLIGHTS FOR THOSE OF US

4982
03:05:03,926 --> 03:05:06,128
WHO CARE SO MUCH ABOUT WHAT

4983
03:05:06,128 --> 03:05:10,599
HAPPENS TREATING PATIENTS WITH

4984
03:05:10,599 --> 03:05:14,337
CANCER, FDA APPROVAL, 1992, IL-2

4985
03:05:14,337 --> 03:05:24,780
FOR METASTATIC RENAL CELL

4986
03:05:25,881 --> 03:05:26,949
CARCINOMA.

4987
03:05:26,949 --> 03:05:29,085
COUNTLESS OTHER MILESTONES ON

4988
03:05:29,085 --> 03:05:32,388
THE ROAD TO SHOWING THAT

4989
03:05:32,388 --> 03:05:35,057
IMMUNOTHERAPY CAN WORK FOR

4990
03:05:35,057 --> 03:05:38,027
PEOPLE WITH CANCER, FOR PEOPLE

4991
03:05:38,027 --> 03:05:40,796
WITH AUTOIMMUNE DISEASES, FOR

4992
03:05:40,796 --> 03:05:42,698
WHO KNOWS, THE ENTIRE FIELD IS

4993
03:05:42,698 --> 03:05:44,233
SO INCREDIBLY WIDE BECAUSE OF

4994
03:05:44,233 --> 03:05:44,867
STEVE'S WORK.

4995
03:05:44,867 --> 03:05:48,037
I JUST WANT TO END WITH ONE LAST

4996
03:05:48,037 --> 03:05:48,738
THING.

4997
03:05:48,738 --> 03:05:49,805
PERHAPS HIS GREATEST LEGACY, AND

4998
03:05:49,805 --> 03:05:53,509
I THINK HE MIGHT EVEN AGREE WITH

4999
03:05:53,509 --> 03:05:55,478
THIS, ARE THE 400 TRAINEES THAT

5000
03:05:55,478 --> 03:05:58,447
HAVE COME THROUGH THE SURGERY

5001
03:05:58,447 --> 03:06:00,516
BRANCH HERE AT THE NATIONAL

5002
03:06:00,516 --> 03:06:03,252
INSTITUTES OF HEALTH.

5003
03:06:03,252 --> 03:06:05,221
LEADERS THROUGHOUT THE COUNTRY

5004
03:06:05,221 --> 03:06:08,491
IN ACADEMIC MEDICAL CENTERS, IN

5005
03:06:08,491 --> 03:06:10,059
INDUSTRY, IN CLINICAL CARE.

5006
03:06:10,059 --> 03:06:12,128
IN HIS TALK TODAY HE WILL

5007
03:06:12,128 --> 03:06:18,067
DISCUSS HIS LATEST EFFORTS USING

5008
03:06:18,067 --> 03:06:22,304
TUMOR INFILTRATING LYMPHOCYTES

5009
03:06:22,304 --> 03:06:24,807
FOR PATIENTS WITH METASTATIC

5010
03:06:24,807 --> 03:06:25,541
EPITHELIAL CANCER.

5011
03:06:25,541 --> 03:06:27,877
I'M DELIGHTED AND HONORED TO ASK

5012
03:06:27,877 --> 03:06:29,278
DR. STEVE ROSENBERG TO COME TO

5013
03:06:29,278 --> 03:06:29,545
THE STAGE.

5014
03:06:29,545 --> 03:06:31,814
[APPLAUSE]

5015
03:06:31,814 --> 03:06:37,887
 

5016
03:06:37,887 --> 03:06:47,930
 

5017
03:06:50,866 --> 03:06:53,069
>> MONICA, THAT WAS A
WONDERFUL

5018
03:06:53,069 --> 03:06:53,402
INTRODUCTION.

5019
03:06:53,402 --> 03:06:54,837
IT'S AN HONOR TO WORK HERE AT

5020
03:06:54,837 --> 03:06:57,573
THE NIH UNDER YOUR LEADERSHIP.

5021
03:06:57,573 --> 03:07:03,479
SO DELIGHTED THAT YOU'RE HERE. 

5022
03:07:03,479 --> 03:07:05,548
I'M GOING TO VERY BRIEFLY

5023
03:07:05,548 --> 03:07:07,183
SUMMARIZE THIS AFTERNOON HOW WE

5024
03:07:07,183 --> 03:07:09,251
GOT TO THIS PLACE, AND WHERE

5025
03:07:09,251 --> 03:07:14,190
WE'RE HEADING IN THE FIELD OF

5026
03:07:14,190 --> 03:07:14,523
IMMUNOLOGY.

5027
03:07:14,523 --> 03:07:17,359
MANY PEOPLE DON'T REALIZE JUST

5028
03:07:17,359 --> 03:07:19,662
HOW RECENT THE DEVELOPMENT OF

5029
03:07:19,662 --> 03:07:22,298
CELLULAR IMMUNOLOGY WAS.

5030
03:07:22,298 --> 03:07:24,033
IN 1980s, ANTIBODIES WERE

5031
03:07:24,033 --> 03:07:27,803
DESCRIBED AND DOMINATED STUDIES

5032
03:07:27,803 --> 03:07:29,939
OF IMMUNOLOGY UNTIL THE 1960s.

5033
03:07:29,939 --> 03:07:31,574
IN 1958, IN FACT, THE "JOURNAL

5034
03:07:31,574 --> 03:07:34,910
OF IMMUNOLOGY" DID NOT EVEN

5035
03:07:34,910 --> 03:07:35,678
INCLUDE THE WORD "LYMPHOCYTE" IN

5036
03:07:35,678 --> 03:07:42,451
THE  INDEX, RARE CELLS, UNKNOWN

5037
03:07:42,451 --> 03:07:45,521
FUNCTION, CIRCULATING IN LARGE

5038
03:07:45,521 --> 03:07:46,589
NUMBERS.

5039
03:07:46,589 --> 03:07:53,028
STARTING IN THE MID-1960s, ITS

5040
03:07:53,028 --> 03:07:55,931
IMPORTANCE BECAME KNOWN AS AN

5041
03:07:55,931 --> 03:07:57,867
INDICATOR OF ALLOGRAFT

5042
03:07:57,867 --> 03:07:59,702
REJECTION, TO PROTECTION AGAINST

5043
03:07:59,702 --> 03:08:03,973
TRANSFER OF MOUSE TUMORS FROM

5044
03:08:03,973 --> 03:08:05,107
ONE MOUSE TO ANOTHER.

5045
03:08:05,107 --> 03:08:10,779
YOU HAD TO USE LYMPHOCYTES,

5046
03:08:10,779 --> 03:08:14,083
GETTING THE FIELD GOING.

5047
03:08:14,083 --> 03:08:16,018
IN THE 1970s, JULY 1, 1974

5048
03:08:16,018 --> 03:08:18,654
WHEN I CAME TO THE NIH, CHIEF OF

5049
03:08:18,654 --> 03:08:22,057
THE SURGERY BRANCH, THERE WAS NO

5050
03:08:22,057 --> 03:08:24,160
CONVINCING EVIDENCE THAT HUMAN

5051
03:08:24,160 --> 03:08:25,361
LYMPHOCYTES WERE REACTIVE WITH

5052
03:08:25,361 --> 03:08:28,531
CANCER, THAT THERE WAS SUCH A

5053
03:08:28,531 --> 03:08:29,932
THING AS HUMAN CANCER ANTIGENS,

5054
03:08:29,932 --> 03:08:31,567
AND NO EFFECT OF IMMUNOTHERAPY

5055
03:08:31,567 --> 03:08:33,636
FOR CANCER IN HUMANS.

5056
03:08:33,636 --> 03:08:37,072
AND WE MADE SOME ATTEMPTS TO

5057
03:08:37,072 --> 03:08:38,574
UTILIZE THE IMMUNE SYSTEM.

5058
03:08:38,574 --> 03:08:40,876
AN EARLIER SPEAKER MENTIONED THE

5059
03:08:40,876 --> 03:08:43,846
FACT WE TRIED TO IMMUNIZE MANY

5060
03:08:43,846 --> 03:08:45,648
PIGS, AND USED THEIR LYMPHOCYTES

5061
03:08:45,648 --> 03:08:48,651
TRANSFERRED INTO PATIENTS, IT

5062
03:08:48,651 --> 03:08:51,086
WAS A NAIVE EVENT.

5063
03:08:51,086 --> 03:08:53,055
DID NOT CAUSE TUMOR RESPONSES

5064
03:08:53,055 --> 03:08:55,090
BUT AN INDICATION OF THE FACT WE

5065
03:08:55,090 --> 03:08:57,493
WERE THINKING HARD ABOUT WAYS WE

5066
03:08:57,493 --> 03:08:58,627
MIGHT USE THE NATURAL IMMUNE

5067
03:08:58,627 --> 03:09:02,798
SYSTEM THAT A PATIENT HAS TO TRY

5068
03:09:02,798 --> 03:09:05,134
TO TREAT THEIR CANCER.

5069
03:09:05,134 --> 03:09:09,538
VERY IMPORTANT TO THE FIELD WAS

5070
03:09:09,538 --> 03:09:12,408
THE DISCOVERY BY MORGAN RESETTI

5071
03:09:12,408 --> 03:09:14,109
AND GALLO IN 1976, ABOUT 7 YEARS

5072
03:09:14,109 --> 03:09:16,579
LATER THE DNA SEQUENCE OF THE

5073
03:09:16,579 --> 03:09:20,449
GENE CODING TRIAL 2 WAS

5074
03:09:20,449 --> 03:09:27,122
DESCRIBED BY TANAGUCI IN JAPAN. 

5075
03:09:27,122 --> 03:09:29,358
BEGAN WORKING TO EXPRESS IL-2

5076
03:09:29,358 --> 03:09:32,428
AND E. COLI AT HIGH

5077
03:09:32,428 --> 03:09:35,464
CONCENTRATION, DETERMINE

5078
03:09:35,464 --> 03:09:36,031
BIOLOGICAL CHARACTERISTICS,

5079
03:09:36,031 --> 03:09:40,669
BEGAN TO APPLY  USE OF IL-2 IN

5080
03:09:40,669 --> 03:09:42,238
THE HUMAN AND MOUSE THAT MIGHT

5081
03:09:42,238 --> 03:09:46,175
BE ABLE TO RECOGNIZE CANCER.

5082
03:09:46,175 --> 03:09:48,811
THAT BEGAN A SERIES OF EFFORTS,

5083
03:09:48,811 --> 03:09:51,146
KNOWING THAT IN FACT IT WAS

5084
03:09:51,146 --> 03:09:52,948
POSSIBLE TO CAUSE LYMPHOCYTES TO

5085
03:09:52,948 --> 03:09:54,717
EXPAND IN VITRO AND VERY LIKELY

5086
03:09:54,717 --> 03:09:57,553
IN VIVO, WE PERFORMED A SERIES

5087
03:09:57,553 --> 03:09:58,887
OF TRIALS HERE AT THE NATIONAL

5088
03:09:58,887 --> 03:10:00,923
INSTITUTES OF HEALTH, FIRST

5089
03:10:00,923 --> 03:10:03,058
USING NATURAL MAMMALIAN IL-2

5090
03:10:03,058 --> 03:10:05,527
THAT WE OBTAIN FROM DUPONT, MADE

5091
03:10:05,527 --> 03:10:07,096
LARGE AMOUNTS IN OUR OWN LAB TO

5092
03:10:07,096 --> 03:10:09,531
USE FOR TREATMENT OF ANIMAL

5093
03:10:09,531 --> 03:10:09,765
MODELS.

5094
03:10:09,765 --> 03:10:15,070
YOU HEARD A LITTLE BIT THIS

5095
03:10:15,070 --> 03:10:17,573
MORNING LACK CELLS WITH

5096
03:10:17,573 --> 03:10:19,775
RECOMBINANT IL-2, TREATED 16

5097
03:10:19,775 --> 03:10:22,578
PATIENTS WITH NATURAL IL-2, NONE

5098
03:10:22,578 --> 03:10:25,314
RESPONDED, ALL WITH WIDELY

5099
03:10:25,314 --> 03:10:26,849
METASTATIC DISEASE, NONE

5100
03:10:26,849 --> 03:10:31,153
RESPONDED TO LAK CELLS WITH IL-2

5101
03:10:31,153 --> 03:10:34,290
AND USED INCREASES DOSES OF IL-2

5102
03:10:34,290 --> 03:10:37,192
TO ATTEMPT TO TREAT PATIENTS.

5103
03:10:37,192 --> 03:10:39,895
AND SO WE TREATED 66 PATIENTS

5104
03:10:39,895 --> 03:10:40,996
WITH WIDELY METASTATIC CANCER,

5105
03:10:40,996 --> 03:10:41,630
NONE RESPONDED.

5106
03:10:41,630 --> 03:10:44,366
ALL WOULD GO ON TO DIE OF THEIR

5107
03:10:44,366 --> 03:10:45,034
CANCER.

5108
03:10:45,034 --> 03:10:48,637
THEY HAD VARIOUS HISTOLOGIC

5109
03:10:48,637 --> 03:10:54,009
TYPES OF DISEASE.

5110
03:10:54,009 --> 03:10:56,412
UNTIL NOVEMBER OF 1984, WE

5111
03:10:56,412 --> 03:11:00,449
FINALLY UTILIZED A HIGH DOSE

5112
03:11:00,449 --> 03:11:03,419
BOLUS IL-2, HALF-LIFE IN HUMANS,

5113
03:11:03,419 --> 03:11:07,690
DEVELOPED BY JIM YANG, AND IT

5114
03:11:07,690 --> 03:11:10,926
WAS THIS PATIENT WHO GAVE ME HER

5115
03:11:10,926 --> 03:11:12,628
PERMISSION TO USE THIS SLIDE,

5116
03:11:12,628 --> 03:11:15,230
THE FIRST PATIENT WITH

5117
03:11:15,230 --> 03:11:17,533
METASTATIC MELANOMA THAT

5118
03:11:17,533 --> 03:11:18,400
RESPONDED TO INTERLEUKIN-2

5119
03:11:18,400 --> 03:11:22,604
THERAPY, WIDESPREAD MEDICAL NO,

5120
03:11:22,604 --> 03:11:23,238
 NO,

5121
03:11:23,238 --> 03:11:24,673
MA'AM -- MELANOMA, DISEASE FREE

5122
03:11:24,673 --> 03:11:26,542
TODAY 40 YEARS LATER.

5123
03:11:26,542 --> 03:11:27,710
WHEN YOU'RE TRYING TO DO

5124
03:11:27,710 --> 03:11:29,712
SOMETHING AND IT HASN'T EVER

5125
03:11:29,712 --> 03:11:32,348
WORKED, YOU DON'T KNOW WHETHER

5126
03:11:32,348 --> 03:11:33,215
WILL WORK.

5127
03:11:33,215 --> 03:11:34,650
ONCE YOU SEE IT HAPPENS ONCE YOU

5128
03:11:34,650 --> 03:11:36,719
AT LEAST KNOW IT'S POSSIBLE AND

5129
03:11:36,719 --> 03:11:41,090
CAN BEGIN TO WORK WITH IT AND

5130
03:11:41,090 --> 03:11:42,291
WORK ON IMPROVING IT.

5131
03:11:42,291 --> 03:11:44,159
WE WENT ON TO TREAT OVER 400

5132
03:11:44,159 --> 03:11:45,594
PATIENTS HERE IN THE CLINICAL

5133
03:11:45,594 --> 03:11:50,866
CENTER WITH HIGH DOSE IL-2. 

5134
03:11:50,866 --> 03:11:52,568
MODEST RESPONSE RATES.

5135
03:11:52,568 --> 03:11:54,136
THE RESIST RESPONSE WAS 17%,

5136
03:11:54,136 --> 03:11:56,505
HALF OF THOSE PATIENTS HOWEVER

5137
03:11:56,505 --> 03:11:57,039
WERE COMPLETE RESPONDERS.

5138
03:11:57,039 --> 03:11:59,475
AND IF YOU HAD A COMPLETE

5139
03:11:59,475 --> 03:12:03,312
RESPONSE, AS YOU HEARD EARLIER

5140
03:12:03,312 --> 03:12:05,047
THIS MORNING, YOU WERE VERY

5141
03:12:05,047 --> 03:12:06,382
LIKELY TO SUSTAIN THAT COMPLETE

5142
03:12:06,382 --> 03:12:08,884
RESPONSE AND VERY LIKELY BE

5143
03:12:08,884 --> 03:12:11,186
CURED.

5144
03:12:11,186 --> 03:12:12,654
AND THE FDA APPROVED

5145
03:12:12,654 --> 03:12:13,922
INTERLEUKIN-2 FINALLY IN 1992

5146
03:12:13,922 --> 03:12:18,193
FOR PATIENTS WITH METASTATIC

5147
03:12:18,193 --> 03:12:21,897
RENAL CANCER, 1998 FOR PATIENTS

5148
03:12:21,897 --> 03:12:22,831
WITH METASTATIC MELANOMA.

5149
03:12:22,831 --> 03:12:27,803
THAT LED US TO BEGIN STUDYING

5150
03:12:27,803 --> 03:12:29,371
HOW DOES IL-2 MEDIATE REGRESSION

5151
03:12:29,371 --> 03:12:30,472
OF CANCER IN HUMANS.

5152
03:12:30,472 --> 03:12:32,841
AND THAT LED US TO EXAMINE A

5153
03:12:32,841 --> 03:12:33,842
LARGE NUMBER OF CELL TYPES

5154
03:12:33,842 --> 03:12:35,911
WITHIN THE HUMAN PERIPHERAL

5155
03:12:35,911 --> 03:12:39,515
BLOOD, LYMPH NODES, FINALLY

5156
03:12:39,515 --> 03:12:43,819
SETTLED ON CELL CALLED TUMOR

5157
03:12:43,819 --> 03:12:45,487
INFILTRATING LYMPHOCYTE, WITHIN

5158
03:12:45,487 --> 03:12:48,190
THE CANCER STROAMA ITSELF THESE

5159
03:12:48,190 --> 03:12:53,529
ARE IMMUNE CELLS THAT INFILL

5160
03:12:53,529 --> 03:12:55,864
 INFILTRATE

5161
03:12:55,864 --> 03:12:56,965
INTO THE STROMA.

5162
03:12:56,965 --> 03:12:59,735
WHEN YOU TAKE THEM OUT THEY CAN

5163
03:12:59,735 --> 03:13:00,903
RECOGNIZE AUTOLOGOUS TUMOR, IN

5164
03:13:00,903 --> 03:13:03,005
VITRO ASSAYS, PUBLISHED IN A

5165
03:13:03,005 --> 03:13:07,643
MOUSE IN 1986, IN THE HUMAN IN

5166
03:13:07,643 --> 03:13:07,843
1987.

5167
03:13:07,843 --> 03:13:10,345
AND 1988 FINALLY BEGAN THE FIRST

5168
03:13:10,345 --> 03:13:12,648
CLINICAL TRIALS WITH TUMOR

5169
03:13:12,648 --> 03:13:13,549
INFILTRATING LYMPHOCYTES IN

5170
03:13:13,549 --> 03:13:15,250
HUMAN, PUBLISHED THIS IN THE NEW

5171
03:13:15,250 --> 03:13:16,652
ENGLAND JOURNAL OF MEDICINE.

5172
03:13:16,652 --> 03:13:18,954
THESE WERE MODEST RESPONSES.

5173
03:13:18,954 --> 03:13:20,522
THEY TENDED NOT TO BE VERY

5174
03:13:20,522 --> 03:13:23,759
DURABLE BUT DID SHOW THAT IN

5175
03:13:23,759 --> 03:13:26,962
FACT INTERLEUKIN-2 COULD IN

5176
03:13:26,962 --> 03:13:30,232
PATIENTS WITH MELANOMA MEDIATE

5177
03:13:30,232 --> 03:13:35,037
SOME REGRESSIONS OF SUBSTANTIAL

5178
03:13:35,037 --> 03:13:36,138
VOLUMES OF DISEASE.

5179
03:13:36,138 --> 03:13:41,009
WE TREATED 192 PATIENTS IN THE

5180
03:13:41,009 --> 03:13:47,850
CLINICAL CENTER WITH AUTOLOGOUS

5181
03:13:47,850 --> 03:13:51,487
TILL, PUBLISHED 2011, INTRODUCED

5182
03:13:51,487 --> 03:13:52,654
LYMPHODEPLETING CHEMOTHERAPY,

5183
03:13:52,654 --> 03:13:56,191
LARGELY WORKED ON BY MARK

5184
03:13:56,191 --> 03:13:57,526
DUDLEY, ADDED IL-2, FOLLOWING

5185
03:13:57,526 --> 03:13:58,961
ADMINISTRATION OF CELLS TO KEEP

5186
03:13:58,961 --> 03:14:00,229
THOSE CELLS ALIVE, AND FROM

5187
03:14:00,229 --> 03:14:04,700
THOSE MODEST RESULT ALSO THAT WE

5188
03:14:04,700 --> 03:14:08,437
REPORTED, IN SCIENCE IN 1986, WE

5189
03:14:08,437 --> 03:14:11,473
ACHIEVED OBJECTIVE RESPONSE

5190
03:14:11,473 --> 03:14:13,041
RATES BY RHESUS CRITERIA, 56%,

5191
03:14:13,041 --> 03:14:19,047
AND OF THE COMPLETE RESPONDERS

5192
03:14:19,047 --> 03:14:20,749
COMPRISED 25% OF ALL PATIENTS.

5193
03:14:20,749 --> 03:14:23,852
AND OF THE 48 PATIENTS THAT HAD

5194
03:14:23,852 --> 03:14:25,187
A COMPLETE RESPONSE, ONLY 2

5195
03:14:25,187 --> 03:14:28,924
RECEIVED MORE THAN A SINGLE

5196
03:14:28,924 --> 03:14:31,727
TREATMENT.

5197
03:14:31,727 --> 03:14:34,730
YOU HEARD FROM DR. YANG EARLIER.

5198
03:14:34,730 --> 03:14:35,797
THEY CAN EXPAND 10,000-FOLD IN

5199
03:14:35,797 --> 03:14:37,633
THE FIRST TWO WEEKS AFTER THEY

5200
03:14:37,633 --> 03:14:41,537
ARE ADMINISTERED, AND THEY CAN

5201
03:14:41,537 --> 03:14:45,507
RECOGNIZE THE CANCER AND MEDIATE

5202
03:14:45,507 --> 03:14:45,874
ITS DESTRUCTION.

5203
03:14:45,874 --> 03:14:50,212
AGAIN, IF HAD YOU A COMPLETE

5204
03:14:50,212 --> 03:14:52,748
RESPONSE, ONE OF THOSE 48, ONLY

5205
03:14:52,748 --> 03:14:55,751
2 HAD EVER RECURRED IN THE FIRST

5206
03:14:55,751 --> 03:14:58,020
10 YEARS FOLLOWING TREATMENT,

5207
03:14:58,020 --> 03:14:59,521
AND SUBSEQUENTLY.

5208
03:14:59,521 --> 03:15:06,094
WERE VERY LIKELY CURED OF THEIR

5209
03:15:06,094 --> 03:15:06,361
MELANOMA.

5210
03:15:06,361 --> 03:15:11,767
THE FDA, THANKS TO EXTRAORDINARY

5211
03:15:11,767 --> 03:15:13,101
EFFORTS GUY BIOTHERAPEUTICS WHO

5212
03:15:13,101 --> 03:15:15,504
TOOK THIS TO THE FDA REPEATEDLY,

5213
03:15:15,504 --> 03:15:19,675
FINALLY RECEIVED FDA APPROVAL IN

5214
03:15:19,675 --> 03:15:22,511
FEBRUARY OF 2024, JUST SEVERAL

5215
03:15:22,511 --> 03:15:23,645
MONTHS AGO.

5216
03:15:23,645 --> 03:15:26,882
IT'S NOW MORE WIDELY AVAILABLE.

5217
03:15:26,882 --> 03:15:28,216
SO THERE WAS A 36-YEAR INTERVAL

5218
03:15:28,216 --> 03:15:32,354
FROM THE FIRST DESCRIPTION OF

5219
03:15:32,354 --> 03:15:36,525
TIL, IN 1988, TO ITS FDA

5220
03:15:36,525 --> 03:15:38,627
APPROVAL IN WIDESPREAD

5221
03:15:38,627 --> 03:15:41,530
APPLICATION.

5222
03:15:41,530 --> 03:15:43,632
VERY SOON AFTER BEGINNING TO

5223
03:15:43,632 --> 03:15:44,833
WORK WITH CELLS, WE BEGAN TO

5224
03:15:44,833 --> 03:15:47,269
WONDER WHETHER OR NOT IT MIGHT

5225
03:15:47,269 --> 03:15:49,538
BE POSSIBLE TO GENETICALLY

5226
03:15:49,538 --> 03:15:51,073
MODIFY THOSE CELLS AND IMPROVE

5227
03:15:51,073 --> 03:15:53,508
THEIR ACTIVITY.

5228
03:15:53,508 --> 03:15:55,243
AND I BEGAN WORKING WITH FRENCH

5229
03:15:55,243 --> 03:15:57,079
ANDERSON AND MICHAEL BLAZE, HERE

5230
03:15:57,079 --> 03:16:02,284
AT THE NIH, TO SEE IF WE

5231
03:16:02,284 --> 03:16:02,951
COULDN'T GENETICALLY MODIFY

5232
03:16:02,951 --> 03:16:05,220
LYMPHOCYTES, INSERT THEM INTO

5233
03:16:05,220 --> 03:16:07,923
PATIENTS, AND LOOK FOR

5234
03:16:07,923 --> 03:16:09,958
IMPROVEMENTS IN THEIR ACTIVITY.

5235
03:16:09,958 --> 03:16:11,893
INITIAL STUDIES, HOWEVER, DEALT

5236
03:16:11,893 --> 03:16:14,296
WITH A PROPOSAL WE MADE TO A

5237
03:16:14,296 --> 03:16:15,964
VARIETY OF THE REVIEW GROUPS TO

5238
03:16:15,964 --> 03:16:19,468
INSERT A GENE, BACTERIAL GENE

5239
03:16:19,468 --> 03:16:20,602
ENCODING NEOMYCIN

5240
03:16:20,602 --> 03:16:21,236
PHOSPHO-TRANSFORAYS THAT WOULD

5241
03:16:21,236 --> 03:16:22,938
ALLOW US TO TRACK CELLS INSIDE

5242
03:16:22,938 --> 03:16:28,243
THE BODY AFTER THEY WERE

5243
03:16:28,243 --> 03:16:31,546
ADMINISTERED, DISTINGUISH THEM

5244
03:16:31,546 --> 03:16:32,247
FROM ENDOGENOUS CIRCULATING

5245
03:16:32,247 --> 03:16:32,547
LYMPHOCYTES.

5246
03:16:32,547 --> 03:16:36,518
THIS TURNED OUT TO BE QUITE A

5247
03:16:36,518 --> 03:16:37,519
COMPLEX APPROVAL PROCESS, SO I

5248
03:16:37,519 --> 03:16:41,289
TOOK THIS PAGE FROM MY

5249
03:16:41,289 --> 03:16:42,190
NOTEBOOKS, I KEPT TRACK OF THE

5250
03:16:42,190 --> 03:16:44,259
REVIEW GROUPS THAT WE HAD TO GO

5251
03:16:44,259 --> 03:16:47,029
THROUGH, AND A VARIETY OF

5252
03:16:47,029 --> 03:16:50,432
INSTITUTES AT THE NIH BECAUSE IT

5253
03:16:50,432 --> 03:16:53,168
INVOLVED SEVERAL OF US,

5254
03:16:53,168 --> 03:16:55,037
DIFFERENT BRANCHES.

5255
03:16:55,037 --> 03:16:59,174
THE RECOMBINANT DNA ADVISORY

5256
03:16:59,174 --> 03:17:00,475
COMMUNITY, THE RAC, PROVIDED

5257
03:17:00,475 --> 03:17:02,477
FINAL APPROVED BEFORE WE COULD

5258
03:17:02,477 --> 03:17:02,778
BEGIN.

5259
03:17:02,778 --> 03:17:05,480
AND THEY FINALLY HAD A VOTE IN

5260
03:17:05,480 --> 03:17:09,518
DECEMBER OF 1988, TO SEE IF IN

5261
03:17:09,518 --> 03:17:10,319
FACT THEY WOULD APPROVAL OUR

5262
03:17:10,319 --> 03:17:13,188
ABILITY TO DO THIS.

5263
03:17:13,188 --> 03:17:14,923
THE VOTE UNFORTUNATELY WAS 16 IN

5264
03:17:14,923 --> 03:17:17,526
FAVOR, 5 AGAINST.

5265
03:17:17,526 --> 03:17:18,694
JAMES WYNGAARDEN, THEN DIRECTOR

5266
03:17:18,694 --> 03:17:21,063
OF THE NIH, FELT BEFORE, FOR THE

5267
03:17:21,063 --> 03:17:23,365
FIRST TIME HUMAN FOREIGN GENES

5268
03:17:23,365 --> 03:17:25,100
WERE INSERTED INTO HUMANS, HE

5269
03:17:25,100 --> 03:17:27,169
INSISTED THE RAC APPROVE IT

5270
03:17:27,169 --> 03:17:27,569
UNANIMOUSLY.

5271
03:17:27,569 --> 03:17:29,938
WE HAD TO GO BACK THROUGH ALL

5272
03:17:29,938 --> 03:17:31,640
THE REVIEW GROUPS, GIVEN THE

5273
03:17:31,640 --> 03:17:35,544
CHANGES THAT WE HAD TO MAKE,

5274
03:17:35,544 --> 03:17:38,780
FINALLY THEY HAD A REVOTE AND

5275
03:17:38,780 --> 03:17:41,616
VOTED 13 IN FAVOR, 0 AGAINST,

5276
03:17:41,616 --> 03:17:44,486
AND 1 ABSTENTION.

5277
03:17:44,486 --> 03:17:46,154
WE WERE GIVEN PERMISSION TO

5278
03:17:46,154 --> 03:17:47,989
BEGIN, TO UTILIZE THESE GENE

5279
03:17:47,989 --> 03:17:48,990
MODIFIED CELLS, SOMETHING WE'LL

5280
03:17:48,990 --> 03:17:54,996
BE TALKING ABOUT IN A FEW

5281
03:17:54,996 --> 03:17:55,230
MINUTES.

5282
03:17:55,230 --> 03:18:05,774
ONLY TO HAVE JEREMY RIFKE N FILE

5283
03:18:07,676 --> 03:18:11,346
A LAWSUIT, THOUGHT IT WAS

5284
03:18:11,346 --> 03:18:13,415
IMMORAL, SETTLED SIX MONTHS

5285
03:18:13,415 --> 03:18:15,183
LATERN 1989 TREATED THE FIRST

5286
03:18:15,183 --> 03:18:17,352
PATIENT, WENT ON TO TREAT 10

5287
03:18:17,352 --> 03:18:21,523
PATIENTS, FIRST 5 WE REPORTED IN

5288
03:18:21,523 --> 03:18:23,625
NEW ENGLAND JOURNAL, CELLS

5289
03:18:23,625 --> 03:18:28,363
RETROVIRALLY TRANSDUCED TO

5290
03:18:28,363 --> 03:18:29,531
INVERT THIS NEOMYCIN PHOSPHOR

5291
03:18:29,531 --> 03:18:31,266
TRANSFERASE, COULD BE DONE

5292
03:18:31,266 --> 03:18:32,534
SAFELY, PASS QUALITY ASSURANCE,

5293
03:18:32,534 --> 03:18:35,403
QUALITY CONTROL TESTS, AND THAT

5294
03:18:35,403 --> 03:18:39,474
ENABLED US TO BEGIN WORK

5295
03:18:39,474 --> 03:18:42,577
ATTEMPTING TO GENETICALLY MODIFY

5296
03:18:42,577 --> 03:18:43,178
CELLS.

5297
03:18:43,178 --> 03:18:44,980
YOU'LL HEAR FROM RICK MORGAN WHO

5298
03:18:44,980 --> 03:18:46,581
PLAYED A VITAL CONTROL, BUT MANY

5299
03:18:46,581 --> 03:18:48,483
YEARS BEFORE WE COULD INSERT

5300
03:18:48,483 --> 03:18:50,585
GENES THAT HELPED IMPROVE THE

5301
03:18:50,585 --> 03:18:52,087
ABILITY OF THE CELLS TO WORK AND

5302
03:18:52,087 --> 03:18:55,590
YOU'LL HEAR FROM DR. MORGAN I

5303
03:18:55,590 --> 03:19:00,162
THINK NEXT OF OUR STUDIES THAT

5304
03:19:00,162 --> 03:19:03,131
ENABLED US TO PUT T-CELL

5305
03:19:03,131 --> 03:19:05,967
RECEPTORS THAT RECOGNIZED

5306
03:19:05,967 --> 03:19:07,302
MELANOCYTE ANTIGENS INTO

5307
03:19:07,302 --> 03:19:08,703
PATIENTS YOU A AUTOLOGOUS

5308
03:19:08,703 --> 03:19:09,704
LYMPHOCYTES, COULD INSERT CELLS

5309
03:19:09,704 --> 03:19:12,140
AFTER GROWING THEM IN IL-2 IN

5310
03:19:12,140 --> 03:19:14,176
PATIENTS, SIX OF THE FIRST 20

5311
03:19:14,176 --> 03:19:15,510
PATIENTS WITH METASTATIC

5312
03:19:15,510 --> 03:19:18,980
MELANOMA HAVE AN OBJECTIVE

5313
03:19:18,980 --> 03:19:20,215
RESPONSE, WE WERE OFF AND

5314
03:19:20,215 --> 03:19:25,520
RUNNING TO FIND BETTER WAYS TO

5315
03:19:25,520 --> 03:19:27,756
INSERT T CELL RECEPTORS AND

5316
03:19:27,756 --> 03:19:29,524
GENES TO IMPROVE THE ACTIVITY OF

5317
03:19:29,524 --> 03:19:29,958
THE CELLS.

5318
03:19:29,958 --> 03:19:33,128
THAT LED FINALLY, NOT FINALLY,

5319
03:19:33,128 --> 03:19:35,564
BUT LED EVENTUALLY TO OF THE

5320
03:19:35,564 --> 03:19:39,801
DEVELOPMENT OF CAR-T CELLS,

5321
03:19:39,801 --> 03:19:43,071
TARGETING RECEPTORS FOR CD19, A

5322
03:19:43,071 --> 03:19:44,372
CELL SURFACE MOLECULE EXPRESSED

5323
03:19:44,372 --> 03:19:48,743
ON NORMAL B LYMPHOCYTES AND MOST

5324
03:19:48,743 --> 03:19:53,048
B CELL MALIGNANCIES, JIM

5325
03:19:53,048 --> 03:19:53,882
COKENKERFER CAME TO MY LAB WITH

5326
03:19:53,882 --> 03:19:56,017
THE IDEA WE SHOULD APPLY TO

5327
03:19:56,017 --> 03:19:57,853
HUMANS, WORKING IN ANIMAL MODELS

5328
03:19:57,853 --> 03:19:59,087
PRECEDED EVERYTHING WE DID IN

5329
03:19:59,087 --> 03:20:00,589
THE HUMAN.

5330
03:20:00,589 --> 03:20:05,160
HE FIRST SHOWED THAT CD19

5331
03:20:05,160 --> 03:20:09,197
TRANSDUCED CELLS TO ELIMINATE

5332
03:20:09,197 --> 03:20:10,532
LYMPHOMAS IN SYNGENEIC MOUSE

5333
03:20:10,532 --> 03:20:13,368
MODELS AND REPORTED FIRST

5334
03:20:13,368 --> 03:20:15,370
INSTANCE OF HUMAN ANTI-CDCAR

5335
03:20:15,370 --> 03:20:17,005
MEDIATING REGRESSION OF LYMPHOMA

5336
03:20:17,005 --> 03:20:19,107
IN HUMANS, FIRST TEN PATIENTS WE

5337
03:20:19,107 --> 03:20:24,212
TREATED IN THE SURGERY BRANCH 6

5338
03:20:24,212 --> 03:20:25,213
EXPERIENCED COMPLETE RESPONSE,

5339
03:20:25,213 --> 03:20:30,485
WIDELY PICKETED UP - PICKED UP

5340
03:20:30,485 --> 03:20:31,086
BY INVESTIGATORS, APPROVED BY

5341
03:20:31,086 --> 03:20:35,290
THE FOOD AND DRUG ADMINISTRATION

5342
03:20:35,290 --> 03:20:35,724
IN 2017.

5343
03:20:35,724 --> 03:20:39,127
THIS IS A PROBLEM WE FACE IN

5344
03:20:39,127 --> 03:20:40,762
CANCER IN THE UNITED STATES.

5345
03:20:40,762 --> 03:20:43,665
STATISTICS OF THE AMERICAN

5346
03:20:43,665 --> 03:20:45,133
CANCER SOCIETY, OVER 600,000

5347
03:20:45,133 --> 03:20:48,203
DEATHS IN THE UNITED STATES EACH

5348
03:20:48,203 --> 03:20:51,373
YEAR FROM CANCER.

5349
03:20:51,373 --> 03:20:54,442
90% OF THEM RESULT FROM THE

5350
03:20:54,442 --> 03:20:55,610
GROWTH OF SOLID EPITHELIAL

5351
03:20:55,610 --> 03:20:56,745
CANCERS, ALMOST ALL OF THE

5352
03:20:56,745 --> 03:20:58,780
ORGANS IN THE BODY CONTAIN

5353
03:20:58,780 --> 03:21:04,819
DUCTS, LINING OF THOSE DUCT ARE

5354
03:21:04,819 --> 03:21:07,222
EPITHELIAL CELLS, MISTAKES ARE

5355
03:21:07,222 --> 03:21:12,360
MAKE, MUTATIONS RESULT IN MOST

5356
03:21:12,360 --> 03:21:12,794
CANCERS.

5357
03:21:12,794 --> 03:21:16,932
AND SO ABOUT SIX OR SEVEN YEARS

5358
03:21:16,932 --> 03:21:19,401
AGO, WE STARTED TO DEVOTE ALL OF

5359
03:21:19,401 --> 03:21:21,136
OUR EFFORTS TO TRYING TO FIND

5360
03:21:21,136 --> 03:21:25,640
WAYS TO USE THE IMMUNE SYSTEM TO

5361
03:21:25,640 --> 03:21:28,376
TARGET THE SOLID EPITHELIAL

5362
03:21:28,376 --> 03:21:30,445
CANCERS THAT RESULT IN 90% OF

5363
03:21:30,445 --> 03:21:32,747
ALL PATIENTS WHO DIE OF CANCER

5364
03:21:32,747 --> 03:21:35,383
TODAY. 

5365
03:21:35,383 --> 03:21:39,421
THAT'S TURNED OUT TO BE QUITE A

5366
03:21:39,421 --> 03:21:40,288
THORNY PROBLEM.

5367
03:21:40,288 --> 03:21:41,056
MAJOR CHALLENGE COULD BE

5368
03:21:41,056 --> 03:21:43,892
FRONTING ALL OF ONCOLOGY BUT

5369
03:21:43,892 --> 03:21:45,093
CERTAINLY CANCER IMMUNOTHERAPY

5370
03:21:45,093 --> 03:21:46,094
IS DEVELOPMENT OF EFFECTIVE

5371
03:21:46,094 --> 03:21:47,629
IMMUNOTHERAPIES FOR THAT GROUP

5372
03:21:47,629 --> 03:21:49,731
OF PATIENTS THAT CANNOT BE CURED

5373
03:21:49,731 --> 03:21:51,833
BY ANY AVAILABLE TREATMENT.

5374
03:21:51,833 --> 03:21:53,902
THE CHECKPOINT MODULATORS HAVE

5375
03:21:53,902 --> 03:21:55,837
HAD MAJOR IMPACT ON ONCOLOGY,

5376
03:21:55,837 --> 03:21:58,573
BUT IN FACT SOLID EPITHELIAL

5377
03:21:58,573 --> 03:22:02,377
CANCERS, G.I. CANCERS, BREAST

5378
03:22:02,377 --> 03:22:05,347
CANCER, OTHERS, TEND NOT TO BE

5379
03:22:05,347 --> 03:22:08,650
RESPONSIVE TO THE CHECKPOINTS.

5380
03:22:08,650 --> 03:22:13,054
AND SO WE BEGAN A SERIES OF

5381
03:22:13,054 --> 03:22:15,056
EFFORTS TO ASK WHETHER OR NOT

5382
03:22:15,056 --> 03:22:20,228
ADOPTIVE CELL THERAPY COULD BE

5383
03:22:20,228 --> 03:22:23,765
EFFECTIVE FOR TREATMENT OF SOLID

5384
03:22:23,765 --> 03:22:24,299
CANCERS.

5385
03:22:24,299 --> 03:22:25,667
I'LL TALK ABOUT THREE APPROACHES

5386
03:22:25,667 --> 03:22:29,037
NOW IN PROGRESS IN THE SURGERY

5387
03:22:29,037 --> 03:22:31,006
BRANCH, ATTEMPTING TO USE

5388
03:22:31,006 --> 03:22:35,343
AUTOLOGOUS LYMPHOCYTES TO TARGET

5389
03:22:35,343 --> 03:22:37,679
THESE SOLID EPITHELIAL CANCERS.

5390
03:22:37,679 --> 03:22:39,848
WE TRY TO USE TIL.

5391
03:22:39,848 --> 03:22:44,586
AS WE GREW THEM FROM MELANOMAS

5392
03:22:44,586 --> 03:22:47,355
TO TREAT, IT DID NOT WORK.

5393
03:22:47,355 --> 03:22:49,524
MELANOMA, YOU HAVE TO TAKE ANY

5394
03:22:49,524 --> 03:22:53,862
LIMB LOW SITES -- LYMPHOCYTES,

5395
03:22:53,862 --> 03:22:56,564
PUT THEM IN A TUMOR, LET THEM

5396
03:22:56,564 --> 03:22:59,067
GROW, IF YOU ADMINISTER THEM

5397
03:22:59,067 --> 03:23:01,036
FOLLOWING CHEMOTHERAPY INDUCE

5398
03:23:01,036 --> 03:23:01,836
ANTES TUMOR RESPONSES IN OVER

5399
03:23:01,836 --> 03:23:05,807
HALF OF MEDICAL  MELANOMA PATIE.

5400
03:23:05,807 --> 03:23:09,511
THAT DOES NOT WORK IN SOLID

5401
03:23:09,511 --> 03:23:12,580
EPITHELIAL PATIENTS, MUCH LESS

5402
03:23:12,580 --> 03:23:13,248
RESPONSIVE TO IMMUNOLOGIC

5403
03:23:13,248 --> 03:23:15,350
MANEUVERS, AND THAT MEANT WE HAD

5404
03:23:15,350 --> 03:23:16,951
TO SOMEHOW SEE IF THERE WERE

5405
03:23:16,951 --> 03:23:18,086
LYMPHOCYTES IN THESE PATIENTS

5406
03:23:18,086 --> 03:23:19,954
THAT WE COULD SELECT AND

5407
03:23:19,954 --> 03:23:25,527
SELECTIVELY GROW THEM TO SEE IF

5408
03:23:25,527 --> 03:23:31,633
WE COULDN'T CAUSE ANTITUMOR

5409
03:23:31,633 --> 03:23:32,400
RESPONSES.

5410
03:23:32,400 --> 03:23:33,535
AN IMPORTANT CLUE ASKING WHETHER

5411
03:23:33,535 --> 03:23:36,671
OR NOT -- FINDING WHAT TIL WERE

5412
03:23:36,671 --> 03:23:38,440
RECOGNIZING ON TUMORS WAS OUR

5413
03:23:38,440 --> 03:23:41,509
OBSERVATION THAT THERE WAS NO

5414
03:23:41,509 --> 03:23:42,777
OFF-TUMOR ON-TARGET TOXICITY IN

5415
03:23:42,777 --> 03:23:45,213
PATIENTS, THAT IS NORMAL CELLS

5416
03:23:45,213 --> 03:23:46,414
WERE NOT INTERFERED WITH, AND

5417
03:23:46,414 --> 03:23:50,018
THAT LED US TO EXPLORE THE ROLE

5418
03:23:50,018 --> 03:23:51,786
OF THE MOST SPECIFIC VARIATION

5419
03:23:51,786 --> 03:23:55,290
IN CANCER COMPARED TO NORMAL

5420
03:23:55,290 --> 03:23:57,625
CELLS, THAT IS ACCUMULATION OF

5421
03:23:57,625 --> 03:23:59,227
CANCER MUTATIONS, ASK WHETHER OR

5422
03:23:59,227 --> 03:24:01,196
NOT COULD SPECIFIC TARGETING OF

5423
03:24:01,196 --> 03:24:04,499
THESE ANTIGENS IF THEY WERE

5424
03:24:04,499 --> 03:24:06,935
IMMUNOGENIC LEAD TO TUMOR

5425
03:24:06,935 --> 03:24:07,635
REGRESSION.

5426
03:24:07,635 --> 03:24:09,437
THE ADVANTAGE OF TARGETING

5427
03:24:09,437 --> 03:24:11,272
MUTATIONS AS A TARGET VIRTUALLY

5428
03:24:11,272 --> 03:24:13,408
ALL CANSERS IS HAVE MUTATIONS IF

5429
03:24:13,408 --> 03:24:15,310
ONE COULD DEVELOP AND APPROACH

5430
03:24:15,310 --> 03:24:16,211
TARGET MUTATIONS ONE MIGHT

5431
03:24:16,211 --> 03:24:18,847
POTENTIALLY BE ABLE TO TREAT A

5432
03:24:18,847 --> 03:24:25,153
WIDE VARIETY OF DIFFERENT CANCER

5433
03:24:25,153 --> 03:24:25,353
TYPES.

5434
03:24:25,353 --> 03:24:25,887
THAT LED INVESTIGATORS IN

5435
03:24:25,887 --> 03:24:28,356
SURGERY BRANCH TO DEVELOP A

5436
03:24:28,356 --> 03:24:29,791
BLUEPRINT FOR IDENTIFYING

5437
03:24:29,791 --> 03:24:32,093
MUTATION REACTIVE CELLS AND

5438
03:24:32,093 --> 03:24:32,827
COMMON EPITHELIAL CANCERS,

5439
03:24:32,827 --> 03:24:35,196
RESECT TUMOR IF YOU JUST FOLLOW

5440
03:24:35,196 --> 03:24:39,801
THIS CLOCKWISE, WE WOULD RESECT

5441
03:24:39,801 --> 03:24:42,337
THE TUMOR, ISOLATE THE GENOMIC

5442
03:24:42,337 --> 03:24:45,607
DNA AND RNA, WHOLE EXOME

5443
03:24:45,607 --> 03:24:47,775
TRANSCRIPTOME SEQUENCING TO

5444
03:24:47,775 --> 03:24:50,078
DETERMINE WHICH GENES WERE BEING

5445
03:24:50,078 --> 03:24:50,345
EXPRESSED.

5446
03:24:50,345 --> 03:24:54,149
WE THEN IN BRIEF WOULD THEN

5447
03:24:54,149 --> 03:24:57,685
SYNTHESIZE 25 SURROUNDING EVERY

5448
03:24:57,685 --> 03:24:59,387
NON-SYNONYMOUS MUTATION IN THE

5449
03:24:59,387 --> 03:25:06,227
CANCER COMPARED TO NORMAL CELLS 

5450
03:25:06,227 --> 03:25:07,896
AND USING PEPTIDES 25 PEPTIDES

5451
03:25:07,896 --> 03:25:09,931
WITH MUTATION IN THE MIDDLE OR

5452
03:25:09,931 --> 03:25:14,636
MANY GENES INSERTED INTO A

5453
03:25:14,636 --> 03:25:15,370
PATIENT'S ANTIGEN-PRESENTING

5454
03:25:15,370 --> 03:25:17,839
CELLS THAT WOULD PRESENT THOSE

5455
03:25:17,839 --> 03:25:20,141
ANTIGENS ON MHC MOLECULES OF

5456
03:25:20,141 --> 03:25:21,943
THAT PATIENT, WOULD CULTURE TIL

5457
03:25:21,943 --> 03:25:23,711
THAT CAUSED TUMOR REGRESSIONS IN

5458
03:25:23,711 --> 03:25:25,680
PATIENTS, SOME THAT DID NOT.

5459
03:25:25,680 --> 03:25:27,849
CO-CULTURE THAT WITH THESE

5460
03:25:27,849 --> 03:25:28,616
ANTIGEN-PRESENTING CELLS

5461
03:25:28,616 --> 03:25:30,618
EXPRESSING ALL OF MUTATIONS IN

5462
03:25:30,618 --> 03:25:35,089
THAT CANCER, AND BY IMMUNOLOGIC

5463
03:25:35,089 --> 03:25:36,658
ASSAYS INTERFERON GAMMA

5464
03:25:36,658 --> 03:25:41,429
SECRETION, UPREGULATION OF

5465
03:25:41,429 --> 03:25:42,764
ACTIVATION MOLECULES SUCH AS OX

5466
03:25:42,764 --> 03:25:44,632
40 COULD IDENTIFY IN POOLS

5467
03:25:44,632 --> 03:25:48,670
ANTIGENS THAT WERE BEING

5468
03:25:48,670 --> 03:25:51,072
RECOGNIZED BY TIL CELLS.

5469
03:25:51,072 --> 03:25:54,976
THE KEY AGAIN WAS TO TAKE THIS

5470
03:25:54,976 --> 03:25:58,146
25 MER WITH NON-SYNONYMOUS

5471
03:25:58,146 --> 03:26:00,815
MUTATION IN THE MIDDLE, T CELLS

5472
03:26:00,815 --> 03:26:02,784
WILL RECOGNIZE PEPTIDES 9 TO 25

5473
03:26:02,784 --> 03:26:04,385
AMINO ACIDS ON THE SURFACE,

5474
03:26:04,385 --> 03:26:06,221
PUTTING THE MUTATION IN THE

5475
03:26:06,221 --> 03:26:09,224
MIDDLE OF THIS CONSTRUCT

5476
03:26:09,224 --> 03:26:14,195
SURROUNDED BY NORMAL AMINO ACID,

5477
03:26:14,195 --> 03:26:16,831
EVERY POTENTIAL 9 TO 25 PEPTIDE

5478
03:26:16,831 --> 03:26:20,101
WOULD BE POTENTIALLY EXPRESSED

5479
03:26:20,101 --> 03:26:23,738
IN THIS 25 MER, AND BY THIS KIND

5480
03:26:23,738 --> 03:26:26,808
OF ASSAY, NO NEED TO PREDICT

5481
03:26:26,808 --> 03:26:27,575
PEPTIDE BINDING OF THESE

5482
03:26:27,575 --> 03:26:28,676
MUTATION, ALL WERE BEING TESTED

5483
03:26:28,676 --> 03:26:31,913
AT THE SAME TIME.

5484
03:26:31,913 --> 03:26:33,147
ALL CANDIDATE PEPTIDES AND MHC

5485
03:26:33,147 --> 03:26:35,550
LOCI, OF COURSE A PEPTIDE

5486
03:26:35,550 --> 03:26:37,318
PRESENTED ON MHC ON THE SURFACE

5487
03:26:37,318 --> 03:26:38,820
THAT IS RECOGNIZED BY IMMUNE

5488
03:26:38,820 --> 03:26:41,522
CELLS, AND THERE WERE NO TUMOR

5489
03:26:41,522 --> 03:26:42,457
CELL LINES NECESSARY.

5490
03:26:42,457 --> 03:26:43,958
IT'S VERY DIFFICULT TO GROW

5491
03:26:43,958 --> 03:26:45,693
EXCEPT FOR MELANOMA AND CERTAIN

5492
03:26:45,693 --> 03:26:48,529
OTHER CANCERS, DIFFICULT TO GROW

5493
03:26:48,529 --> 03:26:52,934
LONG-TERM LINES OF THE COMMON

5494
03:26:52,934 --> 03:26:54,369
EPITHELIAL CANCERS, BY STRINGING

5495
03:26:54,369 --> 03:26:55,670
MUTATIONS TOGETHER WE HAVE AN

5496
03:26:55,670 --> 03:26:59,607
AVATAR OF THE TUMOR ITSELF THAT

5497
03:26:59,607 --> 03:27:02,010
WE COULD STUDY.

5498
03:27:02,010 --> 03:27:05,446
WE THEN STUDIED MANY PATIENTS

5499
03:27:05,446 --> 03:27:09,517
WITH MELANOMA, BUT 130

5500
03:27:09,517 --> 03:27:12,420
CONSECUTIVE PATIENTS WITH

5501
03:27:12,420 --> 03:27:14,522
GASTROINTESTINAL CANCERS.

5502
03:27:14,522 --> 03:27:17,692
MEDIAN OF 123 MUTATIONS PER

5503
03:27:17,692 --> 03:27:18,259
CELL.

5504
03:27:18,259 --> 03:27:23,998
THESE 130 PATIENTS THEREFORE HAD

5505
03:27:23,998 --> 03:27:24,532
20,046 MUTATIONS, SCREENED

5506
03:27:24,532 --> 03:27:25,533
INDIVIDUALLY 15,000 OF THOSE

5507
03:27:25,533 --> 03:27:28,169
MUTATIONS, THEY WERE THE ONES

5508
03:27:28,169 --> 03:27:29,504
BEING EXPRESSED IN THE TUMOR AND

5509
03:27:29,504 --> 03:27:34,008
BY DOING THAT WE COULD IDENTIFY

5510
03:27:34,008 --> 03:27:35,276
210 IMMUNOGENIC MUTATIONS,

5511
03:27:35,276 --> 03:27:38,079
MUTATIONS RECOGNIZED BY A

5512
03:27:38,079 --> 03:27:42,317
PATIENT'S T CELL, IN THESE 130

5513
03:27:42,317 --> 03:27:42,583
PATIENTS.

5514
03:27:42,583 --> 03:27:44,218
INTERESTINGLY 1.3% OF ALL OF THE

5515
03:27:44,218 --> 03:27:46,187
MUTATIONS TURNED OUT TO BE

5516
03:27:46,187 --> 03:27:46,921
IMMUNOGENIC, AND THAT'S A NUMBER

5517
03:27:46,921 --> 03:27:48,790
THAT TURNED OUT TO BE THE CASE

5518
03:27:48,790 --> 03:27:51,259
FOR VIRTUALLY EVERY TUMOR WE

5519
03:27:51,259 --> 03:27:52,493
LOOKED AT, MELANOMA, BREAST

5520
03:27:52,493 --> 03:27:54,562
CANCERS, AND OTHERS.

5521
03:27:54,562 --> 03:27:56,197
INTERESTINGLY, HALF OF THE CELLS

5522
03:27:56,197 --> 03:27:59,434
THAT RECOGNIZE THESE TUMOR

5523
03:27:59,434 --> 03:28:03,204
ANTIGENS, MUTATED ANTIGENS, WERE

5524
03:28:03,204 --> 03:28:05,440
CD8, HALF CD4, AND THE BIG

5525
03:28:05,440 --> 03:28:08,609
SURPRISE IN THIS WAS THAT OF

5526
03:28:08,609 --> 03:28:09,544
THESE 210 NEOANTIGENS RECOGNIZED

5527
03:28:09,544 --> 03:28:13,381
BY A PATIENT'S T CELLS, 209 WERE

5528
03:28:13,381 --> 03:28:15,249
ABSOLUTELY UNIQUE ONLY TO THE

5529
03:28:15,249 --> 03:28:17,385
PATIENT THAT BORE THAT CANCER

5530
03:28:17,385 --> 03:28:19,354
AND WAS NOT SHARED BY ANY OTHER

5531
03:28:19,354 --> 03:28:19,988
PATIENT.

5532
03:28:19,988 --> 03:28:22,523
THE ONLY ANTIGEN THAT WAS SHARED

5533
03:28:22,523 --> 03:28:28,229
BY TWO PATIENTS WAS A KRAS G12 D

5534
03:28:28,229 --> 03:28:31,399
MUTATION RESTRICTED BY CW 0802,

5535
03:28:31,399 --> 03:28:34,702
AND THAT POINTED TO ONE OF THE

5536
03:28:34,702 --> 03:28:37,405
POTENTIAL PROBLEMS OF THE NEED

5537
03:28:37,405 --> 03:28:38,272
FOR SPECIALIZATION,

5538
03:28:38,272 --> 03:28:39,707
PERSONALIZATION OF TREATMENTS

5539
03:28:39,707 --> 03:28:41,275
BECAUSE EACH PATIENT WAS

5540
03:28:41,275 --> 03:28:45,079
RECOGNIZING SOMETHING DIFFERENT

5541
03:28:45,079 --> 03:28:47,582
IN THEIR OWN CANCER.

5542
03:28:47,582 --> 03:28:51,185
WE STUDIED 205 CONSECUTIVE

5543
03:28:51,185 --> 03:28:54,589
PATIENTS, A VARIETY OF CANCER,

5544
03:28:54,589 --> 03:28:56,357
GASTROINTESTINAL, BREAST, SMALL

5545
03:28:56,357 --> 03:28:58,192
CELL LUNG CANCER, OVARIAN,

5546
03:28:58,192 --> 03:29:00,294
PROSTATE, IF YOU GO DOWN THE

5547
03:29:00,294 --> 03:29:01,662
LIST OF ALL THE CANCERS ABOUT

5548
03:29:01,662 --> 03:29:05,199
3/4 OF PATIENTS WILL HAVE T

5549
03:29:05,199 --> 03:29:06,968
CELLS IN THEIR TUMORS, OR

5550
03:29:06,968 --> 03:29:07,668
CIRCULATING, THEY CAN BE

5551
03:29:07,668 --> 03:29:11,239
DETECTED IN THE PERIPHERAL

5552
03:29:11,239 --> 03:29:12,407
BLOOD, ALTHOUGH RARER FREQUENCY,

5553
03:29:12,407 --> 03:29:14,842
ALL OF THOSE WERE UNIQUE TO THE

5554
03:29:14,842 --> 03:29:17,512
INDIVIDUAL PATIENT WITH, AGAIN,

5555
03:29:17,512 --> 03:29:19,113
ONLY THIS KRAS G12 D MUTATION

5556
03:29:19,113 --> 03:29:27,288
DETECTED BY TIL SHARED BY

5557
03:29:27,288 --> 03:29:28,923
PATIENTS, 363 NEOANTIGENS

5558
03:29:28,923 --> 03:29:29,223
RECOGNIZED.

5559
03:29:29,223 --> 03:29:30,792
THAT THEN LED TO REALIZATION OF

5560
03:29:30,792 --> 03:29:34,495
WHAT A CANCER ANTIGEN WAS,

5561
03:29:34,495 --> 03:29:35,062
BASICALLY ANY INTRACELLULAR

5562
03:29:35,062 --> 03:29:37,498
PROTEIN, APPEARED TO BE RANDOM

5563
03:29:37,498 --> 03:29:39,434
SOMATIC MUTATIONS, COULD

5564
03:29:39,434 --> 03:29:41,669
POTENTIALLY BE A CANCER ANTIGEN

5565
03:29:41,669 --> 03:29:48,743
IF IT WAS MUTATED, PROCESSED

5566
03:29:48,743 --> 03:29:54,949
EXTRACELLULARLY TO A PEPTIDE.

5567
03:29:54,949 --> 03:30:02,657
COMPLEX MOLECULE, 1 IN 70 WERE

5568
03:30:02,657 --> 03:30:04,258
NEOANTIGENS, RECOGNIZED BY T

5569
03:30:04,258 --> 03:30:04,525
CELLS.

5570
03:30:04,525 --> 03:30:06,727
SINCE ALMOST ALL PATIENTS HAVE

5571
03:30:06,727 --> 03:30:08,162
MUTATIONS IF WE COULD FIGURE OUT

5572
03:30:08,162 --> 03:30:10,898
A WAY TO TARGET THEM PATIENTS OF

5573
03:30:10,898 --> 03:30:12,200
MANY CANCER TYPES WOULD BE

5574
03:30:12,200 --> 03:30:12,500
ELIGIBLE.

5575
03:30:12,500 --> 03:30:14,502
BAD NEWS, TREATMENT IS GOING TO

5576
03:30:14,502 --> 03:30:17,705
HAVE TO BE HIGHLY

5577
03:30:17,705 --> 03:30:18,439
INDIVIDUALIZED.

5578
03:30:18,439 --> 03:30:18,940
AND THEREFORE COMPLEX.

5579
03:30:18,940 --> 03:30:22,577
BUT, AGAIN, IF WE COULD FIND

5580
03:30:22,577 --> 03:30:25,346
THINGS THAT WORK, WE HAD EVERY

5581
03:30:25,346 --> 03:30:26,848
CONFIDENCE THAT THE GENIUS OF

5582
03:30:26,848 --> 03:30:28,282
AMERICAN INDUSTRY WOULD FIGURE

5583
03:30:28,282 --> 03:30:31,986
OUT WAYS TO MAKE IT AVAILABLE.

5584
03:30:31,986 --> 03:30:33,521
WELL, THAT BEGAN THEN A CLINICAL

5585
03:30:33,521 --> 03:30:33,721
TRIAL.

5586
03:30:33,721 --> 03:30:35,923
YOU'VE SEEN A VARIATION OF THIS

5587
03:30:35,923 --> 03:30:40,194
SLIDE BEFORE, AGAIN IF YOU

5588
03:30:40,194 --> 03:30:41,529
FOLLOW EXCISION OF TUMOR

5589
03:30:41,529 --> 03:30:42,964
CLOCKWISE, WE NOW EXCISE 1 OR

5590
03:30:42,964 --> 03:30:44,165
MORE FROM AN INDIVIDUAL CANCER

5591
03:30:44,165 --> 03:30:45,733
PATIENTS, ALL OF THE PATIENTS

5592
03:30:45,733 --> 03:30:48,803
THAT WE TREAT HAVE ADVANCED

5593
03:30:48,803 --> 03:30:49,871
METASTATIC MALIGNANCY THAT HAVE

5594
03:30:49,871 --> 03:30:51,405
BEEN THROUGH ALL STANDARD

5595
03:30:51,405 --> 03:30:53,508
TREATMENTS, AND OF COURSE FDA

5596
03:30:53,508 --> 03:30:54,976
ONLY ALLOWS EXPERIMENTAL

5597
03:30:54,976 --> 03:30:56,677
TREATMENTS OF UNKNOWN

5598
03:30:56,677 --> 03:31:00,481
EFFECTIVENESS AND UNKNOWN

5599
03:31:00,481 --> 03:31:01,682
TOXICITIES, IN THAT DIFFICULT

5600
03:31:01,682 --> 03:31:03,518
PATIENT POPULATION.

5601
03:31:03,518 --> 03:31:06,687
WE PLATE 24 TO 48 FRAGMENTS FROM

5602
03:31:06,687 --> 03:31:09,423
THE TUMOR, GOOD SPATIAL

5603
03:31:09,423 --> 03:31:11,726
RECOGNITION OF LYMPHOCYTES FROM

5604
03:31:11,726 --> 03:31:13,594
A VARIETY OF SITES.

5605
03:31:13,594 --> 03:31:16,764
EVERY INDIVIDUAL FRAGMENT IS

5606
03:31:16,764 --> 03:31:19,934
TESTED FOR REACTIVITY, AGAINST

5607
03:31:19,934 --> 03:31:21,502
THE PATIENT'S TIL CELLS, THAT

5608
03:31:21,502 --> 03:31:24,238
ENABLES US THEN TO FIND TIL THAT

5609
03:31:24,238 --> 03:31:27,375
LETS US IDENTIFY THE ANTIGEN.

5610
03:31:27,375 --> 03:31:29,510
THOSE FRAGMENTS SHOWN IN VITRO

5611
03:31:29,510 --> 03:31:32,079
TO RECOGNIZE A FRAGMENT WE THEN

5612
03:31:32,079 --> 03:31:33,748
SELECT THAT FRAGMENT OR

5613
03:31:33,748 --> 03:31:37,919
FRAGMENTS ONLY AND GROW THEM IN

5614
03:31:37,919 --> 03:31:42,690
VITRO IN OUR GMP FACILITY, AND

5615
03:31:42,690 --> 03:31:44,659
THEN INFUSE THEM FOLLOWING A

5616
03:31:44,659 --> 03:31:47,261
LYMPHODEPLETION OF THE PATIENT

5617
03:31:47,261 --> 03:31:49,297
THAT HAS MANY ADVANTAGES,

5618
03:31:49,297 --> 03:31:51,732
PREDOMINANT BEING ELIMINATION OF

5619
03:31:51,732 --> 03:31:56,737
T REGULATORY CELLS, MYELOID

5620
03:31:56,737 --> 03:31:58,239
DERIVED SUPPRESSORS, STIMULATES

5621
03:31:58,239 --> 03:31:59,040
ENDOGENOUS CYTOKINE PRODUCTION.

5622
03:31:59,040 --> 03:32:02,043
AND THE FIRST PATIENT WE DID

5623
03:32:02,043 --> 03:32:04,345
THIS ON HAPPENS TO BE IN THE

5624
03:32:04,345 --> 03:32:04,812
AUDIENCE.

5625
03:32:04,812 --> 03:32:07,114
I WASN'T AWARE SHE WAS GOING TO

5626
03:32:07,114 --> 03:32:10,651
BE HERE, 45-YEAR-OLD WOMAN WHO

5627
03:32:10,651 --> 03:32:12,853
HAD A METASTATIC CARCINOMA, 45

5628
03:32:12,853 --> 03:32:17,525
YEARS OLD, SIX CHILDREN. 

5629
03:32:17,525 --> 03:32:18,826
HAD A RIGHT HEPATECTOMY,

5630
03:32:18,826 --> 03:32:21,062
DEVELOPED LUNG AND LIVER

5631
03:32:21,062 --> 03:32:26,367
METASTASES, RECEIVED MULTIPLE

5632
03:32:26,367 --> 03:32:27,702
CHEMOTHERAPY REGIMENS, DID NOT

5633
03:32:27,702 --> 03:32:29,704
RESPOND.

5634
03:32:29,704 --> 03:32:30,571
WE GAVE HER UNSELECTED TIL

5635
03:32:30,571 --> 03:32:31,973
GROWING ALL THE CELLS AND GIVING

5636
03:32:31,973 --> 03:32:33,941
THEM, SHE DID NOT RESPOND.

5637
03:32:33,941 --> 03:32:35,242
WE THEN SELECTED A FRAGMENT THAT

5638
03:32:35,242 --> 03:32:38,212
SEEMED TO BE MUCH MORE REACTIVE

5639
03:32:38,212 --> 03:32:41,282
THAN OTHERS. 

5640
03:32:41,282 --> 03:32:42,483
SHE HAD 26 MUTATIONS.

5641
03:32:42,483 --> 03:32:46,854
ERIC TRAN IN THE LAB IDENTIFIED

5642
03:32:46,854 --> 03:32:51,158
CELLS THAT RECOGNIZED HER B1 IB

5643
03:32:51,158 --> 03:32:51,892
CANCER MUTATION.

5644
03:32:51,892 --> 03:32:56,497
ON YOUR LEFT IS AN EXAMPLE OF

5645
03:32:56,497 --> 03:32:59,500
THE LARGE TUMORS THAT THIS

5646
03:32:59,500 --> 03:33:01,002
PATIENT HAD GROWING IN HER

5647
03:33:01,002 --> 03:33:03,070
LUNGS, CAN YOU SEE YELLOW ARROWS

5648
03:33:03,070 --> 03:33:03,971
POINTING TO THEM.

5649
03:33:03,971 --> 03:33:07,308
LIVER METASTASES AS WELL.

5650
03:33:07,308 --> 03:33:08,376
SHE UNDERWENT DRAMATIC

5651
03:33:08,376 --> 03:33:08,676
REGRESSION.

5652
03:33:08,676 --> 03:33:11,412
ABOUT 3 1/2 YEARS LATER.

5653
03:33:11,412 --> 03:33:16,083
HOWEVER, A FEW NODULES APPEARED

5654
03:33:16,083 --> 03:33:20,488
IN RIGHT LUNG, RESECTED, SHE

5655
03:33:20,488 --> 03:33:22,757
BECAME AND REMAINS DISEASE FREE

5656
03:33:22,757 --> 03:33:25,359
TO THE PRESENT TIME.

5657
03:33:25,359 --> 03:33:26,460
MELINDA, IT'S A DELIGHT TO HAVE

5658
03:33:26,460 --> 03:33:27,128
YOU HERE.

5659
03:33:27,128 --> 03:33:30,297
PLEASE COME AND SAY HELLO TO ME.

5660
03:33:30,297 --> 03:33:38,172
[APPLAUSE] 

5661
03:33:38,172 --> 03:33:41,309
WE BEGAN A SERIES OF THREE

5662
03:33:41,309 --> 03:33:43,744
CONSECUTIVE TRIALS, IN PATIENTS

5663
03:33:43,744 --> 03:33:45,546
WITH SOLID METASTATIC EPITHELIAL

5664
03:33:45,546 --> 03:33:49,750
CANCERS, ALL OF WHOM HAD BEEN

5665
03:33:49,750 --> 03:33:51,719
THROUGH STANDARD TREATMENT.

5666
03:33:51,719 --> 03:33:52,953
AND THOSE THREE TRIALS THAT I'LL

5667
03:33:52,953 --> 03:33:56,857
DISCUSS IN THE NEXT FEW MINUTES

5668
03:33:56,857 --> 03:33:59,327
INVOLVE GIVING TIL NOT SELECTED,

5669
03:33:59,327 --> 03:34:00,928
WE TREATED 18 PATIENTS, MANY

5670
03:34:00,928 --> 03:34:04,298
MORE IN FACT IN TRIALS PRIOR

5671
03:34:04,298 --> 03:34:05,399
WITH NO RESPONSES.

5672
03:34:05,399 --> 03:34:09,236
WE THEN USED OUR SELECTION

5673
03:34:09,236 --> 03:34:13,274
CRITERIA IN 39 PATIENTS, ONLY 3

5674
03:34:13,274 --> 03:34:14,475
OF THOSE PATIENTS RESPONDED.

5675
03:34:14,475 --> 03:34:17,645
BUT THE CELLS THAT WE GAVE WERE

5676
03:34:17,645 --> 03:34:22,316
EXPRESSING VERY HIGH LEVELS OF

5677
03:34:22,316 --> 03:34:24,552
PD-1, AND EXPERIMENTS IN THE

5678
03:34:24,552 --> 03:34:25,686
LABORATORY SHOWED US THAT

5679
03:34:25,686 --> 03:34:29,623
FOLLOWING THE INFUSION OF THESE

5680
03:34:29,623 --> 03:34:31,792
CELLS, THE FREQUENCY OF PD-1 AND

5681
03:34:31,792 --> 03:34:34,862
INTENSITY OF PD-1 EXPRESSION WAS

5682
03:34:34,862 --> 03:34:37,098
INCREASED AS CELLS GREW AND

5683
03:34:37,098 --> 03:34:40,201
RECOGNIZED THE CANCER IN THE

5684
03:34:40,201 --> 03:34:40,434
PATIENT.

5685
03:34:40,434 --> 03:34:43,070
THAT LED US TO A CURRENT TRIAL

5686
03:34:43,070 --> 03:34:44,605
NOW ONGOING, BRINGING YOU UP TO

5687
03:34:44,605 --> 03:34:48,109
DATE, THAT WE GIVE THESE

5688
03:34:48,109 --> 03:34:52,913
SELECTED TILs, ALONG WITH

5689
03:34:52,913 --> 03:34:55,883
PEMBROLIZUMAB, AN ANTI-PD-1

5690
03:34:55,883 --> 03:34:58,385
REAGENT, EIGHT PATIENTS OF 34

5691
03:34:58,385 --> 03:35:00,821
HAD OBJECTIVE RESPONSES BY

5692
03:35:00,821 --> 03:35:02,123
RHESUS CRITERIA, 23.5%.

5693
03:35:02,123 --> 03:35:05,059
IN MANY WAYS I FEEL THE WAY I

5694
03:35:05,059 --> 03:35:06,694
FELT, I FEEL NOW THE WAY I FELT

5695
03:35:06,694 --> 03:35:08,796
WITH THE FIRST IL-2 RESPONSES,

5696
03:35:08,796 --> 03:35:14,368
REALIZING IT WAS POSSIBLE TO SEE

5697
03:35:14,368 --> 03:35:16,003
THESE EPITHELIAL CANCERS

5698
03:35:16,003 --> 03:35:17,772
DISAPPEAR, STIMULATES US TO NOW

5699
03:35:17,772 --> 03:35:19,740
TAKE ADVANTAGE OF THAT

5700
03:35:19,740 --> 03:35:27,047
INFORMATION AND TRY TO IMPROVE

5701
03:35:27,047 --> 03:35:29,583
UPON I YOU CAN SEE EACH LINE

5702
03:35:29,583 --> 03:35:31,118
REPRESENTING A PATIENT, IN THIS

5703
03:35:31,118 --> 03:35:33,187
SPIDER DIAGRAM OF THE SIZE OF

5704
03:35:33,187 --> 03:35:33,654
THEIR TUMORS.

5705
03:35:33,654 --> 03:35:35,723
YOU CAN SEE IN THE UNSELECTED

5706
03:35:35,723 --> 03:35:37,591
TIL A COUPLE PATIENTS SHOWED

5707
03:35:37,591 --> 03:35:39,226
MINOR REGRESSIONS BUT NEVER

5708
03:35:39,226 --> 03:35:41,529
REACHED RECIST CRITERIA.

5709
03:35:41,529 --> 03:35:45,132
WHEN WE GAVE COLLECTED TIL THREE

5710
03:35:45,132 --> 03:35:48,836
PATIENTS GOOD SHOW A REGRESSION.

5711
03:35:48,836 --> 03:35:50,404
WHEN WE ADDED PEMBROLIZUMAB YOU

5712
03:35:50,404 --> 03:35:52,573
CAN SEE THIS MASS OF PATIENTS

5713
03:35:52,573 --> 03:35:55,376
WHOSE TUMORS WERE DECREASING

5714
03:35:55,376 --> 03:35:58,813
FOLLOWING THE ADMINISTRATION OF

5715
03:35:58,813 --> 03:36:05,486
THE CELLS, AND 23.5% OF PATIENTS

5716
03:36:05,486 --> 03:36:07,321
NOW SHOW OBJECTIVE RECIST

5717
03:36:07,321 --> 03:36:09,523
REGRESSIONS, AND WE'VE ONLY

5718
03:36:09,523 --> 03:36:14,428
SUMMARIZED NOW RECENTLY AND

5719
03:36:14,428 --> 03:36:16,096
SUBMITTED MANUSCRIPTS,

5720
03:36:16,096 --> 03:36:17,965
GASTROINTESTINAL PATIENTS WITH

5721
03:36:17,965 --> 03:36:21,435
METASTATIC DISEASE, THREE

5722
03:36:21,435 --> 03:36:25,573
PANCREATIC PATIENTS, ONE

5723
03:36:25,573 --> 03:36:27,641
RESPONDED, ONE

5724
03:36:27,641 --> 03:36:30,978
CHOLANGIOCARCINOMA, 6 OF 28

5725
03:36:30,978 --> 03:36:34,048
COLORECTAL, AND 24% OBJECTIVE

5726
03:36:34,048 --> 03:36:38,285
RESPONSE RATE, AND WE SAW TUMORS

5727
03:36:38,285 --> 03:36:39,954
REGRESS FROM MULTIPLE ORGANS.

5728
03:36:39,954 --> 03:36:44,091
THESE LARGE LUNG METASTASES

5729
03:36:44,091 --> 03:36:46,527
DISAPPEARED COMPLETELY IN THIS

5730
03:36:46,527 --> 03:36:47,561
PATIENT.

5731
03:36:47,561 --> 03:36:50,231
THIS PATIENT WITH A

5732
03:36:50,231 --> 03:36:52,333
CHOLANGIOCARCINOMA HAD BONY

5733
03:36:52,333 --> 03:36:52,900
METASTATIC DISEASE, ERODING

5734
03:36:52,900 --> 03:36:54,835
BONE, YOU CAN SEE WHEN THE

5735
03:36:54,835 --> 03:36:59,173
LEASES DISAPPEARED THE BONE

5736
03:36:59,173 --> 03:36:59,440
REFORMED.

5737
03:36:59,440 --> 03:37:00,841
MULTIPLE INTRAABDOMINAL LYMPH

5738
03:37:00,841 --> 03:37:03,711
NODES SHRANK SUBSTANTIALLY AS

5739
03:37:03,711 --> 03:37:04,011
WELL.

5740
03:37:04,011 --> 03:37:06,547
THIS PATIENT WITH COLON CANCER,

5741
03:37:06,547 --> 03:37:09,617
AN MRI SCAN, YOU CAN SEE

5742
03:37:09,617 --> 03:37:12,152
MULTIPLE LIVER METASTASES, THESE

5743
03:37:12,152 --> 03:37:12,920
PATIENTS PROGRESSED, SHOWN

5744
03:37:12,920 --> 03:37:16,423
PROGRESSION PRIOR TO ALL OTHER

5745
03:37:16,423 --> 03:37:18,726
TREATMENTS, DRAMATIC REGRESSION,

5746
03:37:18,726 --> 03:37:24,965
PARTIAL REGRESSION, OF MANY OF

5747
03:37:24,965 --> 03:37:28,235
THESE LESIONS.

5748
03:37:28,235 --> 03:37:30,304
ANOTHER PATIENT WITH MULTIPLE

5749
03:37:30,304 --> 03:37:31,839
LUNG DEPOSITS.

5750
03:37:31,839 --> 03:37:34,308
THERE'S NO ORGAN THAT HAS NOT

5751
03:37:34,308 --> 03:37:36,010
RESPONDED, ALTHOUGH WE DO NOT

5752
03:37:36,010 --> 03:37:37,077
TREAT PATIENTS WITH BRAIN

5753
03:37:37,077 --> 03:37:38,612
METASTASES SO I CAN'T COMMENT ON

5754
03:37:38,612 --> 03:37:39,713
THAT.

5755
03:37:39,713 --> 03:37:41,248
THIS IS A PANCREATIC CANCER

5756
03:37:41,248 --> 03:37:43,651
PATIENT WHO HAD TWO LESIONS, ONE

5757
03:37:43,651 --> 03:37:46,487
WON'T TO DISAPPEAR, THE OTHER

5758
03:37:46,487 --> 03:37:46,720
SHRANK.

5759
03:37:46,720 --> 03:37:49,523
SO PANCREATIC CANCERS ARE NOT

5760
03:37:49,523 --> 03:37:53,861
RESISTANT TO THIS AS WELL.

5761
03:37:53,861 --> 03:37:55,496
RECENTLY COMPLETE AND SUBMITTED

5762
03:37:55,496 --> 03:37:56,797
FOR PUBLICATION DETAILED

5763
03:37:56,797 --> 03:37:58,866
ANALYSIS OF THESE PATIENTS.

5764
03:37:58,866 --> 03:38:02,903
CONDUCTED BY FRANK LOWERY AND

5765
03:38:02,903 --> 03:38:05,339
STEPHANIE GOFF, AND FOUND

5766
03:38:05,339 --> 03:38:06,507
FACTORS ASSOCIATED WITH

5767
03:38:06,507 --> 03:38:06,974
OBJECTIVES RESPONSES,

5768
03:38:06,974 --> 03:38:08,842
UNFORTUNATELY NOT AS MANY AS WE

5769
03:38:08,842 --> 03:38:11,679
WISHED, BUT AS MIGHT BE

5770
03:38:11,679 --> 03:38:13,113
OBVIOUSLY UNDERSTOOD THE

5771
03:38:13,113 --> 03:38:15,182
RESPONDERS TENDED TO REACT WITH

5772
03:38:15,182 --> 03:38:16,717
MORE ANTIGENS, YOU SAW A LITTLE

5773
03:38:16,717 --> 03:38:19,687
OF THIS FROM PAUL ROBBINS THIS

5774
03:38:19,687 --> 03:38:22,957
MORE THAN, THAN NON-RESPONDERS.

5775
03:38:22,957 --> 03:38:25,926
NUMBER OF REACTIVE CD4 CELLS

5776
03:38:25,926 --> 03:38:28,329
RATHER THAN CD8 CELLS HIGHLY

5777
03:38:28,329 --> 03:38:29,330
CORRELATED WITH LIKELIHOOD OF A

5778
03:38:29,330 --> 03:38:31,165
PATIENT RESPONSE AND WE'RE

5779
03:38:31,165 --> 03:38:35,636
CONTINUING IN DETAIL THOSE

5780
03:38:35,636 --> 03:38:37,304
STUDIES AS WE PROGRESS.

5781
03:38:37,304 --> 03:38:40,040
THIS IS NOT ONLY

5782
03:38:40,040 --> 03:38:40,874
GASTROINTESTINAL CANCER,

5783
03:38:40,874 --> 03:38:41,775
ASTONISHING TO ME THIS PATIENT

5784
03:38:41,775 --> 03:38:44,011
IS ALSO IN THE AUDIENCE, I

5785
03:38:44,011 --> 03:38:46,547
DIDN'T REALIZE SHE WOULD BE

5786
03:38:46,547 --> 03:38:49,650
COMING BUT SHE HAD A METASTATIC

5787
03:38:49,650 --> 03:38:51,819
BREAST CANCER THAT HAD BEEN

5788
03:38:51,819 --> 03:38:55,122
THROUGH SEVEN PRIOR DIFFERENT

5789
03:38:55,122 --> 03:38:56,023
TREATMENTS, CHEMOTHERAPIES,

5790
03:38:56,023 --> 03:38:57,558
HORMONAL AND TARGETED

5791
03:38:57,558 --> 03:39:01,829
TREATMENTS, PRESENTED TO US WITH

5792
03:39:01,829 --> 03:39:03,063
MULTIPLE METASTASES IN HER

5793
03:39:03,063 --> 03:39:03,263
LIVER.

5794
03:39:03,263 --> 03:39:06,700
CAN YOU SEE IN THE CAT SCAN

5795
03:39:06,700 --> 03:39:07,701
PROBABLY INTERNAL MAMMARY NODE

5796
03:39:07,701 --> 03:39:09,536
BEGINNING TO GROW THROUGH THE

5797
03:39:09,536 --> 03:39:10,804
CHEST, GROW THROUGH THE CHEST

5798
03:39:10,804 --> 03:39:11,105
WALL.

5799
03:39:11,105 --> 03:39:13,640
WE TREATED HER WITH HER OWN

5800
03:39:13,640 --> 03:39:15,609
AUTOLOGOUS CELLS ALONG WITH

5801
03:39:15,609 --> 03:39:16,710
PEMBROLIZUMAB, AND EVERYTHING

5802
03:39:16,710 --> 03:39:19,880
HAS DISAPPEARED, AND SHE REMAINS

5803
03:39:19,880 --> 03:39:21,949
DISEASE FREE NOW, OVER FIVE

5804
03:39:21,949 --> 03:39:22,950
YEARS LATER.

5805
03:39:22,950 --> 03:39:24,585
LINDA, DELIGHTED THAT YOU'RE

5806
03:39:24,585 --> 03:39:27,021
HERE TO HELP CELEBRATE THIS

5807
03:39:27,021 --> 03:39:27,354
OCCASION.

5808
03:39:27,354 --> 03:39:29,723
[APPLAUSE]

5809
03:39:29,723 --> 03:39:35,729
 

5810
03:39:35,729 --> 03:39:37,931
 

5811
03:39:37,931 --> 03:39:40,434
GIVEN OUR START, WITH THE

5812
03:39:40,434 --> 03:39:43,270
INSERTION OF RECEPTORS, INTO A

5813
03:39:43,270 --> 03:39:45,572
PATIENT'S NORMAL LYMPHOCYTES TO

5814
03:39:45,572 --> 03:39:46,874
CONVERT NORMAL LYMPHOCYTES TO

5815
03:39:46,874 --> 03:39:48,642
CELLS WITH ANTITUMOR ACTIVITY WE

5816
03:39:48,642 --> 03:39:52,146
BEGAN A SERIES OF TRIALS IN

5817
03:39:52,146 --> 03:39:55,649
WHICH WE COULD IDENTIFY THE

5818
03:39:55,649 --> 03:39:57,718
INDIVIDUAL T-CELL RECEPTORS

5819
03:39:57,718 --> 03:39:58,485
RECOGNIZING PATIENTS' UNIQUE

5820
03:39:58,485 --> 03:40:00,220
ANTIGENS BECAUSE WE COULD

5821
03:40:00,220 --> 03:40:01,889
IDENTIFY THE CELL, WITH QUITE

5822
03:40:01,889 --> 03:40:03,724
STRAIGHTFORWARD AS YOU'LL HEAR

5823
03:40:03,724 --> 03:40:08,228
FROM MARIA PARKER WHO RAN THAT

5824
03:40:08,228 --> 03:40:12,833
STUDY, ONE COULD QUITE READILY

5825
03:40:12,833 --> 03:40:13,434
OBTAIN THE SEQUENCE OF T-CELL

5826
03:40:13,434 --> 03:40:17,304
RECEPTORS FROM THE CELLS OR GENE

5827
03:40:17,304 --> 03:40:19,406
SIGNATURES BEING DEVELOPED IN

5828
03:40:19,406 --> 03:40:22,476
THE LABORATORY BY FRANK LOWERY.

5829
03:40:22,476 --> 03:40:27,815
INSERT THOSE INDIVIDUAL T-CELL

5830
03:40:27,815 --> 03:40:28,916
RECEPTORS TARGETING UNIQUE

5831
03:40:28,916 --> 03:40:32,453
ANTIGENS, INTO A PATIENT, WE

5832
03:40:32,453 --> 03:40:33,854
REPORTED THIS IN NATURE MEDICINE

5833
03:40:33,854 --> 03:40:37,024
JUST A FEW MONTHS AGO.

5834
03:40:37,024 --> 03:40:38,225
THREE OF THE SEVEN PATIENTS THAT

5835
03:40:38,225 --> 03:40:44,131
WE TREATED WITH THEIR OWN UNIQUE

5836
03:40:44,131 --> 03:40:46,467
CELLS SHOWED OBJECTIVE

5837
03:40:46,467 --> 03:40:47,868
REGRESSION OF TUMOR.

5838
03:40:47,868 --> 03:40:49,403
AGAIN, EACH WITH DIFFERENT

5839
03:40:49,403 --> 03:40:49,837
ANTIGEN.

5840
03:40:49,837 --> 03:40:52,873
INTERESTINGLY OF THE CD8 CELLS

5841
03:40:52,873 --> 03:40:53,674
THAT WERE MEDIATING THESE

5842
03:40:53,674 --> 03:40:58,479
RESPONSE THEY HAD THE KINDS OF

5843
03:40:58,479 --> 03:41:00,681
CRITERIA THAT ANOTHER FELLOW IN

5844
03:41:00,681 --> 03:41:02,749
THE LAB IDENTIFIED AS OPTIMAL

5845
03:41:02,749 --> 03:41:04,618
PHENOTYPE OF MELANOMA CELLS THAT

5846
03:41:04,618 --> 03:41:07,721
CAUSE REGRESSION, AND THAT IS

5847
03:41:07,721 --> 03:41:09,523
MORE STEM-LIKE PHENOTYPE CD39

5848
03:41:09,523 --> 03:41:11,325
NEGATIVE CD69 NEGATIVE, LATER ON

5849
03:41:11,325 --> 03:41:13,060
TODAY WE'LL HEAR FROM MORIAH

5850
03:41:13,060 --> 03:41:17,965
PARKER ABOUT THIS TRIAL IN SOME

5851
03:41:17,965 --> 03:41:18,465
DETAIL.

5852
03:41:18,465 --> 03:41:20,367
THESE WERE UNIQUE ANTIGENS.

5853
03:41:20,367 --> 03:41:21,935
THERE ARE SURPRISINGLY FEW

5854
03:41:21,935 --> 03:41:25,973
SHARED ANTIGENS, AS YOU HEARD

5855
03:41:25,973 --> 03:41:27,708
FROM THE ELEGANT STUDIES THAT

5856
03:41:27,708 --> 03:41:30,777
YOU HEARD ABOUT THIS MORNING

5857
03:41:30,777 --> 03:41:31,879
FROM DR. YANG.

5858
03:41:31,879 --> 03:41:37,451
TWO FELLOWS IN THE LABORATORY

5859
03:41:37,451 --> 03:41:40,420
KIM AND LEVIN, USED A HIGHLY

5860
03:41:40,420 --> 03:41:41,955
TARGETED SEQUENCING APPROACH AS

5861
03:41:41,955 --> 03:41:44,358
WELL AS IN VITRO SENSITIZATIONS

5862
03:41:44,358 --> 03:41:46,660
TO TRY TO RAISE T-CELL RECEPTORS

5863
03:41:46,660 --> 03:41:49,930
THAT RECOGNIZED THE TWO MOST

5864
03:41:49,930 --> 03:41:51,465
COMMONLY EXPRESSED MUTATIONS IN

5865
03:41:51,465 --> 03:41:54,301
HUMANS WITH CANCER, AND THAT WAS

5866
03:41:54,301 --> 03:42:04,178
THE KRAS AND P53 MUTATIONS.

5867
03:42:04,178 --> 03:42:07,214
KRAS PRESENT IN 35%, THEY

5868
03:42:07,214 --> 03:42:12,920
IDENTIFIED A LIBRARY OF 14 KRAS

5869
03:42:12,920 --> 03:42:14,121
AND 14 P53 MUTATIONS, T CELLS,

5870
03:42:14,121 --> 03:42:17,157
THAT COULD RECOGNIZE THEM AND WE

5871
03:42:17,157 --> 03:42:18,492
PUBLISHED THAT A COUPLE YEARS

5872
03:42:18,492 --> 03:42:19,993
AGO, ALONG WITH THE SEQUENCE OF

5873
03:42:19,993 --> 03:42:23,730
ALL OF THESE RECEPTORS SO THEY

5874
03:42:23,730 --> 03:42:27,100
COULD BE WIDELY USED BY OTHERS.

5875
03:42:27,100 --> 03:42:28,669
AND SO WE BEGAN OURSELVES TO SEE

5876
03:42:28,669 --> 03:42:31,939
IF WE COULDN'T UTILIZE THESE

5877
03:42:31,939 --> 03:42:33,907
RECEPTORS TO TARGET P53 AND

5878
03:42:33,907 --> 03:42:35,242
KRAS, WE HAVEN'T PUBLISHED ANY

5879
03:42:35,242 --> 03:42:38,378
OF THIS YET.

5880
03:42:38,378 --> 03:42:39,813
INTERESTINGLY, WE HAVE SEEN

5881
03:42:39,813 --> 03:42:42,316
RESPONSES TO A PATIENT'S OWN

5882
03:42:42,316 --> 03:42:44,151
NORMAL CELLS, TRANSDUCED WITH

5883
03:42:44,151 --> 03:42:46,486
ONE OF THE T-CELL RECEPTORS IN

5884
03:42:46,486 --> 03:42:47,888
THIS KRAS LIBRARY.

5885
03:42:47,888 --> 03:42:51,625
YOU CAN SEE THESE METASTATIC

5886
03:42:51,625 --> 03:42:54,161
DEPOSITS IN THE LIVER.

5887
03:42:54,161 --> 03:42:57,231
WHICH BY THREE MONTHS HAD

5888
03:42:57,231 --> 03:42:57,731
DISAPPEARED.

5889
03:42:57,731 --> 03:42:59,600
AND THIS PATIENT WHO HAD THIS

5890
03:42:59,600 --> 03:43:01,134
LARGE LESION AGAIN THE

5891
03:43:01,134 --> 03:43:05,305
PANCREATIC CANCER PATIENT WHO

5892
03:43:05,305 --> 03:43:06,406
RECEIVED ALLOGENEIC CELLS

5893
03:43:06,406 --> 03:43:09,142
TARGETING KRAS WHICH IS

5894
03:43:09,142 --> 03:43:10,110
SHRINKING AND NOW STILL

5895
03:43:10,110 --> 03:43:11,445
SHRINKING NINE MONTHS LATER.

5896
03:43:11,445 --> 03:43:16,683
WE JUST SAW THIS PATIENT IN

5897
03:43:16,683 --> 03:43:18,318
CLINIC EARLIER THIS WEEK.

5898
03:43:18,318 --> 03:43:20,721
THIS PATIENT WITH A DEVASTATING

5899
03:43:20,721 --> 03:43:22,823
RECTAL CANCER HUGE LESIONS IN

5900
03:43:22,823 --> 03:43:26,526
THE LIVER, SHOWED ELIMINATION

5901
03:43:26,526 --> 03:43:27,861
WHEN THEY RECEIVED P53 T-CELL

5902
03:43:27,861 --> 03:43:33,967
RECEPTOR, AGAIN THESE WERE

5903
03:43:33,967 --> 03:43:35,836
RECEPTORS RECOGNIZED, THESE BY

5904
03:43:35,836 --> 03:43:38,171
RESEARCH BY FELLOWS IN THE

5905
03:43:38,171 --> 03:43:38,472
LABORATORY.

5906
03:43:38,472 --> 03:43:41,875
AND YOU CAN SEE THE DRAMATIC

5907
03:43:41,875 --> 03:43:43,644
REDUCTION OR ELIMINATION OF

5908
03:43:43,644 --> 03:43:47,347
SEVERAL OF THESE RECTAL CANCER

5909
03:43:47,347 --> 03:43:52,319
LESIONS OUT TO SEVEN MONTHS. 

5910
03:43:52,319 --> 03:43:54,054
WELL, AS I MENTIONED, I FEEL

5911
03:43:54,054 --> 03:44:01,728
WE'RE AT THE START NOW OF BEING

5912
03:44:01,728 --> 03:44:03,263
ABLE TO TARGET THE SOLID

5913
03:44:03,263 --> 03:44:07,301
EPITHELIAL CANCERS WITH TIL.

5914
03:44:07,301 --> 03:44:10,804
THERE ARE NONE NOW THAT CAN

5915
03:44:10,804 --> 03:44:11,538
TARGET THIS POPULATION.

5916
03:44:11,538 --> 03:44:13,273
LIST HERE A SERIES OF APPROACHES

5917
03:44:13,273 --> 03:44:16,376
NOW BEING STUDIED IN THE BRANCH.

5918
03:44:16,376 --> 03:44:20,647
WE NOW NOW ADOPTIVE CELL THERAPY

5919
03:44:20,647 --> 03:44:22,616
CAN MEDIATION REGRESSION OF

5920
03:44:22,616 --> 03:44:25,452
SOLID EPITHELIAL CANSERS IS,

5921
03:44:25,452 --> 03:44:26,553
EFFORTS UNDERWAY TO APPROVE BY

5922
03:44:26,553 --> 03:44:28,188
ADDING A VACCINE THAT TARGETS

5923
03:44:28,188 --> 03:44:31,024
THE SAME ANTIGEN AS T CELLS

5924
03:44:31,024 --> 03:44:32,893
RECOGNIZE, GENE-GENE SIGNATURES

5925
03:44:32,893 --> 03:44:33,760
TO IDENTIFY ANTITUMOR CELLS, I

5926
03:44:33,760 --> 03:44:36,830
THINK THERE'S BEEN VERY

5927
03:44:36,830 --> 03:44:38,999
IMPRESSIVE WORK DONE BY LEVIN

5928
03:44:38,999 --> 03:44:41,535
AND KIM SHOWING IN VITRO

5929
03:44:41,535 --> 03:44:42,769
SENSITIZATION TO ENHANCE ANTIGEN

5930
03:44:42,769 --> 03:44:46,573
REACTIVITY AND MANY OTHERS, HAVE

5931
03:44:46,573 --> 03:44:48,342
EVERY EXPECTATION OR ARE WORKING

5932
03:44:48,342 --> 03:44:51,178
LARD TO SEE IF WE CAN'T FIND

5933
03:44:51,178 --> 03:44:51,778
IMPROVEMENTS.

5934
03:44:51,778 --> 03:44:53,680
I'D LIKE TO FINISH BY

5935
03:44:53,680 --> 03:44:55,716
EMPHASIZING THE FACT THAT

5936
03:44:55,716 --> 03:44:56,750
VIRTUALLY EVERYTHING THAT I'VE

5937
03:44:56,750 --> 03:44:59,486
SHOWN YOU TODAY WAS PERFORMED BY

5938
03:44:59,486 --> 03:45:00,754
FELLOWS IN THE LABORATORY,

5939
03:45:00,754 --> 03:45:01,788
EITHER SURGICAL FELLOWS THAT

5940
03:45:01,788 --> 03:45:03,090
CAME TO SPEND THREE YEARS WITH

5941
03:45:03,090 --> 03:45:05,859
US, TO LEARN TO DO RESEARCH OR

5942
03:45:05,859 --> 03:45:08,562
PhDs WHO CAME TO THE

5943
03:45:08,562 --> 03:45:09,996
LABORATORY AND WHEN THEY LEAVE

5944
03:45:09,996 --> 03:45:12,065
WE PUT THEIR PHOTOGRAPH UP ON

5945
03:45:12,065 --> 03:45:13,233
THE OUTSIDE OF THE WALL OF THE

5946
03:45:13,233 --> 03:45:14,901
MAIN OFFICE OF THE SURGERY

5947
03:45:14,901 --> 03:45:20,273
BRANCH, AND IT GOES WAY DOWN THE

5948
03:45:20,273 --> 03:45:20,807
HALL.

5949
03:45:20,807 --> 03:45:22,676
AND SO WE'RE INDEBTED TO THESE

5950
03:45:22,676 --> 03:45:24,978
FELLOWS, FOR ALL THE HARD WORK

5951
03:45:24,978 --> 03:45:26,613
THEY HAVE DONE.

5952
03:45:26,613 --> 03:45:29,149
WE'VE ALSO HAD AN OUTSTANDING

5953
03:45:29,149 --> 03:45:30,751
NUMBER OF SENIOR STAFF THAT HAVE

5954
03:45:30,751 --> 03:45:33,320
WORKED WITH US OVER THE YEARS,

5955
03:45:33,320 --> 03:45:35,555
JIM YANG CAME IN MY LAB OUT OF

5956
03:45:35,555 --> 03:45:36,723
HIS RESIDENCY, STAYED 40 YEARS,

5957
03:45:36,723 --> 03:45:38,358
HE'S BEEN A VITAL PART OF

5958
03:45:38,358 --> 03:45:40,093
EVERYTHING THAT WE'VE DONE, ALL

5959
03:45:40,093 --> 03:45:46,466
OF THE DIFFERENT APPROACHES,

5960
03:45:46,466 --> 03:45:47,768
PAUL ROBBINS, MOLECULAR

5961
03:45:47,768 --> 03:45:49,169
BIOLOGIST, MARIA PARKHURST

5962
03:45:49,169 --> 03:45:52,472
RESPONSIBLE FOR CELL GROWTH AND

5963
03:45:52,472 --> 03:45:54,875
INDIVIDUAL TCR PROTOCOLS, NICK

5964
03:45:54,875 --> 03:45:58,278
RESTIFO SPENT 30 YEARS IN THE

5965
03:45:58,278 --> 03:45:59,780
SURGERY BRANCH STUDY ANIMAL

5966
03:45:59,780 --> 03:46:03,617
MODELS AND DEVELOPING PRINCIPLES

5967
03:46:03,617 --> 03:46:07,354
UPON WHICH WE BASE OUR CLINICAL

5968
03:46:07,354 --> 03:46:09,756
TRIALS. 

5969
03:46:09,756 --> 03:46:15,996
YOU HEARD FROM KENICHI, 27

5970
03:46:15,996 --> 03:46:17,330
YEARS, SUZANNE WAS IT'S FIRST

5971
03:46:17,330 --> 03:46:21,401
PERSON EVER TO GIVE A TIL TO

5972
03:46:21,401 --> 03:46:21,668
PATIENTS.

5973
03:46:21,668 --> 03:46:23,904
MARK DUDLEY RAN THE LAB THAT

5974
03:46:23,904 --> 03:46:26,706
GREW THE CELLS THAT WE UTILIZED

5975
03:46:26,706 --> 03:46:28,608
IN OUR CLINICAL TRIALS.

5976
03:46:28,608 --> 03:46:33,713
UDAI IS WORKING ON APPLICATION

5977
03:46:33,713 --> 03:46:37,851
OF TIL FOR PATIENTS, 15 YEARS,

5978
03:46:37,851 --> 03:46:43,423
STEPHANIE GOFF NOW IN CHARGE OF

5979
03:46:43,423 --> 03:46:44,758
OUR GMP FACILITIESES AND

5980
03:46:44,758 --> 03:46:45,926
PROTOCOLS, CAME BACK ON OUR

5981
03:46:45,926 --> 03:46:50,130
SENIOR STAFF AND PLAYS A VITAL

5982
03:46:50,130 --> 03:46:50,764
ROLE.

5983
03:46:50,764 --> 03:46:53,934
PATRICK HWU, REMARKABLE

5984
03:46:53,934 --> 03:46:56,336
SCIENTIST, FIRST PERSON TO EVER

5985
03:46:56,336 --> 03:46:59,139
USE CAR-T CELLS IN PATIENTS,

5986
03:46:59,139 --> 03:47:03,343
FIRST PERSON IN OUR LAB TO

5987
03:47:03,343 --> 03:47:06,947
INSERT FOREIGN GENES INTO CELLS.

5988
03:47:06,947 --> 03:47:10,250
RICK MORGAN WILL FOLLOW MY TALK,

5989
03:47:10,250 --> 03:47:13,954
TALK BECOME STUDIES INSERTING

5990
03:47:13,954 --> 03:47:16,923
GENES. 

5991
03:47:16,923 --> 03:47:18,892
MIKE LOTZE, JIM MULE YOU HERDS

5992
03:47:18,892 --> 03:47:19,860
FROM.

5993
03:47:19,860 --> 03:47:22,262
I MENTION MICHELLE GAYE, STARTED

5994
03:47:22,262 --> 03:47:23,897
AS A SECRETARY/ADMINISTRATIVE

5995
03:47:23,897 --> 03:47:25,131
ASSISTANT, NOW THE GLUE THAT

5996
03:47:25,131 --> 03:47:26,533
HOLDS THE SURGERY BRANCH

5997
03:47:26,533 --> 03:47:28,635
TOGETHER, WORKED WITH ME FOR 36

5998
03:47:28,635 --> 03:47:31,371
YEARS, THREATENING TO RETIRE IN

5999
03:47:31,371 --> 03:47:32,606
DECEMBER.

6000
03:47:32,606 --> 03:47:33,673
[LAUGHTER]

6001
03:47:33,673 --> 03:47:39,479
WHICH IS A FRIGHTENING PROSPECT.

6002
03:47:39,479 --> 03:47:41,248
FINALLY, MY LAST SLIDE, THE

6003
03:47:41,248 --> 03:47:46,152
FIRST WEEK THAT I WAS AN INTERN

6004
03:47:46,152 --> 03:47:48,922
IN SURGERY AT THE HOSPITAL IN

6005
03:47:48,922 --> 03:47:56,763
BOSTON I  I MET ALICE O'CONNOR,A

6006
03:47:56,763 --> 03:47:58,732
NURSE IN THE SURGERY WARD.

6007
03:47:58,732 --> 03:48:00,467
SHE MIGHT TELL THE STORY

6008
03:48:00,467 --> 03:48:07,674
DIFFERENTLY BUT IN FACT  CHASED

6009
03:48:07,674 --> 03:48:08,575
ME SHAMELESSLY FOR FIVE YEARS.

6010
03:48:08,575 --> 03:48:09,543
[LAUGHTER]

6011
03:48:09,543 --> 03:48:11,177
BEFORE WE WERE FINALLY MARRIED,

6012
03:48:11,177 --> 03:48:14,781
AND THIS PAST YEAR WE CELEBRATED

6013
03:48:14,781 --> 03:48:16,249
OUR 57th WEDDING ANNIVERSARY.

6014
03:48:16,249 --> 03:48:19,853
NOW, I'VE WORKED HARD OVER THE

6015
03:48:19,853 --> 03:48:20,053
YEARS.

6016
03:48:20,053 --> 03:48:22,455
[APPLAUSE]

6017
03:48:22,455 --> 03:48:25,191
 

6018
03:48:25,191 --> 03:48:29,896
 

6019
03:48:29,896 --> 03:48:32,566
I WORKED HARD OVER THE YEARS,

6020
03:48:32,566 --> 03:48:33,967
AND THAT STEALS A LOT OF TIME

6021
03:48:33,967 --> 03:48:35,068
AWAY FROM FAMILY.

6022
03:48:35,068 --> 03:48:38,004
BUT ALICE HAS BEEN A REMARKABLE

6023
03:48:38,004 --> 03:48:40,206
SUPPORT, NEVER A WORD OF

6024
03:48:40,206 --> 03:48:40,540
COMPLAINT.

6025
03:48:40,540 --> 03:48:45,779
AND HAS BEEN A VITAL PERSON

6026
03:48:45,779 --> 03:48:47,647
RESPONSIBLE FOR MUCH OF WHAT

6027
03:48:47,647 --> 03:48:48,949
I'VE BEEN ABLE TO DO.

6028
03:48:48,949 --> 03:48:52,118
FIRST 40 YEARS THAT I WAS HERE,

6029
03:48:52,118 --> 03:48:53,353
AT THE NIH, THERE PROBABLY

6030
03:48:53,353 --> 03:48:54,521
WEREN'T 40 DAYS WHEN I WASN'T

6031
03:48:54,521 --> 03:48:58,925
TRAVELING THAT I WAS NOT IN THIS

6032
03:48:58,925 --> 03:49:00,460
HOSPITAL, EITHER SEEING PATIENTS

6033
03:49:00,460 --> 03:49:02,329
OR MEETING WITH FELLOWS ABOUT

6034
03:49:02,329 --> 03:49:03,597
THEIR RESEARCH.

6035
03:49:03,597 --> 03:49:05,932
SO, ALICE, THANK YOU FOR ALL

6036
03:49:05,932 --> 03:49:06,266
YOU'VE DONE.

6037
03:49:06,266 --> 03:49:09,002
[APPLAUSE]

6038
03:49:09,002 --> 03:49:19,045
 

6039
03:49:25,285 --> 03:49:27,087
COULD TAKE QUESTIONS.

6040
03:49:27,087 --> 03:49:34,294
[LAUGHTER] 

6041
03:49:34,294 --> 03:49:40,300
[APPLAUSE] 

6042
03:49:40,300 --> 03:49:41,301
>> YOU SAID THERE WERE 40
DAYS

6043
03:49:41,301 --> 03:49:43,370
IN THE YEARS YOU HAVEN'T BEEN AT

6044
03:49:43,370 --> 03:49:44,604
THE HOSPITAL. 

6045
03:49:44,604 --> 03:49:46,273
WHERE WERE YOU?

6046
03:49:46,273 --> 03:49:56,483
[LAUGHTER] 

6047
03:50:39,959 --> 03:50:41,828
>> WORD OF ADVICE FOR
YOUNG UP

6048
03:50:41,828 --> 03:50:43,029
AND COMING PEOPLE, NEVER

6049
03:50:43,029 --> 03:50:44,564
MODERATE THE SESSION YOUR BOSS

6050
03:50:44,564 --> 03:50:45,131
IS TALKING IN.

6051
03:50:45,131 --> 03:50:50,370
I'D LIKE NOW TO ASK RICK MORGAN

6052
03:50:50,370 --> 03:50:54,841
TO COME UP, VITAL TO OUR EFFORTS

6053
03:50:54,841 --> 03:50:57,677
GIVING GENE THERAPY PATIENTS.

6054
03:50:57,677 --> 03:50:58,445
>> THANK YOU, STEPHANIE.

6055
03:50:58,445 --> 03:51:00,413
SO WHEN I SAW THE SCHEDULE AND

6056
03:51:00,413 --> 03:51:05,118
HAVE TO FOLLOW THE NIH DIRECTOR

6057
03:51:05,118 --> 03:51:06,886
AND DR. ROSENBERG, LIKE, OKAY,

6058
03:51:06,886 --> 03:51:08,288
BUT I'M A GLASS HALF FULL KIND

6059
03:51:08,288 --> 03:51:08,822
OF GUY.

6060
03:51:08,822 --> 03:51:13,326
THANK YOU FOR STAYING TO HEAR MY

6061
03:51:13,326 --> 03:51:13,526
TALK.

6062
03:51:13,526 --> 03:51:15,195
WHEN I ARRIVED HERE IN LATE

6063
03:51:15,195 --> 03:51:17,697
'80s AS A YOUNG POSTDOC, THIS

6064
03:51:17,697 --> 03:51:21,768
PLACE WAS LARGE AND

6065
03:51:21,768 --> 03:51:22,102
INTIMIDATING.

6066
03:51:22,102 --> 03:51:23,837
NOW WHEN I COME BACK IT FEELS

6067
03:51:23,837 --> 03:51:24,604
LIKE HOME.

6068
03:51:24,604 --> 03:51:27,240
SO, WHAT I'M GOING TO DO IS TELL

6069
03:51:27,240 --> 03:51:29,209
YOU SOME STORIES, MANY OF WHICH

6070
03:51:29,209 --> 03:51:31,945
ARE FROM OUR HOME HERE AT THE

6071
03:51:31,945 --> 03:51:32,145
NCI.

6072
03:51:32,145 --> 03:51:35,882
AND SET UP THE NEXT FEW TALKS SO

6073
03:51:35,882 --> 03:51:41,654
LET'S GO THROUGH THE ORIGINS OF

6074
03:51:41,654 --> 03:51:44,190
T-CELL RECEPTOR GENE THERAPY.

6075
03:51:44,190 --> 03:51:47,026
YOU NOW KNOW THIS CONCEPT.

6076
03:51:47,026 --> 03:51:49,863
IF YOU CAN IDENTIFY ANTIGEN

6077
03:51:49,863 --> 03:51:52,398
REACTIVE CELL, TECHNOLOGY EXISTS

6078
03:51:52,398 --> 03:51:54,367
TO IDENTIFY THOSE RECEPTORS THAT

6079
03:51:54,367 --> 03:51:56,236
ARE RECOGNIZING THE TUMOR.

6080
03:51:56,236 --> 03:52:01,141
SO ALPHA CHAIN, BETA CHAIN,

6081
03:52:01,141 --> 03:52:02,041
HETERODIMERE T-CELL RECEPTOR,

6082
03:52:02,041 --> 03:52:06,412
ONCE IDENTIFIED YOU CAN MOVE

6083
03:52:06,412 --> 03:52:07,614
THROUGH MOLECULAR CLONING

6084
03:52:07,614 --> 03:52:09,115
TECHNIQUES INTO A VECTOR THAT

6085
03:52:09,115 --> 03:52:10,450
ALLOWS YOU TO TAKE THE MOLECULE

6086
03:52:10,450 --> 03:52:12,752
AND GET IT INTO ANOTHER CELL.

6087
03:52:12,752 --> 03:52:14,020
YOU NEED TO VECTORIZE.

6088
03:52:14,020 --> 03:52:16,589
AND THEN YOU HAVE TO PRODUCE

6089
03:52:16,589 --> 03:52:17,223
THESE REAGENTS UNDER CONDITIONS

6090
03:52:17,223 --> 03:52:19,626
THAT YOU CAN GIVE IT TO A

6091
03:52:19,626 --> 03:52:19,859
PATIENT.

6092
03:52:19,859 --> 03:52:20,527
GOING THROUGH THE SAFETY

6093
03:52:20,527 --> 03:52:22,128
QUALIFICATIONS YOU NEED TO DO

6094
03:52:22,128 --> 03:52:24,798
BEFORE YOU CAN GIVE THIS REAGENT

6095
03:52:24,798 --> 03:52:25,465
TO PATIENT CELLS.

6096
03:52:25,465 --> 03:52:29,702
ONCE YOU'VE DONE THAT YOU VERIFY

6097
03:52:29,702 --> 03:52:34,207
THE POTENCY AND SPECIFICITY, AND

6098
03:52:34,207 --> 03:52:36,943
WHAT YOU'LL SEE AGAIN THIS IS

6099
03:52:36,943 --> 03:52:38,912
NOT -- IT'S A JOURNEY.

6100
03:52:38,912 --> 03:52:41,748
WE'VE HEARD ABOUT JOURNEYS.

6101
03:52:41,748 --> 03:52:45,585
T-CELL RECEPTOR GENE THERAPY IS

6102
03:52:45,585 --> 03:52:46,786
NO SHORTER A JOURNEY THAN THE

6103
03:52:46,786 --> 03:52:50,290
OTHERS YOU HEARD ABOUT TODAY.

6104
03:52:50,290 --> 03:52:52,358
BEGINNING IN 1986, THE VERY

6105
03:52:52,358 --> 03:52:53,459
FIRST MURINE T-CELL RECEPTORS

6106
03:52:53,459 --> 03:52:56,095
MOVED FROM ONE T CELL TO ANOTHER

6107
03:52:56,095 --> 03:52:57,530
T CELL.

6108
03:52:57,530 --> 03:52:59,833
AND THAT AFFORDED NEW T CELL

6109
03:52:59,833 --> 03:53:01,568
WITH THE SPECIFICITY FROM THE

6110
03:53:01,568 --> 03:53:03,837
ORIGINAL CELL, AGAIN SETTING THE

6111
03:53:03,837 --> 03:53:08,241
PREMISE YOU COULD TAKE THIS

6112
03:53:08,241 --> 03:53:09,108
HETERODIMER AND GET SPECIFICITY

6113
03:53:09,108 --> 03:53:10,076
OF ORIGINAL CELL.

6114
03:53:10,076 --> 03:53:14,581
OVER THE NEXT DECADE OR SO MORE

6115
03:53:14,581 --> 03:53:16,216
OF THESE ANTIGEN RECEPTORS WERE

6116
03:53:16,216 --> 03:53:17,851
CLONED PARTICULARLY IN SURGERY

6117
03:53:17,851 --> 03:53:20,487
BRANCH, THEY WERE THEN

6118
03:53:20,487 --> 03:53:23,656
TRANSFERRED IN 1995 BY MIKE'S

6119
03:53:23,656 --> 03:53:25,091
GROUP TO ANOTHER T CELL, SHOWED

6120
03:53:25,091 --> 03:53:28,061
T CELL NOW HAD ABILITY TO

6121
03:53:28,061 --> 03:53:29,462
RECOGNIZE THE TUMOR.

6122
03:53:29,462 --> 03:53:30,897
SO THAT WAS THE BASIC

6123
03:53:30,897 --> 03:53:31,197
TECHNOLOGY.

6124
03:53:31,197 --> 03:53:33,433
IT TOOK SOME TIME THEN ABOUT A

6125
03:53:33,433 --> 03:53:36,603
DECADE TO TAKE THAT GENE

6126
03:53:36,603 --> 03:53:38,271
TRANSFER TECHNOLOGY INTO ARE

6127
03:53:38,271 --> 03:53:40,240
EXPAND TO BE USED FOR HUMAN

6128
03:53:40,240 --> 03:53:41,207
CLINICAL APPLICATIONS.

6129
03:53:41,207 --> 03:53:50,850
SO WHAT I'M GOING TO DO IS GO

6130
03:53:50,850 --> 03:53:52,852
THROUGH THE APPLICATIONS, IT'S

6131
03:53:52,852 --> 03:53:55,588
BEEN AN AMAZING 20, 30 YEARS OF

6132
03:53:55,588 --> 03:54:02,262
HUMAN T-CELL RECEPTOR GENE

6133
03:54:02,262 --> 03:54:05,865
TRANSFER EXPERIMENTS.

6134
03:54:05,865 --> 03:54:06,766
FIRST TIME LYMPHOCYTES SHOWED

6135
03:54:06,766 --> 03:54:10,169
SHOWN IN HUMANS, A REPORT IN

6136
03:54:10,169 --> 03:54:12,138
"SCIENCE" IN 26.

6137
03:54:12,138 --> 03:54:14,974
THIS WAS TAKING A MELANOCYTE

6138
03:54:14,974 --> 03:54:15,975
DIFFERENTIATION ANTIGEN T-CELL

6139
03:54:15,975 --> 03:54:19,045
RECEPTOR CLONED BY THE BRANCH,

6140
03:54:19,045 --> 03:54:23,616
PUTTING INTO RETROVIRAL VECTOR,

6141
03:54:23,616 --> 03:54:25,051
PROTOCOL STARTS WITH APHERESIS,

6142
03:54:25,051 --> 03:54:26,085
YOU THEN USE GENE TRANSFER

6143
03:54:26,085 --> 03:54:29,389
TECHNOLOGY TO PUT IN THE NEW

6144
03:54:29,389 --> 03:54:32,358
RECEPTOR INTO THE T CELL, T CELL

6145
03:54:32,358 --> 03:54:34,227
HAS TWO RECEPTORS, THERE ARE

6146
03:54:34,227 --> 03:54:35,995
TRICKS TO MINIMIZE ANY POTENTIAL

6147
03:54:35,995 --> 03:54:38,498
CROSS-REACTIVITY BUT THAT'S A

6148
03:54:38,498 --> 03:54:40,566
TOPIC WHICH WE WON'T GET TO

6149
03:54:40,566 --> 03:54:40,767
TODAY.

6150
03:54:40,767 --> 03:54:42,468
EXPAND THOSE CELLS TO LARGE

6151
03:54:42,468 --> 03:54:43,002
NUMBERS.

6152
03:54:43,002 --> 03:54:44,203
RETURN THEM TO THE PATIENT FROM

6153
03:54:44,203 --> 03:54:45,838
WHICH THEY CAME.

6154
03:54:45,838 --> 03:54:47,774
NOW YOU'VE GIVEN THAT PATIENT AN

6155
03:54:47,774 --> 03:54:56,482
EXTRA BOOST OF A TUMOR-REACTIVE

6156
03:54:56,482 --> 03:54:57,216
POTENTIALLY TUMOR REACTIVE

6157
03:54:57,216 --> 03:54:57,884
LYMPHOCYTES, THE SAME

6158
03:54:57,884 --> 03:55:02,588
CHEMOTHERAPY THAT TIL PATIENTS

6159
03:55:02,588 --> 03:55:05,858
GET, WE DID PEPTIDE VACCINES AS

6160
03:55:05,858 --> 03:55:06,092
WELL.

6161
03:55:06,092 --> 03:55:08,161
WE DID IN A SMALL NUMBER OF

6162
03:55:08,161 --> 03:55:11,230
PATIENTS, ABOUT 12% OF INITIAL

6163
03:55:11,230 --> 03:55:13,299
PATIENTS RESPONDED, YOU COULD

6164
03:55:13,299 --> 03:55:15,501
GET DRAMATIC TUMOR REGRESSIONS,

6165
03:55:15,501 --> 03:55:18,671
LOOKING AT THE DRAMATIC MELANOMA

6166
03:55:18,671 --> 03:55:22,875
METASTASES TO THE DELIVER,

6167
03:55:22,875 --> 03:55:29,148
REGRESSION SMALL ENOUGH SURGEONS

6168
03:55:29,148 --> 03:55:31,684
EXCISED IT.

6169
03:55:31,684 --> 03:55:34,654
YOU COULD GENETICALLY ENGINEER A

6170
03:55:34,654 --> 03:55:35,521
NORMAL LYMPHOCYTE TO MEDIATE

6171
03:55:35,521 --> 03:55:36,856
TUMOR REGRESSION.

6172
03:55:36,856 --> 03:55:39,359
THAT ALLOWED US TO EXPAND

6173
03:55:39,359 --> 03:55:40,360
THINKING.

6174
03:55:40,360 --> 03:55:43,730
THIS INITIAL STUDY, THIS WASN'T

6175
03:55:43,730 --> 03:55:45,131
ACTIVE T-CELL RECEPTOR, BRANCH

6176
03:55:45,131 --> 03:55:47,100
FOCUSED ON MORE POTENT

6177
03:55:47,100 --> 03:55:48,768
RECEPTORS, YOU COULD DETECT

6178
03:55:48,768 --> 03:55:50,403
LOWER AMOUNTS OF POTENTIALLY

6179
03:55:50,403 --> 03:55:55,441
ANTIGEN ON THE SURFACE. 

6180
03:55:55,441 --> 03:56:05,952
HERE IS AN EXAMPLE REPORTED IN

6181
03:56:06,986 --> 03:56:08,254
2009, ISOLATED THEM, TREATED A

6182
03:56:08,254 --> 03:56:11,724
NUMBER OF PATIENTS, AND INDEED

6183
03:56:11,724 --> 03:56:13,059
RESPONSE RATE PARTICULARLY WITH

6184
03:56:13,059 --> 03:56:15,561
THE MART RECEPTOR WENT UP FROM

6185
03:56:15,561 --> 03:56:19,499
12 TO 13% TO 13%, SHOWING

6186
03:56:19,499 --> 03:56:21,701
OBJECTIVE RESPONSES.

6187
03:56:21,701 --> 03:56:27,607
INCLUDING BRAIN METASTASES,

6188
03:56:27,607 --> 03:56:29,475
HAVING THAT DIFFERENTIAL ANTIGEN

6189
03:56:29,475 --> 03:56:31,010
AFFORDED ABILITY TO RECOGNIZE

6190
03:56:31,010 --> 03:56:33,212
NORMAL MELANOCYTES.

6191
03:56:33,212 --> 03:56:35,481
WE DID SEE TOXICITY IN THE SKIN,

6192
03:56:35,481 --> 03:56:40,653
EYE, IN THE EAR, WHERE NORMAL

6193
03:56:40,653 --> 03:56:41,754
MELANOCYTES RESIDE.

6194
03:56:41,754 --> 03:56:43,156
THE FIELD THOUGHT DIFFERENTLY,

6195
03:56:43,156 --> 03:56:45,258
ARE THERE OTHER ANTIGENS COULD

6196
03:56:45,258 --> 03:56:49,729
YOU TARGET WHICH DON'T HAVE THIS

6197
03:56:49,729 --> 03:56:50,830
ON-TARGET OFF-TUMOR TOXICITY.

6198
03:56:50,830 --> 03:56:54,667
ONE THOUGHT WAS CLASS OF

6199
03:56:54,667 --> 03:56:55,835
ANTIGENS, CANCER GERMLINE WHICH

6200
03:56:55,835 --> 03:56:57,603
PAUL ROBBINS REFERRED TO THIS

6201
03:56:57,603 --> 03:57:01,541
MORE THAN, PAUL PUBLISHED

6202
03:57:01,541 --> 03:57:03,609
BEAUTIFUL STUDIES SHOWING

6203
03:57:03,609 --> 03:57:05,178
DRAMATIC RESPONSES, DURABLE.

6204
03:57:05,178 --> 03:57:07,146
NOT PARTICULARLY HIGHLY

6205
03:57:07,146 --> 03:57:10,450
EXPRESSED, ON MOST EPITHELIAL

6206
03:57:10,450 --> 03:57:11,851
CANCERS.

6207
03:57:11,851 --> 03:57:15,822
ANOTHER CANCER TEST ANTIGEN,

6208
03:57:15,822 --> 03:57:21,294
MAGE, MORE HIGHLY EXPRESSED.

6209
03:57:21,294 --> 03:57:24,130
LOOKING AT T-CELL RECEPTORS.

6210
03:57:24,130 --> 03:57:26,732
IN 2013, BOTH SURGERY BRANCH AS

6211
03:57:26,732 --> 03:57:33,539
WELL AS CARL JUNE'S GROUP AT

6212
03:57:33,539 --> 03:57:36,042
UPenn PUBLISHED REPORTS WHERE

6213
03:57:36,042 --> 03:57:40,446
THEY WERE ISOLATED, MODIFIED,

6214
03:57:40,446 --> 03:57:41,414
ENHANCED REACTIVITY AGAINST

6215
03:57:41,414 --> 03:57:43,249
MAG-A3, GIVEN TO A NUMBER OF

6216
03:57:43,249 --> 03:57:44,250
CANCER PATIENTS.

6217
03:57:44,250 --> 03:57:45,785
IN THE SURGERY BRANCH TRIAL FIVE

6218
03:57:45,785 --> 03:57:53,126
OUT OF NINE PATIENTS WHO GOT

6219
03:57:53,126 --> 03:57:54,927
THIS ANTI-MAGE-A-3 RECEPTORS HAD

6220
03:57:54,927 --> 03:57:57,163
TUMOR REGRESSION.

6221
03:57:57,163 --> 03:58:01,968
AT THE SAME TIME, THREE OF NINE

6222
03:58:01,968 --> 03:58:05,471
DEVELOPED NEUROTOXICITY,

6223
03:58:05,471 --> 03:58:06,606
DEVELOPED WITHIN FIRST WEEK,

6224
03:58:06,606 --> 03:58:13,913
PROGRESSIVE, TWO DIED FROM

6225
03:58:13,913 --> 03:58:15,081
MASSIVE NEUROINFLAMMATORY

6226
03:58:15,081 --> 03:58:15,314
DISEASE.

6227
03:58:15,314 --> 03:58:16,782
UNRELATED BUT AT THE SAME TIME

6228
03:58:16,782 --> 03:58:27,326
PENN GROUP TREATED WHO PATIENTS

6229
03:58:33,566 --> 03:58:36,135
WITH THEIR ANTI-MAGE-A3

6230
03:58:36,135 --> 03:58:36,402
RECEPTORS.

6231
03:58:36,402 --> 03:58:42,141
BOTH GROUPS, WE DIDN'T SEE THIS

6232
03:58:42,141 --> 03:58:42,808
COMING.

6233
03:58:42,808 --> 03:58:45,511
WHAT WE FOUND WAS TWO TYPES OF

6234
03:58:45,511 --> 03:58:45,845
EXAMPLES.

6235
03:58:45,845 --> 03:58:49,916
IN THE SURGERY BRANCH EXAMPLE WE

6236
03:58:49,916 --> 03:58:53,953
KNEW THAT OUR MAGE A-3 RECEPTOR

6237
03:58:53,953 --> 03:58:56,055
COULD RECOGNIZE OTHER MEMBERS OF

6238
03:58:56,055 --> 03:58:59,225
THE FAMILY, 9 AND 12.

6239
03:58:59,225 --> 03:59:01,961
THERE'S A VERY SMALL AMOUNT,

6240
03:59:01,961 --> 03:59:09,168
RARE NEURONS IN THE BRAIN WHICH

6241
03:59:09,168 --> 03:59:10,369
EXPRESS PROBABLY MAGE-A12, WE

6242
03:59:10,369 --> 03:59:12,872
BELIEVE THAT'S WHAT OCCURRED IN

6243
03:59:12,872 --> 03:59:15,942
THE SURGERY BRANCH CASES, ENOUGH

6244
03:59:15,942 --> 03:59:19,679
T CELLS MADE THEIR WAY INTO CNS,

6245
03:59:19,679 --> 03:59:21,447
BUT NOT A UNIFORM FINDING

6246
03:59:21,447 --> 03:59:24,250
BECAUSE ONLY THREE OF THE NINE

6247
03:59:24,250 --> 03:59:26,118
PATIENTS TREATED HAD THIS

6248
03:59:26,118 --> 03:59:26,719
NEUROLOGICAL TOXICITY.

6249
03:59:26,719 --> 03:59:31,924
IN THE CASE OF THE PENN GROUP,

6250
03:59:31,924 --> 03:59:33,125
DIFFERENT RECEPTOR, THEIR

6251
03:59:33,125 --> 03:59:35,561
RECEPTOR HAD NOW AGAIN MODIFIED

6252
03:59:35,561 --> 03:59:38,264
RECEPTOR, ABILITY TO RECOGNIZE

6253
03:59:38,264 --> 03:59:39,131
DISSIMILAR PROTEIN, TITAN,

6254
03:59:39,131 --> 03:59:43,302
HIGHLY EXPRESSED IN

6255
03:59:43,302 --> 03:59:45,171
CARDIOMYOCYTES, A PEPTIDE COULD

6256
03:59:45,171 --> 03:59:47,240
BE RECOGNIZED BY THE T-CELL

6257
03:59:47,240 --> 03:59:48,541
RECEPTOR AGAINST THEIR T-CELL

6258
03:59:48,541 --> 03:59:49,542
RECEPTOR.

6259
03:59:49,542 --> 03:59:54,480
THAT WAS EXAMPLE AGAIN OF OFF

6260
03:59:54,480 --> 03:59:56,182
TARGET OFF TUMOR REACTIVITY.

6261
03:59:56,182 --> 03:59:58,517
THIS GAVE PAUSE TO THE FIELD.

6262
03:59:58,517 --> 04:00:00,353
WHAT ELSE CAN WE DO?

6263
04:00:00,353 --> 04:00:04,857
ONE CLEAR EXAMPLE OF WHAT MIGHT

6264
04:00:04,857 --> 04:00:07,793
BE AN IDEAL TARGET WOULD BE

6265
04:00:07,793 --> 04:00:10,863
VIRAL ASSOCIATED ANTIGENS FROM

6266
04:00:10,863 --> 04:00:13,733
FOR EXAMPLE HPV, AND CHRISTIAN

6267
04:00:13,733 --> 04:00:17,570
HENDRICKS IN THE BRANCH

6268
04:00:17,570 --> 04:00:19,705
DEVELOPED SPECIFIC RECEPTORS

6269
04:00:19,705 --> 04:00:24,110
AGAINST HPV A-6 PROTEIN.

6270
04:00:24,110 --> 04:00:25,511
IN 12 PATIENTS ADMINISTERED

6271
04:00:25,511 --> 04:00:28,514
THESE T CELLS TO THESE PATIENTS,

6272
04:00:28,514 --> 04:00:29,148
TWO PATIENTS RESPONDED.

6273
04:00:29,148 --> 04:00:32,985
WHAT I THINK IS REMARKABLE WAS

6274
04:00:32,985 --> 04:00:35,321
THEY WERE GIVEN VERY LARGE

6275
04:00:35,321 --> 04:00:37,089
NUMBERS OF T-CELL RECEPTOR

6276
04:00:37,089 --> 04:00:38,691
ENGINEERED CELLS, OVER 100

6277
04:00:38,691 --> 04:00:40,893
BILLION, THERE WAS NO

6278
04:00:40,893 --> 04:00:41,994
SIGNIFICANT TOXICITIES NOTICED.

6279
04:00:41,994 --> 04:00:44,397
SO IF YOU HAVE THE RIGHT T-CELL

6280
04:00:44,397 --> 04:00:48,768
RECEPTOR YOU CAN ADMINISTER IT,

6281
04:00:48,768 --> 04:00:55,107
IN LARGE NUMBERS, YOU'LL NOT SEE

6282
04:00:55,107 --> 04:00:55,708
POTENTIALLY TOXICITIES RELATED

6283
04:00:55,708 --> 04:00:56,375
SPECIFICALLY TO THE RECEPTOR PER

6284
04:00:56,375 --> 04:00:56,642
SE.

6285
04:00:56,642 --> 04:00:58,177
WHAT WAS ALSO FOUND IN

6286
04:00:58,177 --> 04:00:59,312
CHRISTIAN'S PAPER WAS WHEN YOU

6287
04:00:59,312 --> 04:01:02,782
PUT A LOT OF IMMUNE PRESSURE ON

6288
04:01:02,782 --> 04:01:05,484
A CANCER, YOU'RE GOING TO SEE

6289
04:01:05,484 --> 04:01:05,751
PUSHBACK.

6290
04:01:05,751 --> 04:01:07,486
IN THIS CASE IMMUNE ESCAPE WAS

6291
04:01:07,486 --> 04:01:10,656
IN THE FORM OF FRAME SHIFT

6292
04:01:10,656 --> 04:01:11,857
MUTATION IN INTERFERON GAMMA

6293
04:01:11,857 --> 04:01:16,796
RECEPTOR AS WELL AS HLA LOSS.

6294
04:01:16,796 --> 04:01:17,863
CERTAINLY AGAIN THESE HPV

6295
04:01:17,863 --> 04:01:19,732
STUDIES, IF YOU GET THE RIGHT

6296
04:01:19,732 --> 04:01:21,934
RECEPTOR, YOU HAVE A THERAPY CAN

6297
04:01:21,934 --> 04:01:23,002
YOU ADMINISTER SAFELY.

6298
04:01:23,002 --> 04:01:24,737
THAT LED TO WHETHER WE ARE

6299
04:01:24,737 --> 04:01:26,272
TODAY, AND TO THE TALKS YOU'LL

6300
04:01:26,272 --> 04:01:27,707
HEAR TO FOLLOW ME.

6301
04:01:27,707 --> 04:01:32,945
THIS CONCEPT OF THE NEOANTIGEN

6302
04:01:32,945 --> 04:01:33,813
ANTI-T-CELL RECEPTOR.

6303
04:01:33,813 --> 04:01:36,248
AND THESE ARE TWO PUBLICATIONS

6304
04:01:36,248 --> 04:01:38,451
YOU'LL HEAR FROM MARIA AND

6305
04:01:38,451 --> 04:01:38,751
FRANK.

6306
04:01:38,751 --> 04:01:40,720
I'M GOING TO PLUG ERIC'S PAPER,

6307
04:01:40,720 --> 04:01:42,922
HOW TO MAKE SOME RECEPTORS

6308
04:01:42,922 --> 04:01:44,423
BETTER, BUT THAT'S WHERE THE

6309
04:01:44,423 --> 04:01:46,192
FIELD IS GOING.

6310
04:01:46,192 --> 04:01:50,463
AND WHERE WE ARE NOW AGAIN WE

6311
04:01:50,463 --> 04:01:53,666
NOW HAVE AN APPROVED T-CELL

6312
04:01:53,666 --> 04:01:55,267
RECEPTOR-BASED MEDICINE.

6313
04:01:55,267 --> 04:01:58,137
IT TOOK, AGAIN, A FEW DECADES

6314
04:01:58,137 --> 04:02:06,212
BUT THIS IS REPORT PUBLISHED  IN

6315
04:02:06,212 --> 04:02:08,414
THE LANCET THIS YEAR, A COMPANY

6316
04:02:08,414 --> 04:02:10,149
CALLED ADAPT IMMUNE FROM THE

6317
04:02:10,149 --> 04:02:13,252
U.K., TREATED 52 PATIENTS IN A

6318
04:02:13,252 --> 04:02:15,388
MULTI-NATIONAL TRIAL IN 23

6319
04:02:15,388 --> 04:02:18,591
SITES, YOU CAN SEE FROM THE

6320
04:02:18,591 --> 04:02:20,760
WATERFALL PLOTS, SPIDER PLOTS,

6321
04:02:20,760 --> 04:02:25,798
THAT WHEN PATIENTS RECEIVED

6322
04:02:25,798 --> 04:02:27,366
THEIR ANTI-MAGE A-4 T-CELL

6323
04:02:27,366 --> 04:02:29,969
RECEPTOR, YOU GOT A SIGNIFICANT

6324
04:02:29,969 --> 04:02:31,937
OBJECTIVE RESPONSE RATE, ALMOST

6325
04:02:31,937 --> 04:02:34,473
40% OF SYNOVIAL SARCOMA PATIENTS

6326
04:02:34,473 --> 04:02:35,875
HAD OBJECTIVE RESPONSE, OVERALL

6327
04:02:35,875 --> 04:02:39,478
SURVIVAL NOW GOING OUT TO 17

6328
04:02:39,478 --> 04:02:39,712
MONTHS.

6329
04:02:39,712 --> 04:02:40,780
THESE ARE HEAVILY PRE-TREATED

6330
04:02:40,780 --> 04:02:41,046
PATIENTS.

6331
04:02:41,046 --> 04:02:44,417
SO REALLY AN INDICATION THAT YOU

6332
04:02:44,417 --> 04:02:45,918
GET THE RIGHT RECEPTOR AND

6333
04:02:45,918 --> 04:02:49,555
ADMINISTER IT, YOU CAN ACTUALLY

6334
04:02:49,555 --> 04:02:51,190
GET DURABLE CANCER REGRESSIONS.

6335
04:02:51,190 --> 04:02:54,794
SO IT'S BEEN A LONG JOURNEY TO

6336
04:02:54,794 --> 04:02:56,362
GET US WHERE WE ARE TODAY.

6337
04:02:56,362 --> 04:02:58,197
WE DO AGAIN HAVE THE FIRST

6338
04:02:58,197 --> 04:02:59,732
MEDICINE, YOU'LL HEAR THE NEXT

6339
04:02:59,732 --> 04:03:04,770
FEW SLIDES SOME REALLY EXCITING

6340
04:03:04,770 --> 04:03:05,504
WORK.

6341
04:03:05,504 --> 04:03:08,274
I WANT TO END TO PERSONALLY

6342
04:03:08,274 --> 04:03:09,208
THANK DR. ROSENBERG.

6343
04:03:09,208 --> 04:03:13,712
MOST OF YOU DON'T KNOW THIS, BUT

6344
04:03:13,712 --> 04:03:16,682
STEVE SAVED MY CAREER.

6345
04:03:16,682 --> 04:03:18,217
IN 2000 THE GENOME INSTITUTE

6346
04:03:18,217 --> 04:03:19,351
DECIDED TO CLOSE THE CLINICAL

6347
04:03:19,351 --> 04:03:20,219
GENE THERAPY BRANCH.

6348
04:03:20,219 --> 04:03:22,188
I WAS OUT OF A JOB.

6349
04:03:22,188 --> 04:03:25,658
I DID NOT KNOW WHAT I WAS GOING

6350
04:03:25,658 --> 04:03:27,426
TO DO NEXT.

6351
04:03:27,426 --> 04:03:29,295
AND STEVE, WHO IS ALWAYS, AGAIN,

6352
04:03:29,295 --> 04:03:31,831
YEARS AHEAD OF US IN THINKING,

6353
04:03:31,831 --> 04:03:33,766
UNDERSTOOD THAT THE TECHNOLOGY

6354
04:03:33,766 --> 04:03:35,835
WHICH HAD BEEN DEVELOPED IN THE

6355
04:03:35,835 --> 04:03:36,936
GENOME INSTITUTE TO TREAT

6356
04:03:36,936 --> 04:03:38,571
GENETIC DISEASES WAS WHAT HE WAS

6357
04:03:38,571 --> 04:03:40,539
LOOKING FOR TO BRING TO THE

6358
04:03:40,539 --> 04:03:41,974
SURGERY BRANCH TO DEVELOP THOSE

6359
04:03:41,974 --> 04:03:43,275
NEW CLASSES OF MEDICINES WHICH

6360
04:03:43,275 --> 04:03:44,477
YOU'VE HEARD ABOUT AND WE

6361
04:03:44,477 --> 04:03:47,246
CONTINUE TO HEAR ABOUT TODAY.

6362
04:03:47,246 --> 04:03:47,780
SO THANK YOU, STEVE.

6363
04:03:47,780 --> 04:03:55,855
[APPLAUSE] 

6364
04:03:55,855 --> 04:04:00,793
 

6365
04:04:00,793 --> 04:04:03,529
LET'S HEAR SOME SCIENCE.

6366
04:04:03,529 --> 04:04:09,535
 

6367
04:04:09,535 --> 04:04:14,273
 

6368
04:04:14,273 --> 04:04:22,581
>> I WELCOME DR. MARIA

6369
04:04:22,581 --> 04:04:23,649
PARKHURST, RESPONSIBLE FOR

6370
04:04:23,649 --> 04:04:24,750
NEOANTIGEN WORK YOU HEARD US

6371
04:04:24,750 --> 04:04:26,852
TALK ABOUT TODAY.

6372
04:04:26,852 --> 04:04:29,154
WELCOME.

6373
04:04:29,154 --> 04:04:32,758
 

6374
04:04:32,758 --> 04:04:34,727
>> THANK YOU FOR THE

6375
04:04:34,727 --> 04:04:35,160
INTRODUCTION.

6376
04:04:35,160 --> 04:04:39,431
DR. ROSENBERG, I DON'T HAVE

6377
04:04:39,431 --> 04:04:40,332
ANYTHING VERY PARTICULAR

6378
04:04:40,332 --> 04:04:41,734
WONDERFULLY THING TO SAY LIKE

6379
04:04:41,734 --> 04:04:44,703
SOME OTHER PEOPLE HAVE, BUT

6380
04:04:44,703 --> 04:04:46,338
SEEING YOU FOR 30 YEARS IT'S

6381
04:04:46,338 --> 04:04:47,439
BEEN AN AMAZING RIDE, I'M

6382
04:04:47,439 --> 04:04:48,707
THANKFUL TO STILL BE ON IT.

6383
04:04:48,707 --> 04:04:49,842
THANK YOU FOR THAT.

6384
04:04:49,842 --> 04:04:52,778
TODAY I'D LIKE TO PRESENT SOME

6385
04:04:52,778 --> 04:04:56,849
RECENT EFFORTS AT IDENTIFYING

6386
04:04:56,849 --> 04:04:57,516
PERSONALIZED NEOANTIGEN REACTIVE

6387
04:04:57,516 --> 04:05:04,390
T-CELL RECEPTORS FROM TIL AND

6388
04:05:04,390 --> 04:05:07,326
USE IN PATIENTS WITH SOLID

6389
04:05:07,326 --> 04:05:11,063
EPITHELIAL CANCERS.

6390
04:05:11,063 --> 04:05:12,798
OUR STRATEGIES SHOWN HERE, WE

6391
04:05:12,798 --> 04:05:14,900
FIRST RESECT, DISSECT INTO SMALL

6392
04:05:14,900 --> 04:05:16,635
PIECES, ALLOW T CELLS TO

6393
04:05:16,635 --> 04:05:20,072
EMIGRATE IN THE PRESENCE OF

6394
04:05:20,072 --> 04:05:22,575
IL-2, AND AT THE SAME -- WRONG

6395
04:05:22,575 --> 04:05:22,841
WAY.

6396
04:05:22,841 --> 04:05:26,946
WE ISOLATE DNA AND RNA FROM

6397
04:05:26,946 --> 04:05:29,515
THOSE TUMOR SPECIMENS, PERFORM

6398
04:05:29,515 --> 04:05:34,286
SEQUENCING, IDENTIFY SOMATIC

6399
04:05:34,286 --> 04:05:36,155
MUTATIONS, MAKE PEPTIDES AS YOU

6400
04:05:36,155 --> 04:05:40,192
PREVIOUSLY HEARD, AND WE

6401
04:05:40,192 --> 04:05:43,262
INTRODUCE THOSE INTO AUTOLOGOUS

6402
04:05:43,262 --> 04:05:46,332
ANTIGEN PRESENTING CELLS,

6403
04:05:46,332 --> 04:05:49,602
CO-CULTURE WITH TIL, FROM TIL

6404
04:05:49,602 --> 04:05:54,540
FRAGMENTS, EVALUATE RECOGNITION

6405
04:05:54,540 --> 04:05:57,543
BASED ON INTERFERON GAMMA

6406
04:05:57,543 --> 04:05:59,445
SECRETION AND INSTEAD OF

6407
04:05:59,445 --> 04:06:01,747
SELECTING TIL FOR PATIENT

6408
04:06:01,747 --> 04:06:05,451
TREATMENT WE WOULD THEN SINGLE

6409
04:06:05,451 --> 04:06:08,954
CELL SORT INDIVIDUAL CELLS AND

6410
04:06:08,954 --> 04:06:10,723
SEQUENCE TO IDENTIFY INDIVIDUAL

6411
04:06:10,723 --> 04:06:13,125
TCR ALPHA AND BETA CHAINS.

6412
04:06:13,125 --> 04:06:14,693
AS ONE EXAMPLE OF AN INITIAL TIL

6413
04:06:14,693 --> 04:06:19,765
SCREEN THIS IS A PATIENT, 4378,

6414
04:06:19,765 --> 04:06:22,868
FOR THIS PATIENT WE TESTED 24

6415
04:06:22,868 --> 04:06:24,970
INDIVIDUAL TIL FRAGMENTS

6416
04:06:24,970 --> 04:06:30,309
AGAINST -- FOR RECOGNIZE OF 133

6417
04:06:30,309 --> 04:06:33,078
VARIANTS ENCODED IN SEVEN

6418
04:06:33,078 --> 04:06:34,813
CONSTRUCTS, MULTIPLE FRAGMENTS

6419
04:06:34,813 --> 04:06:45,357
RECOGNIZED FNG 1 IN RED STARS, 2

6420
04:06:46,925 --> 04:06:51,130
IN BLUE STARS.

6421
04:06:51,130 --> 04:06:53,565
WE DECONVOLUTED ANTIGENS,

6422
04:06:53,565 --> 04:06:55,200
NEOANTIGEN BY PULSING INDIVIDUAL

6423
04:06:55,200 --> 04:06:57,736
25 AMINO ACID PEPTIDES DERIVED

6424
04:06:57,736 --> 04:06:59,905
FROM TMG OF INTEREST ON THE

6425
04:06:59,905 --> 04:07:01,740
PATIENT'S CONTROLS AND THERE

6426
04:07:01,740 --> 04:07:04,243
THIS CASE IDENTIFIED REACTIVITY

6427
04:07:04,243 --> 04:07:09,081
ASSOCIATED WITH TMG 1 TO BE THIS

6428
04:07:09,081 --> 04:07:12,685
PROTEIN, MUTATED GCLM, INVOLVED

6429
04:07:12,685 --> 04:07:17,289
IN GLUTATHIONE SYNTHESIS.

6430
04:07:17,289 --> 04:07:19,825
FOR TMG 2 REACTIVITY, A PROTEIN

6431
04:07:19,825 --> 04:07:21,026
INVOLVED IN ALCOHOL METABOLISM.

6432
04:07:21,026 --> 04:07:23,328
SO ONCE WE HAD THIS INFORMATION

6433
04:07:23,328 --> 04:07:27,700
IN MIND, WE THEN WON'T TO SORT

6434
04:07:27,700 --> 04:07:31,537
THE INDIVIDUAL CELLS TO IDENTIFY

6435
04:07:31,537 --> 04:07:33,038
T-CELL RECEPTORS MEDIATING THOSE

6436
04:07:33,038 --> 04:07:33,572
REACTIVITIES.

6437
04:07:33,572 --> 04:07:42,448
FOR ONE FRAGMENT WE ISOLATED CD8

6438
04:07:42,448 --> 04:07:45,217
CELLS THAT UPREGULATED 4 11B,

6439
04:07:45,217 --> 04:07:47,286
AND SEQUENCING WE IDENTIFIED

6440
04:07:47,286 --> 04:07:50,789
SINGLE DOMINANT T-CELL RECEPTOR

6441
04:07:50,789 --> 04:07:52,991
SHOWN HERE, SAME FOR TMG 2

6442
04:07:52,991 --> 04:07:55,160
REACTIVE CELLS.

6443
04:07:55,160 --> 04:07:57,362
THE REACTIVE POPULATION WAS A

6444
04:07:57,362 --> 04:07:58,664
POPULATION OF CD8 CD4 DOUBLE

6445
04:07:58,664 --> 04:08:07,973
POSITIVE CELLS BUT WE ISOLATED

6446
04:08:07,973 --> 04:08:10,275
INDIVIDUAL 4-1BB CELLS.

6447
04:08:10,275 --> 04:08:12,544
ONCE WE HAD THIS INFORMATION IN

6448
04:08:12,544 --> 04:08:14,646
HAND, WE WANT TO GENERATE FULL

6449
04:08:14,646 --> 04:08:17,149
LENGTH CONSTRUCTS, WE DID THIS

6450
04:08:17,149 --> 04:08:19,785
BY GENERATING PROTEIN SEQUENCE,

6451
04:08:19,785 --> 04:08:23,822
TCR ALPHA AND BETA CHAIN REGIONS

6452
04:08:23,822 --> 04:08:25,891
ARE GRAFTED MURINE CONSTANT

6453
04:08:25,891 --> 04:08:30,496
REGIONS, SEPARATED ALPHA AND

6454
04:08:30,496 --> 04:08:32,998
BETA CHAINS, TO GENERATE A FULL

6455
04:08:32,998 --> 04:08:33,866
LENGTH T-CELL RECEPTOR ALPHA

6456
04:08:33,866 --> 04:08:36,068
BETA CONSTRUCTS.

6457
04:08:36,068 --> 04:08:39,371
THIS IS AN EXAMPLE, HUMAN MOUSE

6458
04:08:39,371 --> 04:08:44,710
HYBRID BETA CHAIN FOLLOWED BY IN

6459
04:08:44,710 --> 04:08:51,483
RED P2A SEQUENCE, FOLLOWED BY

6460
04:08:51,483 --> 04:08:53,018
HYBRID HUMAN-MOUSE ALPHA CHAIN,

6461
04:08:53,018 --> 04:08:54,553
INTRODUCED MODIFICATIONS IN

6462
04:08:54,553 --> 04:08:57,289
YELLOW TO ENHANCE EXPRESSION OR

6463
04:08:57,289 --> 04:08:59,792
TO FACILITATE CLONING.

6464
04:08:59,792 --> 04:09:03,762
WE CODON OPTIMIZED, CLONED INTO

6465
04:09:03,762 --> 04:09:05,397
RETROVIRAL VECTOR.

6466
04:09:05,397 --> 04:09:07,699
WE THEN PRODUCED RETROVIRUSES

6467
04:09:07,699 --> 04:09:10,636
ENCODING TCRs, AND DO THIS BY

6468
04:09:10,636 --> 04:09:15,474
INTRODUCING T-CELL RECEPTOR IN

6469
04:09:15,474 --> 04:09:17,976
VECTOR WITH ENVELOPE VECTOR,

6470
04:09:17,976 --> 04:09:21,814
INTO 293GP CELLS WITH GAGPOL

6471
04:09:21,814 --> 04:09:24,316
GENES, WE PRODUCE SOME

6472
04:09:24,316 --> 04:09:25,083
RETROVIRAL-PRODUCING CELLS AND

6473
04:09:25,083 --> 04:09:29,588
USE THESE AS YOU'VE HEARD TO

6474
04:09:29,588 --> 04:09:31,456
INTRODUCE T-CELL RECEPTOR GENES

6475
04:09:31,456 --> 04:09:39,097
INTO PATIENT'S PERIPHERAL BLOOD

6476
04:09:39,097 --> 04:09:42,067
LYMPHOCYTES. 

6477
04:09:42,067 --> 04:09:44,770
WE CAN USE ANTI-MURINE ANTIBODY

6478
04:09:44,770 --> 04:09:46,438
TO EVALUATE EXPRESSION OF TCRs

6479
04:09:46,438 --> 04:09:49,274
WE INTRODUCE, CAN YOU SEE FOR

6480
04:09:49,274 --> 04:09:53,579
THE GCLM PCR WE HAVE 77%

6481
04:09:53,579 --> 04:09:54,913
TRANSDUCTION EFFICIENCY, AND THE

6482
04:09:54,913 --> 04:09:56,882
CELLS ARE EQUALLY DIVIDED

6483
04:09:56,882 --> 04:09:59,051
BETWEEN CD4s AND CD8s.

6484
04:09:59,051 --> 04:10:01,119
WE EVALUATED CELL FUNCTION BY

6485
04:10:01,119 --> 04:10:03,222
LOOKING AT INTERFERON GAMMA

6486
04:10:03,222 --> 04:10:06,959
SECRETION, IN RESPONSE TO EITHER

6487
04:10:06,959 --> 04:10:11,430
DENDRITIC CELLS OR MUTANT

6488
04:10:11,430 --> 04:10:13,198
PEPTIDE PULSED DENDRITIC CELLS,

6489
04:10:13,198 --> 04:10:14,833
THIS RECEPTOR CLEARLY MEDIATES

6490
04:10:14,833 --> 04:10:18,103
RECOGNITION OF THE MUTANT GCLM

6491
04:10:18,103 --> 04:10:19,805
PEPTIDE.

6492
04:10:19,805 --> 04:10:23,141
THIS IS THE SIMILAR DATA THAT WE

6493
04:10:23,141 --> 04:10:24,343
IDENTIFIED, CLEARLY HAVE WHAT WE

6494
04:10:24,343 --> 04:10:26,745
BELIEVE TO BE TWO GOOD CELL

6495
04:10:26,745 --> 04:10:28,480
RECEPTORS FOR PATIENT TREATMENT.

6496
04:10:28,480 --> 04:10:37,356
FOR MANY CLASS 1 RECEPTORS WE'VE

6497
04:10:37,356 --> 04:10:40,859
ISOLATED ELEMENTS BY PEPTIDE

6498
04:10:40,859 --> 04:10:41,560
PULSING MINIMAL EPITOPES

6499
04:10:41,560 --> 04:10:43,929
TRANSFECTED WITH EACH OF THE

6500
04:10:43,929 --> 04:10:45,330
PATIENTS HLA MOLECULES.

6501
04:10:45,330 --> 04:10:49,368
AND IN THIS CASE IDENTIFIED THAT

6502
04:10:49,368 --> 04:10:52,037
THE GCLM PCR RECOGNIZED THAT

6503
04:10:52,037 --> 04:10:57,376
PEPTIDE IN CONTEXT OF HLA 25,

6504
04:10:57,376 --> 04:11:00,012
ALDA 2 TCR RECOGNIZED PROTEIN IN

6505
04:11:00,012 --> 04:11:01,113
THE CONTEXT OF HLA 2.

6506
04:11:01,113 --> 04:11:03,615
SO WITH ALL THIS BACKGROUND

6507
04:11:03,615 --> 04:11:05,217
INFORMATION WE WERE READY TO

6508
04:11:05,217 --> 04:11:07,352
TRANSLATE TO GO TO THE CLINIC.

6509
04:11:07,352 --> 04:11:09,421
AND THERE WAS ONE HURDLE THAT

6510
04:11:09,421 --> 04:11:12,257
HAD TO BE OVERCOME.

6511
04:11:12,257 --> 04:11:15,460
FOR EVERY T-CELL RECEPTOR WE

6512
04:11:15,460 --> 04:11:18,330
PREVIOUSLY MADE, INTENT WAS TO

6513
04:11:18,330 --> 04:11:19,631
TREAT A LOT OF PATIENTS WITH A

6514
04:11:19,631 --> 04:11:22,901
SINGLE PRODUCT.

6515
04:11:22,901 --> 04:11:23,869
WE MADE T-CELL RECEPTOR

6516
04:11:23,869 --> 04:11:25,170
SUPERNATANTS, A SINGLE PACKAGING

6517
04:11:25,170 --> 04:11:26,738
CELL LINE, MAKING A MASTER BANK

6518
04:11:26,738 --> 04:11:33,645
OF THAT CELL LINE AND MAKING GLP

6519
04:11:33,645 --> 04:11:36,048
QUALITY RETROVIRAL SUPERNATANTS.

6520
04:11:36,048 --> 04:11:39,351
THE AMOUNT OF TIME AND COST IN

6521
04:11:39,351 --> 04:11:40,819
PRODUCING AND QUALIFYING THE

6522
04:11:40,819 --> 04:11:47,659
CELL LINE AND SUPERNATANTS MADE

6523
04:11:47,659 --> 04:11:49,294
IT IMPRACTICAL TO TREAT AN

6524
04:11:49,294 --> 04:11:50,929
INDIVIDUAL PATIENT WITH SMALL

6525
04:11:50,929 --> 04:11:53,665
AMOUNT OF T CELL RECEPTOR.

6526
04:11:53,665 --> 04:11:55,801
A HUGE EFFORT BY STEVE FELDMAN

6527
04:11:55,801 --> 04:12:01,206
IN THE LAB HE AND NOW RACHEL

6528
04:12:01,206 --> 04:12:02,941
BIER DEVELOPED A GLP PROCESS

6529
04:12:02,941 --> 04:12:05,477
THAT IS NOW FDA APPROVED THAT

6530
04:12:05,477 --> 04:12:07,679
ALLOWS US TO USE TRANSIENTLY

6531
04:12:07,679 --> 04:12:10,315
TRANSFECTED 293 CELLS TO PRODUCE

6532
04:12:10,315 --> 04:12:11,717
GLP QUALITY RETROVIRUSES, IT'S

6533
04:12:11,717 --> 04:12:16,121
SHOWN HERE BASICALLY ON DAY

6534
04:12:16,121 --> 04:12:18,190
ZERO, A VIAL FROM MASTER CELL

6535
04:12:18,190 --> 04:12:21,159
BANK IS THAWED, EXPANDED TO

6536
04:12:21,159 --> 04:12:23,028
LARGE NUMBERS, TRANSFECTION IS

6537
04:12:23,028 --> 04:12:26,398
DONE ON DAY 11, BY

6538
04:12:26,398 --> 04:12:27,933
CO-TRANSFECTING WITH RETROVIRAL

6539
04:12:27,933 --> 04:12:35,474
TCR CONSTRUCT, THIS RD 114 ARE

6540
04:12:35,474 --> 04:12:37,509
VECTOR.

6541
04:12:37,509 --> 04:12:41,713
IT'S HARVESTED, TREATED TO

6542
04:12:41,713 --> 04:12:46,852
REMOVE PLASMA, CRYOPRESERVEED.

6543
04:12:46,852 --> 04:12:53,325
WE TAKE PERIPHERAL BLOOD

6544
04:12:53,325 --> 04:12:56,061
LYMPHOCYTES FROM PATIENT, INSERT

6545
04:12:56,061 --> 04:12:57,562
USING GMP QUALITY RETROVIRAL

6546
04:12:57,562 --> 04:12:59,064
PRODUCTS, EXPAND THOSE TO LARGE

6547
04:12:59,064 --> 04:13:03,268
NUMBERS IN THE CLINIC USING

6548
04:13:03,268 --> 04:13:04,669
SECOND SIMULATION AND FINALLY

6549
04:13:04,669 --> 04:13:09,041
REINFUSE INTO THE PATIENT AFTER

6550
04:13:09,041 --> 04:13:10,042
LYMPHODEPLETING CHEMOTHERAPY.

6551
04:13:10,042 --> 04:13:12,344
SO, IN ORDER TO CHARACTERIZE

6552
04:13:12,344 --> 04:13:17,816
INFUSED CELLS WE DO A FEW SIMPLE

6553
04:13:17,816 --> 04:13:18,650
MANEUVERS.

6554
04:13:18,650 --> 04:13:19,551
CLEARLY EVALUATE THE

6555
04:13:19,551 --> 04:13:21,219
TRANSDUCTION EFFICIENCY LOOKING

6556
04:13:21,219 --> 04:13:22,954
AT EXPRESSION OF MOUSE T-CELL

6557
04:13:22,954 --> 04:13:23,822
RECEPTOR CONSTANT REGION.

6558
04:13:23,822 --> 04:13:26,458
AND THEN WE DO SOME BASIC

6559
04:13:26,458 --> 04:13:29,594
PHENOTYPIC EVALUATION OF THE TCR

6560
04:13:29,594 --> 04:13:34,766
TRANSDUCED CELLS BY LOOKING AT

6561
04:13:34,766 --> 04:13:37,936
CD4 AND CD8, AND CD39 AND CD69,

6562
04:13:37,936 --> 04:13:40,105
IN THIS PATIENT POPULATION YOU

6563
04:13:40,105 --> 04:13:43,442
CAN SEE ABOUT 53% OF CELLS

6564
04:13:43,442 --> 04:13:47,913
TRANSDUCED, A LOT MORE CD4 CELLS

6565
04:13:47,913 --> 04:13:51,817
THAT WERE EXPRESSING THAN CD8,

6566
04:13:51,817 --> 04:14:02,327
DESPITE THE FACT IT WAS  A CD8

6567
04:14:02,861 --> 04:14:03,128
RECEPTOR.

6568
04:14:03,128 --> 04:14:04,463
SURPRISINGLY, VERY ENCOURAGING

6569
04:14:04,463 --> 04:14:07,232
FROM OUR STANDPOINT, MAJORITY OF

6570
04:14:07,232 --> 04:14:09,468
CELLS WERE CD39, 69 DOUBLE

6571
04:14:09,468 --> 04:14:11,670
NEGATIVE, A PHENOTYPE PREVIOUSLY

6572
04:14:11,670 --> 04:14:15,373
ASSOCIATED WITH RESPONSES IN

6573
04:14:15,373 --> 04:14:17,242
PATIENTS TREATED WITH TIL IN

6574
04:14:17,242 --> 04:14:19,744
SETTING OF MELANOMA.

6575
04:14:19,744 --> 04:14:21,847
THIS IS THE ALDH 2 RECEPTOR,

6576
04:14:21,847 --> 04:14:25,450
SAME DATA FOR THAT, MAJORITY OF

6577
04:14:25,450 --> 04:14:28,753
THE CELLS WERE CD 4, EFFECTOR

6578
04:14:28,753 --> 04:14:33,125
MEMORY PHENOTYPE BUT LARGE

6579
04:14:33,125 --> 04:14:34,860
PERCENTAGE, MAJORITY WERE CD39,

6580
04:14:34,860 --> 04:14:36,628
69 DOUBLE NEGATIVE.

6581
04:14:36,628 --> 04:14:38,930
WE EVALUATED FUNCTION OF THE

6582
04:14:38,930 --> 04:14:40,465
INFUSED CELLS LOOKING AT

6583
04:14:40,465 --> 04:14:42,968
RECOGNIZE OF TITRATED PEPTIDE ON

6584
04:14:42,968 --> 04:14:43,969
THE PATIENT'S AUTOLOGOUS

6585
04:14:43,969 --> 04:14:45,704
DENDRITIC CELLS, BY LOOKING AT

6586
04:14:45,704 --> 04:14:46,905
INTERFERON GAMMA SECRETION, YOU

6587
04:14:46,905 --> 04:14:50,308
CAN SEE THAT IF WE USE MINIMAL

6588
04:14:50,308 --> 04:14:52,711
EPITOPE IT'S RECOGNIZED DOWN TO

6589
04:14:52,711 --> 04:14:55,280
ABOUT ONE NANOGRAM PER MILL,

6590
04:14:55,280 --> 04:14:57,215
ALDL 2 RECEPTOR WAS EVEN MORE

6591
04:14:57,215 --> 04:14:59,518
SENSITIVE THAN THAT.

6592
04:14:59,518 --> 04:15:06,057
WE ALSO LOOKED AT SECRETION OF

6593
04:15:06,057 --> 04:15:12,430
OTHER CYTOKINES, GRANZYME B AND

6594
04:15:12,430 --> 04:15:14,065
ARE HIGHLY FUNCTIONAL.

6595
04:15:14,065 --> 04:15:17,669
AS WE HEARD TODAY, IT'S BEEN

6596
04:15:17,669 --> 04:15:18,637
WELL ESTABLISHED THAT METASTATIC

6597
04:15:18,637 --> 04:15:26,945
TUMORS CAN BE VERY HETEROGENEOUS

6598
04:15:26,945 --> 04:15:29,247
IN EXPRESSION OF ANTIGENS, FOR

6599
04:15:29,247 --> 04:15:31,983
EVERY TUMOR NOW WE ROUTINELY

6600
04:15:31,983 --> 04:15:36,588
EVALUATE BOTH TUMOR CELL

6601
04:15:36,588 --> 04:15:38,456
NEOANTIGEN CLONALITY, LOSS OF

6602
04:15:38,456 --> 04:15:38,823
HETEROZYGOSITY.

6603
04:15:38,823 --> 04:15:41,092
THIS PATIENT THAT I KEEP

6604
04:15:41,092 --> 04:15:42,427
REFERRING TO, WE SEQUENCED SEVEN

6605
04:15:42,427 --> 04:15:44,529
INDIVIDUAL FRAGMENTS FROM THIS

6606
04:15:44,529 --> 04:15:45,931
PATIENT, ESTIMATED THE

6607
04:15:45,931 --> 04:15:49,201
PERCENTAGE OF TUMOR CELLS THAT

6608
04:15:49,201 --> 04:15:51,937
HAD EITHER GCLM MUTATION OR ALDH

6609
04:15:51,937 --> 04:15:55,874
2 MUTATION, YOU CAN SEE THAT THE

6610
04:15:55,874 --> 04:15:57,976
ALDH 2 MUTATION APPEARS CLONAL,

6611
04:15:57,976 --> 04:16:01,813
100% OF THE CELLS IN EVERY

6612
04:16:01,813 --> 04:16:03,548
FRAGMENT THAT WE SEQUENCED HAD

6613
04:16:03,548 --> 04:16:06,518
THAT MUTATION.

6614
04:16:06,518 --> 04:16:09,487
HOWEVER, THE GCLM MUTATION WAS

6615
04:16:09,487 --> 04:16:10,589
SUBCLONAL, ONLY ACTUALLY FOUND

6616
04:16:10,589 --> 04:16:15,060
IN TWO OF THE SEVEN FRAGMENTS WE

6617
04:16:15,060 --> 04:16:15,493
EVALUATED.

6618
04:16:15,493 --> 04:16:23,435
WE FOUND NO CLEAR EVIDENCE OF

6619
04:16:23,435 --> 04:16:24,836
CLASS 1 HLA LOH.

6620
04:16:24,836 --> 04:16:26,471
THIS PATIENT DID HAVE A PARTIAL

6621
04:16:26,471 --> 04:16:32,477
RESPONSE TO TREATMENT SO WE HAD

6622
04:16:32,477 --> 04:16:34,913
TWO BIOPSIES POST TREATMENT,

6623
04:16:34,913 --> 04:16:39,384
MUTATION WAS CLONALLY PRESENT IN

6624
04:16:39,384 --> 04:16:42,454
THE ALDT 2 MUTATION IN BOTH BUT

6625
04:16:42,454 --> 04:16:43,888
THE GCLM MUTATION WAS

6626
04:16:43,888 --> 04:16:44,756
UNDETECTABLE.

6627
04:16:44,756 --> 04:16:48,360
THERE WAS NO EVIDENCE OF CLASS 1

6628
04:16:48,360 --> 04:16:48,593
LOH.

6629
04:16:48,593 --> 04:16:49,628
THIS INFLUENCED OUR DECISION

6630
04:16:49,628 --> 04:16:51,863
ABOUT HOW TO COMBINE THE TWO

6631
04:16:51,863 --> 04:16:53,198
TCRs FOR PATIENT TREATMENT.

6632
04:16:53,198 --> 04:16:59,004
WE GAVE 2/3 OF THE INFUSED

6633
04:16:59,004 --> 04:17:01,506
SAMPLES, ALDH 2 TCR TRANSDUCED

6634
04:17:01,506 --> 04:17:03,575
CELLS, A THIRD WERE GCLM

6635
04:17:03,575 --> 04:17:04,576
TRANSDUCED CELLS.

6636
04:17:04,576 --> 04:17:07,379
THIS IS A SUMMARY OF ALL THE

6637
04:17:07,379 --> 04:17:09,748
PATIENTS THUS FAR, IN PARTICULAR

6638
04:17:09,748 --> 04:17:11,916
WE'VE TREATED 11 PATIENTS, 8

6639
04:17:11,916 --> 04:17:13,885
WITH COLORECTAL, TWO BREAST

6640
04:17:13,885 --> 04:17:15,320
CANCER, ONE WITH NON-SMALL CELL

6641
04:17:15,320 --> 04:17:25,764
LUNG CARS NO,  CARCINOMA.

6642
04:17:26,531 --> 04:17:29,768
AND IN FOUR PATIENTS BECAUSE WE

6643
04:17:29,768 --> 04:17:32,804
SAW SOMETIMES THIS EXPRESSION OF

6644
04:17:32,804 --> 04:17:36,741
THE TCR WE WANTED IN A T CELL

6645
04:17:36,741 --> 04:17:38,877
EXPRESSING OPPOSITE CO-RECEPTOR

6646
04:17:38,877 --> 04:17:40,845
WE SELECTED FOR APPROPRIATE IN

6647
04:17:40,845 --> 04:17:42,514
SOME, TREATED FOUR PATIENTS WITH

6648
04:17:42,514 --> 04:17:44,683
CELLS ENRICHED FOR APPROPRIATE

6649
04:17:44,683 --> 04:17:44,983
CO-RECEPTOR.

6650
04:17:44,983 --> 04:17:49,721
I DIDN'T PUT THE DATA ON THE

6651
04:17:49,721 --> 04:17:51,690
TABLE, WE TARGETED ONE CLONAL

6652
04:17:51,690 --> 04:17:52,957
NEOANTIGEN, DIDN'T TREAT ANY

6653
04:17:52,957 --> 04:17:55,894
PATIENTS WITH CLASS 1 LOH

6654
04:17:55,894 --> 04:17:57,629
RELEVANT TO THE RESTRICTION

6655
04:17:57,629 --> 04:18:01,333
ELEMENT ASSOCIATED WITH TUMOR

6656
04:18:01,333 --> 04:18:01,599
TREATMENT.

6657
04:18:01,599 --> 04:18:03,535
MOST OF THE PATIENTS GOT ON THE

6658
04:18:03,535 --> 04:18:05,503
ORDER OF ONE TIMES 10 TO THE

6659
04:18:05,503 --> 04:18:10,975
11th CELLS, AND AT LEAST 50%

6660
04:18:10,975 --> 04:18:11,276
TRANSDUCED.

6661
04:18:11,276 --> 04:18:13,178
AND MAJORITY OF CELLS, EVERY

6662
04:18:13,178 --> 04:18:15,246
PATIENT HAD EFFECTOR MEMORY

6663
04:18:15,246 --> 04:18:16,448
PHENOTYPE, FORTUNATE WERE ABLE

6664
04:18:16,448 --> 04:18:18,850
TO GIVE EVERY PATIENT AT LEAST

6665
04:18:18,850 --> 04:18:21,686
10% USUALLY GREATER OF THESE

6666
04:18:21,686 --> 04:18:24,322
CD39 CD69 DOUBLE NEGATIVE CELLS,

6667
04:18:24,322 --> 04:18:27,525
TEN TO 100 TIMES THE PERCENTAGE

6668
04:18:27,525 --> 04:18:30,128
OF CELLS WE NORMALLY GIVE WITH

6669
04:18:30,128 --> 04:18:31,763
SELECTED TIL THAT HAD THIS

6670
04:18:31,763 --> 04:18:32,731
POPULATION.

6671
04:18:32,731 --> 04:18:36,067
THREE PATIENTS HAD PARTIAL

6672
04:18:36,067 --> 04:18:37,602
REJECTIVE RESPONSES BY RECIST

6673
04:18:37,602 --> 04:18:44,876
CRITERIA, 4 TO 7 MONTHS, ONE

6674
04:18:44,876 --> 04:18:47,746
RECEIVED A CD4 T-CELL RECEPTOR.

6675
04:18:47,746 --> 04:18:50,181
WE'VE ALSO TREATED SEVEN

6676
04:18:50,181 --> 04:18:51,583
PATIENTS PREVIOUSLY TREATED WITH

6677
04:18:51,583 --> 04:18:53,752
TIL OR ANOTHER T CELL-BASED

6678
04:18:53,752 --> 04:18:55,086
THERAPY TARGETING THE SAME

6679
04:18:55,086 --> 04:18:57,622
NEOANTIGENS WE DID IN OUR SECOND

6680
04:18:57,622 --> 04:19:00,024
THERAPY WITH THE TCRs.

6681
04:19:00,024 --> 04:19:01,993
AND WE DIDN'T SEE ANY RESPONSES

6682
04:19:01,993 --> 04:19:03,728
IN THIS GROUP, AND WE SPECULATE

6683
04:19:03,728 --> 04:19:10,068
THIS MAY LIKELY BE THE FACT WE

6684
04:19:10,068 --> 04:19:11,903
TARGETED THE SAME NEOANTIGENS

6685
04:19:11,903 --> 04:19:13,538
INEFFECTIVELY TARGETED IN THE

6686
04:19:13,538 --> 04:19:14,239
FIRST TREATMENT.

6687
04:19:14,239 --> 04:19:16,107
WE'VE TREATED THREE PATIENTS

6688
04:19:16,107 --> 04:19:16,875
WITH BREAST CANCER,

6689
04:19:16,875 --> 04:19:18,209
COMPASSIONATE EXEMPTION,

6690
04:19:18,209 --> 04:19:19,277
UNFORTUNATELY NONE OF THOSE

6691
04:19:19,277 --> 04:19:20,412
PATIENTS RESPONDED TO THERAPY.

6692
04:19:20,412 --> 04:19:23,214
IN SOME PATIENTS WE EVALUATED

6693
04:19:23,214 --> 04:19:27,152
PERSISTENCE OF TRANSDUCED CELLS,

6694
04:19:27,152 --> 04:19:31,423
IN PERIPHERAL CIRCULATION, WE

6695
04:19:31,423 --> 04:19:36,594
DISTINGUISHED BETWEEN  THE TWO

6696
04:19:36,594 --> 04:19:38,763
BECAUSE THERE'S AN ANTIBODY

6697
04:19:38,763 --> 04:19:39,464
AVAILABLE.

6698
04:19:39,464 --> 04:19:44,235
THIS IS WHAT PRE-TREATMENT LOOKS

6699
04:19:44,235 --> 04:19:52,243
LIKE, DAY 7 POST TREATMENT 15%

6700
04:19:52,243 --> 04:19:55,647
EXPRESSED GCLM TCR, REPRESENTING

6701
04:19:55,647 --> 04:20:06,191
THE WAY INFUSION WE PROVIDED TO

6702
04:20:08,293 --> 04:20:16,000
THE PATIENT. 

6703
04:20:16,000 --> 04:20:19,704
WE EVALUATED PERSISTENCE IN THE

6704
04:20:19,704 --> 04:20:21,239
FIRST SEVEN PATIENTS, THUS FAR.

6705
04:20:21,239 --> 04:20:22,474
AND IF WE LOOK AT THE

6706
04:20:22,474 --> 04:20:24,542
NON-RESPONDERS YOU CAN SEE TWO

6707
04:20:24,542 --> 04:20:29,147
OF THE NON-RESPONDERS, IN TWO

6708
04:20:29,147 --> 04:20:30,148
NON-RESPONDERS THE TCR

6709
04:20:30,148 --> 04:20:31,449
TRANSDUCED CELLS DWINDLED AND

6710
04:20:31,449 --> 04:20:33,418
WERE NOT APPARENT BEYOND ABOUT

6711
04:20:33,418 --> 04:20:34,486
DAY 40 AFTER TREATMENT.

6712
04:20:34,486 --> 04:20:36,821
BUT FOR TWO OF THE OTHER

6713
04:20:36,821 --> 04:20:37,689
NON-RESPONDERS WE COULD READILY

6714
04:20:37,689 --> 04:20:41,693
DETECT CELLS, YOU CAN SEE THE

6715
04:20:41,693 --> 04:20:44,262
LAST PATIENT WHO 50 DAYS STILL

6716
04:20:44,262 --> 04:20:46,998
HAD 60% OF CIRCULATING CDs 3

6717
04:20:46,998 --> 04:20:48,032
CELLS EXPRESSING T-CELL RECEPTOR

6718
04:20:48,032 --> 04:20:49,634
WE GAVE HER.

6719
04:20:49,634 --> 04:20:52,070
WHEN WE LOOKED AT RESPONDERS WE

6720
04:20:52,070 --> 04:20:54,672
HAVE LARGER TIME POINTS

6721
04:20:54,672 --> 04:20:56,107
AVAILABLE FOR RESPONDING

6722
04:20:56,107 --> 04:20:59,077
PATIENTS, WE COULD DETECT

6723
04:20:59,077 --> 04:21:00,512
TRANSDUCED CELLS IN EVERY

6724
04:21:00,512 --> 04:21:03,147
PATIENT, AT EVERY TIME POINT WE

6725
04:21:03,147 --> 04:21:04,115
EVALUATED.

6726
04:21:04,115 --> 04:21:06,851
AND I'LL SHOW A FEW EXAMPLES OF

6727
04:21:06,851 --> 04:21:07,752
RESPONSES.

6728
04:21:07,752 --> 04:21:09,153
THIS PATIENT HAD REGRESSION OF

6729
04:21:09,153 --> 04:21:16,794
LEFT LUNG LESION AS WELL AS

6730
04:21:16,794 --> 04:21:18,363
MEEDALSTINAL LYMPH NODES, THIS

6731
04:21:18,363 --> 04:21:27,539
HAD RETRO PERITONEAL, DOCUMENTED

6732
04:21:27,539 --> 04:21:30,408
LUNG DISEASE, RETRO PERITONEAL

6733
04:21:30,408 --> 04:21:32,043
LYMPH NODES AND PERIHEPATIC

6734
04:21:32,043 --> 04:21:32,610
TUMORS.

6735
04:21:32,610 --> 04:21:35,013
SO, I WAS GOING TO PRESENT A

6736
04:21:35,013 --> 04:21:37,415
LITTLE BIT OF ADDITIONAL DATA

6737
04:21:37,415 --> 04:21:40,385
ABOUT PATIENTS WHOM WE ATTEMPTED

6738
04:21:40,385 --> 04:21:46,057
TO TARGET T CELLS AGAINST THESE

6739
04:21:46,057 --> 04:21:47,926
COMMON DRIVER MUTATIONS, BUT DR.

6740
04:21:47,926 --> 04:21:48,693
ROSENBERG PRESENTED THAT, WE

6741
04:21:48,693 --> 04:21:49,994
DON'T NEED TO GO INTO THAT

6742
04:21:49,994 --> 04:21:50,328
FURTHER.

6743
04:21:50,328 --> 04:21:57,135
WE NOW HAVE A LIBRARY OF 39

6744
04:21:57,135 --> 04:22:00,171
REACTIVE T-CELL RECEPTORS, 23

6745
04:22:00,171 --> 04:22:04,108
KRAS, AND WE HAVE TREATED 26

6746
04:22:04,108 --> 04:22:05,843
PATIENTS WITH A VARIETY OF

6747
04:22:05,843 --> 04:22:06,311
THESE.

6748
04:22:06,311 --> 04:22:07,512
THESE ARE PATIENTS THAT COME TO

6749
04:22:07,512 --> 04:22:09,714
US WITHOUT HAVING TO DO A

6750
04:22:09,714 --> 04:22:11,449
RESECTION, IF WE HAVE SEQUENCING

6751
04:22:11,449 --> 04:22:13,318
INFORMATION, IF THEY HAVE THAT

6752
04:22:13,318 --> 04:22:16,287
PARTICULAR HOT SPOT MUTATION AND

6753
04:22:16,287 --> 04:22:17,522
APPROPRIATE HLA RESTRICTION

6754
04:22:17,522 --> 04:22:21,192
ELEMENT WE CAN GIVE AN OFF THE

6755
04:22:21,192 --> 04:22:22,393
SHELF REAGENT QUICKLY.

6756
04:22:22,393 --> 04:22:24,596
T CELLS THAT RECOGNIZE UNIQUE

6757
04:22:24,596 --> 04:22:27,665
SOMATIC MUTATIONS CAN BE FOUND

6758
04:22:27,665 --> 04:22:28,433
IN TIL.

6759
04:22:28,433 --> 04:22:29,767
FROM THE COMMON EPITHELIAL

6760
04:22:29,767 --> 04:22:31,402
CANSERS IS AND TCRs THAT

6761
04:22:31,402 --> 04:22:33,538
MEDIATE CAN READILY BE

6762
04:22:33,538 --> 04:22:36,407
IDENTIFIED, ISOLATED, USED TO

6763
04:22:36,407 --> 04:22:38,042
GENETICALLY MODIFY PBL.

6764
04:22:38,042 --> 04:22:41,679
CELL TRANSFER THERAPY WITH PBL

6765
04:22:41,679 --> 04:22:43,514
TO EXPRESS PERSONALIZED

6766
04:22:43,514 --> 04:22:44,282
NEOANTIGEN RECEPTORS, CAN

6767
04:22:44,282 --> 04:22:46,718
MEDIATE REGRESSIONS IN PATIENTS

6768
04:22:46,718 --> 04:22:47,685
WITH COLORECTAL CANCERS

6769
04:22:47,685 --> 04:22:51,389
REFRACTORY TO ALL OTHER

6770
04:22:51,389 --> 04:22:52,056
TREATMENTS.

6771
04:22:52,056 --> 04:22:54,125
WE HAVE NOT IDENTIFIED ANY

6772
04:22:54,125 --> 04:22:55,126
CORRELATES WITH CLINICAL

6773
04:22:55,126 --> 04:22:56,694
RESPONSE BUT AS YOU'LL PROBABLY

6774
04:22:56,694 --> 04:22:58,096
HEAR THROUGHOUT THE FEW DAYS A

6775
04:22:58,096 --> 04:22:59,831
LOOT OF PEOPLE ARE PURSUING

6776
04:22:59,831 --> 04:23:01,032
STRATEGIES TO IMPROVE THE

6777
04:23:01,032 --> 04:23:02,667
THERAPY, AND I WOULD SAY ONE

6778
04:23:02,667 --> 04:23:05,403
MAJOR EFFORT OR TWO MAJOR

6779
04:23:05,403 --> 04:23:07,271
EFFORTS ONGOING IN THE LAB THAT

6780
04:23:07,271 --> 04:23:11,209
ARE REALLY DESIGNED TO OVERCOME

6781
04:23:11,209 --> 04:23:14,045
THESE BARRIERS OF EXPRESSION AND

6782
04:23:14,045 --> 04:23:15,647
LOSS OF HETEROZYGOSITY TO

6783
04:23:15,647 --> 04:23:16,881
IDENTIFY MORE T-CELL RECEPTORS

6784
04:23:16,881 --> 04:23:18,650
FOR EACH PATIENT AND DEVELOP

6785
04:23:18,650 --> 04:23:20,184
PRACTICAL METHODS FOR TREATING

6786
04:23:20,184 --> 04:23:22,587
PATIENTS WITH THESE MORE DIVERSE

6787
04:23:22,587 --> 04:23:27,859
T CELL POPULATIONS, AND I THINK

6788
04:23:27,859 --> 04:23:29,527
DR. LOWERY AFTER ME WILL

6789
04:23:29,527 --> 04:23:30,895
DESCRIBE THESE EFFORTS.

6790
04:23:30,895 --> 04:23:34,298
THANK YOU VERY MUCH FOR YOUR

6791
04:23:34,298 --> 04:23:34,732
KIND ATTENTION.

6792
04:23:34,732 --> 04:23:37,635
[APPLAUSE]

6793
04:23:37,635 --> 04:23:43,474
 

6794
04:23:43,474 --> 04:23:51,149
 

6795
04:23:51,149 --> 04:23:52,250
>> DR. FRANK LOWERY WILL
TALK

6796
04:23:52,250 --> 04:23:55,319
MORE ABOUT HOW WE'RE BROADENING

6797
04:23:55,319 --> 04:23:57,288
OUR TCR HUNT.

6798
04:23:57,288 --> 04:24:00,658
HE SERVES RESEARCH CAPACITY BUT

6799
04:24:00,658 --> 04:24:03,828
MOVING THINGS FROM THE LAB INTO

6800
04:24:03,828 --> 04:24:06,464
OUR GMP SPACES.

6801
04:24:06,464 --> 04:24:07,932
 

6802
04:24:07,932 --> 04:24:08,966
>> THANK YOU, DR. GOFF.

6803
04:24:08,966 --> 04:24:12,036
IT'S AN HONOR TO BE HERE.

6804
04:24:12,036 --> 04:24:18,476
THANK YOU TO DR. PARKHURST FOR

6805
04:24:18,476 --> 04:24:19,243
GIVING CONTEXTUALIZATION, AND

6806
04:24:19,243 --> 04:24:21,345
FOR TAKING ME UNDER YOUR WING

6807
04:24:21,345 --> 04:24:23,848
WHEN I GOT HERE AND SHOWING -- I

6808
04:24:23,848 --> 04:24:25,283
CAME IN WITH NO IMMUNOLOGY

6809
04:24:25,283 --> 04:24:27,251
BACKGROUND, A CANCER BIOLOGIST

6810
04:24:27,251 --> 04:24:28,786
IN GRADUATE SCHOOL, AND MARIA

6811
04:24:28,786 --> 04:24:30,888
SHOWED ME THE COMPLICATED NATURE

6812
04:24:30,888 --> 04:24:35,259
OF OUR T CELL ASSAYS, HOW TO

6813
04:24:35,259 --> 04:24:35,827
DISCOVER NEOANTIGENS, CLONE

6814
04:24:35,827 --> 04:24:39,864
TCRs, APPRECIATIVE TO HER FOR

6815
04:24:39,864 --> 04:24:40,064
THAT.

6816
04:24:40,064 --> 04:24:42,366
SO ANYONE WHO HAS EXPERIENCE IN

6817
04:24:42,366 --> 04:24:46,337
PATIENT CARE OR FAMILY MEMBER OR

6818
04:24:46,337 --> 04:24:48,706
DEALT WITH CANCER, MAJOR

6819
04:24:48,706 --> 04:24:51,209
LIMITING FACTOR IN DEVELOPING

6820
04:24:51,209 --> 04:24:52,577
THESE SPECIALIZED LAST DITCH

6821
04:24:52,577 --> 04:24:54,412
THERAPIES FOR PATIENTS DEALING

6822
04:24:54,412 --> 04:24:56,047
WITH ADVANCED METASTATIC DISEASE

6823
04:24:56,047 --> 04:24:58,349
IS TIME.

6824
04:24:58,349 --> 04:25:00,218
THAT'S THE ONLY NON-NEGOTIABLE.

6825
04:25:00,218 --> 04:25:03,187
SO WHEN WE'RE STARTING THE CLOCK

6826
04:25:03,187 --> 04:25:06,791
ON OUR TCR HUNT FOLLOWING TIL

6827
04:25:06,791 --> 04:25:09,193
SCREEN, ALREADY AN SEQUENCE

6828
04:25:09,193 --> 04:25:10,194
RESOURCE INTENSIVE AND TIME

6829
04:25:10,194 --> 04:25:12,296
INTENSIVE SEARCH, WHEN WE ONLY

6830
04:25:12,296 --> 04:25:14,132
START LOOKING FOR TCR FOLLOWING

6831
04:25:14,132 --> 04:25:17,235
TIL SCREENS, IT MEANS WE'RE

6832
04:25:17,235 --> 04:25:18,736
ADDING TWO MONTHS OR MORE OF

6833
04:25:18,736 --> 04:25:21,539
LOST TIME TO THAT CLOCK THAT THE

6834
04:25:21,539 --> 04:25:25,309
PATIENT'S DON'T HAVE HAVE TO

6835
04:25:25,309 --> 04:25:25,643
SPARE.

6836
04:25:25,643 --> 04:25:28,379
ONE POINT TO MAKE, IF WE GO

6837
04:25:28,379 --> 04:25:30,782
HUNTING FOR TCRs BASED OFF TIL

6838
04:25:30,782 --> 04:25:32,183
SCREEN DATA, OUR TCR TARGETS ARE

6839
04:25:32,183 --> 04:25:34,152
ONLY GOING TO BE LIMITED TO

6840
04:25:34,152 --> 04:25:36,120
THOSE THAT WE OBSERVED IN

6841
04:25:36,120 --> 04:25:36,788
FUNCTIONAL REACTIVITY SCREEN OF

6842
04:25:36,788 --> 04:25:37,321
THE TIL.

6843
04:25:37,321 --> 04:25:40,091
SO IF THE TIL WERE TOO EXHAUSTED

6844
04:25:40,091 --> 04:25:41,092
TO SHOW FUNCTIONAL REACTIVITY WE

6845
04:25:41,092 --> 04:25:42,193
WON'T PICK IT UP.

6846
04:25:42,193 --> 04:25:44,929
IF THE REACTIVITY WAS TOO WEAK

6847
04:25:44,929 --> 04:25:47,198
WE MIGHT MISS THAT WAY.

6848
04:25:47,198 --> 04:25:48,299
WE'LL BE LIMITED IN OUR

6849
04:25:48,299 --> 04:25:50,067
POTENTIAL NUMBER OF TARGETS WE

6850
04:25:50,067 --> 04:25:51,602
CAN HUNT THAT WAY.

6851
04:25:51,602 --> 04:25:54,639
AND THAT WHEN WE FIND THE

6852
04:25:54,639 --> 04:25:55,973
POTENTIAL CANDIDATE TCR THAT

6853
04:25:55,973 --> 04:26:00,244
SEEMS TO BE TUMOR MUTATION

6854
04:26:00,244 --> 04:26:01,212
REACTIVE, THE IDENTIFICATION,

6855
04:26:01,212 --> 04:26:02,947
SEQUENCING, THAT'S ONLY THE

6856
04:26:02,947 --> 04:26:04,048
FIRST STEP.

6857
04:26:04,048 --> 04:26:07,351
ULTIMATELY WE HAVE TO VALIDATE

6858
04:26:07,351 --> 04:26:08,119
MUTATION SPECIFIC, WE'RE SO

6859
04:26:08,119 --> 04:26:12,490
LUCKY TO BE HERE AT SURGERY

6860
04:26:12,490 --> 04:26:13,524
BRANCH, BUT THE GMP

6861
04:26:13,524 --> 04:26:15,259
QUALIFICATION, PREP OF A

6862
04:26:15,259 --> 04:26:17,328
PERSONALIZED CANCER TREATMENT IS

6863
04:26:17,328 --> 04:26:20,164
ANOTHER RESOURCE INTENSIVE PART

6864
04:26:20,164 --> 04:26:22,033
OF THE PROCESS.

6865
04:26:22,033 --> 04:26:26,070
SO, ONE MAJOR QUESTION THAT WE

6866
04:26:26,070 --> 04:26:28,940
SET OFF ON, AND ORIGINAL HUNT

6867
04:26:28,940 --> 04:26:31,542
WORK WAS WITH DR. KRISHNAN, MY

6868
04:26:31,542 --> 04:26:32,743
PARTNER IN CRIME IN A LOT OF

6869
04:26:32,743 --> 04:26:33,644
THIS STUFF.

6870
04:26:33,644 --> 04:26:38,149
ONE QUESTION WAS CAN TUMOR

6871
04:26:38,149 --> 04:26:39,450
RELEVANT TCRs BE PREDICTED

6872
04:26:39,450 --> 04:26:41,953
BASED ON SHARED PHENOTYPES?

6873
04:26:41,953 --> 04:26:44,488
ONE DUTY IS TCRs CAN BE USED

6874
04:26:44,488 --> 04:26:46,224
IF IT'S A TUMOR-SPECIFIC TCR YOU

6875
04:26:46,224 --> 04:26:48,960
CAN INTRODUCE IT INTO A

6876
04:26:48,960 --> 04:26:50,728
SECONDARY LYMPHOCYTE AND USE IT

6877
04:26:50,728 --> 04:26:53,464
TO REDIRECT SPECIFICITY TOWARDS

6878
04:26:53,464 --> 04:26:54,899
YOUR TARGET OF CHOICE.

6879
04:26:54,899 --> 04:26:56,968
THE OTHER BEAUTY AS A RESEARCHER

6880
04:26:56,968 --> 04:26:58,936
THAT THE TCR SERVES AS BARCODE

6881
04:26:58,936 --> 04:27:00,905
AND CAN YOU HAVE THAT BE A

6882
04:27:00,905 --> 04:27:02,773
BENCHMARK FOR THE CELL OF

6883
04:27:02,773 --> 04:27:04,508
INTEREST THAT EXPRESSES THAT

6884
04:27:04,508 --> 04:27:05,543
TCR.

6885
04:27:05,543 --> 04:27:07,778
ALL IT TAKES IS THE ROSETTA

6886
04:27:07,778 --> 04:27:09,780
STONE HAVING THE TCR REACTIVITY

6887
04:27:09,780 --> 04:27:11,682
DATA ALLOWS YOU TO TRACK THE

6888
04:27:11,682 --> 04:27:14,352
CLONES THAT HAVE THE SAME

6889
04:27:14,352 --> 04:27:14,652
REACTIVITY.

6890
04:27:14,652 --> 04:27:15,319
SO BASICALLY THAT'S THE

6891
04:27:15,319 --> 04:27:17,521
BACKGROUND IN HOW WE WERE ABLE

6892
04:27:17,521 --> 04:27:22,460
TO USE RNA SEQUENCING ANALYSIS

6893
04:27:22,460 --> 04:27:24,962
TETHERED TO FIND SHARED REACTIVE

6894
04:27:24,962 --> 04:27:25,263
PHENOTYPES.

6895
04:27:25,263 --> 04:27:26,597
AS A BRIEF BACKGROUND I DON'T

6896
04:27:26,597 --> 04:27:30,434
WANT TO GO INTO THE PUBLISHED

6897
04:27:30,434 --> 04:27:32,970
WORK, BUT OUR STUDY IN 202

6898
04:27:32,970 --> 04:27:36,007
SHOWED MAJORITY OF NEOANTIGEN

6899
04:27:36,007 --> 04:27:37,575
REACTIVE TCRs, THAT MARIA HAD

6900
04:27:37,575 --> 04:27:39,644
FOUND, I WAS LUCKY ENOUGH TO

6901
04:27:39,644 --> 04:27:44,015
SHARE MY WORK IN SORTING TO GET

6902
04:27:44,015 --> 04:27:51,255
THIS, BUT WE HAD BUILT A BANK OF

6903
04:27:51,255 --> 04:27:54,825
TCRs FOR PATIENTS, WITH

6904
04:27:54,825 --> 04:27:56,260
PRESERVED AVAILABLE WE STUDIED

6905
04:27:56,260 --> 04:27:57,795
THEM, ASKED THE QUESTION WHAT

6906
04:27:57,795 --> 04:28:00,131
STATE WERE THE CELLS BEARING

6907
04:28:00,131 --> 04:28:02,300
NEOANTIGEN REACTIVE CELLS IN.

6908
04:28:02,300 --> 04:28:04,368
WE ANALYZED TEN PATIENTS, NINE

6909
04:28:04,368 --> 04:28:07,104
HAD KNOWN REACTIVITY, WE SAW

6910
04:28:07,104 --> 04:28:09,640
THERE WAS REMARKABLE BIAS IN

6911
04:28:09,640 --> 04:28:13,377
LOCATION OF THE KNOWN NEOANTIGEN

6912
04:28:13,377 --> 04:28:15,913
REACTIVE TCRs, CD 4s IN THIS

6913
04:28:15,913 --> 04:28:21,919
STATE, CD8S IN EFFECTOR-LIKE

6914
04:28:21,919 --> 04:28:22,453
STATE.

6915
04:28:22,453 --> 04:28:23,220
WE BEEFED UP KNOWLEDGE, WHAT

6916
04:28:23,220 --> 04:28:26,390
ABOUT OTHER CELLS IN THE

6917
04:28:26,390 --> 04:28:27,024
CLUSTERS, REPREDICTED MORE

6918
04:28:27,024 --> 04:28:29,560
REACTIVITY BASED ON THE SHARED

6919
04:28:29,560 --> 04:28:31,062
PHENOTYPE AND ARCHIVAL SAMPLES,

6920
04:28:31,062 --> 04:28:31,996
AND SHOWED INDEED WHEN YOU

6921
04:28:31,996 --> 04:28:33,864
LOOKED FURTHER INTO THESE

6922
04:28:33,864 --> 04:28:39,003
CLUSTERS YOU FOUND MORE CD8

6923
04:28:39,003 --> 04:28:45,042
REACTIVE HERE AND MORE CD4

6924
04:28:45,042 --> 04:28:47,979
REACTIVE NEOTCRs HERE.

6925
04:28:47,979 --> 04:28:53,217
ONCE WE ASSEMBLED THE DATABASE,

6926
04:28:53,217 --> 04:28:54,018
WE LOOKED AT DIFFERENTIALLY

6927
04:28:54,018 --> 04:29:00,124
EXPRESSED GENES OF THE TUMOR

6928
04:29:00,124 --> 04:29:01,892
SPECIFIC CELLS, PERFORMED ROC

6929
04:29:01,892 --> 04:29:03,527
ANALYSIS.

6930
04:29:03,527 --> 04:29:07,698
IDENTIFIED WHAT WE CALLED NEOTCR

6931
04:29:07,698 --> 04:29:09,800
SIGNATURE, SENSITIVE FOR CD4

6932
04:29:09,800 --> 04:29:12,336
CELLS IN OUR STUDY, AND 8

6933
04:29:12,336 --> 04:29:14,071
SIGNATURE FOR CD8s.

6934
04:29:14,071 --> 04:29:16,374
NOTABLY THERE BE WERE SHARED

6935
04:29:16,374 --> 04:29:26,350
GENES AMONG THESE CD4 AND 8

6936
04:29:26,350 --> 04:29:33,224
STATES, NOT EXPRESSING MEMORY

6937
04:29:33,224 --> 04:29:34,658
STEM-LIKE MARKERS.

6938
04:29:34,658 --> 04:29:36,727
NOW, WHEN WE COMPARED OUR

6939
04:29:36,727 --> 04:29:38,696
SIGNATURES TO STUDIES DONE IN

6940
04:29:38,696 --> 04:29:41,232
OTHER TYPES OF TUMOR SOLID

6941
04:29:41,232 --> 04:29:42,199
GENES, ET CETERA, BASICALLY

6942
04:29:42,199 --> 04:29:45,202
PEOPLE AROUND THE WORLD OBSERVED

6943
04:29:45,202 --> 04:29:48,873
THE SAME PHENOMENON IN BLADDER

6944
04:29:48,873 --> 04:29:52,476
CANCER, LUNG CANCER, MELANOMA,

6945
04:29:52,476 --> 04:29:53,477
ET CETERA.

6946
04:29:53,477 --> 04:30:02,453
OUR SHARED STATE IS A COMMON

6947
04:30:02,453 --> 04:30:02,787
PHENOMENON.

6948
04:30:02,787 --> 04:30:07,425
IF WE LEARN THIS KNOWLEDGE IN

6949
04:30:07,425 --> 04:30:09,693
ARCHIVAL HOW CAN WE USE THIS

6950
04:30:09,693 --> 04:30:10,461
GOING FORWARD?

6951
04:30:10,461 --> 04:30:12,897
IF WE HAVE A PATIENT TUMOR IS

6952
04:30:12,897 --> 04:30:17,568
RESECTED, IMMEDIATELY START

6953
04:30:17,568 --> 04:30:22,306
HUNTING FOR TCR, WE TAKE FRESH

6954
04:30:22,306 --> 04:30:24,141
TUMOR DIGEST, ISOLATE, WE'RE NOT

6955
04:30:24,141 --> 04:30:26,110
JUST SEQUENCING ENTIRE TUMOR,

6956
04:30:26,110 --> 04:30:31,715
ARTIFICIALLY ENRICHING THE

6957
04:30:31,715 --> 04:30:34,552
LYMPHOCYTE COMPONENT.

6958
04:30:34,552 --> 04:30:37,088
WE PERFORMED SAME TRANSCRIPTOMIC

6959
04:30:37,088 --> 04:30:38,689
CLUSTERS ON THE ARCHIVAL SAMPLES

6960
04:30:38,689 --> 04:30:41,659
BUT NOW WE OBVIOUSLY HAVE SOME

6961
04:30:41,659 --> 04:30:44,095
BIAS IN OUR SIGNATURES.

6962
04:30:44,095 --> 04:30:51,068
THE FIRST STEP IS LOOK FOR

6963
04:30:51,068 --> 04:30:51,735
CLUSTERS THAT SELF-ASSEMBLE,

6964
04:30:51,735 --> 04:30:53,571
AROUND CAN YOU PROJECT ON THE

6965
04:30:53,571 --> 04:30:54,805
CLUSTERS AND MARK HOT REGIONS

6966
04:30:54,805 --> 04:30:56,640
THAT ARE A GOOD FIT FOR

6967
04:30:56,640 --> 04:30:56,941
SIGNATURES.

6968
04:30:56,941 --> 04:30:59,376
AND THEN BASED ON THAT YOU CAN

6969
04:30:59,376 --> 04:31:02,246
RECONSTRUCT AS DR. MORGAN TALKED

6970
04:31:02,246 --> 04:31:05,850
ABOUT, THE ALPHA BETA PAIR,

6971
04:31:05,850 --> 04:31:07,151
EXPRESS IN DONOR PLBR, SECRETARY

6972
04:31:07,151 --> 04:31:08,252
TO THE SAME PERSONALIZED

6973
04:31:08,252 --> 04:31:11,422
SCREENING METHODS WE'VE USED FOR

6974
04:31:11,422 --> 04:31:11,722
TIL.

6975
04:31:11,722 --> 04:31:13,090
AND IF YOU FIND VALIDATED

6976
04:31:13,090 --> 04:31:16,460
REACTIVE ONE THAT CAN BE A

6977
04:31:16,460 --> 04:31:17,128
TREATMENT CANDIDATE TCR.

6978
04:31:17,128 --> 04:31:22,166
I WANT TO SHOW HOW THIS LOOKS IN

6979
04:31:22,166 --> 04:31:26,303
PRACTICE, BUT IF YOU GETS MORE

6980
04:31:26,303 --> 04:31:28,072
IN THE WEEDS, NO PRIOR KNOWLEDGE

6981
04:31:28,072 --> 04:31:37,982
OF SAMPLE COMING IN, YOU NEED TO

6982
04:31:37,982 --> 04:31:42,887
PERFORM TRANSCRIPTOMIC

6983
04:31:42,887 --> 04:31:45,089
CLUSTERING, USE THE BIOCONDUCTOR

6984
04:31:45,089 --> 04:31:45,723
ALGORITHM, SCORES INDIVIDUAL

6985
04:31:45,723 --> 04:31:49,994
CELLS FOR FITNESS TO A GIVEN

6986
04:31:49,994 --> 04:31:50,261
SIGNATURE.

6987
04:31:50,261 --> 04:31:52,296
YOU'RE SEEING HOW WELL CELLS IN

6988
04:31:52,296 --> 04:31:57,234
PATIENT A'S TUMOR MAPS TO KNOWN

6989
04:31:57,234 --> 04:31:58,435
PREVIOUSLY DESCRIBED SIGNATURES,

6990
04:31:58,435 --> 04:32:00,504
WITHIN THAT POPULATION, AGAIN NO

6991
04:32:00,504 --> 04:32:01,939
IDEA OF REACTIVITY, WE DON'T

6992
04:32:01,939 --> 04:32:05,109
HAVE THE PATIENT'S TUMOR

6993
04:32:05,109 --> 04:32:06,443
SEQUENCING DATA YET, THIS SET OF

6994
04:32:06,443 --> 04:32:10,014
CELLS HAS A GREAT FIT FOR NEO8,

6995
04:32:10,014 --> 04:32:12,183
CD8 REACTIVE TO THE PATIENT'S

6996
04:32:12,183 --> 04:32:17,821
TUMOR ANTIGENS, WE ALSO HAVE THE

6997
04:32:17,821 --> 04:32:19,990
OPTION CITIED OF LIMITING TO

6998
04:32:19,990 --> 04:32:23,427
CELLS DEMARCATED CAN LOOK AT

6999
04:32:23,427 --> 04:32:24,228
CLUSTERS THAT SELF-ASSEMBLE,

7000
04:32:24,228 --> 04:32:27,765
I'LL SHOW WHAT I MEAN IN A

7001
04:32:27,765 --> 04:32:28,966
SECOND.

7002
04:32:28,966 --> 04:32:37,741
OCCASIONALLY UNAMBIGUOUS,

7003
04:32:37,741 --> 04:32:39,276
CLUSTER DEFINES ITSELF, WE

7004
04:32:39,276 --> 04:32:42,112
SCREEN AGAINST PATIENT

7005
04:32:42,112 --> 04:32:44,415
TUMOR-SPECIFIC REAGENTS,

7006
04:32:44,415 --> 04:32:44,715
PEPTIDES.

7007
04:32:44,715 --> 04:32:45,716
TMGS, TUMOR ORGANOIDS WHEN

7008
04:32:45,716 --> 04:32:47,351
AVAILABLE.

7009
04:32:47,351 --> 04:32:51,088
HERE IS ONE EXAMPLE, A COLON

7010
04:32:51,088 --> 04:32:53,924
CANCER, LIVER METASTASIS.

7011
04:32:53,924 --> 04:32:55,659
GENERALIZED CLUSTERING.

7012
04:32:55,659 --> 04:33:00,030
I SHOWED SELECTED GENES HERE,

7013
04:33:00,030 --> 04:33:01,265
I'M SORRY IT'S SMALL, UPPER

7014
04:33:01,265 --> 04:33:04,768
RIGHT PART OF THE MAP IS LARGELY

7015
04:33:04,768 --> 04:33:05,469
CD4.

7016
04:33:05,469 --> 04:33:08,372
LOWER INTO THE LEFT CD8.

7017
04:33:08,372 --> 04:33:12,309
AS THE BRIEFEST SHORT HAND FOR

7018
04:33:12,309 --> 04:33:17,514
SIGNATURES, CXCL 13 IS ONE GENE

7019
04:33:17,514 --> 04:33:18,782
THAT'S SHARED, HIGHLIGHTING THIS

7020
04:33:18,782 --> 04:33:21,952
REGION HERE, THIS REGION HERE.

7021
04:33:21,952 --> 04:33:26,957
YOU HAVE TO -- THE HUMAN MIND

7022
04:33:26,957 --> 04:33:29,193
ISN'T DESIGNED TO JUMP BACK AND

7023
04:33:29,193 --> 04:33:29,526
FORTH.

7024
04:33:29,526 --> 04:33:33,530
IF YOU NOTE REGIONS HIGHLIGHTED

7025
04:33:33,530 --> 04:33:36,400
IT WOULD BE CLUSTER DOWN HERE,

7026
04:33:36,400 --> 04:33:41,672
THE POSITIVE REGION, AND C17 IS

7027
04:33:41,672 --> 04:33:47,611
THIS TINY CLUSTER DEMARCATED

7028
04:33:47,611 --> 04:33:47,945
HERE.

7029
04:33:47,945 --> 04:33:50,014
WHEN PROJECTED ON THE MAP,

7030
04:33:50,014 --> 04:33:52,049
PRETEND YOU DON'T KNOW THE

7031
04:33:52,049 --> 04:33:53,417
CLUSTERING IDENTITY, YOU LOOK

7032
04:33:53,417 --> 04:33:56,353
FOR HOT SPOTS, YOU SAY ON THE

7033
04:33:56,353 --> 04:34:00,190
NEO4 SIGNATURE A HOT SPOT HERE,

7034
04:34:00,190 --> 04:34:02,159
HERE, HERE.

7035
04:34:02,159 --> 04:34:03,494
NOW, NEO8 SIGNATURE HIGHLIGHTS

7036
04:34:03,494 --> 04:34:05,362
ONE REGION, SO NEO4 IS NOW

7037
04:34:05,362 --> 04:34:09,533
PICKING UP CLUSTER THAT I WOULD

7038
04:34:09,533 --> 04:34:13,737
SUGGEST IS CD8 CLUSTER.

7039
04:34:13,737 --> 04:34:17,941
CXCL 13 POSITIVE UP HERE, ONE

7040
04:34:17,941 --> 04:34:21,211
ADDITIONAL CLUSTER, TREG,

7041
04:34:21,211 --> 04:34:25,816
DEMARCATED BY FOXP3, THREE HOT

7042
04:34:25,816 --> 04:34:33,557
SPOTS FOR CD4 SIGNATURE, AND I'M

7043
04:34:33,557 --> 04:34:34,792
PROJECTING ONES VALIDATED TO BE

7044
04:34:34,792 --> 04:34:35,893
TUMOR MUTATION SPECIFIC.

7045
04:34:35,893 --> 04:34:39,196
IN THIS CASE ONLY ONE OUT OF 13

7046
04:34:39,196 --> 04:34:41,532
PREDICTED CD4s WAS REACTIVE

7047
04:34:41,532 --> 04:34:43,634
BUT DID LIVE WITHIN CLUSTER 17,

7048
04:34:43,634 --> 04:34:45,703
IN FACT A SINGLE CELL WAS HIGHLY

7049
04:34:45,703 --> 04:34:48,539
SCORING FOR SIGNATURE, NOT A

7050
04:34:48,539 --> 04:34:56,246
CLONALLY EXPANDED CELL BUT

7051
04:34:56,246 --> 04:35:03,787
SEQUENCING AGAINST RANDOM MU.

7052
04:35:03,787 --> 04:35:05,522
TEN WERE REACTIVE.

7053
04:35:05,522 --> 04:35:07,491
THE VAST BIAS WHERE CELLS

7054
04:35:07,491 --> 04:35:09,259
HOUSING REACTIVE CELLS WERE IN

7055
04:35:09,259 --> 04:35:11,762
CLUSTER 9, WE DON'T SEE A HOT

7056
04:35:11,762 --> 04:35:13,731
SPOT IN ADDITIONAL CLUSTER,

7057
04:35:13,731 --> 04:35:15,566
EXCEPTIONAL CASINGS OF CELLS

7058
04:35:15,566 --> 04:35:17,768
BEARING TCRs FOUND IN OTHER

7059
04:35:17,768 --> 04:35:18,335
STATES.

7060
04:35:18,335 --> 04:35:20,404
SIGNATURE IS NOT A RULE.

7061
04:35:20,404 --> 04:35:23,107
YOU'RE CAPTURING CELLS IN

7062
04:35:23,107 --> 04:35:25,542
MULTIPLE STATES OF EXHAUSTION OR

7063
04:35:25,542 --> 04:35:27,277
ACTIVATION, BUT BY AND LARGE

7064
04:35:27,277 --> 04:35:30,013
THEIR FOCAL POINT IS DOWN HERE.

7065
04:35:30,013 --> 04:35:32,116
WE PERFORMED THE SAME ANALYSIS

7066
04:35:32,116 --> 04:35:34,284
IN SECOND PATIENT, RECTAL CANCER

7067
04:35:34,284 --> 04:35:36,220
LUNG METASTASIS.

7068
04:35:36,220 --> 04:35:38,655
THIS HAD LESS OF A CLEAR

7069
04:35:38,655 --> 04:35:40,858
DEMARCATION PATTERN WHERE THE

7070
04:35:40,858 --> 04:35:44,461
REACTIVITY WAS HOUSED, TINY

7071
04:35:44,461 --> 04:35:46,530
CLUSTER, CXCL 13 HOT, CD8 HOT

7072
04:35:46,530 --> 04:35:47,097
RIGHT HERE.

7073
04:35:47,097 --> 04:35:51,702
AND THEN A REGION OF THIS

7074
04:35:51,702 --> 04:35:53,570
CLUSTER THAT WAS POSITIVE UP

7075
04:35:53,570 --> 04:35:58,909
HERE, NOT EVEN A LARGE REGION

7076
04:35:58,909 --> 04:35:59,209
WHATSOEVER.

7077
04:35:59,209 --> 04:36:00,244
LOOKING AT SIGNATURE PROJECTIONS

7078
04:36:00,244 --> 04:36:02,446
THIS IS MORE CONFUSING, NOT ONE

7079
04:36:02,446 --> 04:36:04,848
CLEAR ANSWER WHERE REACTIVITIES

7080
04:36:04,848 --> 04:36:06,183
MIGHT HAVE BEEN HOUSED.

7081
04:36:06,183 --> 04:36:07,951
SO WE THINK THIS IS A CHANCE,

7082
04:36:07,951 --> 04:36:09,653
WE'RE LUCKY TO BE HERE, THIS IS

7083
04:36:09,653 --> 04:36:11,388
A CHANCE TO LEARN MORE.

7084
04:36:11,388 --> 04:36:14,558
YOU STRETCH THE LIMIT SOMETIMES

7085
04:36:14,558 --> 04:36:19,396
AND IF IT'S AM  AMBIGUOUS YOU ME

7086
04:36:19,396 --> 04:36:20,164
MORE TCRs.

7087
04:36:20,164 --> 04:36:22,032
I MADE THEM FROM THIS REGION

7088
04:36:22,032 --> 04:36:24,968
RIGHT HERE SCORING HIGHLY FOR

7089
04:36:24,968 --> 04:36:25,636
NEO8 SIGNATURE HERE.

7090
04:36:25,636 --> 04:36:27,938
FROM THIS FORK UP HERE THAT

7091
04:36:27,938 --> 04:36:31,875
SCORED HIGHLY FOR NEO4, AND THEN

7092
04:36:31,875 --> 04:36:33,944
ADDITIONALLY FOR CELLS SCATTERED

7093
04:36:33,944 --> 04:36:35,612
IN DIFFERENT STATES, IMPERFECT

7094
04:36:35,612 --> 04:36:39,316
FIT FOR OUR KNOWN SIGNATURES BUT

7095
04:36:39,316 --> 04:36:41,718
MIGHT BE FRUITFUL IF WE GO

7096
04:36:41,718 --> 04:36:42,820
LOOKING.

7097
04:36:42,820 --> 04:36:47,524
HERE IS VALIDATED TCRs.

7098
04:36:47,524 --> 04:36:50,294
32 PREDICTED, 9 REACTIVE TO 5

7099
04:36:50,294 --> 04:36:50,594
NEOANTIGENS.

7100
04:36:50,594 --> 04:36:54,031
THREE VERSES ONE, TWO VERSES

7101
04:36:54,031 --> 04:36:56,099
ANOTHER, TWO VERSUS ANOTHER, AND

7102
04:36:56,099 --> 04:36:58,936
THEN ONE VERSUS ANOTHER RANDOM

7103
04:36:58,936 --> 04:37:00,170
MUTATION.

7104
04:37:00,170 --> 04:37:01,438
YOU CAN SEE CD4s ARE

7105
04:37:01,438 --> 04:37:03,140
INTERESTING IN THAT A FEW OF

7106
04:37:03,140 --> 04:37:06,310
THEM WERE IN THAT FORK AREA

7107
04:37:06,310 --> 04:37:07,411
WHERE I PREDICTED CD4 REACTIVE

7108
04:37:07,411 --> 04:37:12,883
CELLS WOULD BE BUT A NUMBER WERE

7109
04:37:12,883 --> 04:37:17,254
CO-CLUSTERING WITH CD8 POSITIVE

7110
04:37:17,254 --> 04:37:19,423
CLUSTER, BY SIGNATURE THEY

7111
04:37:19,423 --> 04:37:20,324
SCORED HIGHLY.

7112
04:37:20,324 --> 04:37:25,562
THERE WAS A CLONE FOUND IN THE

7113
04:37:25,562 --> 04:37:28,165
TREG CLUSTER AT LEAST ONE, SAME

7114
04:37:28,165 --> 04:37:29,733
HERE WITH REACTIVE CD8 SAW --

7115
04:37:29,733 --> 04:37:32,402
SORRY, GETTING CUT OFF AT THE

7116
04:37:32,402 --> 04:37:32,636
BOTTOM.

7117
04:37:32,636 --> 04:37:41,445
WE SAW OF 24 PREDICTED CD8S, 14

7118
04:37:41,445 --> 04:37:44,748
REACTIVE, TO VAN GOGH LIKE 1,

7119
04:37:44,748 --> 04:37:47,151
ORPHAN TCR REACTIVE TO ORGANOID.

7120
04:37:47,151 --> 04:37:48,452
CD8s WERE MORE CENTRALLY

7121
04:37:48,452 --> 04:37:53,290
LOCATED RIGHT HERE IN THIS ONE

7122
04:37:53,290 --> 04:37:53,657
REGION.

7123
04:37:53,657 --> 04:37:56,593
LAST IS ANOTHER RECENT SAMPLE.

7124
04:37:56,593 --> 04:38:02,099
THIS WAS CONFUSING THERE WAS NO

7125
04:38:02,099 --> 04:38:07,137
GREAT HOT SPOT CLUSTER, DIDN'T

7126
04:38:07,137 --> 04:38:10,073
HAVE 103, CXCL 13, CD39 IN THE

7127
04:38:10,073 --> 04:38:10,641
SAME REGION.

7128
04:38:10,641 --> 04:38:16,346
JUST AS A QUICK CHECK YOU CAN

7129
04:38:16,346 --> 04:38:17,548
SEE CXCL 13 IS IN THE SOUTHERN

7130
04:38:17,548 --> 04:38:19,883
PORTION OF THIS LARGE CLUSTER.

7131
04:38:19,883 --> 04:38:21,818
CD8s ARE PROBABLY MORE POORLY

7132
04:38:21,818 --> 04:38:23,120
DEFINED HERE BUT IN GENERAL TO

7133
04:38:23,120 --> 04:38:25,789
THE RIGHT-HAND SIDE OF THE MAP.

7134
04:38:25,789 --> 04:38:28,191
CD4s ARE LARGELY OVER HERE, AT

7135
04:38:28,191 --> 04:38:29,826
THE GENE EXPRESSION LEVEL ON AN

7136
04:38:29,826 --> 04:38:32,663
INDIVIDUAL CELL MIGHT BE HARD TO

7137
04:38:32,663 --> 04:38:35,065
PICK UP CD4s BY SINGLE CELL

7138
04:38:35,065 --> 04:38:35,732
SEQUENCING.

7139
04:38:35,732 --> 04:38:38,101
WE PROJECTED THE SIGNATURES NOW,

7140
04:38:38,101 --> 04:38:40,437
CD8s ARE IN THIS REGION OVER

7141
04:38:40,437 --> 04:38:44,374
HERE, THAT DIDN'T HAVE CXCL 13,

7142
04:38:44,374 --> 04:38:45,909
A PARTIAL FIT FOR THE SIGNATURE,

7143
04:38:45,909 --> 04:38:51,048
THE POINT OF HAVING A DEEP

7144
04:38:51,048 --> 04:38:54,117
MULTIPLEX 240 GENE SIGNATURE,

7145
04:38:54,117 --> 04:38:56,420
NOT EVERY SAMPLE WILL HAVE THE

7146
04:38:56,420 --> 04:38:57,588
BEST FIT.

7147
04:38:57,588 --> 04:39:00,257
CD8s PREDICTED TO BE HERE,

7148
04:39:00,257 --> 04:39:02,326
CD4s HERE, TREG CLUSTERS UP

7149
04:39:02,326 --> 04:39:02,859
HERE.

7150
04:39:02,859 --> 04:39:04,962
WHEN WE PREDICTED THESE AGAIN WE

7151
04:39:04,962 --> 04:39:06,129
WERE VERY LOOSE ABOUT OUR

7152
04:39:06,129 --> 04:39:07,798
DEFINITION OF WHAT MIGHT BE A

7153
04:39:07,798 --> 04:39:11,401
HIT HERE BECAUSE WE WANTED TO

7154
04:39:11,401 --> 04:39:13,837
PUSH LIMITS.

7155
04:39:13,837 --> 04:39:22,145
FOR CD4s PREDICTED 30 TCRs,

7156
04:39:22,145 --> 04:39:23,880
4 REACTIVE.

7157
04:39:23,880 --> 04:39:25,515
s CD4s WERE NOT TIGHTLY

7158
04:39:25,515 --> 04:39:26,416
LOCATED HERE.

7159
04:39:26,416 --> 04:39:29,686
IF WE MADE IT BASED ON THAT

7160
04:39:29,686 --> 04:39:32,189
CLUSTER THAT WAS A CXCL 13 HERE

7161
04:39:32,189 --> 04:39:34,091
WOULD HAVE MISSED THESE GUYS,

7162
04:39:34,091 --> 04:39:36,693
BASED ON THE SIGNATURE, PEPPERED

7163
04:39:36,693 --> 04:39:40,464
THROUGHOUT THIS CD4 REGION.

7164
04:39:40,464 --> 04:39:43,500
CD8s WE PREDICTED 41 TCRs,

7165
04:39:43,500 --> 04:39:45,269
ONE SHOWED REACTIVITY.

7166
04:39:45,269 --> 04:39:46,570
AND INTERESTINGLY ENOUGH THIS

7167
04:39:46,570 --> 04:39:50,941
CD8 TCR IN THIS REGION, AGAIN IT

7168
04:39:50,941 --> 04:39:53,443
WAS AVOIDING CXCL 13 HOT REGION

7169
04:39:53,443 --> 04:39:54,111
HERE, IN AN INTERESTING

7170
04:39:54,111 --> 04:39:58,482
TRANSITIONAL STATE WHERE IT HAD

7171
04:39:58,482 --> 04:39:59,583
CD103, NOT CD39, INTERESTINGLY

7172
04:39:59,583 --> 04:40:01,785
ENOUGH THIS IS THE SAME TCR

7173
04:40:01,785 --> 04:40:02,753
MARIA FOUND THROUGH TIL

7174
04:40:02,753 --> 04:40:05,155
SCREENING FOR THIS PATIENT.

7175
04:40:05,155 --> 04:40:07,224
THAT MIGHT BE NOTEWORTHY.

7176
04:40:07,224 --> 04:40:11,528
SO I SHOWED THREE EXAMPLES.

7177
04:40:11,528 --> 04:40:13,497
WE'VE, KRISHNAN AND MY GROUP,

7178
04:40:13,497 --> 04:40:15,766
COMPLETED SCREENING OF EIGHT

7179
04:40:15,766 --> 04:40:25,208
ADDITIONAL SAMPLES THAT

7180
04:40:25,208 --> 04:40:27,277
COLORECTAL, BREAST, PANCREATIC

7181
04:40:27,277 --> 04:40:29,112
CANCER, SIX ADDITIONAL SAMPLES

7182
04:40:29,112 --> 04:40:31,314
IN THE SEQUENCING PIPELINE.

7183
04:40:31,314 --> 04:40:33,850
I HOPED TO SHOW TCR CLUSTERS CAN

7184
04:40:33,850 --> 04:40:38,989
BE OBVIOUS AND WELL DEFINED OR

7185
04:40:38,989 --> 04:40:39,356
VERY AMBIGUOUS.

7186
04:40:39,356 --> 04:40:44,995
IF I HAVE A FEW MINUTES LEFT, I

7187
04:40:44,995 --> 04:40:47,064
WANT TO RETROSPECTIVELY

7188
04:40:47,064 --> 04:40:49,032
REANALYZE NEW SAMPLES SINCE

7189
04:40:49,032 --> 04:40:52,569
PUBLICATION BASED ON PATIENTS

7190
04:40:52,569 --> 04:40:54,504
SINCE 2023.

7191
04:40:54,504 --> 04:40:57,374
AND REVISIT THE QUESTION DO

7192
04:40:57,374 --> 04:40:59,009
THESE PREDICTED TCRs HAVE

7193
04:40:59,009 --> 04:41:01,511
SIMILAR PHENOTYPE TO INDEPENDENT

7194
04:41:01,511 --> 04:41:04,247
SAMPLES PREVIOUSLY, SO WE

7195
04:41:04,247 --> 04:41:05,916
CO-CLUSTERED T CELLS FROM 11

7196
04:41:05,916 --> 04:41:08,652
SAMPLES WITH REACTIVITY AS WELL

7197
04:41:08,652 --> 04:41:10,387
AS TWO SAMPLES FROM PATIENTS TIL

7198
04:41:10,387 --> 04:41:16,493
HARVESTS IN THE PAST MONTH. 

7199
04:41:16,493 --> 04:41:18,362
CO-CLUSTERED INTO ONE UMAP, 22

7200
04:41:18,362 --> 04:41:21,131
CLUSTERS OVERALL.

7201
04:41:21,131 --> 04:41:22,666
PROJECT OUR VALIDATED NEOANTIGEN

7202
04:41:22,666 --> 04:41:25,168
REACTIVE CELLS THEY FELL WITHIN

7203
04:41:25,168 --> 04:41:26,036
SEVERAL DISTINCT REGIONS, NOT

7204
04:41:26,036 --> 04:41:28,572
JUST THE TWO THAT WE HAD COME TO

7205
04:41:28,572 --> 04:41:29,773
EXPECT PREVIOUSLY.

7206
04:41:29,773 --> 04:41:32,376
AND YOU CAN SEE ALL TIL

7207
04:41:32,376 --> 04:41:34,144
BREAKDOWN IS HERE, YOU GENERALLY

7208
04:41:34,144 --> 04:41:37,414
HAVE YOUR LOWEST NUMBERED

7209
04:41:37,414 --> 04:41:41,518
CLUSTERS, TOP RANKED, HERE A

7210
04:41:41,518 --> 04:41:47,057
CLEAR BIAS C3 IS AN AREA, A HOT

7211
04:41:47,057 --> 04:41:50,660
SPOT FOR CD8s, C4 ANOTHER HOT

7212
04:41:50,660 --> 04:41:52,963
SPOT FOR CD8s.

7213
04:41:52,963 --> 04:41:56,266
C6 IS THE TREG CLUSTER, IN THIS

7214
04:41:56,266 --> 04:42:00,437
CASE INCLUDES SOME CD8 REACTIVE

7215
04:42:00,437 --> 04:42:03,707
CELLS THAT EXPRESS FOXP3, C 16

7216
04:42:03,707 --> 04:42:05,675
TRADITIONAL CLUSTER, INTERESTING

7217
04:42:05,675 --> 04:42:14,751
HERE NOTABLE CLUSTER WAS C14,

7218
04:42:14,751 --> 04:42:16,520
CXCL 13 CLUSTER, THIS IS SHOWING

7219
04:42:16,520 --> 04:42:22,859
THE TWO YET TO BE TESTED

7220
04:42:22,859 --> 04:42:25,695
SAMPLES, 4632 IS COLORECTAL,

7221
04:42:25,695 --> 04:42:26,897
LUNG METASTASIS, NICELY

7222
04:42:26,897 --> 04:42:29,099
REPRESENTED HOT SPOT IN C3 WITH

7223
04:42:29,099 --> 04:42:34,404
REACTIVITY IN OTHER SAMPLES.

7224
04:42:34,404 --> 04:42:37,407
AND 4632 COLORECTAL TO LIVER

7225
04:42:37,407 --> 04:42:38,742
METASTASIS, A NICE REGION HERE

7226
04:42:38,742 --> 04:42:41,845
AS WELL AS THIS GRANULATION

7227
04:42:41,845 --> 04:42:45,382
POSITIVE CXCL 13 REGION HERE.

7228
04:42:45,382 --> 04:42:46,583
HERE I'VE REPRODUCED THE SAME

7229
04:42:46,583 --> 04:42:48,084
FIGURE IN THE ORIGINAL PAPER, IF

7230
04:42:48,084 --> 04:42:52,222
WE LOOK AT GENE EXPRESSION, YOU

7231
04:42:52,222 --> 04:42:53,957
CAN SEE CXCL 13 IS POSITIVE

7232
04:42:53,957 --> 04:42:57,961
AMONG MOST REGIONS OF REACTIVITY

7233
04:42:57,961 --> 04:42:59,830
BUT NOTABLY ABSENT HERE.

7234
04:42:59,830 --> 04:43:02,032
CD39 IS LOWER HERE.

7235
04:43:02,032 --> 04:43:03,667
THE REGION IS TOX POSITIVE, NOT

7236
04:43:03,667 --> 04:43:04,968
LIKE THESE ARE STEM LIKE CELLS

7237
04:43:04,968 --> 04:43:08,638
BUT THEY DO NOT HAVE THE SAME

7238
04:43:08,638 --> 04:43:09,239
DYSFUNCTIONAL PHENOTYPE WE'RE

7239
04:43:09,239 --> 04:43:11,908
USED TO SEEING IN ALL THE

7240
04:43:11,908 --> 04:43:12,475
SAMPLES.

7241
04:43:12,475 --> 04:43:14,444
NOW IF YOU COMPARE OUR

7242
04:43:14,444 --> 04:43:17,380
SIGNATURES TO EVERYONE ELSE'S

7243
04:43:17,380 --> 04:43:19,883
SIGNATURES, THERE IS A NICE

7244
04:43:19,883 --> 04:43:22,819
OVERLAP OF A CONSERVED PROGRAM

7245
04:43:22,819 --> 04:43:26,890
THAT'S NOT 243 GENES LONG, ONLY

7246
04:43:26,890 --> 04:43:30,961
21 GENES LONG FOR CD8S, VERY FEW

7247
04:43:30,961 --> 04:43:32,929
COMMON TO ALL CD4s, SHOWING

7248
04:43:32,929 --> 04:43:33,897
OUR SIGNATURE NEEDS REFINEMENT

7249
04:43:33,897 --> 04:43:34,097
STILL.

7250
04:43:34,097 --> 04:43:36,533
WE WANT IT TO BE A CATCH-ALL BUT

7251
04:43:36,533 --> 04:43:38,168
CLEARLY IT'S HARD TO BE A

7252
04:43:38,168 --> 04:43:39,469
CATCH-ALL IN EVERY INDIVIDUAL

7253
04:43:39,469 --> 04:43:39,936
SAMPLE.

7254
04:43:39,936 --> 04:43:41,805
SO THIS IS WHERE WE'RE GOING TO

7255
04:43:41,805 --> 04:43:44,908
PUT FURTHER EFFORT INTO THE

7256
04:43:44,908 --> 04:43:45,308
FUTURE.

7257
04:43:45,308 --> 04:43:46,076
DETERMINING WHAT THE BEST

7258
04:43:46,076 --> 04:43:49,579
VERSION OF THIS SIGNATURE IS.

7259
04:43:49,579 --> 04:43:51,014
SO IN CONCLUSION THE NEOANTIGEN

7260
04:43:51,014 --> 04:43:54,517
SIGNATURES CAN BE USED TO

7261
04:43:54,517 --> 04:44:00,023
PREDICT RELEVANT  TCRs, WE DO

7262
04:44:00,023 --> 04:44:02,092
SEE BOTTLENECKS IN THE CANCER

7263
04:44:02,092 --> 04:44:07,364
IMMUNOGENICITY WHERE WE FIND

7264
04:44:07,364 --> 04:44:08,431
REDUNDANCY, YOU MIGHT FIND A

7265
04:44:08,431 --> 04:44:10,834
TOTAL OF ONLY TWO TARGETS,

7266
04:44:10,834 --> 04:44:16,106
ANOTHER SPACE  TO LOOK INTO DR.

7267
04:44:16,106 --> 04:44:19,175
GROSS'S WORK ON DARK MATTER, IF

7268
04:44:19,175 --> 04:44:20,277
THEY HAVE THIS EXHAUSTION

7269
04:44:20,277 --> 04:44:22,479
SIGNATURE WHY AREN'T THEY

7270
04:44:22,479 --> 04:44:24,881
RECOGNIZING OUR ANTIGENS.

7271
04:44:24,881 --> 04:44:26,950
THIS IS ALL LIVE ANALYSIS,

7272
04:44:26,950 --> 04:44:29,819
ONGOING ON CURRENT CLINICAL

7273
04:44:29,819 --> 04:44:33,657
SAMPLES, KNOWLEDGE CONTINUES TO

7274
04:44:33,657 --> 04:44:35,058
EVOLVE.

7275
04:44:35,058 --> 04:44:36,293
TO ACKNOWLEDGE DR. ROSENBERG, AN

7276
04:44:36,293 --> 04:44:37,594
HONOR TO HAVE GOTTEN TO WORK

7277
04:44:37,594 --> 04:44:38,361
WITH YOU.

7278
04:44:38,361 --> 04:44:40,096
YOU'RE NOT SUPPOSED TO MEET YOUR

7279
04:44:40,096 --> 04:44:42,065
HEROES, IF YOU GET THE PRIVILEGE

7280
04:44:42,065 --> 04:44:44,701
TO WORK WITH ONE, IT'S BEEN

7281
04:44:44,701 --> 04:44:45,902
AMAZING.

7282
04:44:45,902 --> 04:44:47,437
THANK YOU.

7283
04:44:47,437 --> 04:44:51,141
MY TEAM, THANK YOU FOR ALL THE

7284
04:44:51,141 --> 04:44:51,641
WORK.

7285
04:44:51,641 --> 04:44:52,676
AND KRISHNA AND LAB MEMBERS,

7286
04:44:52,676 --> 04:44:55,512
THANK YOU FOR THE SCREENING OF

7287
04:44:55,512 --> 04:44:58,815
ADDITIONAL SAMPLES.

7288
04:44:58,815 --> 04:44:59,683
AND PARTICULARLY SIVASISH FOR

7289
04:44:59,683 --> 04:45:00,350
HIS WORK.

7290
04:45:00,350 --> 04:45:02,319
WE'RE SHORT ON TIME.

7291
04:45:02,319 --> 04:45:04,821
IF YOU HAVE QUESTIONS, PLEASE

7292
04:45:04,821 --> 04:45:05,088
E-MAIL.

7293
04:45:05,088 --> 04:45:05,488
THANK YOU.

7294
04:45:05,488 --> 04:45:08,024
[APPLAUSE]

7295
04:45:08,024 --> 04:45:14,130
 

7296
04:45:14,130 --> 04:45:16,099
 

7297
04:45:16,099 --> 04:45:18,768
>> THANK YOU. 

7298
04:45:18,768 --> 04:45:22,272
I'D LIKE TO INTRODUCE DR. ERIC

7299
04:45:22,272 --> 04:45:22,639
TRAN.

7300
04:45:22,639 --> 04:45:24,007
WE HAVE CAUGHT UP A LITTLE BIT

7301
04:45:24,007 --> 04:45:26,843
BUT I WOULD ASK THAT AT THE

7302
04:45:26,843 --> 04:45:31,448
CONCLUSION WE'LL HAVE A

7303
04:45:31,448 --> 04:45:33,817
10-MINUTE BREAK RATHER THAN 15.

7304
04:45:33,817 --> 04:45:38,154
HERE REGO. 

7305
04:45:38,154 --> 04:45:38,722
HERE WE GO.

7306
04:45:38,722 --> 04:45:41,324
>> IT'S WONDERFUL TO BE
BACK ON

7307
04:45:41,324 --> 04:45:41,558
CAMPUS.

7308
04:45:41,558 --> 04:45:45,061
IT'S AN ABSOLUTE HONOR TO BE

7309
04:45:45,061 --> 04:45:46,429
HERE CELEBRATING DR. ROSENBERG'S

7310
04:45:46,429 --> 04:45:47,464
50 YEARS AT NCI.

7311
04:45:47,464 --> 04:45:51,501
I KNOW MOST OF YOU THINK 50

7312
04:45:51,501 --> 04:45:52,369
YEARS OF RESEARCH IS A LONG TIME

7313
04:45:52,369 --> 04:45:54,471
BUT IF YOU ASK HIM HE WILL SAY

7314
04:45:54,471 --> 04:45:57,640
THAT HE FEELS LIKE HE'S JUST

7315
04:45:57,640 --> 04:45:58,675
GETTING STARTED.

7316
04:45:58,675 --> 04:46:00,043
WITH THAT, HERE WE GO.

7317
04:46:00,043 --> 04:46:02,679
I'M GOING TO SWITCH GEARS A

7318
04:46:02,679 --> 04:46:04,781
LITTLE BIT AND I KNOW I'M GOING

7319
04:46:04,781 --> 04:46:07,384
TO DISCUSS A PROJECT WHERE IF

7320
04:46:07,384 --> 04:46:08,952
YOU GOT A GOOD T-CELL RECEPTOR,

7321
04:46:08,952 --> 04:46:12,989
A GOOD TIL THAT TARGETS A

7322
04:46:12,989 --> 04:46:14,557
NEOANTIGEN WHAT CAN WE DO TO

7323
04:46:14,557 --> 04:46:16,593
ENHANCE THE T CELLS.

7324
04:46:16,593 --> 04:46:18,695
HERE ARE MY DISCLOSURES.

7325
04:46:18,695 --> 04:46:21,097
HERE IS GENERAL STRATEGIES OF

7326
04:46:21,097 --> 04:46:24,501
THE FIELD, PURSUING TO ENHANCE

7327
04:46:24,501 --> 04:46:25,368
CELLULAR THERAPIES.

7328
04:46:25,368 --> 04:46:27,670
A MAJOR ADVANTAGE IS THAT HAVE

7329
04:46:27,670 --> 04:46:30,073
YOU THE ABILITY TO MANIPULATE

7330
04:46:30,073 --> 04:46:31,775
THE CELLS EX VIVO, YOU CAN

7331
04:46:31,775 --> 04:46:33,176
MANIPULATE THE HOST IN VIVO.

7332
04:46:33,176 --> 04:46:35,145
AND SO I'M NOT GOING THROUGH IN

7333
04:46:35,145 --> 04:46:37,981
TOO MUCH DETAIL HERE BUT WE CAN

7334
04:46:37,981 --> 04:46:39,382
MANIPULATE CELL MANUFACTURED

7335
04:46:39,382 --> 04:46:41,384
CONDITIONS TO GENERATE POTENT T

7336
04:46:41,384 --> 04:46:42,919
CELLS, YOUNGER STEM-LIKE CELLS,

7337
04:46:42,919 --> 04:46:45,088
LEVERAGE CELLS TYPES, FOCUS ON

7338
04:46:45,088 --> 04:46:47,390
ALPHA-BETA T CELLS BUT OTHERS

7339
04:46:47,390 --> 04:46:50,226
MIST BE ADVANTAGEOUS.

7340
04:46:50,226 --> 04:46:53,530
HARNESSING RECEPTORS THAT TARGET

7341
04:46:53,530 --> 04:46:54,597
MULTIPLE ANTIGENS MAY OVERCOME

7342
04:46:54,597 --> 04:46:55,699
TUMOR HETEROGENEITY.

7343
04:46:55,699 --> 04:46:57,434
WE CAN GENE ENGINEER CELLS AND

7344
04:46:57,434 --> 04:46:59,069
KNOCK OUT GENES THAT INHIBIT T

7345
04:46:59,069 --> 04:47:00,170
CELL ACTIVITY.

7346
04:47:00,170 --> 04:47:05,108
WE CAN KNOCK IN GENES THAT

7347
04:47:05,108 --> 04:47:07,610
ENHANCE T CELL ACTIVITY.

7348
04:47:07,610 --> 04:47:08,912
IN VIVO SIDE, HOST

7349
04:47:08,912 --> 04:47:11,214
LYMPHODEPLETION APPEARS TO BE

7350
04:47:11,214 --> 04:47:12,315
IMPORTANT TO ENHANCE CELL

7351
04:47:12,315 --> 04:47:14,284
THERAPY, WE CAN DELIVER

7352
04:47:14,284 --> 04:47:15,919
CYTOKINES, CHECKPOINT BLOCKADE,

7353
04:47:15,919 --> 04:47:19,122
IMMUNE AGONIST, VACCINES, TUMOR

7354
04:47:19,122 --> 04:47:20,423
TARGETING SMALL MOLECULES,

7355
04:47:20,423 --> 04:47:21,958
AGENTS THAT MODULATE MYELOID AND

7356
04:47:21,958 --> 04:47:22,625
TREGS.

7357
04:47:22,625 --> 04:47:26,596
TODAY I'M GOING TO FOCUS ON ONE

7358
04:47:26,596 --> 04:47:31,835
WORK IN PROGRESS PROJECT THAT

7359
04:47:31,835 --> 04:47:33,336
DEALS WITH CHIMERIC RECEPTORS.

7360
04:47:33,336 --> 04:47:37,140
MOST PEOPLE THINK ABOUT CHIMERIC

7361
04:47:37,140 --> 04:47:38,508
ANTIGEN RECEPTORS, HIGHLIGHTED

7362
04:47:38,508 --> 04:47:41,377
ON THE LEFT.

7363
04:47:41,377 --> 04:47:42,679
THESE TARGET ANTIGEN, DELIVER

7364
04:47:42,679 --> 04:47:43,980
T-CELL ACTIVATION SIGNAL.

7365
04:47:43,980 --> 04:47:50,787
I'M NOT FOCUSING ON  CHIMERIC

7366
04:47:50,787 --> 04:47:52,522
ANTIGEN RECEPTORS BUT

7367
04:47:52,522 --> 04:47:55,158
NON-ANTIGEN RECEPTORS.

7368
04:47:55,158 --> 04:47:57,760
HERE IS AS EXAMPLE, SWITCH

7369
04:47:57,760 --> 04:48:00,530
RECEPTORS, YOU REQUEST HAVE A

7370
04:48:00,530 --> 04:48:05,969
CHIMERIC RECEPTOR WITH AN

7371
04:48:05,969 --> 04:48:07,837
EXTRACELLULAR DOMAIN FUSED.

7372
04:48:07,837 --> 04:48:09,706
BY BINDING THE T CELL GETS A

7373
04:48:09,706 --> 04:48:10,573
POSITIVE SIGNAL INSTEAD OF

7374
04:48:10,573 --> 04:48:17,514
NEGATIVE SILL NAIL. -- SIGNAL.

7375
04:48:17,514 --> 04:48:23,353
THE TYPE OF IS A CCR.

7376
04:48:23,353 --> 04:48:26,723
THERE ARE SEVERAL EXAMPLES OF

7377
04:48:26,723 --> 04:48:28,158
CHIMERIC CYTOKINE RECEPTORS,

7378
04:48:28,158 --> 04:48:29,025
HIGHLIGHTED HERE, SO

7379
04:48:29,025 --> 04:48:34,063
EXTRACELLULAR DOMAINS MADE UP OF

7380
04:48:34,063 --> 04:48:35,932
IL-4 RECEPTOR, TGF-BETA

7381
04:48:35,932 --> 04:48:37,233
RECEPTOR, STITCHED ON TO

7382
04:48:37,233 --> 04:48:45,408
INTRACELLULAR SIGNALING DOMAINS.

7383
04:48:45,408 --> 04:48:46,309
THINKING ABOUT THIS CONCEPT,

7384
04:48:46,309 --> 04:48:48,711
WHAT ARE THE KEY CHARACTERISTICS

7385
04:48:48,711 --> 04:48:51,114
THAT MIGHT MAKE AN IDEAL

7386
04:48:51,114 --> 04:48:52,215
CHIMERIC CYTOKINE RECEPTOR.

7387
04:48:52,215 --> 04:48:55,818
ONE OF THE CHARACTERISTICS IS

7388
04:48:55,818 --> 04:48:57,887
THAT EXTRACELLULAR DOMAIN BINDS

7389
04:48:57,887 --> 04:48:59,455
TO CYTOKINE NOT BENEFICIAL FOR T

7390
04:48:59,455 --> 04:49:00,957
CELL FUNCTION U DON'T WANT TO

7391
04:49:00,957 --> 04:49:03,059
TAKE A POSITIVE SIGNAL FROM T

7392
04:49:03,059 --> 04:49:04,794
CELL BUT POTENTIALLY NEUTRAL OR

7393
04:49:04,794 --> 04:49:07,630
NEGATIVE SIGNAL TURNING INTO A

7394
04:49:07,630 --> 04:49:17,040
POSITIVE. 

7395
04:49:17,040 --> 04:49:19,976
REGULATED, NOT EXPRESSED, AND

7396
04:49:19,976 --> 04:49:21,311
RESISTANT TO TUMOR

7397
04:49:21,311 --> 04:49:23,479
MICROENVIRONMENT CONDITIONS SUCH

7398
04:49:23,479 --> 04:49:25,348
AS ACIDIC ENVIRONMENT.

7399
04:49:25,348 --> 04:49:25,915
INTRACELLULAR DOMAIN SHOULD

7400
04:49:25,915 --> 04:49:29,052
DELIVER A SIGNAL THAT PROMOTES T

7401
04:49:29,052 --> 04:49:30,153
CELL FUNCTION.

7402
04:49:30,153 --> 04:49:34,757
SO HOW DO WE IDENTIFY SUITABLE

7403
04:49:34,757 --> 04:49:36,860
CYTOKINES TO TRIGGER RECEPTOR?

7404
04:49:36,860 --> 04:49:38,494
ONE OF THE THINGS WHEN WE HAVE

7405
04:49:38,494 --> 04:49:40,763
CLINICAL TRIALS WE'RE ABLE TO

7406
04:49:40,763 --> 04:49:42,098
TREAT PATIENTS AND ANALYZE THEIR

7407
04:49:42,098 --> 04:49:42,966
SERUM.

7408
04:49:42,966 --> 04:49:44,400
SO I'M GOING TO FOCUS ONE OF THE

7409
04:49:44,400 --> 04:49:47,103
FIRST THINGS WE LOOKED AT WAS

7410
04:49:47,103 --> 04:49:51,074
LOOKING AT CYTOKINES IN THESE

7411
04:49:51,074 --> 04:49:54,911
PATIENTS AFTER CELL TRANSFER.

7412
04:49:54,911 --> 04:50:00,049
SO, THE PATIENTS ARE FROM THIS

7413
04:50:00,049 --> 04:50:06,422
PUBLICATION TWE YEARS AGO, MET

7414
04:50:06,422 --> 04:50:07,390
METASTATIC PANCREAS CANCER,

7415
04:50:07,390 --> 04:50:08,391
SUMMARIZING THOSE TWO PATIENTS

7416
04:50:08,391 --> 04:50:13,529
HERE IN THIS TABLE. 

7417
04:50:13,529 --> 04:50:14,497
BOTH RECEIVED LYMPHODEPLETION

7418
04:50:14,497 --> 04:50:19,135
REGIMEN, 0361 GOT SURGERY BRANCH

7419
04:50:19,135 --> 04:50:22,472
TYPE LYMPHODEPLETION, 4483

7420
04:50:22,472 --> 04:50:23,773
SLIGHTLY DOSE REDUCED REGIMEN,

7421
04:50:23,773 --> 04:50:25,475
BOTH RECEIVED GOOD NUMBER OF

7422
04:50:25,475 --> 04:50:28,077
CELLS, CLOSE TO 30 BILLION IN

7423
04:50:28,077 --> 04:50:30,480
ONE CASE, 16 BILLION IN THE

7424
04:50:30,480 --> 04:50:31,247
OTHER.

7425
04:50:31,247 --> 04:50:32,982
WE SUPPORTED THOSE TRANSFERRED T

7426
04:50:32,982 --> 04:50:35,084
CELLS WITH HIGH DOSE

7427
04:50:35,084 --> 04:50:35,618
INTERLEUKIN-2.

7428
04:50:35,618 --> 04:50:38,921
FOR ONE PATIENT BEST RESPONSE

7429
04:50:38,921 --> 04:50:42,425
LASTED ONE MONTH, THE OTHER BEST

7430
04:50:42,425 --> 04:50:44,827
RESPONSE WAS P.R. 72% REDUCTION

7431
04:50:44,827 --> 04:50:47,997
IN METASTATIC TUMORS FOR SIX

7432
04:50:47,997 --> 04:50:49,766
MONTHS, LASTED 12 MONTHS.

7433
04:50:49,766 --> 04:50:52,168
PERSISTENCE OF CELLS WAS GOOD.

7434
04:50:52,168 --> 04:50:54,337
SO ABOUT 90% FOR FIRST PATIENT,

7435
04:50:54,337 --> 04:50:55,238
AT ONE MONTH.

7436
04:50:55,238 --> 04:50:57,540
13% FOR THE OTHER PATIENT.

7437
04:50:57,540 --> 04:51:00,176
BUT THE FACT THAT THEY DID NOT

7438
04:51:00,176 --> 04:51:01,110
ACHIEVE DURABLE COMPLETE

7439
04:51:01,110 --> 04:51:02,912
RESPONSE MEANS WE HAVE ROOM TO

7440
04:51:02,912 --> 04:51:05,214
IMPROVE TO MAKE THIS THERAPY

7441
04:51:05,214 --> 04:51:07,483
BETTER.

7442
04:51:07,483 --> 04:51:08,284
THE CELLS ARE PERSISTENT,

7443
04:51:08,284 --> 04:51:10,153
SUGGESTING WE MIGHT BE ABLE TO

7444
04:51:10,153 --> 04:51:10,887
BOOST THEIR FUNCTION.

7445
04:51:10,887 --> 04:51:14,857
THESE ARE THE TWO PATIENTS

7446
04:51:14,857 --> 04:51:16,693
SAMPLES SERUM CYTOKINE DATA.

7447
04:51:16,693 --> 04:51:18,895
WE FOCUSED ON T CELL EFFECTOR

7448
04:51:18,895 --> 04:51:19,329
CYTOKINE.

7449
04:51:19,329 --> 04:51:21,397
THESE ARE THE TWO PATIENTS SHOWN

7450
04:51:21,397 --> 04:51:27,537
HERE, THESE ARE THE CLASSIC T

7451
04:51:27,537 --> 04:51:28,972
CELL EFFECTOR CYTOKINES, AND YOU

7452
04:51:28,972 --> 04:51:32,675
CAN SEE THAT IN BOTH PATIENTS

7453
04:51:32,675 --> 04:51:35,078
THESE EFFECTOR CYTOKINES ARE

7454
04:51:35,078 --> 04:51:37,146
ELEVATED, SLIGHTLY DIFFERENT

7455
04:51:37,146 --> 04:51:38,581
KINETICS, FOR 4483 WE HAVE PEAK

7456
04:51:38,581 --> 04:51:42,618
AT ONE DAY AFTER CELL TRANSFER,

7457
04:51:42,618 --> 04:51:45,521
3061 PEAKED AT FOUR DAYS POST

7458
04:51:45,521 --> 04:51:47,657
CELL TRANSFER.

7459
04:51:47,657 --> 04:51:50,493
TNF SPIKES AT 50 TO 150

7460
04:51:50,493 --> 04:51:52,462
PICOGRAMS PER ML, AND THEN

7461
04:51:52,462 --> 04:51:57,533
CONTINUES ON ALMOST GOES BACK TO

7462
04:51:57,533 --> 04:51:58,167
BASELINE.

7463
04:51:58,167 --> 04:52:00,136
INTERFERON GAMMA SPIKES AT 150

7464
04:52:00,136 --> 04:52:02,638
FOR BOTH PATIENTS AND STAYS

7465
04:52:02,638 --> 04:52:07,143
ELEVATED FOR 11 DAYS AFTER CELL

7466
04:52:07,143 --> 04:52:09,245
TRANSFER.

7467
04:52:09,245 --> 04:52:11,080
AND SIMILAR GNCF RETURNED BACK

7468
04:52:11,080 --> 04:52:15,118
TO BASELINE RAPIDLY.

7469
04:52:15,118 --> 04:52:17,787
THE CYTOKINES TREATED BY

7470
04:52:17,787 --> 04:52:20,056
INTERFERON GAMMA, MAINLY BECAUSE

7471
04:52:20,056 --> 04:52:23,659
THE CYTOKINES SPIKED AT

7472
04:52:23,659 --> 04:52:25,428
APPRECIABLE LEVEL, 150 PICOGRAMS

7473
04:52:25,428 --> 04:52:26,863
PER ML, SUSTAINED, WE THINK

7474
04:52:26,863 --> 04:52:28,264
AFTER T CELL TRANSFER YOU WANT

7475
04:52:28,264 --> 04:52:29,699
TO GIVE T CELLS A GOOD SIGNAL

7476
04:52:29,699 --> 04:52:33,503
FOR A GOOD NUMBER OF DAYS AND

7477
04:52:33,503 --> 04:52:36,506
WITH ELEVATION IN CYTOKINES AT

7478
04:52:36,506 --> 04:52:39,876
LEAST 11 DAYS OUT.

7479
04:52:39,876 --> 04:52:42,845
SO, EXPLOITING INTERFERON GAMMA

7480
04:52:42,845 --> 04:52:44,914
PATHWAY TO ENHANCE T CELL-BASED

7481
04:52:44,914 --> 04:52:45,481
THERAPIES INTERFERON GAMMA

7482
04:52:45,481 --> 04:52:52,021
LEVELS ARE ELEVATED IN PATIENT

7483
04:52:52,021 --> 04:52:54,223
SERUM.

7484
04:52:54,223 --> 04:52:58,261
INTERFERON GAMMA IS PRODUCED

7485
04:52:58,261 --> 04:53:01,664
UPON TCR ENGAGEMENT, ANTIGEN

7486
04:53:01,664 --> 04:53:04,167
DEPENDENT, SELF-LIMITING.

7487
04:53:04,167 --> 04:53:05,802
YOU GET INTERFERON GAMMA

7488
04:53:05,802 --> 04:53:08,671
PRODUCTION AFTER IT'S GONE,

7489
04:53:08,671 --> 04:53:12,942
EVENTUALLY DECAYING OVER TIME.

7490
04:53:12,942 --> 04:53:16,679
INTERFERON GAMMA SIGNAL CAN BE

7491
04:53:16,679 --> 04:53:19,849
DETRIMENTAL, CAN LEAD TO T CELL

7492
04:53:19,849 --> 04:53:20,283
DEATH.

7493
04:53:20,283 --> 04:53:22,452
INTERFERON GAMMA MAY BE MORE

7494
04:53:22,452 --> 04:53:24,854
STABLE IN ACIDIC CONDITIONS

7495
04:53:24,854 --> 04:53:29,092
COMPARED TO INTERLEUKIN 2, NOT

7496
04:53:29,092 --> 04:53:33,729
ACTIVE AT PH 6 OR LESS.

7497
04:53:33,729 --> 04:53:36,165
THIS IS A SCHEMATIC OF THE

7498
04:53:36,165 --> 04:53:39,235
DESIGN OF THE CYTOKINE

7499
04:53:39,235 --> 04:53:41,504
RECEPTORS, A WILDTYPE, RECEPTOR

7500
04:53:41,504 --> 04:53:44,373
ON LEFT, EXISTS AS TWO

7501
04:53:44,373 --> 04:53:50,913
HETERODIMERS OF INTERFERON GAMMA

7502
04:53:50,913 --> 04:53:53,883
R 1, R 1 BINDS TO DIMER OF

7503
04:53:53,883 --> 04:53:54,750
INTERFERON GAMMA, EXPOSES THE

7504
04:53:54,750 --> 04:53:56,853
SITE THAT ALLOWS FOR BINDING OF

7505
04:53:56,853 --> 04:54:02,191
R 1 AND R 2 TO INITIATE

7506
04:54:02,191 --> 04:54:05,495
CROSS-PHOSPHORYLATION OF

7507
04:54:05,495 --> 04:54:07,964
RECEPTOR SUBUNITS RECRUITING

7508
04:54:07,964 --> 04:54:11,467
STAT1 SO INTERFERON GAMMA

7509
04:54:11,467 --> 04:54:12,568
INITIATES STAT1 SIGNAL.

7510
04:54:12,568 --> 04:54:14,537
INITIAL DESIGNS LOOK LIKE THIS.

7511
04:54:14,537 --> 04:54:20,676
SO FIRST IS CALLED CONVENTIONAL

7512
04:54:20,676 --> 04:54:23,980
CHIMERIC CYTOKINE RECEPTOR, WE

7513
04:54:23,980 --> 04:54:24,947
REPLACED TRANSMEMBRANE AND

7514
04:54:24,947 --> 04:54:27,150
CYTOPLASMIC DOMAINS OF WILD TYPE

7515
04:54:27,150 --> 04:54:28,684
INTERFERON GAMMA WITH RECEPTOR

7516
04:54:28,684 --> 04:54:29,886
OF CHOICE.

7517
04:54:29,886 --> 04:54:31,888
THE OTHER TYPE OF CHIMERIC

7518
04:54:31,888 --> 04:54:36,025
CYTOKINE RECEPTOR IS THE DOMAIN

7519
04:54:36,025 --> 04:54:37,894
SWATH CHIMERIC CYTOKINE

7520
04:54:37,894 --> 04:54:45,568
RECEPTORS, R 1 AND R 2 STAY WILD

7521
04:54:45,568 --> 04:54:48,504
TYPE EXCEPT FOR STAT1.

7522
04:54:48,504 --> 04:54:51,340
DETAILS THERE, WE DECIDED TO

7523
04:54:51,340 --> 04:54:53,643
LOOK AT STAT5 ACTIVATING

7524
04:54:53,643 --> 04:54:56,279
RECEPTORS AND SO AS WAS SHOWN

7525
04:54:56,279 --> 04:54:58,247
THIS MORNING, ALL SIGNS POINT TO

7526
04:54:58,247 --> 04:55:01,417
IL-2, WE THINK IT'S A POTENT T

7527
04:55:01,417 --> 04:55:06,022
CELL CYTOKINE, WE KNOW IT'S

7528
04:55:06,022 --> 04:55:06,255
POTENT.

7529
04:55:06,255 --> 04:55:09,191
WE TESTED INTERLEUKIN-2,

7530
04:55:09,191 --> 04:55:11,360
INTRACELLULAR DOMAINS, IL-3,

7531
04:55:11,360 --> 04:55:15,631
IL7, GM-CSF, AND FOR THE DOMAIN

7532
04:55:15,631 --> 04:55:19,035
SWAP CRRs WE PLACED STAT1

7533
04:55:19,035 --> 04:55:22,638
BINDING DOMAIN WITH IL-2

7534
04:55:22,638 --> 04:55:26,242
RECEPTOR STAT5 BINDING DOMAIN

7535
04:55:26,242 --> 04:55:27,910
FOR SIGNALING, TYROSINE 5110, WE

7536
04:55:27,910 --> 04:55:29,979
HAVE ANOTHER CONSTRUCT THAT HAS

7537
04:55:29,979 --> 04:55:33,382
THE SAME TYROSINE RESIDUE BUT

7538
04:55:33,382 --> 04:55:35,117
MUTATED SOX BINDING SITE,

7539
04:55:35,117 --> 04:55:37,186
SUPPRESSES CYTOKINE SIGNALING TO

7540
04:55:37,186 --> 04:55:40,923
HOPEFULLY ENHANCE STAT5

7541
04:55:40,923 --> 04:55:42,124
PHOSPHORYLATION.

7542
04:55:42,124 --> 04:55:43,326
WE REPLACED C-TERMINAL RESIDUE,

7543
04:55:43,326 --> 04:55:47,263
21 AMINO ACIDS OF THE

7544
04:55:47,263 --> 04:55:56,005
C-TERMINAL, IL-2 R BAITA GROWTH

7545
04:55:56,005 --> 04:56:00,509
HORMONE RECEPTOR SITES, AS WELL

7546
04:56:00,509 --> 04:56:04,814
AS CYTOPLASTIC DOMAINS, AND

7547
04:56:04,814 --> 04:56:05,514
ERYTHROPOEITIN RECEPTOR STITCHED

7548
04:56:05,514 --> 04:56:06,849
ON A BINDING SITE.

7549
04:56:06,849 --> 04:56:09,252
THIS IS OUR MODEL SYSTEM.

7550
04:56:09,252 --> 04:56:15,024
WE HAVE A TCR THAT RECOGNIZES

7551
04:56:15,024 --> 04:56:17,226
KRAS G12 EPITOPE.

7552
04:56:17,226 --> 04:56:19,261
CO-TRANSDUCE THAT WITH OUR

7553
04:56:19,261 --> 04:56:21,497
INTERFERON GAMMA R 1 R 2

7554
04:56:21,497 --> 04:56:25,001
CHIMERIC RECEPTOR, TWO VECTORS

7555
04:56:25,001 --> 04:56:26,869
HERE, CO-TRANSDUCED, C CELLS

7556
04:56:26,869 --> 04:56:29,171
THAT EXPRESS KRAS AND CHIMERIC

7557
04:56:29,171 --> 04:56:30,373
CYTOKINE RECEPTOR.

7558
04:56:30,373 --> 04:56:32,775
AND THEN WE EVALUATE EXPRESSION

7559
04:56:32,775 --> 04:56:35,511
OF THE CHIMERIC CYTOKINE

7560
04:56:35,511 --> 04:56:36,746
RECEPTOR, TRANSDUCTION

7561
04:56:36,746 --> 04:56:39,882
EFFICIENCY, TEST BIOCHEMICAL

7562
04:56:39,882 --> 04:56:41,851
FUNCTION BY PHOSPHO-STAT5 AND

7563
04:56:41,851 --> 04:56:43,386
TEST IN VITRO SERIAL KILLING

7564
04:56:43,386 --> 04:56:44,387
AGAINST TUMOR CELL LINES.

7565
04:56:44,387 --> 04:56:47,657
AND JUST HERE IS AN EXAMPLE OF A

7566
04:56:47,657 --> 04:56:52,361
PLOT SHOWING EXPRESSION AFTER

7567
04:56:52,361 --> 04:56:53,896
CO-TRANSDUCTION, TCRs HAVE

7568
04:56:53,896 --> 04:56:56,098
MOST CONSTANT REGIONS, ALPHA

7569
04:56:56,098 --> 04:57:00,469
BETA, WE CAN STAIN WITH MOUSE

7570
04:57:00,469 --> 04:57:02,638
ANTIBODY, THIS IS INTERFERON

7571
04:57:02,638 --> 04:57:06,509
GAMMA R 1, 20 TO 30%

7572
04:57:06,509 --> 04:57:08,477
TRANSDUCTION OF THE TCR AND

7573
04:57:08,477 --> 04:57:09,912
CHIMERIC RECEPTOR.

7574
04:57:09,912 --> 04:57:11,113
WHEN TESTING FOR BIOCHEMICAL

7575
04:57:11,113 --> 04:57:13,049
FUNCTION WE TAKE THESE CELLS,

7576
04:57:13,049 --> 04:57:15,151
WASH THEM, STARVE THEM OF

7577
04:57:15,151 --> 04:57:17,653
CYTOKINE OVERNIGHT AND STIMULATE

7578
04:57:17,653 --> 04:57:19,522
THEM WITH IL-2 OR INTERFERON

7579
04:57:19,522 --> 04:57:19,855
GAMMA.

7580
04:57:19,855 --> 04:57:22,591
WHAT WE HAVE HERE IS

7581
04:57:22,591 --> 04:57:25,094
TCR-ENGINEERED T CELLS ALONE.

7582
04:57:25,094 --> 04:57:27,630
STIMULATE WITH IL-2, YOU GET

7583
04:57:27,630 --> 04:57:29,031
NICE PHOSPHO-STAT5, WHEN YOU HIT

7584
04:57:29,031 --> 04:57:32,001
THEM WITH DOSES OF INTERFERON

7585
04:57:32,001 --> 04:57:35,071
DAM GAMMA WE DON'T GET

7586
04:57:35,071 --> 04:57:37,206
PHOSPHO-STAT5 BUT TEST TCR PLUS

7587
04:57:37,206 --> 04:57:47,750
INTERFERON GAMMA R 1 IL-2R BETA

7588
04:57:49,018 --> 04:57:52,021
CHIMERIC RECEPTOR GOOD STAT5,

7589
04:57:52,021 --> 04:57:55,091
YOU MIGHT RECALL THIS FROM THE

7590
04:57:55,091 --> 04:57:56,959
SERUM DATA, CERTAINLY ACHIEVABLE

7591
04:57:56,959 --> 04:58:00,996
IN PATIENTS AFTER CELL TRANSFER.

7592
04:58:00,996 --> 04:58:02,965
SO WHEN WE JUST SUMMARIZE ALL

7593
04:58:02,965 --> 04:58:05,334
THE OTHER CHIMERIC RECEPTORS

7594
04:58:05,334 --> 04:58:10,206
THAT I DESCRIBED, THEY ARE SHOWN

7595
04:58:10,206 --> 04:58:11,807
HERE, IL-3, IL-2, IL7, YOU CAN

7596
04:58:11,807 --> 04:58:15,678
SEE FOR THE MOST PART MOST OF

7597
04:58:15,678 --> 04:58:19,148
THE RECEPTORS FUNCTION

7598
04:58:19,148 --> 04:58:19,915
BIOCHEMICALLY TO ELICIT

7599
04:58:19,915 --> 04:58:24,086
PHOSPHO-STAT5, DMFI IS

7600
04:58:24,086 --> 04:58:24,954
DIFFERENT.

7601
04:58:24,954 --> 04:58:29,125
IL-2 AND GM-CSF INTRACELLULAR

7602
04:58:29,125 --> 04:58:33,496
DOMAINS ACHIEVE HIGHEST LEVELS

7603
04:58:33,496 --> 04:58:34,864
OF PHOSPHO-STAT5.

7604
04:58:34,864 --> 04:58:37,867
DOMAIN SWAP WE GET HIGH

7605
04:58:37,867 --> 04:58:39,835
FREQUENCIES OF PHOSPHO-STAT5,

7606
04:58:39,835 --> 04:58:43,572
BUT THE MFI IS LOWER THAN THE

7607
04:58:43,572 --> 04:58:44,740
CONVENTIONAL INTERFERON GAMMA

7608
04:58:44,740 --> 04:58:47,076
CHIMERIC RECEPTORS.

7609
04:58:47,076 --> 04:58:48,911
WE HAVE EVIDENCE THAT

7610
04:58:48,911 --> 04:58:51,013
FRANKENSTEIN RECEPTORS SEEM TO

7611
04:58:51,013 --> 04:58:51,981
WORK BIOCHEMICALLY, SO WE WANT

7612
04:58:51,981 --> 04:58:54,617
TO TEST THEIR FUNCTION.

7613
04:58:54,617 --> 04:59:01,190
DID THEY ENHANCE TCR T-CELL

7614
04:59:01,190 --> 04:59:01,423
THERAPY?

7615
04:59:01,423 --> 04:59:03,926
WE GOT ONLY 20 TO 30%

7616
04:59:03,926 --> 04:59:05,795
CO-TRANSDUCTION FACT SORTED THE

7617
04:59:05,795 --> 04:59:07,763
POPULATION OF DOUBLE POSITIVE

7618
04:59:07,763 --> 04:59:09,999
AND RAPIDLY EXPANDED THEM, OVER

7619
04:59:09,999 --> 04:59:14,036
90% OF CELLS EXPRESS BOTH TCR

7620
04:59:14,036 --> 04:59:17,973
AND INTERFERON GAMMA CHIMERIC

7621
04:59:17,973 --> 04:59:23,445
RECEPTOR, CO-CULTURE WITH H PAC

7622
04:59:23,445 --> 04:59:24,947
CELLS THAT NATURALLY EXPRESSES,

7623
04:59:24,947 --> 04:59:31,754
AND WE ENGINEERED THESE CELLS TO

7624
04:59:31,754 --> 04:59:34,156
EXPRESS GFP AS WELL.

7625
04:59:34,156 --> 04:59:36,859
ON DAY ZERO WE ADD 10,000

7626
04:59:36,859 --> 04:59:38,961
PANCREAS CANCER CELLS EVERY TWO

7627
04:59:38,961 --> 04:59:43,432
DAYS, IN A SERIAL KILL CAPACITY.

7628
04:59:43,432 --> 04:59:46,635
THIS GRAPH HERE IS REALLY THE

7629
04:59:46,635 --> 04:59:49,505
POSITIVE CONTROL, A TCR

7630
04:59:49,505 --> 04:59:50,439
ENGINEERED CELL, WITHOUT

7631
04:59:50,439 --> 04:59:51,207
CHIMERIC CYTOKINE RECEPTOR, IN

7632
04:59:51,207 --> 04:59:53,309
THE PRESENCE OR ABSENCE OF IL-2.

7633
04:59:53,309 --> 04:59:55,711
WITHOUT IL-2 YOU CAN SEE TCR IS

7634
04:59:55,711 --> 04:59:58,981
QUITE POTENT ON ITS OWN FOR THE

7635
04:59:58,981 --> 05:00:00,850
FIRST COUPLE KILLS.

7636
05:00:00,850 --> 05:00:06,088
STARTS TO LOSE ACTIVITY. 

7637
05:00:06,088 --> 05:00:07,523
THIS IS GFP.

7638
05:00:07,523 --> 05:00:09,258
THE ENGINEERED CELLS CONTINUE TO

7639
05:00:09,258 --> 05:00:13,195
KILL OVER SIX OR SEVEN ROUNDS OF

7640
05:00:13,195 --> 05:00:17,466
TUMOR CELL WITH MORE IL-2.

7641
05:00:17,466 --> 05:00:19,768
RECEPTORS WILL LOOK LIKE THE

7642
05:00:19,768 --> 05:00:21,737
BLUE LINE HERE IN ABSENCE OF

7643
05:00:21,737 --> 05:00:22,171
IL-2.

7644
05:00:22,171 --> 05:00:23,372
SO THIS IS WHAT THE DATA LOOKS

7645
05:00:23,372 --> 05:00:26,642
LIKE WHEN WE DO THE SERIAL KILL

7646
05:00:26,642 --> 05:00:29,178
ASSAY. 

7647
05:00:29,178 --> 05:00:32,381
THIS IS THE CHIMERIC RECEPTOR,

7648
05:00:32,381 --> 05:00:34,450
DOES IMPROVE SERIAL KILL.

7649
05:00:34,450 --> 05:00:35,985
CANCER CELLS.

7650
05:00:35,985 --> 05:00:40,022
SIMILAR WITH IL-3 RECEPTOR AND

7651
05:00:40,022 --> 05:00:46,795
GMPSF AS WELL.

7652
05:00:46,795 --> 05:00:49,498
SEEMS TO BE SOMEWHAT

7653
05:00:49,498 --> 05:00:50,833
RECAPITULATING ADDITION OF IL-2,

7654
05:00:50,833 --> 05:00:54,470
IN THE ABSENCE OF INTERLEUKIN-2

7655
05:00:54,470 --> 05:00:55,971
SO PRESUMABLY INTERFERON GAMMA

7656
05:00:55,971 --> 05:00:57,740
IS BEING MADE BY T CELLS, TAKEN

7657
05:00:57,740 --> 05:01:00,910
OUT AND SIGNALING THROUGH AN

7658
05:01:00,910 --> 05:01:02,111
IL-2 PATHWAY.

7659
05:01:02,111 --> 05:01:07,950
WHEN WE LOOK AT THE DOMAIN

7660
05:01:07,950 --> 05:01:08,517
SWAPPED CYTOKINE RECEPTORS,

7661
05:01:08,517 --> 05:01:09,785
INTERESTINGLY YOU CAN SEE THAT

7662
05:01:09,785 --> 05:01:12,621
EVERY SINGLE ONE OF THEM DOES

7663
05:01:12,621 --> 05:01:14,723
WORSE THAN THE TCR ALONE.

7664
05:01:14,723 --> 05:01:17,626
DESPITE HIGH FREQUENCY OF

7665
05:01:17,626 --> 05:01:19,395
PHOSPHO-STAT5, LOWER MFI TO BE

7666
05:01:19,395 --> 05:01:21,263
GRANTED, BUT THEY ALL DO WORSE

7667
05:01:21,263 --> 05:01:22,932
IN TCR SHOWN IN BLACK.

7668
05:01:22,932 --> 05:01:25,534
WE HAVE A HYPOTHESIS WHY THIS

7669
05:01:25,534 --> 05:01:27,069
MIGHT BE, WE'LL GET TO IN A

7670
05:01:27,069 --> 05:01:27,303
MINUTE.

7671
05:01:27,303 --> 05:01:32,975
THIS WAS I THINK UNEXPECTED

7672
05:01:32,975 --> 05:01:33,309
FINDING.

7673
05:01:33,309 --> 05:01:35,511
SO, WE WANTED TO DIVE DEEPER

7674
05:01:35,511 --> 05:01:38,547
INTO THE BIOLOGY OF THIS AND SO

7675
05:01:38,547 --> 05:01:43,585
WE WANTED TO TEST IMPACT OF THE

7676
05:01:43,585 --> 05:01:44,920
TRANSMEMBRANE DOMAIN, ALSO

7677
05:01:44,920 --> 05:01:46,455
INTRACELLULAR RECEPTOR PARTNER

7678
05:01:46,455 --> 05:01:48,624
ON FUNCTION OF THESE RECEPTORS.

7679
05:01:48,624 --> 05:01:52,595
AND SO THIS IS ORIGINAL DESIGN.

7680
05:01:52,595 --> 05:01:55,130
AGAIN TRANSMEMBRANE DOMAIN AND

7681
05:01:55,130 --> 05:01:56,665
CYTOPLASMIC DOMAIN FROM

7682
05:01:56,665 --> 05:01:57,599
INTRACELLULAR RECEPTOR.

7683
05:01:57,599 --> 05:02:02,371
WHAT WE DID WAS A TRANSMEMBRANE

7684
05:02:02,371 --> 05:02:05,641
DOMAIN SWAP SO NOW DERIVED FROM

7685
05:02:05,641 --> 05:02:09,712
INTERFERON GAMMA R1 AND R 2, AND

7686
05:02:09,712 --> 05:02:12,014
DURING SWAP AND INTRACELLULAR

7687
05:02:12,014 --> 05:02:17,119
PARTNER SWAP, LONGEST CHANGE ON

7688
05:02:17,119 --> 05:02:19,254
SHORTEST CHANGE AND VICE VERSA,

7689
05:02:19,254 --> 05:02:20,656
TWO ADDITIONAL CONSTRUCTS TO SEE

7690
05:02:20,656 --> 05:02:24,827
IF THAT WOULD ENHANCE OR IMPAIR

7691
05:02:24,827 --> 05:02:25,160
RECEPTORS.

7692
05:02:25,160 --> 05:02:27,329
SO I'VE SHOWN THIS DATA HERE.

7693
05:02:27,329 --> 05:02:32,167
I'M GOING TO GO THROUGH

7694
05:02:32,167 --> 05:02:33,469
INTERLEUKIN-2 AND ALSO GM-CSF,

7695
05:02:33,469 --> 05:02:38,941
ORIGINAL DESIGNS, WHEN WE DO THE

7696
05:02:38,941 --> 05:02:41,443
TRANSMEMBRANE SWAP, YOU CAN SEE

7697
05:02:41,443 --> 05:02:43,512
THAT NOW THEY LOSE ABILITY TO

7698
05:02:43,512 --> 05:02:48,450
CONTROL THE TUMOR CELLS.

7699
05:02:48,450 --> 05:02:50,119
SIMILARLY THEY LOSE ABILITY TO

7700
05:02:50,119 --> 05:02:53,288
CONTROL TUMOR CELLS.

7701
05:02:53,288 --> 05:02:57,459
ONCE YOU DO BOTH TRANSMEMBRANE

7702
05:02:57,459 --> 05:02:58,761
AND INTRACELLULAR PARTNER SWAP

7703
05:02:58,761 --> 05:03:00,295
IT DOES BETTER, SO THIS

7704
05:03:00,295 --> 05:03:02,598
PHENOTYPE NOW LOOKS MORE LIKE IF

7705
05:03:02,598 --> 05:03:04,900
YOU JUST ADDED IL-2.

7706
05:03:04,900 --> 05:03:15,477
FOR THE  GMPCSF, THESE ARE THINS

7707
05:03:20,049 --> 05:03:22,284
YOU HAVE TO TEST EMPIRICALLY

7708
05:03:22,284 --> 05:03:25,521
WITH NO REAL PATTERN WOULD THIS

7709
05:03:25,521 --> 05:03:26,088
TRANSMEMBRANE INTRACELLULAR

7710
05:03:26,088 --> 05:03:27,623
DOUGH PLAIN TO USE.

7711
05:03:27,623 --> 05:03:29,591
WE CAN CONCLUDE THAT

7712
05:03:29,591 --> 05:03:31,894
TRANSMEMBRANE DOMAIN AND PARTNER

7713
05:03:31,894 --> 05:03:33,862
SWAB, INTRACELLULAR SWAP, CAN BE

7714
05:03:33,862 --> 05:03:36,832
IMPORTANT FOR FUNCTION.

7715
05:03:36,832 --> 05:03:40,002
DESPITE THIS ENCOURAGING DATA

7716
05:03:40,002 --> 05:03:45,107
SERIAL KILL DATA, THE CHIMERIC

7717
05:03:45,107 --> 05:03:46,575
RECEPTORS DON'T RECAPITULATE

7718
05:03:46,575 --> 05:03:49,078
PROLIFERATIVE SIGNAL OF IL-2

7719
05:03:49,078 --> 05:03:49,945
RECEPTOR.

7720
05:03:49,945 --> 05:03:52,781
WE TOOK TCR ENGINEERED CELLS AND

7721
05:03:52,781 --> 05:03:56,952
WITH CHIMERIC RECEPTOR, OUR BEST

7722
05:03:56,952 --> 05:03:59,788
CYTOKINE INTERFERON GAMMA

7723
05:03:59,788 --> 05:04:01,223
CHIMERIC RECEPTOR, EXPANDED IN

7724
05:04:01,223 --> 05:04:04,059
THE PRESENCE OF EITHER HIGH DOSE

7725
05:04:04,059 --> 05:04:06,128
IL-2 OR INTERFERON GAMMA.

7726
05:04:06,128 --> 05:04:09,665
WITH IL-2 ALONE, WITH TCR ALONE,

7727
05:04:09,665 --> 05:04:14,603
GOOD EXPANSION, NOT MUCH WITH

7728
05:04:14,603 --> 05:04:16,572
INTERFERON GAMMA.

7729
05:04:16,572 --> 05:04:19,174
HIGH DOSE  INTERFERON GAMMA DOES

7730
05:04:19,174 --> 05:04:22,144
NOT GET TO LEVEL OF IL-2, MOST

7731
05:04:22,144 --> 05:04:26,515
OF THE TIMELESS THAN HALF FOLD

7732
05:04:26,515 --> 05:04:29,518
EXPANSION THAN IL-2, NOT QUITE

7733
05:04:29,518 --> 05:04:31,820
FULLY RECAPITULATING THE SIGNAL.

7734
05:04:31,820 --> 05:04:34,957
BACK TO THE HYPOTHESIS, THE ODD

7735
05:04:34,957 --> 05:04:37,392
FINDING THAT DOMAIN SWAP

7736
05:04:37,392 --> 05:04:39,361
RECEPTORS WEREN'T DOING WELL,

7737
05:04:39,361 --> 05:04:41,964
THIS IS OUR ONGOING HYPOTHESIS

7738
05:04:41,964 --> 05:04:44,299
WHY THE CHIMERIC CYTOKINE

7739
05:04:44,299 --> 05:04:46,702
RECEPTOR DOESN'T MEDIATE FULL

7740
05:04:46,702 --> 05:04:47,369
PROLIFERATIVE IL-2 SIGNAL.

7741
05:04:47,369 --> 05:04:51,607
T CELLS AT SOME POINT CAN

7742
05:04:51,607 --> 05:04:52,941
EXPRESS WILD TYPE INTERFERON

7743
05:04:52,941 --> 05:04:54,109
GAMMA RECEPTOR SHOWN HERE.

7744
05:04:54,109 --> 05:04:56,645
WE FORCE EXPRESSION OF THE

7745
05:04:56,645 --> 05:05:06,288
CHIMERIC RECEPTOR HERE, R 1 AND

7746
05:05:06,288 --> 05:05:09,091
R 32, POSSIBILITY OF MIXED DIMER

7747
05:05:09,091 --> 05:05:09,691
FORMATION.

7748
05:05:09,691 --> 05:05:15,230
THERE'S A POSSIBILITY THEY COULD

7749
05:05:15,230 --> 05:05:21,537
BIND AND MEDIATE SIGNALING 

7750
05:05:21,537 --> 05:05:30,412
DETRIMENTAL TO THE T CELL.

7751
05:05:30,412 --> 05:05:31,847
SO THERE'S CERTAINLY A

7752
05:05:31,847 --> 05:05:34,249
POSSIBILITY THERE MAY BE MIXED

7753
05:05:34,249 --> 05:05:38,854
DIMER FORMATION HERE.

7754
05:05:38,854 --> 05:05:40,322
WITH THAT, THIS IS A WORK IN

7755
05:05:40,322 --> 05:05:43,959
PROGRESS BUT THOUGHT IT WAS AN

7756
05:05:43,959 --> 05:05:47,863
INTERESTING AND NEED WHY THE TO

7757
05:05:47,863 --> 05:05:48,397
SHARE.

7758
05:05:48,397 --> 05:05:50,132
WE KNOW TARGETING ONCOGENIC

7759
05:05:50,132 --> 05:05:53,435
DRIVER MUTATIONS CAN MEDIATE

7760
05:05:53,435 --> 05:06:01,410
REGRESSION OF METASTATIC CANCERS

7761
05:06:01,410 --> 05:06:11,687
BUT IMPROVEMENTS ARE NEEDED.

7762
05:06:11,687 --> 05:06:16,959
EN  WE FOUND OUT THAT

7763
05:06:16,959 --> 05:06:18,026
TRANSMEMBRANE DOMAIN AND

7764
05:06:18,026 --> 05:06:19,361
INTRACELLULAR FUSION PARTNER IS

7765
05:06:19,361 --> 05:06:19,628
IMPORTANT.

7766
05:06:19,628 --> 05:06:23,498
LEAD CANDIDATE DOES NOT FULLY

7767
05:06:23,498 --> 05:06:24,600
RECAPITULATE IL-2 SIGNALING WE

7768
05:06:24,600 --> 05:06:29,538
THINK BECAUSE OF MIXED RECEPTOR

7769
05:06:29,538 --> 05:06:29,771
DIMERS.

7770
05:06:29,771 --> 05:06:31,707
WE'RE GOING TO KNOCK OUT TO SEE

7771
05:06:31,707 --> 05:06:34,343
IF THAT ENHANCES ACTIVITY OF

7772
05:06:34,343 --> 05:06:35,844
CHIMERIC CYTOKINE RECEPTORS, AND

7773
05:06:35,844 --> 05:06:37,846
PERFORM IN VITRO STRESS TESTING

7774
05:06:37,846 --> 05:06:40,015
OF THE CHIMERIC CYTOKINE

7775
05:06:40,015 --> 05:06:41,683
RECEPTORS USING ACIDIC

7776
05:06:41,683 --> 05:06:43,852
CONDITIONS, PRESENCE OF

7777
05:06:43,852 --> 05:06:44,119
TGF-BETA.

7778
05:06:44,119 --> 05:06:49,658
AND WE RECENTLY GOT IACUC

7779
05:06:49,658 --> 05:06:51,960
APPROVAL, WE'LL BE TESTING IN

7780
05:06:51,960 --> 05:06:53,161
MOUSE TUMOR MODELS.

7781
05:06:53,161 --> 05:06:55,364
I'M RUNNING OUT OF TIME.

7782
05:06:55,364 --> 05:06:57,866
FLASHING OUT GENERAL STRATEGIES

7783
05:06:57,866 --> 05:06:59,301
TO ENHANCE CELL THERAPIES, I

7784
05:06:59,301 --> 05:07:00,235
SHOWED ONE PROJECT.

7785
05:07:00,235 --> 05:07:02,137
I WANT TO HIGHLIGHT IN RED WE'RE

7786
05:07:02,137 --> 05:07:03,905
WORKING ON MULTIPLE FACETS ON

7787
05:07:03,905 --> 05:07:07,075
TRYING TO IMPROVE THIS THERAPY,

7788
05:07:07,075 --> 05:07:08,043
ESPECIALLY MANUFACTURED

7789
05:07:08,043 --> 05:07:08,510
CONDITIONS.

7790
05:07:08,510 --> 05:07:14,950
WE FOUND THIS MAKES A MUCH MORE

7791
05:07:14,950 --> 05:07:18,020
POTENT CELL, SO WE'RE MOVING

7792
05:07:18,020 --> 05:07:23,925
AHEAD WITH ADDING TGF-BETA TO

7793
05:07:23,925 --> 05:07:24,559
CELLS.

7794
05:07:24,559 --> 05:07:32,034
WE'RE TAKING A PAGE, HARNESS

7795
05:07:32,034 --> 05:07:36,305
FROM PERIPHERAL BLOOD.

7796
05:07:36,305 --> 05:07:37,639
OVEREXPRESSED TD 40, TO ENHANCE

7797
05:07:37,639 --> 05:07:39,574
T CELLS.

7798
05:07:39,574 --> 05:07:40,876
AND WE'RE WORKING ON NEXT

7799
05:07:40,876 --> 05:07:42,311
CLINICAL TRIAL, CONSIDERING ALL

7800
05:07:42,311 --> 05:07:44,813
THESE FACTORS TO COMBINE WITH

7801
05:07:44,813 --> 05:07:46,581
OUR TCR ENGINEERED T CELLS.

7802
05:07:46,581 --> 05:07:47,582
WITH THAT I'D LIKE TO

7803
05:07:47,582 --> 05:07:49,084
ACKNOWLEDGE A LOT OF PEOPLE

7804
05:07:49,084 --> 05:07:49,284
HERE.

7805
05:07:49,284 --> 05:07:51,053
ALL THE WORK I SHOWED WITH

7806
05:07:51,053 --> 05:07:53,555
CHIMERIC RECEPTOR DONE BY MY

7807
05:07:53,555 --> 05:07:56,291
POSTDOC, WHO IS AN EXTREMELY

7808
05:07:56,291 --> 05:07:56,992
DEDICATED AND HARD-WORKING

7809
05:07:56,992 --> 05:07:57,826
POSTDOC IN MY LAB.

7810
05:07:57,826 --> 05:08:00,462
I WANT TO ACKNOWLEDGE THE WHOLE

7811
05:08:00,462 --> 05:08:04,066
INSTITUTE MAINLY BECAUSE IT

7812
05:08:04,066 --> 05:08:05,367
TAKES A VILLAGE TO GET THE

7813
05:08:05,367 --> 05:08:06,735
PROGRAM UP AND RUNNING, THAT'S

7814
05:08:06,735 --> 05:08:09,237
WHY THERE'S SO MANY PEOPLE ON

7815
05:08:09,237 --> 05:08:10,238
THIS ACKNOWLEDGMENT SLIDE.

7816
05:08:10,238 --> 05:08:12,407
WALTER IS OUR DIRECTOR OF OUR

7817
05:08:12,407 --> 05:08:14,509
CANCER RESEARCH, AND HE'S BEEN

7818
05:08:14,509 --> 05:08:16,144
SUPER SUPPORTIVE OF OUR CELL

7819
05:08:16,144 --> 05:08:16,845
THERAPY EFFORTS.

7820
05:08:16,845 --> 05:08:21,183
SADLY HE WILL BE RETIRING  AT TE

7821
05:08:21,183 --> 05:08:22,918
END OF THE YEAR, DR. ROSENBERG,

7822
05:08:22,918 --> 05:08:25,020
THANK YOU FOR EVERYTHING YOU'VE

7823
05:08:25,020 --> 05:08:27,956
DONE FOR THE PATIENTS, FOR THE

7824
05:08:27,956 --> 05:08:29,057
FIELD, AND PERSONALLY FOR MYSELF

7825
05:08:29,057 --> 05:08:30,726
BECAUSE YOU HELPED ME DEVELOP

7826
05:08:30,726 --> 05:08:33,128
INTO THE SCIENTIST I AM TODAY.

7827
05:08:33,128 --> 05:08:35,630
LAST AND NOT LEAST PATIENTS AND

7828
05:08:35,630 --> 05:08:37,699
THEIR FAMILIES, IT'S WHAT DRIVES

7829
05:08:37,699 --> 05:08:40,135
US AND IT'S OUR REASON FOR

7830
05:08:40,135 --> 05:08:40,402
EXISTING.

7831
05:08:40,402 --> 05:08:40,869
THANK YOU VERY MUCH.

7832
05:08:40,869 --> 05:08:42,270
HAPPY TO ANSWER ANY QUESTIONS.

7833
05:08:42,270 --> 05:08:44,473
[APPLAUSE]

7834
05:08:44,473 --> 05:08:50,512
 

7835
05:08:50,512 --> 05:08:56,418
 

7836
05:08:56,418 --> 05:08:59,921
>> YOU IF QUESTIONS FOR
DR. TRAN

7837
05:08:59,921 --> 05:09:00,856
FIND HIM DURING THE BREAK.

7838
05:09:00,856 --> 05:09:00,989
RECONVENE BY 3:45, WE'LL ONLY BE

7839
05:09:00,989 --> 05:09:02,224
A FEW MINUTES BEHIND SCHEDULE.

7840
05:09:02,224 --> 05:09:07,195
PLEASE ENJOY THE BREAK.

7841
05:09:07,195 --> 05:09:15,604
FIRST THING YOU MIGHT NOTICE I'M

7842
05:09:15,604 --> 05:09:17,205
NOT RACHEL BYER WHO COULDN'T BE

7843
05:09:17,205 --> 05:09:17,706
HERE TODAY.

7844
05:09:17,706 --> 05:09:20,876
I HAVE THE HONOR OF MODERATING.

7845
05:09:20,876 --> 05:09:24,146
I'D LIKE TO BRING UP ONE OF THE

7846
05:09:24,146 --> 05:09:27,416
ALUMNI LEADERS THAT DR.

7847
05:09:27,416 --> 05:09:34,523
ROSENBERG MENTORS, THE PRESIDENT

7848
05:09:34,523 --> 05:09:35,290
APARTMENT OF MOFFITT,INE

7849
05:09:35,290 --> 05:09:40,228
MODIFIED T CELLS, IF

7850
05:09:40,228 --> 05:09:42,531
MICROINJECTION TO CRISPR

7851
05:09:42,531 --> 05:09:42,831
TECHNOLOGY.

7852
05:09:42,831 --> 05:09:43,732
>> THANK YOU.

7853
05:09:43,732 --> 05:09:46,268
IT'S A PRIVILEGE TO BE HERE,

7854
05:09:46,268 --> 05:09:47,035
WHAT AN HONOR.

7855
05:09:47,035 --> 05:09:50,305
THE 14 YEARS I SPENT NEAR

7856
05:09:50,305 --> 05:09:52,174
BETHESDA WITH DR. ROSENBERG, I

7857
05:09:52,174 --> 05:09:53,375
CHERISH MY WHOLE LIFE.

7858
05:09:53,375 --> 05:09:54,743
THERE'S NO BETTER PLACE ON THE

7859
05:09:54,743 --> 05:09:59,281
PLAN  TO DEVELOP AS A PHYSICIAN

7860
05:09:59,281 --> 05:10:00,482
SCIENTIST THAN SURGERY BRANCH

7861
05:10:00,482 --> 05:10:01,116
THE NCI.

7862
05:10:01,116 --> 05:10:04,519
EVERY TIME I COME BACK IT FEELS

7863
05:10:04,519 --> 05:10:07,055
LIKE I'M COMING HOME.

7864
05:10:07,055 --> 05:10:08,924
WE DIDN'T JUST LEARN A LOT BUT

7865
05:10:08,924 --> 05:10:13,295
HAD FUN TOO, DIDN'T WE?

7866
05:10:13,295 --> 05:10:17,866
WE DID TRIATHLONS, WE HAD TRAVEL

7867
05:10:17,866 --> 05:10:20,602
SLIDES DURING SEMINARS, SKITS AT

7868
05:10:20,602 --> 05:10:23,972
CHRISTMASTIME, WE EVEN HAD A

7869
05:10:23,972 --> 05:10:27,042
SURGERY BRANCH ROCK BAND.

7870
05:10:27,042 --> 05:10:28,777
STEVE LABUDI WAS THE DRUMMER.

7871
05:10:28,777 --> 05:10:31,880
DO YOU KNOW WHAT WE WERE CALLED?

7872
05:10:31,880 --> 05:10:32,581
PROTOCOL VIOLATION.

7873
05:10:32,581 --> 05:10:32,948
VERY GOOD.

7874
05:10:32,948 --> 05:10:37,352
THAT WAS THE NAME OF OUR ROCK

7875
05:10:37,352 --> 05:10:37,652
BAND.

7876
05:10:37,652 --> 05:10:40,155
SURGERY BRANCH BAND WAS PROTOCOL

7877
05:10:40,155 --> 05:10:40,522
VIOLATION.

7878
05:10:40,522 --> 05:10:42,691
WHEN WE DID TRIALS WE HAD NO

7879
05:10:42,691 --> 05:10:43,325
VIOLATIONS.

7880
05:10:43,325 --> 05:10:47,062
WHAT WE STARTED WITH WAS NOT CAR

7881
05:10:47,062 --> 05:10:49,998
T BUT TNF.

7882
05:10:49,998 --> 05:10:53,835
WE'RE CYTOKINE PLACE, RIGHT?

7883
05:10:53,835 --> 05:11:02,944
TNF CAUSED TUMORS TO  REGRESS,

7884
05:11:02,944 --> 05:11:04,846
WHEN WE PUT THE GENE IN IT

7885
05:11:04,846 --> 05:11:09,618
DIDN'T CRANK OUT SO MUCH TNF.

7886
05:11:09,618 --> 05:11:16,858
IT WAS A CHALLENGE, EARLY DAYS

7887
05:11:16,858 --> 05:11:19,027
OF GENE TRANSFER.

7888
05:11:19,027 --> 05:11:20,795
WE SAID LET'S JUST INJECT THE

7889
05:11:20,795 --> 05:11:31,172
CELLS ONE AT A TIME WITH A

7890
05:11:31,172 --> 05:11:31,506
MICROINJECTOR.

7891
05:11:31,506 --> 05:11:34,242
YOU HAD TO HIT THEM IN THE

7892
05:11:34,242 --> 05:11:35,777
NUCLEUS, IF YOU PUT TOO MUCH

7893
05:11:35,777 --> 05:11:40,081
VOLUME IN THEY WOULD EXPLODE.

7894
05:11:40,081 --> 05:11:41,883
IT'S ALSO WHERE WE STORED THE

7895
05:11:41,883 --> 05:11:45,720
MOUSE BEDDING, I CAME OUT

7896
05:11:45,720 --> 05:11:47,789
SMELLING LIKE MOUSE BEDDING.

7897
05:11:47,789 --> 05:11:50,091
IT WORKED BUT WASN'T REALLY THAT

7898
05:11:50,091 --> 05:11:56,598
SCALABLE AS YOU MIGHT IMAGINE.

7899
05:11:56,598 --> 05:12:05,440
WE GOT RETROVIRUSES TO WORK,

7900
05:12:05,440 --> 05:12:05,974
OPTIMIZING EVERYTHING.

7901
05:12:05,974 --> 05:12:07,943
WE HAD ALL OF THIS STUFF WE

7902
05:12:07,943 --> 05:12:11,212
COULD DO BY PUTTING GENES INTO T

7903
05:12:11,212 --> 05:12:17,052
CELLS AND ONE THING THAT WE

7904
05:12:17,052 --> 05:12:21,089
STARTED WITH, WORKING WITH

7905
05:12:21,089 --> 05:12:26,661
SOMEONE ON A SABBATICAL,

7906
05:12:26,661 --> 05:12:34,469
PRE-FIRST  GENERATION, THIS WAS

7907
05:12:34,469 --> 05:12:35,670
OUR VECTOR.

7908
05:12:35,670 --> 05:12:39,474
WE HAD THREE ACTUALLY, ONE FOR

7909
05:12:39,474 --> 05:12:40,241
OVARIAN, BREAST, COLON.

7910
05:12:40,241 --> 05:12:42,010
THE ONLY ONE THAT WORKED, WE

7911
05:12:42,010 --> 05:12:43,545
DIDN'T KNOW WHY, OVARIAN.

7912
05:12:43,545 --> 05:12:46,147
WE WENT WITH IT.

7913
05:12:46,147 --> 05:12:50,552
AND THIS IS OUR FIRST PAPER,

7914
05:12:50,552 --> 05:12:57,559
1993, SHOWING THAT WE COULD GET

7915
05:12:57,559 --> 05:12:59,728
MELANOMA TIL TO RECOGNIZE AND

7916
05:12:59,728 --> 05:13:02,597
KILL OVARIAN CANCER WHEN WE PUT

7917
05:13:02,597 --> 05:13:07,302
IN CHIMERIC ALPHA RECEPTOR

7918
05:13:07,302 --> 05:13:11,339
AGAINST ALPHA FOLATE RECEPTOR.

7919
05:13:11,339 --> 05:13:17,946
THIS IS TIL 1143, AN INCREDIBLE

7920
05:13:17,946 --> 05:13:22,450
TIL LINE.

7921
05:13:22,450 --> 05:13:26,154
JIM YANG HELPED WITH IN VIVO

7922
05:13:26,154 --> 05:13:28,023
STUDIES, WE SHOWED WITH CANCER

7923
05:13:28,023 --> 05:13:30,959
MODELS WE COULD GET THIS TO WORK

7924
05:13:30,959 --> 05:13:31,860
IN VIVO.

7925
05:13:31,860 --> 05:13:35,664
AND WE COULD PUT THIS INTO BONE

7926
05:13:35,664 --> 05:13:37,532
MARROW GETTING THIS TO WORK IN

7927
05:13:37,532 --> 05:13:39,834
MICE, EVEN WHEN WE DEPLETED T

7928
05:13:39,834 --> 05:13:40,602
CELLS.

7929
05:13:40,602 --> 05:13:43,004
THIS RECEPTOR WORKED IN OTHER

7930
05:13:43,004 --> 05:13:44,005
EFFECTOR CELLS LIKE NK CELLS.

7931
05:13:44,005 --> 05:13:47,175
SO IT WAS A VERY EXCITING TIME.

7932
05:13:47,175 --> 05:13:50,345
WE THOUGHT LET'S TAKE IT TO THE

7933
05:13:50,345 --> 05:13:50,578
CLINIC.

7934
05:13:50,578 --> 05:13:54,582
WE DID TAKE IT TO A PHASE 1

7935
05:13:54,582 --> 05:13:56,117
STUDY IN OVARIAN CANCER, WHICH

7936
05:13:56,117 --> 05:14:00,388
WAS ALSO WE HAD A COMMENTARY IN

7937
05:14:00,388 --> 05:14:03,024
THE 20th ANNIVERSARY CCR ISSUE

7938
05:14:03,024 --> 05:14:05,427
ABOUT THIS FIRST CHIMERIC

7939
05:14:05,427 --> 05:14:06,761
ANTIGEN RECEPTOR TRIAL.

7940
05:14:06,761 --> 05:14:09,164
WE DIDN'T GET ANY RESPONDERS.

7941
05:14:09,164 --> 05:14:11,566
AT THE SAME TIME IT WAS SAFE, AN

7942
05:14:11,566 --> 05:14:17,706
EARLY STAGE, WE DIDN'T HAVE

7943
05:14:17,706 --> 05:14:21,543
CO-STIM MOLECULES AND WERE

7944
05:14:21,543 --> 05:14:23,478
GETTING NEUTRALIZING ANTIBODY

7945
05:14:23,478 --> 05:14:23,945
ISSUES.

7946
05:14:23,945 --> 05:14:26,681
WE GOT FIRST GENERATION, SECOND,

7947
05:14:26,681 --> 05:14:28,750
THIRD GENERATION VECTORS.

7948
05:14:28,750 --> 05:14:32,687
AND YOU'LL HEAR FROM THE NEXT

7949
05:14:32,687 --> 05:14:33,988
SPEAKERS WILL FDA APPROVAL AND

7950
05:14:33,988 --> 05:14:36,291
SUCCESSS FROM THE CAR PRODUCTS.

7951
05:14:36,291 --> 05:14:38,793
WHAT'S NEXT?

7952
05:14:38,793 --> 05:14:40,128
NOW THE TECHNOLOGY WENT FROM

7953
05:14:40,128 --> 05:14:42,030
MICRO INJECTION TO NOW YOU CAN

7954
05:14:42,030 --> 05:14:43,732
PRETTY MUCH TAKE OUT ANY GENE

7955
05:14:43,732 --> 05:14:45,700
YOU WANT IN A LYMPHOCYTE.

7956
05:14:45,700 --> 05:14:47,368
IT'S AMAZING.

7957
05:14:47,368 --> 05:14:48,770
YOU MAKE THE GUIDES.

7958
05:14:48,770 --> 05:14:50,872
WE'VE WORKED ON MANY DIFFERENT

7959
05:14:50,872 --> 05:14:51,172
GENES.

7960
05:14:51,172 --> 05:14:52,707
YOU CAN TAKE A GENE OUT WITH

7961
05:14:52,707 --> 05:14:55,009
CRISPR, PUT A GENE IN, REPLACE A

7962
05:14:55,009 --> 05:14:56,010
GENE, CHANGE THE GENE.

7963
05:14:56,010 --> 05:14:58,179
IT'S SO MUCH THAT YOU CAN DO

7964
05:14:58,179 --> 05:14:59,848
TODAY THAT WE COULDN'T DO BACK

7965
05:14:59,848 --> 05:15:00,048
THEN.

7966
05:15:00,048 --> 05:15:03,118
WE'RE HAVING A LOT OF FUN WITH

7967
05:15:03,118 --> 05:15:03,318
THAT.

7968
05:15:03,318 --> 05:15:09,858
THIS WAS SAM FIX IN THE LAB, YOU

7969
05:15:09,858 --> 05:15:10,658
CAN TAKE TGF-BETA RECEPTOR,

7970
05:15:10,658 --> 05:15:18,099
KNOCK IT OUT, YOU DO NOT SEE

7971
05:15:18,099 --> 05:15:18,566
PHOSPHO-MATTER.

7972
05:15:18,566 --> 05:15:21,035
WE PUBLISHED A REVIEW IN CANCER

7973
05:15:21,035 --> 05:15:22,804
DISCOVERY OF ALL THE DIFFERENT

7974
05:15:22,804 --> 05:15:24,973
WAYS YOU COULD USE CRISPR FOR T

7975
05:15:24,973 --> 05:15:25,974
CELL THERAPEUTICS.

7976
05:15:25,974 --> 05:15:28,576
YOU CAN MAKE THE CELLS LESS

7977
05:15:28,576 --> 05:15:34,315
TOXIC, TAKE OUT THE BREAKS, SO

7978
05:15:34,315 --> 05:15:35,417
IT'S AN EXCITING WORLD.

7979
05:15:35,417 --> 05:15:37,051
THIS IS WHAT WE DID OVER THE

7980
05:15:37,051 --> 05:15:38,453
LAST FEW YEARS.

7981
05:15:38,453 --> 05:15:42,824
WE SAID WHY DON'T WE CHANGE

7982
05:15:42,824 --> 05:15:44,793
METABOLISM OF T CELLS AND HELP

7983
05:15:44,793 --> 05:15:47,429
THE T CELLS PROLIFERATE AT TUMOR

7984
05:15:47,429 --> 05:15:48,096
SITE.

7985
05:15:48,096 --> 05:15:52,000
WE TOOK 300 METABOLISM GENES,

7986
05:15:52,000 --> 05:15:54,869
AGNOSTIC WAY, shRNA, PUT THEM

7987
05:15:54,869 --> 05:15:56,938
INTO THE CELLS DEVELOPED LEER,

7988
05:15:56,938 --> 05:15:58,606
AND INJECTED THEM INTO THE

7989
05:15:58,606 --> 05:16:00,742
ANIMALS AND TOOK OUT THE B 16

7990
05:16:00,742 --> 05:16:03,511
MELANOMAS AND SAID, ALL RIGHT,

7991
05:16:03,511 --> 05:16:06,781
WHAT KNOCKDOWNS ARE PRESENT

7992
05:16:06,781 --> 05:16:11,920
THERE?

7993
05:16:11,920 --> 05:16:13,955
IT'S VERY AGNOSTIC DOING THE

7994
05:16:13,955 --> 05:16:20,495
WHOLE SCREEN IN VIVO, A TALENTED

7995
05:16:20,495 --> 05:16:25,500
SCIENTIST WITH US, SORAYA.

7996
05:16:25,500 --> 05:16:28,036
A GENE ALLOWED US TO GET MORE T

7997
05:16:28,036 --> 05:16:29,737
CELLS AT THE TUMOR SITE WHEN WE

7998
05:16:29,737 --> 05:16:31,172
KNOCKED IT OUT.

7999
05:16:31,172 --> 05:16:35,143
WE DID THIS CONFIRMATION WITH

8000
05:16:35,143 --> 05:16:35,476
CRISPR.

8001
05:16:35,476 --> 05:16:37,879
THEN THE WORK BEGINS BECAUSE I

8002
05:16:37,879 --> 05:16:40,548
DON'T KNOW ALL 20,000 GENES AND

8003
05:16:40,548 --> 05:16:42,250
SO YOU'RE USING A LOT OF

8004
05:16:42,250 --> 05:16:45,820
WIKIPEDIA TO FIGURE OUT WHAT

8005
05:16:45,820 --> 05:16:47,822
THEY DO.

8006
05:16:47,822 --> 05:16:51,226
WITH THE PDHB COMPLEX, IT TAKES

8007
05:16:51,226 --> 05:16:53,528
YOUR PYRUVATE, CONVERTS TO

8008
05:16:53,528 --> 05:16:56,064
ACETYLCHOLATE, ALLOWS YOUR

8009
05:16:56,064 --> 05:17:00,435
GLUCOSE TO GO INTO OXIDATIVE

8010
05:17:00,435 --> 05:17:01,069
PHOSPHORYLATION PATHWAY, CAUSING

8011
05:17:01,069 --> 05:17:04,472
THE T CELLS TO GO INTO

8012
05:17:04,472 --> 05:17:05,139
GLYCOLYSIS BY BLOCKING IT,

8013
05:17:05,139 --> 05:17:06,007
OPPOSITE OF WHAT I THOUGHT WE

8014
05:17:06,007 --> 05:17:09,444
SHOULD HAVE DONE BUT IT'S WHAT

8015
05:17:09,444 --> 05:17:10,478
THE DATA SHOWED.

8016
05:17:10,478 --> 05:17:17,585
WE DID THIS TEN TIMES TO MAKE

8017
05:17:17,585 --> 05:17:20,355
SURE IT WAS RIGHT.

8018
05:17:20,355 --> 05:17:23,524
, BEING A SURGERY BRANCH.

8019
05:17:23,524 --> 05:17:26,694
THIS JUST SHOWED IN OUR 3D

8020
05:17:26,694 --> 05:17:28,863
MODEL, WE'RE USING TO USE 3D

8021
05:17:28,863 --> 05:17:31,165
MODELS MORE BECAUSE IT

8022
05:17:31,165 --> 05:17:33,601
RECAPITULATES WHAT WE SEE IN

8023
05:17:33,601 --> 05:17:34,135
VIVO MORE.

8024
05:17:34,135 --> 05:17:44,679
SO THIS IS -- LET'S ME JUST TAKE

8025
05:17:46,014 --> 05:17:46,414
THIS.

8026
05:17:46,414 --> 05:17:48,650
I'M GOING TO PLAY THIS VIDEO.

8027
05:17:48,650 --> 05:17:51,085
T CELLS ARE LABELED IN GREEN.

8028
05:17:51,085 --> 05:17:52,220
HERE THIS PURPLE BLOB ARE

8029
05:17:52,220 --> 05:17:52,587
TUMORS.

8030
05:17:52,587 --> 05:17:56,224
THIS IS THE KNOCKOUT CELLS.

8031
05:17:56,224 --> 05:17:57,325
THESE ARE THE NON-TARGETING

8032
05:17:57,325 --> 05:17:57,559
CONTROL.

8033
05:17:57,559 --> 05:18:00,295
YOU CAN SEE WHEN WE PUT T CELLS

8034
05:18:00,295 --> 05:18:04,465
TOGETHER WITH THE TUMOR YOU GET

8035
05:18:04,465 --> 05:18:08,069
HUGE PROLIFERATION OF THE T

8036
05:18:08,069 --> 05:18:13,541
CELLS WHEN YOU KNOCK OUT THE

8037
05:18:13,541 --> 05:18:24,052
PDHB GENE, I DON'T HAVE TIME TO

8038
05:18:24,052 --> 05:18:26,788
SHOW THE MECHANISMS.

8039
05:18:26,788 --> 05:18:29,991
WE'RE TAKING GLUCOSE, INSTEAD OF

8040
05:18:29,991 --> 05:18:32,727
OXIDATIVE PHOSPHORYLATION WE ARE

8041
05:18:32,727 --> 05:18:34,262
GOING TO AEROBIC GLYCOLYSIS,

8042
05:18:34,262 --> 05:18:36,564
EVEN THOUGH OXYGEN IS AROUND

8043
05:18:36,564 --> 05:18:41,369
WE'RE SENDING THEM THROUGH

8044
05:18:41,369 --> 05:18:44,339
GLYCOLYTIC PATHWAY, INCREASING

8045
05:18:44,339 --> 05:18:48,509
PENTOSE PHOSPATE PATHWAY,

8046
05:18:48,509 --> 05:18:51,779
OXIDATIVE AND NON-OXIDATIVE,

8047
05:18:51,779 --> 05:18:53,047
INCREASING LIPID SYNTHESIS, ALL

8048
05:18:53,047 --> 05:18:55,717
THINGS T CELLS NEED TO

8049
05:18:55,717 --> 05:18:56,017
PROLIFERATE.

8050
05:18:56,017 --> 05:18:57,385
SOUNDS FAMILIAR BECAUSE CANCER

8051
05:18:57,385 --> 05:18:58,720
CELLS DO THIS.

8052
05:18:58,720 --> 05:19:03,091
IT'S CALLED THE WARBURG EFFECT.

8053
05:19:03,091 --> 05:19:05,793
CANCER CELLS USE EVEN IN

8054
05:19:05,793 --> 05:19:07,996
PRESENCE OF OXYGEN UNDERGO

8055
05:19:07,996 --> 05:19:09,864
AEROBIC GLYCOLYSIS SO THEY CAN

8056
05:19:09,864 --> 05:19:11,065
MAKE ALL THESE SUBSTANCES,

8057
05:19:11,065 --> 05:19:14,669
IMPORTANT FOR THEM TO

8058
05:19:14,669 --> 05:19:15,136
PROLIFERATE.

8059
05:19:15,136 --> 05:19:18,506
I RECOLLECT NICK CALCULATED THE

8060
05:19:18,506 --> 05:19:20,808
NUMBERING OF LUNCHES WE HAD

8061
05:19:20,808 --> 05:19:24,212
TOGETHER, ALL OF US, IT WAS

8062
05:19:24,212 --> 05:19:25,079
BETWEEN THREE AND FOUR THOUSAND,

8063
05:19:25,079 --> 05:19:27,382
SO ONE OF THOSE LUNCHES I

8064
05:19:27,382 --> 05:19:29,684
REMEMBER STEVE WAS TALKING ABOUT

8065
05:19:29,684 --> 05:19:30,685
A DREAM EXPERIMENT WHERE MAYBE

8066
05:19:30,685 --> 05:19:32,887
THE T CELLS COULD BE LIKE

8067
05:19:32,887 --> 05:19:34,655
LEUKEMIA CELLS AND JUST

8068
05:19:34,655 --> 05:19:36,524
PROLIFERATE OUT, ALL OVER THE

8069
05:19:36,524 --> 05:19:36,724
TUMOR.

8070
05:19:36,724 --> 05:19:37,558
REMEMBER THAT?

8071
05:19:37,558 --> 05:19:39,761
AND JUST TAKE OVER THE TUMOR.

8072
05:19:39,761 --> 05:19:41,863
SO THIS IS A BIT LIKE THAT.

8073
05:19:41,863 --> 05:19:43,898
IT'S IN THAT DIRECTION WHERE

8074
05:19:43,898 --> 05:19:51,239
WE'RE GIVING THE T CELLS

8075
05:19:51,239 --> 05:19:56,377
TUMOR-LIKE CAPABILITIES TO

8076
05:19:56,377 --> 05:19:58,046
UNDERGO WARBURG EFFECT, AEROBIC

8077
05:19:58,046 --> 05:19:59,347
GLYCOLYSIS, SO THAT WE CAN --

8078
05:19:59,347 --> 05:20:07,121
THEY CAN MAKE ALL THE SUBSTANCES

8079
05:20:07,121 --> 05:20:09,390
THEY NEED TO GROW.

8080
05:20:09,390 --> 05:20:14,095
WHEN WE LOOK IN HUMAN DATABASE,

8081
05:20:14,095 --> 05:20:14,762
RESPONDERS VERSUS

8082
05:20:14,762 --> 05:20:15,763
NON-RESPONDERS, A WONDERFUL GUY

8083
05:20:15,763 --> 05:20:17,398
AT THE BROAD, WE SAW THAT

8084
05:20:17,398 --> 05:20:19,801
ACTUALLY IN SOME OF HIS

8085
05:20:19,801 --> 05:20:25,940
RESPONDER SUBSETS, IN GREEN

8086
05:20:25,940 --> 05:20:36,384
HERE, YOU CAN SEE THAT THE

8087
05:20:40,121 --> 05:20:41,055
CYTOTOXIC LYMPHOCYTES HAVE LOW

8088
05:20:41,055 --> 05:20:41,689
PDHB.

8089
05:20:41,689 --> 05:20:43,124
THAT'S ALL OF THE DATA I'M

8090
05:20:43,124 --> 05:20:43,357
SHOWING.

8091
05:20:43,357 --> 05:20:47,061
I WANTED TO TELL YOU ABOUT

8092
05:20:47,061 --> 05:20:47,395
MOFFITT.

8093
05:20:47,395 --> 05:20:49,464
WE'RE REALLY BIG ON CELL

8094
05:20:49,464 --> 05:20:49,897
THERAPY.

8095
05:20:49,897 --> 05:20:52,533
I DON'T KNOW IF WE SHOULD BE

8096
05:20:52,533 --> 05:21:00,508
CALLED SURGERY DOWN SOUTH OR

8097
05:21:00,508 --> 05:21:02,276
MOFFITT NORTH, JUST JOKING.

8098
05:21:02,276 --> 05:21:06,414
WHY ARE WE SO FOCUSED ON CELL

8099
05:21:06,414 --> 05:21:07,815
THERAPY, 1300 INFUSIONS ON THE

8100
05:21:07,815 --> 05:21:08,216
FLOOR?

8101
05:21:08,216 --> 05:21:09,951
WE INVITE YOU TO COME DOWN AND

8102
05:21:09,951 --> 05:21:11,052
VISIT US.

8103
05:21:11,052 --> 05:21:13,321
THE STORY IS THAT ONE OF OUR

8104
05:21:13,321 --> 05:21:15,823
CHAIRMAN OF THE BOARD WAS

8105
05:21:15,823 --> 05:21:17,058
SENATOR CONNIE MACK, REMEMBER

8106
05:21:17,058 --> 05:21:17,692
HIM?

8107
05:21:17,692 --> 05:21:20,495
HE WAS A SENATOR, PUSHED FOR

8108
05:21:20,495 --> 05:21:24,499
DOUBLING OF THE NIH BUDGET, HE

8109
05:21:24,499 --> 05:21:25,199
LOVED READING.

8110
05:21:25,199 --> 05:21:28,102
ONE DAY IN D.C. HE WAS EARLY FOR

8111
05:21:28,102 --> 05:21:29,737
A MOVIE WITH HIS WIFE PRISCILLA,

8112
05:21:29,737 --> 05:21:31,305
WALKS INTO A BOOK STORE, GUESS

8113
05:21:31,305 --> 05:21:33,441
WHAT I PICKS UP.

8114
05:21:33,441 --> 05:21:34,242
THE TRANSFORMED CELL.

8115
05:21:34,242 --> 05:21:38,713
HE PICKS UP THE TRANSFORMED

8116
05:21:38,713 --> 05:21:38,913
CELL.

8117
05:21:38,913 --> 05:21:40,348
HIS BROTHER DIED OF MELANOMA,

8118
05:21:40,348 --> 05:21:42,550
REALLY INTERESTED IN IT.

8119
05:21:42,550 --> 05:21:45,052
HE READ IT VORACIOUSLY, GOT HOLD

8120
05:21:45,052 --> 05:21:46,053
OF DR. ROSENBERG, BECAME GOOD

8121
05:21:46,053 --> 05:21:47,889
FRIENDS WITH HIM.

8122
05:21:47,889 --> 05:21:49,657
THEN WHEN HE BECAME CHAIRMAN OF

8123
05:21:49,657 --> 05:21:50,858
THE BOARD AT MOFFITT, HE SAID

8124
05:21:50,858 --> 05:21:53,294
WE'VE GOT TO DO THIS CELL

8125
05:21:53,294 --> 05:21:56,998
THERAPY AT MOFFITT, HOW DO WE DO

8126
05:21:56,998 --> 05:21:59,500
IT? 

8127
05:21:59,500 --> 05:22:04,572
DR. ROSENBERG SAID RECRUIT JIM

8128
05:22:04,572 --> 05:22:09,810
YULET. 

8129
05:22:09,810 --> 05:22:11,012
THEY WENT TO MICHIGAN, 2003, THE

8130
05:22:11,012 --> 05:22:12,513
REST IS HISTORY.

8131
05:22:12,513 --> 05:22:14,282
IT'S SO FOCUSED ON CELL THERAPY

8132
05:22:14,282 --> 05:22:18,019
BECAUSE OF THE TRANSFORMED CELL.

8133
05:22:18,019 --> 05:22:19,754
WE HAVE OUR OWN CELL THERAPY

8134
05:22:19,754 --> 05:22:20,721
PRODUCTION FACILITY.

8135
05:22:20,721 --> 05:22:23,257
WE EVEN STARTED GENE ENGINEERING

8136
05:22:23,257 --> 05:22:25,092
FACILITY SO WE CAN GET ALL OF

8137
05:22:25,092 --> 05:22:29,897
THE VIRAL VECTORS, MAKE THOSE

8138
05:22:29,897 --> 05:22:30,798
OURSELVES NOW.

8139
05:22:30,798 --> 05:22:32,600
WE DIDN'T BUY A MICROINJECTOR,

8140
05:22:32,600 --> 05:22:35,369
MAYBE THAT WILL BE ON THE LIST.

8141
05:22:35,369 --> 05:22:38,439
THEN WE ALSO -- PEOPLE SAY, OH,

8142
05:22:38,439 --> 05:22:41,075
CELL THERAPY, IT'S NOT SCALABLE.

8143
05:22:41,075 --> 05:22:42,844
THAT'S ABSOLUTELY FALSE.

8144
05:22:42,844 --> 05:22:45,146
IT IS 100% SCALABLE.

8145
05:22:45,146 --> 05:22:47,882
MAY NOT BE SCALED BY BIOLOGISTS

8146
05:22:47,882 --> 05:22:48,249
LIKE OURSELVES.

8147
05:22:48,249 --> 05:22:50,051
IT'S GOING TO BE SCALED BY

8148
05:22:50,051 --> 05:22:50,818
ENGINEERS.

8149
05:22:50,818 --> 05:22:53,554
THESE ENGINEERED ARE A DIFFERENT

8150
05:22:53,554 --> 05:22:54,088
SPECIES.

8151
05:22:54,088 --> 05:22:54,655
MATERIALS, THEY UNDERSTAND.

8152
05:22:54,655 --> 05:22:57,525
THIS WAS A VERY SPECIAL ENGINEER

8153
05:22:57,525 --> 05:22:58,960
RECRUITED TO START OUR

8154
05:22:58,960 --> 05:23:00,494
ENGINEERING PROGRAM, GREG

8155
05:23:00,494 --> 05:23:01,028
SAWYER.

8156
05:23:01,028 --> 05:23:02,663
HE HAD ADVANCED MELANOMA, HE

8157
05:23:02,663 --> 05:23:05,066
WENT ON A CLINICAL TRIAL AT

8158
05:23:05,066 --> 05:23:05,299
MOFFITT.

8159
05:23:05,299 --> 05:23:07,134
HE WAS WORKING ON THE MARS

8160
05:23:07,134 --> 05:23:07,935
ROVER.

8161
05:23:07,935 --> 05:23:09,870
CLINICAL TRIAL AT MOFFITT FOR

8162
05:23:09,870 --> 05:23:13,274
ADVANCE THE MELANOMA TEN YEARS

8163
05:23:13,274 --> 05:23:13,608
AGO.

8164
05:23:13,608 --> 05:23:17,111
JEFF WEBER PUT HIM ON A TRIAL OF

8165
05:23:17,111 --> 05:23:17,445
IMMUNOTHERAPY.

8166
05:23:17,445 --> 05:23:18,880
HE'S ALIVE, IMMEDIATELY STOPPED

8167
05:23:18,880 --> 05:23:20,948
WORKING WITH NASA, NOW HE'S

8168
05:23:20,948 --> 05:23:21,816
WORKING ON CANCER.

8169
05:23:21,816 --> 05:23:25,219
ONE OF HIS GOALS IS TO SCALE

8170
05:23:25,219 --> 05:23:26,320
CELL THERAPY.

8171
05:23:26,320 --> 05:23:28,656
EVEN WITH THE CAR Ts APPROVED,

8172
05:23:28,656 --> 05:23:29,924
ONLY 20% OF THE PATIENTS THAT

8173
05:23:29,924 --> 05:23:31,025
SHOULD BE GETTING THOSE ARE

8174
05:23:31,025 --> 05:23:31,459
GETTING THOSE.

8175
05:23:31,459 --> 05:23:33,327
ONE OF THE REASONS IS

8176
05:23:33,327 --> 05:23:33,628
SCALABILITY.

8177
05:23:33,628 --> 05:23:35,162
WE HAVE TO FOCUS ON THIS.

8178
05:23:35,162 --> 05:23:37,465
IT'S GOING TO BE THROUGH

8179
05:23:37,465 --> 05:23:38,199
ENGINEERS.

8180
05:23:38,199 --> 05:23:39,333
WORKING WITH ENGINEERS.

8181
05:23:39,333 --> 05:23:40,201
SO WE'RE HAPPY.

8182
05:23:40,201 --> 05:23:41,936
THIS IS I WANTED TO THANK OUR

8183
05:23:41,936 --> 05:23:42,103
LAB.

8184
05:23:42,103 --> 05:23:46,440
I WANT TO MAKE A TRIBUTE TO DEB.

8185
05:23:46,440 --> 05:23:48,309
OUR MD/PHD STUDENT PASSED AWAY A

8186
05:23:48,309 --> 05:23:49,944
COUPLE YEARS AGO.

8187
05:23:49,944 --> 05:23:51,779
I THANK THE NCI SURGERY GROUP

8188
05:23:51,779 --> 05:23:54,348
FOR GIVING HER A NOVEL T-CELL

8189
05:23:54,348 --> 05:23:57,618
RECEPTOR, THE BEST CHANCE

8190
05:23:57,618 --> 05:23:57,885
POSSIBLE.

8191
05:23:57,885 --> 05:23:59,920
SO NOT ONLY IS THIS A GREAT

8192
05:23:59,920 --> 05:24:02,323
PLACE, IT'S OUR HOME.

8193
05:24:02,323 --> 05:24:04,158
IT'S A PLACE WHERE INCREDIBLE

8194
05:24:04,158 --> 05:24:05,359
COMPASSIONATE CARE IS GIVEN, SO

8195
05:24:05,359 --> 05:24:06,460
THE CLINICAL SERVICE HERE IS

8196
05:24:06,460 --> 05:24:07,795
LIKE NO OTHER.

8197
05:24:07,795 --> 05:24:10,064
WE REALLY APPRECIATE YOUR HELP

8198
05:24:10,064 --> 05:24:10,665
WITH DEB.

8199
05:24:10,665 --> 05:24:12,266
JUST SHOWS HOW MUCH MORE WE HAVE

8200
05:24:12,266 --> 05:24:13,601
TO DO.

8201
05:24:13,601 --> 05:24:16,537
I WANT TO TELL YOU THROUGH MY

8202
05:24:16,537 --> 05:24:17,538
LEADERSHIP JOURNEY WHAT WOULD

8203
05:24:17,538 --> 05:24:18,406
STEVE ABOUT, I THINK.

8204
05:24:18,406 --> 05:24:23,210
WHEN I GET IN A BIND, IT'S WHAT

8205
05:24:23,210 --> 05:24:23,644
I THINK.

8206
05:24:23,644 --> 05:24:24,445
MANY QUOTES.

8207
05:24:24,445 --> 05:24:25,846
PUSHING THE ENVELOPE.

8208
05:24:25,846 --> 05:24:28,582
HE JUST SAID KEEP DOING THAT.

8209
05:24:28,582 --> 05:24:29,583
BEING PATIENT.

8210
05:24:29,583 --> 05:24:31,419
IF YOU KEEP THE PATIENT'S BEST

8211
05:24:31,419 --> 05:24:32,653
INTEREST AT HEART IT WILL ALWAYS

8212
05:24:32,653 --> 05:24:33,754
BE THE RIGHT DECISION.

8213
05:24:33,754 --> 05:24:35,489
WHEN I GET IN A BIND I THINK

8214
05:24:35,489 --> 05:24:36,924
WHAT WOULD STEVE DO?

8215
05:24:36,924 --> 05:24:39,860
HE'S ALWAYS IN MY HEAD.

8216
05:24:39,860 --> 05:24:42,830
I WANT TO END, MY INVOLVEMENT,

8217
05:24:42,830 --> 05:24:46,434
WE WERE VERY EXCITED TO START

8218
05:24:46,434 --> 05:24:47,868
THE ROSENBERG FUND, YOU HEARD

8219
05:24:47,868 --> 05:24:50,838
FROM ONE OF OUR FIRST

8220
05:24:50,838 --> 05:24:51,672
RECIPIENTS.

8221
05:24:51,672 --> 05:24:54,342
AND STEVE HAS DONE SO MUCH FOR

8222
05:24:54,342 --> 05:24:55,976
YOUNG FACULTY, WHAT BETTER

8223
05:24:55,976 --> 05:24:57,411
PERSON, THERE'S NO BETTER PERSON

8224
05:24:57,411 --> 05:25:00,481
IN THE UNIVERSE TO REPRESENT A

8225
05:25:00,481 --> 05:25:03,117
SCHOLARSHIP FOR YOUNG FACULTY.

8226
05:25:03,117 --> 05:25:06,487
EVERY YEAR WE GET 50 TO 100

8227
05:25:06,487 --> 05:25:06,954
APPLICATIONS, FUND ONE

8228
05:25:06,954 --> 05:25:08,789
INCREDIBLY FORTUNATE PERSON.

8229
05:25:08,789 --> 05:25:10,658
IT CHANGES THEIR LIFE.

8230
05:25:10,658 --> 05:25:12,526
WE'RE CONTINUING TO TRY TO RAISE

8231
05:25:12,526 --> 05:25:14,161
MORE MONEY TO HELP MORE PEOPLE

8232
05:25:14,161 --> 05:25:16,797
AND HERE IS THE CODE, IF YOU OR

8233
05:25:16,797 --> 05:25:18,766
YOUR COMPANY WANTS TO FURTHER

8234
05:25:18,766 --> 05:25:21,268
ENDOW THIS AWARD THAT'S GOING TO

8235
05:25:21,268 --> 05:25:22,803
GO ON FOREVER, WELL BEYOND US,

8236
05:25:22,803 --> 05:25:29,577
SO IT WILL GO ON FOR FOREVER.

8237
05:25:29,577 --> 05:25:33,180
REBECCA GREGORY IS OUR HEAD OF

8238
05:25:33,180 --> 05:25:34,615
FUNDRAISING AT SITC, SHE'S RIGHT

8239
05:25:34,615 --> 05:25:36,183
THERE, TALK TO HER IF YOU HAVE

8240
05:25:36,183 --> 05:25:38,919
IDEAS HOW TO FURTHER ENDOW THIS

8241
05:25:38,919 --> 05:25:40,221
INCREDIBLY IMPORTANT PROGRAM FOR

8242
05:25:40,221 --> 05:25:41,422
THE ROSENBERG SCHOLARSHIP.

8243
05:25:41,422 --> 05:25:45,159
THANKS FOR YOUR TIME, IT'S SUCH

8244
05:25:45,159 --> 05:25:55,236
AN HONOR TO BE HERE.

8245
05:25:55,236 --> 05:25:56,170
[APPLAUSE]

8246
05:25:56,170 --> 05:25:58,072
>> THANK YOU FOR THE LOOK
BACK

8247
05:25:58,072 --> 05:25:59,640
AND ACTUALLY INJECTING INTO THE

8248
05:25:59,640 --> 05:26:01,075
NUCLEUS OF THE CELL, SOMETHING I

8249
05:26:01,075 --> 05:26:03,010
DON'T THINK ANYBODY HAS THOUGHT

8250
05:26:03,010 --> 05:26:05,713
ABOUT FOR A WHILE, FORTUNATELY

8251
05:26:05,713 --> 05:26:05,946
FOR ME.

8252
05:26:05,946 --> 05:26:09,350
I'D LIKE TO WELCOME OUR NEXT

8253
05:26:09,350 --> 05:26:17,024
SPEAKER, JIM KOCHENDERFER SPENT

8254
05:26:17,024 --> 05:26:19,427
TIME IN THE ROSENBERG LAB, SINCE

8255
05:26:19,427 --> 05:26:21,095
DEVELOPED A SUCCESSFUL LAB AND

8256
05:26:21,095 --> 05:26:21,962
CLINICAL OPPORTUNITIES OF HIS

8257
05:26:21,962 --> 05:26:24,465
OWN WHICH LED TO DEVELOPMENT OF

8258
05:26:24,465 --> 05:26:27,067
CD19 FOR PATIENTS WITH LYMPHOMA.

8259
05:26:27,067 --> 05:26:30,404
PLEASE WELCOME JIM TO THE STAGE.

8260
05:26:30,404 --> 05:26:37,077
 

8261
05:26:37,077 --> 05:26:43,751
 

8262
05:26:43,751 --> 05:26:47,354
>> I'D LIKE TO THANK THE

8263
05:26:47,354 --> 05:26:49,123
ORGANIZERS FOR INVITING ME TO

8264
05:26:49,123 --> 05:26:50,324
TALK TODAY.

8265
05:26:50,324 --> 05:26:51,992
I'M FROM SENIOR INVESTIGATOR AND

8266
05:26:51,992 --> 05:26:53,861
SURGERY BRANCH, CONTINUING TO

8267
05:26:53,861 --> 05:26:55,062
WORK WITH DR. ROSENBERG,

8268
05:26:55,062 --> 05:26:58,666
PRIVILEGED AND THANKFUL TO DO

8269
05:26:58,666 --> 05:26:58,833
SO.

8270
05:26:58,833 --> 05:27:00,968
I'M GOING TO TALK ABOUT

8271
05:27:00,968 --> 05:27:06,540
HEMATOLOGIC 

8272
05:27:06,540 --> 05:27:07,408
HEMATOLOGIC MALIGNANCIES, IT'S

8273
05:27:07,408 --> 05:27:08,175
ALL I DO.

8274
05:27:08,175 --> 05:27:10,544
I STARTED WORKING WITH STEVE IN

8275
05:27:10,544 --> 05:27:13,080
MARCH OF 2007, THAT WAS LIKE

8276
05:27:13,080 --> 05:27:14,114
DEFINITELY THE BEST PROFESSIONAL

8277
05:27:14,114 --> 05:27:15,216
DECISION OF MY LIFE.

8278
05:27:15,216 --> 05:27:19,253
I WAS THE ONLY PERSON WORKING ON

8279
05:27:19,253 --> 05:27:20,221
HEMATOLOGIC MALIGNANCIES, STEVE

8280
05:27:20,221 --> 05:27:22,556
SUGGESTED THAT I WORK ON THIS

8281
05:27:22,556 --> 05:27:23,691
ANTI-CD19 CAR T CELL PROJECT.

8282
05:27:23,691 --> 05:27:28,896
I WAS GOING TO WORK ON SOME TYPE

8283
05:27:28,896 --> 05:27:30,431
OF HEMATOLOGIC PROJECT, THAT

8284
05:27:30,431 --> 05:27:33,467
SUGGESTION POINTS OUT LIKE ONE

8285
05:27:33,467 --> 05:27:35,336
OF THE MOST IMPORTANT ATTRIBUTES

8286
05:27:35,336 --> 05:27:39,473
HE HAS WHICH IS ABILITY TO PICK

8287
05:27:39,473 --> 05:27:40,941
THE RIGHT PROJECT TO WORK ON.

8288
05:27:40,941 --> 05:27:44,645
THE MOST IMPORTANT THING HE SAID

8289
05:27:44,645 --> 05:27:46,947
IS PICKING THE RIGHT PROJECT TO

8290
05:27:46,947 --> 05:27:48,382
WORK ON, SO THANKFUL HE'S SO

8291
05:27:48,382 --> 05:27:49,683
GOOD AT PICKING THE RIGHT

8292
05:27:49,683 --> 05:27:52,086
PROJECT BECAUSE THAT HELPED OUT

8293
05:27:52,086 --> 05:27:53,521
MY CAREER IMMENSELY.

8294
05:27:53,521 --> 05:27:56,891
MORE THAN ONCE.

8295
05:27:56,891 --> 05:27:58,893
SO, ANOTHER POINT BACK IN THE

8296
05:27:58,893 --> 05:28:00,728
OLD DAYS OF 2007, IT WAS SUCH A

8297
05:28:00,728 --> 05:28:03,364
SMALL FIELD BACK THEN, ONLY A

8298
05:28:03,364 --> 05:28:05,432
FEW LABS ACROSS THE COUNTRY

8299
05:28:05,432 --> 05:28:07,201
DOING ADOPTIVE T-CELL THERAPY

8300
05:28:07,201 --> 05:28:08,836
FOR CANCER.

8301
05:28:08,836 --> 05:28:11,772
AND THERE WAS MINIMAL INDUSTRY

8302
05:28:11,772 --> 05:28:12,873
INVOLVEMENT SPECIFICALLY WITH

8303
05:28:12,873 --> 05:28:14,775
CELL THERAPY AT THAT TIME.

8304
05:28:14,775 --> 05:28:16,644
AND I THINK THE FIRST PART OF MY

8305
05:28:16,644 --> 05:28:18,946
TALK WILL SHOW HOW THAT CHANGED

8306
05:28:18,946 --> 05:28:26,820
SO MUCH, IN A SHORT PERIOD OF

8307
05:28:26,820 --> 05:28:27,021
TIME.

8308
05:28:27,021 --> 05:28:29,356
SO, THIS ANTI-CD19 CAR PROJECT

8309
05:28:29,356 --> 05:28:33,561
WE WORKED ON AS I MENTIONED

8310
05:28:33,561 --> 05:28:38,532
STARTED IN 2007.

8311
05:28:38,532 --> 05:28:40,534
I DESIGNED FMC 6328 DIS

8312
05:28:40,534 --> 05:28:43,470
PUBLISHED IN JOURNAL OF

8313
05:28:43,470 --> 05:28:45,439
IMMUNOTHERAPY IN 2009.

8314
05:28:45,439 --> 05:28:46,874
AND ALMOST IMMEDIATELY STARTED A

8315
05:28:46,874 --> 05:28:49,476
CLINICAL TRIAL ONE OF THE

8316
05:28:49,476 --> 05:28:51,278
STRENGTHS OF THE NCI TO

8317
05:28:51,278 --> 05:28:58,886
TRANSLATE THINGS INTO CLINICAL

8318
05:28:58,886 --> 05:28:59,119
TRIALS.

8319
05:28:59,119 --> 05:29:01,188
TRIAL WAS SUCCESSFUL, THE FIRST

8320
05:29:01,188 --> 05:29:03,357
PERSON, THAT'S THE CT SCANNER,

8321
05:29:03,357 --> 05:29:05,893
MASS IN CHEST, PLEURAL EFFUSION,

8322
05:29:05,893 --> 05:29:14,768
18 WEEKS LATER GONE, PLEURAL

8323
05:29:14,768 --> 05:29:17,137
EFFUSION IS GONE, ZERO TOXICITY,

8324
05:29:17,137 --> 05:29:18,906
AN AMAZING FIRST PATIENT.

8325
05:29:18,906 --> 05:29:19,907
EVEN MORE AMAZING THAN CLINICAL

8326
05:29:19,907 --> 05:29:22,543
RESPONSE IF YOU CAN SEE THE FLOW

8327
05:29:22,543 --> 05:29:25,179
PLOT THERE, MAINLY FOCUSING ON

8328
05:29:25,179 --> 05:29:28,115
CD19 ON THE Y-AXIS, BEFORE CAR T

8329
05:29:28,115 --> 05:29:32,186
CELL INFUSION HAD CELLS IN HIS

8330
05:29:32,186 --> 05:29:36,523
BLOOD, UPPER LEFT QUAD RANT,

8331
05:29:36,523 --> 05:29:37,992
THAT'S BONE MARROW, NOT BLOOD,

8332
05:29:37,992 --> 05:29:39,827
36 WEEKS LATER NO CD19 POSITIVE

8333
05:29:39,827 --> 05:29:43,764
CELLS AT ALL IN HIS BODY, I WENT

8334
05:29:43,764 --> 05:29:46,500
TO SHOW DR. ROSENBERG THE PLOTS,

8335
05:29:46,500 --> 05:29:49,770
INCREDIBLE TO ME THIS WORKED SO

8336
05:29:49,770 --> 05:29:51,105
WELL THAT WE ERADICATED EVERY

8337
05:29:51,105 --> 05:29:55,809
LAST B CELL IN THIS PATIENT,

8338
05:29:55,809 --> 05:29:58,112
BLOOD, BONE MARROW, COULDN'T

8339
05:29:58,112 --> 05:30:01,248
FIND ANY B CELLS, INCREDIBLE.

8340
05:30:01,248 --> 05:30:03,450
I DID MOUSE STUDIES THAT

8341
05:30:03,450 --> 05:30:05,452
REPLICATED THE SAME THING.

8342
05:30:05,452 --> 05:30:07,621
HE SAID WE DID MOUSE STUDIES

8343
05:30:07,621 --> 05:30:09,390
FIRST, THEN HUMAN, I WAS

8344
05:30:09,390 --> 05:30:12,893
ACTUALLY WORKING ON BOTH AT THE

8345
05:30:12,893 --> 05:30:13,661
SAME TIME.

8346
05:30:13,661 --> 05:30:15,429
WE SHOWED THAT.

8347
05:30:15,429 --> 05:30:20,100
AND THEN OVER THE YEARS THERE WE

8348
05:30:20,100 --> 05:30:23,837
WERE MAKING RAPID PROGRESS,

8349
05:30:23,837 --> 05:30:27,207
ITERATIONS ON THIS ANTI-CD19 CAR

8350
05:30:27,207 --> 05:30:29,309
T CELL APPROACH, THIS WAS OUR

8351
05:30:29,309 --> 05:30:33,681
FINAL ITERATION IN SURGERY

8352
05:30:33,681 --> 05:30:44,058
BRANCH USING LOW DOSE

8353
05:30:44,692 --> 05:30:46,060
FLUDARABINE AND

8354
05:30:46,060 --> 05:30:47,261
CYCLOPHOSPHAMIDE, THE

8355
05:30:47,261 --> 05:30:54,134
CONDITIONING REGIMEN WE SETTLED

8356
05:30:54,134 --> 05:30:56,770
HERE, THAT'S COMMONLY USED NOW

8357
05:30:56,770 --> 05:30:59,506
BY PRETTY MUCH ALL COMMERCIAL

8358
05:30:59,506 --> 05:31:00,541
CAR PRODUCTS, FIRST DONE IN

8359
05:31:00,541 --> 05:31:02,142
SURGERY BRANCH IN THE SETTING OF

8360
05:31:02,142 --> 05:31:02,910
CAR-T CELLS.

8361
05:31:02,910 --> 05:31:04,878
IN OUR FINAL ITERATION IN A

8362
05:31:04,878 --> 05:31:09,249
PAPER IN JOURNAL OF CLINICAL

8363
05:31:09,249 --> 05:31:10,484
ONCOLOGY 2017, 45% OF PATIENTS

8364
05:31:10,484 --> 05:31:12,786
HAD DURATIONS OF RESPONSE

8365
05:31:12,786 --> 05:31:14,354
GREATER THAN TWO YEARS, 45% OF

8366
05:31:14,354 --> 05:31:16,256
THE TOTAL PATIENTS IN THE TRIAL

8367
05:31:16,256 --> 05:31:18,225
HAD DURATION OF RESPONSE GREATER

8368
05:31:18,225 --> 05:31:19,660
THAN TWO YEARS.

8369
05:31:19,660 --> 05:31:23,397
JUST A COUPLE EXAMPLES OF THESE

8370
05:31:23,397 --> 05:31:24,098
PATIENTS, THE LARGE BURDEN OF

8371
05:31:24,098 --> 05:31:34,541
THE DISEASE THAT COULD BE

8372
05:31:36,176 --> 05:31:46,754
ELIMINATED, THE RED -- OOPS.

8373
05:31:46,754 --> 05:31:55,229
I'M NOT SURE HOW TO DO THE

8374
05:31:55,229 --> 05:31:55,996
POINTER.

8375
05:31:55,996 --> 05:31:57,865
RED AREA IS LYMPHOMA, A LARGE

8376
05:31:57,865 --> 05:31:59,800
MASS IS GONE TEN MONTHS LATER.

8377
05:31:59,800 --> 05:32:01,869
THE HEART AND KIDNEYS STILL RED

8378
05:32:01,869 --> 05:32:04,838
BECAUSE THEY ARE AT THE PLACE

8379
05:32:04,838 --> 05:32:06,273
WHERE THE CONTRAST ACCUMULATES.

8380
05:32:06,273 --> 05:32:09,309
BUT THE PATIENT WAS IN COMPLETE

8381
05:32:09,309 --> 05:32:11,845
REMISSION, SHOWN BELOW THE

8382
05:32:11,845 --> 05:32:13,213
YELLOW PART IS LYMPHOMA,

8383
05:32:13,213 --> 05:32:13,814
COMPLETELY GONE.

8384
05:32:13,814 --> 05:32:19,620
ONE OF MANY PATIENTS IN THE

8385
05:32:19,620 --> 05:32:21,822
TRIAL WITH GREAT OUTCOME.

8386
05:32:21,822 --> 05:32:24,558
2020 PUBLISHED A PAPER WITH

8387
05:32:24,558 --> 05:32:26,627
KATIE, A FELLOW WORKING WITH ME,

8388
05:32:26,627 --> 05:32:31,565
LONG-TERM FOLLOW-UP FROM THIS

8389
05:32:31,565 --> 05:32:35,502
TRIAL, MEDIAN EVENT FREE

8390
05:32:35,502 --> 05:32:37,437
SURVIVAL 55 MONTHS, 51% OF THE

8391
05:32:37,437 --> 05:32:39,706
PATIENTS HAD RESPONSES GREATER

8392
05:32:39,706 --> 05:32:42,943
THAN 3 YEARS, AND LONGEST

8393
05:32:42,943 --> 05:32:43,944
SURVIVING PATIENT, PICTURE IN

8394
05:32:43,944 --> 05:32:45,579
YOUR PROGRAM WITH DR. ROSENBERG,

8395
05:32:45,579 --> 05:32:49,483
IS STILL IN COMPLETE REMISSION,

8396
05:32:49,483 --> 05:32:51,018
HE'S BEEN IN EVENT-FREE SURVIVAL

8397
05:32:51,018 --> 05:32:55,422
FOR 14 YEARS, SO THAT'S THE

8398
05:32:55,422 --> 05:32:56,056
LONGEST CONTINUING SURVIVING CAR

8399
05:32:56,056 --> 05:32:58,725
T PATIENT IN THE WORLD.

8400
05:32:58,725 --> 05:33:02,429
YOU CAN SEE THE GRAPH WITH

8401
05:33:02,429 --> 05:33:03,497
EVENT-FREE SURVIVALS, B CELL

8402
05:33:03,497 --> 05:33:05,966
MALIGNANCIES, LOW GRADE LIMB

8403
05:33:05,966 --> 05:33:08,168
FOAMA CLL, WE TREATED ALL THREE

8404
05:33:08,168 --> 05:33:08,635
TYPES.

8405
05:33:08,635 --> 05:33:14,508
ALSO THE GRAPH ON THE RIGHT-HAND

8406
05:33:14,508 --> 05:33:18,445
SIDE SHOWING THE PLATEAU IN

8407
05:33:18,445 --> 05:33:19,313
EVENT-FREE SURVIVAL IN LARGE

8408
05:33:19,313 --> 05:33:24,251
B-CELL LYMPHOMA PATIENTS THAT

8409
05:33:24,251 --> 05:33:25,986
ATTAIN C.R.

8410
05:33:25,986 --> 05:33:30,457
HOW THE FIELD HAS CHANGED WE NOW

8411
05:33:30,457 --> 05:33:32,860
HAVE FOUR FDA-APPROVED PRODUCTS.

8412
05:33:32,860 --> 05:33:36,163
I WON'T READ OUT THE NAMES

8413
05:33:36,163 --> 05:33:36,530
THERE.

8414
05:33:36,530 --> 05:33:38,232
IT'S BASICALLY THE EXACT PRODUCT

8415
05:33:38,232 --> 05:33:40,434
WE USED IN SURGERY BRANCH, FINAL

8416
05:33:40,434 --> 05:33:44,905
ITERATION, A LOT OF PEOPLE WENT

8417
05:33:44,905 --> 05:33:46,874
INTO, YOU KNOW, MAKING THAT

8418
05:33:46,874 --> 05:33:47,875
PRODUCT, MAKING THAT A

8419
05:33:47,875 --> 05:33:48,976
COMMERCIAL PRODUCT BUT IN

8420
05:33:48,976 --> 05:33:55,415
SURGERY BRANCH PEOPLE THAT WENT

8421
05:33:55,415 --> 05:33:58,952
INTO THAT, CERTAINLY MARK DUDLEY

8422
05:33:58,952 --> 05:34:06,526
AND STEVE FELDMAN WERE

8423
05:34:06,526 --> 05:34:10,464
INSTRUMENTAL, RICK MORGAN WAS A

8424
05:34:10,464 --> 05:34:12,199
HUGE HELP, GENETIC ENGINEERING,

8425
05:34:12,199 --> 05:34:12,766
MOLECULAR BIOLOGY.

8426
05:34:12,766 --> 05:34:17,971
IT COMES DOWN TO TWO CAR T CELL

8427
05:34:17,971 --> 05:34:20,541
PRODUCTS, BOTH USE THE SAME CAR

8428
05:34:20,541 --> 05:34:25,012
WE MADE IN SURGERY BRANCH.

8429
05:34:25,012 --> 05:34:29,283
FOUR CAR T CELL PRODUCTS AND I

8430
05:34:29,283 --> 05:34:32,019
JUST CHECKED THIS WEEK BECAUSE I

8431
05:34:32,019 --> 05:34:33,420
THOUGHT IT WOULD BE INTERESTING,

8432
05:34:33,420 --> 05:34:38,125
OF THE CAR THAT WAS MADE IN

8433
05:34:38,125 --> 05:34:39,993
SURGERY BRANCH BACK IN 2007,

8434
05:34:39,993 --> 05:34:41,194
KITE TREATED GREATER THAN 23,000

8435
05:34:41,194 --> 05:34:43,063
PATIENTS, THAT'S AS OF TWO DAYS

8436
05:34:43,063 --> 05:34:45,599
AGO, I ASKED THEM.

8437
05:34:45,599 --> 05:34:47,901
THAT'S UP TO DATE NUMBER.

8438
05:34:47,901 --> 05:34:57,411
YOU CAN SEE HOW MUCH IT GREW.

8439
05:34:57,411 --> 05:35:01,348
WE HAVE FDA-APPROVED CARS FOR

8440
05:35:01,348 --> 05:35:04,851
LYMPHOMA INDICATIONS, ACUTE

8441
05:35:04,851 --> 05:35:07,120
LYMPHOID LEUKEMIA, CHRONIC

8442
05:35:07,120 --> 05:35:07,788
LYMPHOCYTIC LEUKEMIA, MULTIPLE

8443
05:35:07,788 --> 05:35:10,023
MYELOMA TWO CAR T CELL PRODUCTS

8444
05:35:10,023 --> 05:35:13,160
FDA APPROVED.

8445
05:35:13,160 --> 05:35:14,361
THAT WAS THE HISTORICAL PART OF

8446
05:35:14,361 --> 05:35:15,195
THE TALK.

8447
05:35:15,195 --> 05:35:18,732
NOW I'M GOING TO TALK ABOUT SOME

8448
05:35:18,732 --> 05:35:20,701
OF STUFF GOING ON MY LAB NOW.

8449
05:35:20,701 --> 05:35:24,037
I HAVE A LAB IN SURGERY BRANCH.

8450
05:35:24,037 --> 05:35:28,942
WE STILL DO ALL CELL THERAPY FOR

8451
05:35:28,942 --> 05:35:32,512
HEMATOLOGIC MALIGNANCY.

8452
05:35:32,512 --> 05:35:35,515
THE FIRST IS FOR GAMMADELTA T

8453
05:35:35,515 --> 05:35:37,317
CELL MALIGNANCIES, EXTREMELY

8454
05:35:37,317 --> 05:35:41,421
RARE TYPE OF MALIGNANCY.

8455
05:35:41,421 --> 05:35:43,924
IT HAS A HETERODIMER, THEY MAKE

8456
05:35:43,924 --> 05:35:50,631
UP 1 TO 10% OF BLOOD T CELLS. 

8457
05:35:50,631 --> 05:35:54,134
MOST OF THE EXPRESS B DELTA 2

8458
05:35:54,134 --> 05:35:56,436
RECEPTOR, THE ROLE IS NOT CLEAR.

8459
05:35:56,436 --> 05:35:58,939
THERE'S EVIDENCE THEY ARE

8460
05:35:58,939 --> 05:36:02,009
IMPORTANT FOR IMMUNITY,

8461
05:36:02,009 --> 05:36:04,945
ESPECIALLY AGAINST CERTAIN

8462
05:36:04,945 --> 05:36:07,814
PATHOGENS, MYCOBACTERIA,

8463
05:36:07,814 --> 05:36:08,682
TUBERCULOSIS.

8464
05:36:08,682 --> 05:36:10,417
THERE'S NO IMMUNODEFICIENCY

8465
05:36:10,417 --> 05:36:10,917
DISEASE CHARACTERIZED BY

8466
05:36:10,917 --> 05:36:12,285
DEFICIENCY, WE CAN'T SAY WHAT

8467
05:36:12,285 --> 05:36:20,927
HAPPENS IF A PATIENT LACKS ALL

8468
05:36:20,927 --> 05:36:23,430
THEIR GAMMADELTA T CELLS.

8469
05:36:23,430 --> 05:36:26,066
THESE ARE VERY RARE

8470
05:36:26,066 --> 05:36:27,601
MALIGNANCIES, WHICH IS ACTUALLY

8471
05:36:27,601 --> 05:36:28,902
SOMETIMES CONSIDERED A PLUS WHEN

8472
05:36:28,902 --> 05:36:29,903
YOU'RE AN NIH INVESTIGATOR

8473
05:36:29,903 --> 05:36:32,072
BECAUSE IT'S SOMETHING THAT

8474
05:36:32,072 --> 05:36:34,074
WE'RE ENCOURAGED TO LEARN TO

8475
05:36:34,074 --> 05:36:35,475
TREAT VERY RARE DISEASES THAT

8476
05:36:35,475 --> 05:36:37,144
INDUSTRY MIGHT NOT HAVE AN

8477
05:36:37,144 --> 05:36:39,212
INTEREST IN AND BIGGER GROUPS

8478
05:36:39,212 --> 05:36:40,947
MIGHT NOT HAVE INTEREST IN.

8479
05:36:40,947 --> 05:36:50,257
SO, YOU CAN SEE WE HAVE

8480
05:36:50,257 --> 05:36:53,193
HEPATOSPLENIC T CELL LYMPHOMA,

8481
05:36:53,193 --> 05:36:55,295
FIVE YEAR OVERALL SURVIVAL 10 TO

8482
05:36:55,295 --> 05:36:56,396
20%.

8483
05:36:56,396 --> 05:36:57,597
T CELL ACUTE LYMPHOPLASTIC

8484
05:36:57,597 --> 05:37:00,333
LEUKEMIA, ANOTHER SERIOUS TYPE

8485
05:37:00,333 --> 05:37:09,743
OF LEUKEMIA, AND THEN VERY RARE

8486
05:37:09,743 --> 05:37:11,244
INTESTINAL LYMPHOMA, 7 TO 7.5

8487
05:37:11,244 --> 05:37:15,882
MONTHS, DISEASES I HELP TO

8488
05:37:15,882 --> 05:37:17,851
TREAT -- LEADERSHIP TO TREAT

8489
05:37:17,851 --> 05:37:19,352
WITH A GAMMADELTA CAR.

8490
05:37:19,352 --> 05:37:22,222
WE CONSTRUCTED A SERIES OF

8491
05:37:22,222 --> 05:37:23,757
CARs, TO SHOW SOME OF THE

8492
05:37:23,757 --> 05:37:25,959
EFFORT INTO MAKING CARs WE

8493
05:37:25,959 --> 05:37:28,161
ASSESS TEN ANTIGEN RECOGNITION

8494
05:37:28,161 --> 05:37:34,935
DOMAINS AND SELECT THE TWO BEST

8495
05:37:34,935 --> 05:37:35,702
FOR EVALUATION.

8496
05:37:35,702 --> 05:37:40,941
A POSTDOC IN MY LAB MADE 23 TO

8497
05:37:40,941 --> 05:37:42,909
COME UP WITH FACTORS NOW IN THE

8498
05:37:42,909 --> 05:37:45,112
FINAL STAGES OF EVALUATING WHICH

8499
05:37:45,112 --> 05:37:53,420
I'LL TALK ABOUT IN THE NEXT FEW

8500
05:37:53,420 --> 05:37:53,754
SLIDES.

8501
05:37:53,754 --> 05:37:56,523
WE TESTED VARIOUS PARTS OF THE

8502
05:37:56,523 --> 05:37:58,225
CARs, SOME DIAGRAMS OF CARs

8503
05:37:58,225 --> 05:38:00,093
WE TESTED, ONE FACTOR THAT I

8504
05:38:00,093 --> 05:38:01,628
HAVE FOUND RECENTLY WHICH CAN BE

8505
05:38:01,628 --> 05:38:03,797
AN IMPORTANT FACTOR IN CAR

8506
05:38:03,797 --> 05:38:09,402
FUNCTION IS LINKER, CARs HAVE

8507
05:38:09,402 --> 05:38:11,671
A SINGLE CHAIN FV, HEAVY CHAIN

8508
05:38:11,671 --> 05:38:15,408
RARABLE DOMAIN, LIGHT CHAIN OF

8509
05:38:15,408 --> 05:38:16,610
ANTIBODY, JOINED BY LINKER, AND

8510
05:38:16,610 --> 05:38:23,183
THE ONE WE USE IN MY CAREER HAS

8511
05:38:23,183 --> 05:38:25,051
BEEN 218 LINKER, WHITTLOW

8512
05:38:25,051 --> 05:38:25,285
LINKER.

8513
05:38:25,285 --> 05:38:28,522
WE'VE BEEN TESTING A LONGER

8514
05:38:28,522 --> 05:38:36,863
VERSION OF A G 4S LINKER.

8515
05:38:36,863 --> 05:38:45,705
LINKING THAT CAN SOMETIMES HELP

8516
05:38:45,705 --> 05:38:49,576
WITH CAR FUNCTION.

8517
05:38:49,576 --> 05:38:50,644
PERHAPS HAVING FUNCTIONAL

8518
05:38:50,644 --> 05:38:51,411
ADVANTAGES.

8519
05:38:51,411 --> 05:38:55,482
AND WE ALSO CAREFULLY LOOKED AT

8520
05:38:55,482 --> 05:38:56,816
THE TRANSMEMBRANE DOMAIN,

8521
05:38:56,816 --> 05:38:58,218
SOMETIMES DOESN'T GET THE MOST

8522
05:38:58,218 --> 05:38:59,653
ATTENTION IN CARs.

8523
05:38:59,653 --> 05:39:01,721
BUT WE FOUND TO BE VERY

8524
05:39:01,721 --> 05:39:02,422
IMPORTANT.

8525
05:39:02,422 --> 05:39:10,897
SO THE CARs ON THIS PAGE ONE

8526
05:39:10,897 --> 05:39:19,206
HAS A LONGER LINKER, AND 228

8527
05:39:19,206 --> 05:39:20,974
CARs, SO, AGAIN, WE WON'T TALK

8528
05:39:20,974 --> 05:39:26,012
ABOUT ALL 23 CARs BUT JUST

8529
05:39:26,012 --> 05:39:28,381
THOSE FOUR, AND THE PROCESS WE

8530
05:39:28,381 --> 05:39:29,716
GO THROUGH FIRST TO DO

8531
05:39:29,716 --> 05:39:30,717
EXPRESSION ANALYSIS TO SEE IF

8532
05:39:30,717 --> 05:39:32,252
THE CAR IS EXPRESSED ON THE T

8533
05:39:32,252 --> 05:39:36,523
CELLS, IN VITRO FUNCTIONAL

8534
05:39:36,523 --> 05:39:42,462
TESTING USING INTERFERON GAMMA,

8535
05:39:42,462 --> 05:39:46,166
ELISAs TO START WITH, AND

8536
05:39:46,166 --> 05:39:50,103
WE'RE EVALUATING CD28-CONTAINING

8537
05:39:50,103 --> 05:39:52,739
CARs TO SINGLE CHAIN, FOR FOUR

8538
05:39:52,739 --> 05:39:54,274
CARs, AND RED BAR SHOWING THE

8539
05:39:54,274 --> 05:39:56,710
ONE WE FOUND OUT TO HAVE THE

8540
05:39:56,710 --> 05:39:58,979
HIGHEST DEGREE OF SPECIFIC

8541
05:39:58,979 --> 05:40:06,219
RECOGNITION OF OUR TARGET CELLS,

8542
05:40:06,219 --> 05:40:09,189
WHICH WAS MGDL 28D AGAINST THREE

8543
05:40:09,189 --> 05:40:13,894
GAMMADELTA LYMPHOMA T CELL

8544
05:40:13,894 --> 05:40:17,631
LINES, WITH NEGATIVE CONTROL

8545
05:40:17,631 --> 05:40:19,466
CELL K 562, MINIMAL INTERFERON

8546
05:40:19,466 --> 05:40:23,403
GAMMA RELEASED THERE, T CELLS

8547
05:40:23,403 --> 05:40:23,803
ALONE.

8548
05:40:23,803 --> 05:40:30,977
THIS WAS ALL STANDARD ELISA, TO

8549
05:40:30,977 --> 05:40:33,847
DETERMINE THE CAR WHICH

8550
05:40:33,847 --> 05:40:44,090
RECOGNIZED MOST STRONGLY THE

8551
05:40:44,090 --> 05:40:44,557
LYMPHOMA CELLS.

8552
05:40:44,557 --> 05:40:48,929
WE'VE STARTED TESTING IN MICE,

8553
05:40:48,929 --> 05:40:52,098
USING NSG MICE, HIGHLY

8554
05:40:52,098 --> 05:40:53,199
IMMUNOCOMPROMISED MICE THAT GET

8555
05:40:53,199 --> 05:40:55,702
A SINGLE TREATMENT OF SINGLE

8556
05:40:55,702 --> 05:40:57,804
INJECTION OF CAR-T CELLS AFTER

8557
05:40:57,804 --> 05:41:02,509
THE TUMOR CELLS ARE ESTABLISHED.

8558
05:41:02,509 --> 05:41:04,244
DAY ZERO, MALIGNANCY ESTABLISHED

8559
05:41:04,244 --> 05:41:04,811
IN MICE.

8560
05:41:04,811 --> 05:41:10,850
THEY RECEIVE INJECTION OF T

8561
05:41:10,850 --> 05:41:12,285
CELLS ON DAY ZERO.

8562
05:41:12,285 --> 05:41:17,557
THEY DAYS LATER CANCER STARTING

8563
05:41:17,557 --> 05:41:24,130
TO DROP,.

8564
05:41:24,130 --> 05:41:29,135
WE HAVE A DOSE-DEPENDENT

8565
05:41:29,135 --> 05:41:30,136
REJECTION OF THE TUMOR.

8566
05:41:30,136 --> 05:41:31,971
THIS WAS A NICE OUTCOME.

8567
05:41:31,971 --> 05:41:34,841
WE'RE LEANING TOWARD THAT CAR.

8568
05:41:34,841 --> 05:41:37,143
HAVEN'T DECIDED WHICH TO GO

8569
05:41:37,143 --> 05:41:41,848
FORWARD YET, TESTING A COUPLE,

8570
05:41:41,848 --> 05:41:42,716
HAVEN'T DECIDED WHAT HINGE

8571
05:41:42,716 --> 05:41:44,150
REGION TO USE.

8572
05:41:44,150 --> 05:41:47,120
BUT THE OVERALL GOAL IS BECAUSE

8573
05:41:47,120 --> 05:41:48,855
THESE GAMMADELTA T CELL

8574
05:41:48,855 --> 05:41:56,529
MALIGNANCIES ARE RARE WITH BAD

8575
05:41:56,529 --> 05:41:58,031
PROGNOSIS, TO CONDUCT A CLINICAL

8576
05:41:58,031 --> 05:41:59,999
TRIAL, WE'RE PLANNING ON

8577
05:41:59,999 --> 05:42:02,535
STARTING A SMALL PHASE 3 TRIAL

8578
05:42:02,535 --> 05:42:05,405
ONCE WE GET OPTIMAL CAR DETECTED

8579
05:42:05,405 --> 05:42:08,908
AND FINISH MORE MOUSE

8580
05:42:08,908 --> 05:42:10,110
EXPERIMENTS, GET REGULATORY

8581
05:42:10,110 --> 05:42:11,411
APPROVALS, HOPEFULLY IN THE NEXT

8582
05:42:11,411 --> 05:42:12,846
COUPLE YEARS WILL START A TRIAL

8583
05:42:12,846 --> 05:42:16,516
TESTING ONE OF THESE CARs

8584
05:42:16,516 --> 05:42:26,860
AGAINST GAMMADELTA T CELL

8585
05:42:26,860 --> 05:42:27,660
MALIGNANCIES.

8586
05:42:27,660 --> 05:42:28,962
FINAL SEGMENT, THIS IS COMING

8587
05:42:28,962 --> 05:42:30,463
BACK TO A LOT OF PREVIOUS TALKS

8588
05:42:30,463 --> 05:42:34,167
FOR THE DAY, PEOPLE IN THE

8589
05:42:34,167 --> 05:42:36,569
BRANCH WORKING WITH NEOEPITOPE

8590
05:42:36,569 --> 05:42:38,104
SPECIFIC T-CELL RECEPTORS, AND

8591
05:42:38,104 --> 05:42:40,840
AGAIN I'M UTILIZING EXPERTISE OF

8592
05:42:40,840 --> 05:42:42,375
MY COLLEAGUES TO HELP APPLY

8593
05:42:42,375 --> 05:42:47,213
THINGS THEY HAVE DONE IN SOLID

8594
05:42:47,213 --> 05:42:49,916
TUMORS TO HEMATOLOGIC

8595
05:42:49,916 --> 05:42:50,950
MALIGNANCIES.

8596
05:42:50,950 --> 05:42:53,787
SOME TCRs HAVE BEEN COVERED TO

8597
05:42:53,787 --> 05:42:54,554
STREET HEMATOLOGIC MALIGNANCIES.

8598
05:42:54,554 --> 05:42:58,691
THE REASON I WANT TO DO THIS

8599
05:42:58,691 --> 05:43:01,094
CAR-T CELLS ARE EFFECTIVE MORE B

8600
05:43:01,094 --> 05:43:08,668
CELL, BUT IDEAL TARGETS FOR

8601
05:43:08,668 --> 05:43:19,245
OTHER  MALIGNANCIES ARE HARDER O

8602
05:43:20,447 --> 05:43:22,015
IDENTIFY.

8603
05:43:22,015 --> 05:43:27,253
WE KNOW THAT AML AND

8604
05:43:27,253 --> 05:43:30,657
MYELODYSPLASTIC SYNDROME ARE

8605
05:43:30,657 --> 05:43:35,361
SUSCEPTIBLE BECAUSE THEY HAVE

8606
05:43:35,361 --> 05:43:36,996
BEEN TREATED WITH ALLOGENEIC

8607
05:43:36,996 --> 05:43:39,399
TRANSPLANT SINCE THE 70s, IT

8608
05:43:39,399 --> 05:43:40,533
HAS SIDE EFFECTS,

8609
05:43:40,533 --> 05:43:42,902
GRAFT-VERSUS-HOST DISEASE CAN BE

8610
05:43:42,902 --> 05:43:44,237
DEADLY.

8611
05:43:44,237 --> 05:43:48,408
WE HOPE TO ENHANCE OR REPLACE

8612
05:43:48,408 --> 05:43:49,676
ALLOGENEIC TRANSPLANT.

8613
05:43:49,676 --> 05:43:50,376
THAT'S THE GOAL.

8614
05:43:50,376 --> 05:43:53,546
WE'RE A LONG WAY FOR AML, BUT AT

8615
05:43:53,546 --> 05:43:55,949
LEAST WE CAN MAYBE ENHANCE IT OR

8616
05:43:55,949 --> 05:44:00,653
REPLACE IT IN SOME CASES.

8617
05:44:00,653 --> 05:44:02,188
UNLIKE CAR-T CELLS, ANOTHER

8618
05:44:02,188 --> 05:44:06,993
ADVANTAGE THEY CAN TARGET

8619
05:44:06,993 --> 05:44:07,760
INTRACELLULAR ANTIGENS.

8620
05:44:07,760 --> 05:44:13,166
SO THE NEOANTIGEN SOMATIC

8621
05:44:13,166 --> 05:44:15,668
MUTATIONS ARISE IN TUMOR CELLS,

8622
05:44:15,668 --> 05:44:23,676
SOMETIMES SOMATIC MUTATIONS TO

8623
05:44:23,676 --> 05:44:27,213
GIVE RISE TO NEW EPITOPES,

8624
05:44:27,213 --> 05:44:28,181
RECOGNIZED BY TCRs, THIS HAS

8625
05:44:28,181 --> 05:44:30,383
BEEN A TARGET OF INTENSIVE

8626
05:44:30,383 --> 05:44:32,118
EFFORTS IN THERAPY BRANCH FOR A

8627
05:44:32,118 --> 05:44:33,653
LONG TIME.

8628
05:44:33,653 --> 05:44:39,792
AND TWO OF THE NEOANTIGENS ARE

8629
05:44:39,792 --> 05:44:44,531
TP 53 AND RAS, I SAY RAS TO MEAN

8630
05:44:44,531 --> 05:44:46,699
KRAS, H-RAS, N-RAS.

8631
05:44:46,699 --> 05:44:52,505
I PUT THEM ALL TOGETHER TO SAVE

8632
05:44:52,505 --> 05:44:52,739
TIME.

8633
05:44:52,739 --> 05:44:56,309
SO WE'RE TESTING A VARIETY OF

8634
05:44:56,309 --> 05:45:00,613
TCRs, WHICH ARE HERE IN THIS

8635
05:45:00,613 --> 05:45:03,583
TABLE, A TOTAL OF EIGHT WE'RE

8636
05:45:03,583 --> 05:45:04,584
EVALUATING FOR USE WITH

8637
05:45:04,584 --> 05:45:05,752
HEMATOLOGIC MALIGNANCIES.

8638
05:45:05,752 --> 05:45:15,061
THE FIRST THREE ARE TARGETING

8639
05:45:15,061 --> 05:45:18,498
TP53 NEOEPITOPES, THEN WE HAVE

8640
05:45:18,498 --> 05:45:19,799
FIVE RAS EPITOPES.

8641
05:45:19,799 --> 05:45:26,039
SO SEVERAL SURGERY BRANCH

8642
05:45:26,039 --> 05:45:29,342
INVESTIGATORS DISCOVERED THESE

8643
05:45:29,342 --> 05:45:30,743
TCRs, AND THE LIBRARIES, MUCH

8644
05:45:30,743 --> 05:45:35,381
OF THE WORK DONE BY LEVIN AND

8645
05:45:35,381 --> 05:45:37,584
KIM IN PUBLICATIONS AT THE

8646
05:45:37,584 --> 05:45:40,653
BOTTOM OF THE SLIDE.

8647
05:45:40,653 --> 05:45:45,792
SO WE'VE BEEN TESTING THESE TO

8648
05:45:45,792 --> 05:45:49,862
EVALUATE THEIR ABILITY TO SHOW

8649
05:45:49,862 --> 05:45:52,365
RECOGNITION OF HEMATOLOGIC

8650
05:45:52,365 --> 05:45:54,667
MALIGNANCIES, ALSO TO CONFIRM

8651
05:45:54,667 --> 05:45:56,002
THE FINE SPECIFICITY.

8652
05:45:56,002 --> 05:46:02,208
THIS SLIDE IS SHOWING AN

8653
05:46:02,208 --> 05:46:03,242
EXPERIMENT WHERE WE TRANSDUCE

8654
05:46:03,242 --> 05:46:08,581
CELLS WITH HLA FOR ONE OF THE

8655
05:46:08,581 --> 05:46:14,420
NEOEPITOPES, TRANSFECT WITH GENE

8656
05:46:14,420 --> 05:46:15,388
ENCODING THE NEOEPITOPE OR WILD

8657
05:46:15,388 --> 05:46:18,124
TYPE GENE TO SHOW FINE

8658
05:46:18,124 --> 05:46:20,426
SPECIFICITY OF THE TCRs.

8659
05:46:20,426 --> 05:46:22,061
YOU CAN SEE THAT INTERFERON GAM

8660
05:46:22,061 --> 05:46:23,930
IS ON THE Y-AXIS.

8661
05:46:23,930 --> 05:46:26,199
THE BLUE BAR INDICATES A LOT OF

8662
05:46:26,199 --> 05:46:27,867
INTERFERON GAMMA RELEASE WITH

8663
05:46:27,867 --> 05:46:32,005
THE RIGHT HLA TYPE, A-1, WITH

8664
05:46:32,005 --> 05:46:35,541
THE RIGHT MUTATION, G12B RAS IN

8665
05:46:35,541 --> 05:46:36,743
THE SAME CELL.

8666
05:46:36,743 --> 05:46:40,146
IF WE LACK COMPONENTS SUCH AS

8667
05:46:40,146 --> 05:46:42,015
LACKING THE RIGHT MUTATION OR

8668
05:46:42,015 --> 05:46:45,184
LACKING THE RIGHT HLA TYPE,

8669
05:46:45,184 --> 05:46:45,918
THERE'S MINIMAL INTERFERON GAMMA

8670
05:46:45,918 --> 05:46:46,386
RELEASE.

8671
05:46:46,386 --> 05:46:51,824
AGAIN, THIS IS LIKE THE KEY, WE

8672
05:46:51,824 --> 05:46:54,060
NEED SPECIFICITY.

8673
05:46:54,060 --> 05:46:56,596
OF ALL THE EIGHT TCRs THE

8674
05:46:56,596 --> 05:46:58,998
TABLE ON THE RIGHT SHOWS RATIO

8675
05:46:58,998 --> 05:47:02,268
OF INTERFERON GAMMA RELEASE WHEN

8676
05:47:02,268 --> 05:47:04,137
THE COS CELL WAS TRANSFECTED,

8677
05:47:04,137 --> 05:47:08,941
YOU CAN SEE THERE'S A LARGE

8678
05:47:08,941 --> 05:47:10,910
RATIO OF INTERFERON GAMMA

8679
05:47:10,910 --> 05:47:12,679
RELEASE WITH MUTATED VERSUS WILD

8680
05:47:12,679 --> 05:47:13,746
TYPE WITH HIGHER INTERFERON

8681
05:47:13,746 --> 05:47:18,384
GAMMA BEING WITH MUTATED GENE IN

8682
05:47:18,384 --> 05:47:19,452
THE CELL.

8683
05:47:19,452 --> 05:47:20,753
AND, AGAIN, SUBSTANTIAL

8684
05:47:20,753 --> 05:47:23,389
INTERFERON GAMMA RELEASED IN ALL

8685
05:47:23,389 --> 05:47:24,590
THESE EXPERIMENTS, ALL TCRs

8686
05:47:24,590 --> 05:47:25,692
WORKED WONDERFULLY AS EXPECTED.

8687
05:47:25,692 --> 05:47:28,194
WE'VE GONE ON TO START TESTING

8688
05:47:28,194 --> 05:47:30,496
AGAINST LEUKEMIA IN MICE,

8689
05:47:30,496 --> 05:47:32,365
MULTIPLE MYELOMA.

8690
05:47:32,365 --> 05:47:36,002
THIS SHOWS MULTIPLE MYELOMA, NSG

8691
05:47:36,002 --> 05:47:39,505
MICE, STARTED A TUMOR CELL LINE

8692
05:47:39,505 --> 05:47:42,008
KMS 26 LUCIFERASE, AFTER

8693
05:47:42,008 --> 05:47:43,776
ESTABLISHED DAY ZERO AGAIN

8694
05:47:43,776 --> 05:47:48,281
ESTABLISHED TUMOR BURDEN, WE

8695
05:47:48,281 --> 05:47:52,518
HAVE UNTREATED MICE, IRRELEVANT,

8696
05:47:52,518 --> 05:47:54,420
AND MICE THAT REACHED TCR CELLS.

8697
05:47:54,420 --> 05:47:57,490
MICE THAT RECEIVED THE CORRECT T

8698
05:47:57,490 --> 05:48:01,828
CELLS, R 175H, A GOOD T-CELL

8699
05:48:01,828 --> 05:48:04,130
RECEPTOR HAD CLEARANCE OF THEIR

8700
05:48:04,130 --> 05:48:05,031
MULTIPLE MYELOMA, AND ALL THE

8701
05:48:05,031 --> 05:48:12,004
WAY DOWN TO THE END OF THE

8702
05:48:12,004 --> 05:48:14,307
EXPERIMENT WE DIDN'T SEE

8703
05:48:14,307 --> 05:48:16,442
RELAPSE, NOW USED WITH MULTIPLE

8704
05:48:16,442 --> 05:48:20,613
MYELOMA AND AML CELL LINE, WORKS

8705
05:48:20,613 --> 05:48:23,716
AGAINST BOTH HEMATOLOGIC

8706
05:48:23,716 --> 05:48:24,584
MALIGNANCIES, SURVIVAL IN

8707
05:48:24,584 --> 05:48:30,623
AGREEMENT WITH MOUSE IMAGES.

8708
05:48:30,623 --> 05:48:37,764
WITH THE NEOEPITOPE PROJECT WE

8709
05:48:37,764 --> 05:48:40,466
HAVE T CELLS SPECIFICALLY

8710
05:48:40,466 --> 05:48:42,034
RECOGNIZING CORRECT NEOEPITOPES,

8711
05:48:42,034 --> 05:48:43,102
ELIMINATING TUMORS IN MICE, WE

8712
05:48:43,102 --> 05:48:44,737
HELP TO START A CLINICAL TRIAL

8713
05:48:44,737 --> 05:48:46,939
MAKING USE AGAIN OF OUR GREAT

8714
05:48:46,939 --> 05:48:47,807
COLLABORATION WITH OUR

8715
05:48:47,807 --> 05:48:52,211
COLLEAGUES IN SURGERY BRANCH

8716
05:48:52,211 --> 05:48:54,046
WHETHER WE HAVE USABLE T CELL

8717
05:48:54,046 --> 05:48:55,782
TCR VECTORS AVAILABLE TO USE IN

8718
05:48:55,782 --> 05:48:56,816
A CLINICAL TRIAL.

8719
05:48:56,816 --> 05:49:02,789
WE'RE WELL ALONG THE WAY OF

8720
05:49:02,789 --> 05:49:04,524
GETTING REGULATORY APPROVAL,

8721
05:49:04,524 --> 05:49:05,992
HOPEFULLY TREATING PATIENTS

8722
05:49:05,992 --> 05:49:06,526
EARLY IN 2025.

8723
05:49:06,526 --> 05:49:11,030
I'D LIKE TO JUST FINISH UP,

8724
05:49:11,030 --> 05:49:13,032
THANKING DR. ROSENBERG AND

8725
05:49:13,032 --> 05:49:15,134
CO-WORKERS, LAUREN CUTMORE,

8726
05:49:15,134 --> 05:49:20,206
KATHERINE CAP, WHO DID THE IN

8727
05:49:20,206 --> 05:49:23,309
VITRO WORK, OTHER COLLEAGUES IN

8728
05:49:23,309 --> 05:49:24,944
MY LAB, AND OTHERS.

8729
05:49:24,944 --> 05:49:33,686
AGAIN, THANKS TO EVERYBODY. 

8730
05:49:33,686 --> 05:49:43,729
 

8731
05:49:47,033 --> 05:49:47,266
[APPLAUSE]

8732
05:49:47,266 --> 05:49:48,000
>> THANK YOU, JIM.

8733
05:49:48,000 --> 05:49:49,202
WE'VE COME TO THE LAST TALK OF

8734
05:49:49,202 --> 05:49:50,303
THE DAY.

8735
05:49:50,303 --> 05:49:54,907
THANK YOU FOR STICKING WITH US.

8736
05:49:54,907 --> 05:49:56,676
I'M EXCITED TO HEAR DR. MACKALL

8737
05:49:56,676 --> 05:49:58,110
SPEAK BECAUSE WE'RE SEEING

8738
05:49:58,110 --> 05:50:00,713
EVIDENCE CAR IN SOLID CANCERS IS

8739
05:50:00,713 --> 05:50:03,249
HAVING CLINICAL BENEFIT AND NOW

8740
05:50:03,249 --> 05:50:04,784
MORE OBJECTIVE RESPONSES, AND

8741
05:50:04,784 --> 05:50:07,954
ALWAYS HAPPY TO HEAR HER TALK

8742
05:50:07,954 --> 05:50:09,288
ABOUT HER WORK.

8743
05:50:09,288 --> 05:50:11,224
PLEASE WELCOME DR. MACKALL TO

8744
05:50:11,224 --> 05:50:11,557
THE STAGE.

8745
05:50:11,557 --> 05:50:14,060
[APPLAUSE]

8746
05:50:14,060 --> 05:50:17,797
 

8747
05:50:17,797 --> 05:50:18,564
>> THANK YOU.

8748
05:50:18,564 --> 05:50:20,199
I MIGHT BE THE ONLY SPEAKER

8749
05:50:20,199 --> 05:50:22,935
TODAY NOT A MEMBER OF THE

8750
05:50:22,935 --> 05:50:24,904
SURGERY BRANCH.

8751
05:50:24,904 --> 05:50:28,608
AND I HOPE THAT MAYBE I COULD BE

8752
05:50:28,608 --> 05:50:30,076
CONSIDERED AN HONORARY MEMBER

8753
05:50:30,076 --> 05:50:34,380
BECAUSE IN FACT I HAVE THE

8754
05:50:34,380 --> 05:50:37,683
SIMILAR SLIDE THAT YOU'VE SEEN

8755
05:50:37,683 --> 05:50:40,753
TODAY, IN 1985 I WAS AN INTERN

8756
05:50:40,753 --> 05:50:42,855
IN AKRON, OHIO, HAVING GRADUATED

8757
05:50:42,855 --> 05:50:44,523
FROM A LOCAL MEDICAL SCHOOL

8758
05:50:44,523 --> 05:50:46,659
THERE, WITH AN INTEREST IN

8759
05:50:46,659 --> 05:50:48,327
ONCOLOGY, DOING AN INTERNAL

8760
05:50:48,327 --> 05:50:49,528
MEDICINE PEDIATRICS RESIDENCY.

8761
05:50:49,528 --> 05:50:56,536
I KNEW I WANTED TO DO ONCOLOGY.

8762
05:50:56,536 --> 05:50:58,170
I HADN'T DECIDED PEDIATRIC OR

8763
05:50:58,170 --> 05:50:58,371
ADULT.

8764
05:50:58,371 --> 05:50:59,805
I REMEMBER THIS LIKE YESTERDAY,

8765
05:50:59,805 --> 05:51:02,308
I LEARNED TODAY THAT THE PATIENT

8766
05:51:02,308 --> 05:51:03,943
WHO RESPONDED IN THIS PAPER I

8767
05:51:03,943 --> 05:51:07,446
GUESS IS WITH US TODAY, IT'S

8768
05:51:07,446 --> 05:51:10,416
JUST AMAZING TO SEE IT COME FULL

8769
05:51:10,416 --> 05:51:10,650
CIRCLE.

8770
05:51:10,650 --> 05:51:12,818
I SAID THAT'S WHAT I WANT TO DO.

8771
05:51:12,818 --> 05:51:14,220
WHERE WAS IT BEING DONE?

8772
05:51:14,220 --> 05:51:16,989
AT THE NIH.

8773
05:51:16,989 --> 05:51:19,025
IN 1989, I MOVED FROM OHIO TO

8774
05:51:19,025 --> 05:51:20,927
THE NIH, AND WAS HERE FOR 27

8775
05:51:20,927 --> 05:51:21,127
YEARS.

8776
05:51:21,127 --> 05:51:23,429
I WAS NEVER ON THE THIRD FLOOR.

8777
05:51:23,429 --> 05:51:25,598
I WAS FIRST ON THE 13th FLOOR,

8778
05:51:25,598 --> 05:51:28,367
THEN FIRST FLOOR, BUT DECIDED TO

8779
05:51:28,367 --> 05:51:30,770
PURSUE PEDIATRICS, BUT WITH THE

8780
05:51:30,770 --> 05:51:33,506
GOAL OF DEVELOPING IMMUNOTHERAPY

8781
05:51:33,506 --> 05:51:34,373
FOR CHILDREN'S CANCERS.

8782
05:51:34,373 --> 05:51:36,242
I DIDN'T HAVE ROLE MODELS IN

8783
05:51:36,242 --> 05:51:38,311
THAT SPACE BUT HAD STEVE

8784
05:51:38,311 --> 05:51:40,279
ROSENBERG AS A ROLE MODEL.

8785
05:51:40,279 --> 05:51:43,149
AND HE REALLY TAUGHT ME WHAT

8786
05:51:43,149 --> 05:51:44,684
NEEDED TO BE DONE.

8787
05:51:44,684 --> 05:51:48,187
THE NIH INTRAMURAL PROGRAM

8788
05:51:48,187 --> 05:51:51,023
SHOWED ME HOW TO TAKE IDEAS FROM

8789
05:51:51,023 --> 05:51:52,658
BENCH TO BEDSIDE.

8790
05:51:52,658 --> 05:51:54,527
I'M GOING TO TALK AND GET

8791
05:51:54,527 --> 05:51:57,797
EVERYBODY OUT ON TIME, ABOUT THE

8792
05:51:57,797 --> 05:51:58,898
PROSPECT OF USING CAR-T CELLS

8793
05:51:58,898 --> 05:51:59,999
FOR SOLID TUMORS.

8794
05:51:59,999 --> 05:52:02,969
AND I KNOW THERE MAY BE SOME

8795
05:52:02,969 --> 05:52:05,905
AMONG US WHO THINK THAT WILL

8796
05:52:05,905 --> 05:52:09,308
NEVER WORK BECAUSE, YES, THERE

8797
05:52:09,308 --> 05:52:11,043
ARE NO TRULY TUMOR-SPECIFIC CELL

8798
05:52:11,043 --> 05:52:12,044
SURFACE MOLECULES.

8799
05:52:12,044 --> 05:52:14,113
BUT IT IS MY BELIEF AND I THINK

8800
05:52:14,113 --> 05:52:15,982
BACKED UP BY DATA THAT THERE ARE

8801
05:52:15,982 --> 05:52:18,150
SEVERAL MOLECULES FOR WHICH

8802
05:52:18,150 --> 05:52:19,485
THERE IS A POTENTIAL THERAPEUTIC

8803
05:52:19,485 --> 05:52:22,321
WINDOW WHERE WE CAN THREAD IT

8804
05:52:22,321 --> 05:52:24,290
BASED UPON THE RELATIVELY HIGHER

8805
05:52:24,290 --> 05:52:26,592
ANTIGEN DENSITY THAT CAR-T CELLS

8806
05:52:26,592 --> 05:52:29,428
NEED TO FIRE AND THEREFORE THEY

8807
05:52:29,428 --> 05:52:30,630
WILL IGNORE NORMAL TISSUES.

8808
05:52:30,630 --> 05:52:32,898
WE ALL KNOW THAT THE CAR T CELL

8809
05:52:32,898 --> 05:52:34,567
RESULTS IN SOLID TUMORS HAVE

8810
05:52:34,567 --> 05:52:35,968
BEEN NOTHING LIKE WHAT WE'VE

8811
05:52:35,968 --> 05:52:37,169
SEEN IN LIQUID TUMORS BUT I

8812
05:52:37,169 --> 05:52:40,306
WOULD ARGUE THAT IN THE LAST FEW

8813
05:52:40,306 --> 05:52:42,608
YEARS WE HAVE STARTED TO SEE

8814
05:52:42,608 --> 05:52:43,175
SIGNALS OF ACTIVITY.

8815
05:52:43,175 --> 05:52:46,979
AND THIS IS A LIST OF SOME OF

8816
05:52:46,979 --> 05:52:47,613
THOSE.

8817
05:52:47,613 --> 05:52:50,850
YOU'LL NOTE THAT QUITE A FEW ARE

8818
05:52:50,850 --> 05:52:52,485
HAPPENING IN PEDIATRICS.

8819
05:52:52,485 --> 05:52:54,687
AND UNLIKE ADULT CANCERS WE'VE

8820
05:52:54,687 --> 05:52:57,423
HEARD SO MUCH TODAY ABOUT

8821
05:52:57,423 --> 05:52:58,858
MUTATED NEOANTIGENS, ABILITY TO

8822
05:52:58,858 --> 05:53:00,192
GO AFTER MOTHER NATURE'S KEY

8823
05:53:00,192 --> 05:53:02,928
CELL, TO RECOGNIZE THESE NEW

8824
05:53:02,928 --> 05:53:05,631
ANTIGENS BUT TUMORS IN CHILDREN

8825
05:53:05,631 --> 05:53:07,933
ARE TYPICALLY VERY, VERY

8826
05:53:07,933 --> 05:53:11,437
[ LOWLY

8827
05:53:11,437 --> 05:53:11,670
MUTATED.

8828
05:53:11,670 --> 05:53:13,639
WE HAVE TO PARTICULAR THE IMMUNE

8829
05:53:13,639 --> 05:53:15,174
SYSTEM INTO RESPONDING TO

8830
05:53:15,174 --> 05:53:15,541
TUMORS.

8831
05:53:15,541 --> 05:53:20,513
I'LL TALK ABOUT ONE STORY USING

8832
05:53:20,513 --> 05:53:25,451
A CAR TARGETING GD2 GANGLIACIDE,

8833
05:53:25,451 --> 05:53:27,720
IN DIFFUSE MIDLINE GLIOMA DRIVEN

8834
05:53:27,720 --> 05:53:33,559
BY MUTATION IN THE H3 HISTONE,

8835
05:53:33,559 --> 05:53:34,393
THAT PREVENTS TRIMETHYLATION,

8836
05:53:34,393 --> 05:53:36,629
UNABLE TO TURN OFF GENES.

8837
05:53:36,629 --> 05:53:38,931
IT LEADS TO WIDESPREAD

8838
05:53:38,931 --> 05:53:39,532
TRANSCRIPTIONAL DYSREGULATION

8839
05:53:39,532 --> 05:53:41,233
AND ONE OF THE GENES THAT GETS

8840
05:53:41,233 --> 05:53:43,069
TURNED ON ARE THE GENES THAT

8841
05:53:43,069 --> 05:53:48,007
DRIVE THE PRODUCTION OF THIS GD2

8842
05:53:48,007 --> 05:53:48,607
GANG LEOCIDE.

8843
05:53:48,607 --> 05:53:52,144
WHAT WE'VE DISCOVERED IN THE

8844
05:53:52,144 --> 05:53:59,051
LABORATORY OF A PIONEERING

8845
05:53:59,051 --> 05:54:00,052
NEURAL ONCOLOGIST AT STANFORD,

8846
05:54:00,052 --> 05:54:02,922
TUMORS THAT ARE NOT DRIVEN BY

8847
05:54:02,922 --> 05:54:05,524
THAT ONCOGENE DO NOT, NORMAL

8848
05:54:05,524 --> 05:54:06,926
TISSUES EXPRESS SOME, IT'S MANY

8849
05:54:06,926 --> 05:54:08,160
LOGS LOWER.

8850
05:54:08,160 --> 05:54:10,696
THIS IS A TRULY DEVASTATING

8851
05:54:10,696 --> 05:54:12,098
TUMOR, SHOWN IN GREEN ARE

8852
05:54:12,098 --> 05:54:15,935
PATIENTS THAT HAVE THE H3 MUTANT

8853
05:54:15,935 --> 05:54:16,502
VERSION.

8854
05:54:16,502 --> 05:54:18,037
ESSENTIALLY THEY ALL DIE.

8855
05:54:18,037 --> 05:54:19,872
THERE'S A MEDIAN SURVIVAL OF

8856
05:54:19,872 --> 05:54:21,307
NINE TO ELEVEN MONTHS.

8857
05:54:21,307 --> 05:54:25,144
AND IN THE MODERN DAY OF 2024,

8858
05:54:25,144 --> 05:54:26,812
WE HAVE NO FDA APPROVED

8859
05:54:26,812 --> 05:54:30,082
THERAPIES FOR THIS DISEASE.

8860
05:54:30,082 --> 05:54:32,351
A CHILD IS DIAGNOSED, THE

8861
05:54:32,351 --> 05:54:33,119
PEDIATRIC ONCOLOGIST SAYS WE'RE

8862
05:54:33,119 --> 05:54:35,755
GOING TO OFFER YOUR CHILD

8863
05:54:35,755 --> 05:54:36,555
PALLIATIVE RADIOTHERAPY, THAT'S

8864
05:54:36,555 --> 05:54:38,824
ALL WE HAVE TO OFFER.

8865
05:54:38,824 --> 05:54:41,894
SO WE DESPERATELY NEED NEW

8866
05:54:41,894 --> 05:54:43,028
THERAPY.

8867
05:54:43,028 --> 05:54:46,031
MEDIAN SURVIVAL FOR DIPG VERSION

8868
05:54:46,031 --> 05:54:47,466
IS NINE MONTHS.

8869
05:54:47,466 --> 05:54:49,769
THAT WHICH EXPRESSED HIGH

8870
05:54:49,769 --> 05:54:50,436
LITERALLY, MY COLLEAGUE MICHELLE

8871
05:54:50,436 --> 05:54:52,938
KNOCKED ON MY DOOR AND SAID

8872
05:54:52,938 --> 05:54:55,007
AREN'T YOU WORKING ON GD2 CAR?

8873
05:54:55,007 --> 05:54:58,577
MeSH DIDN'T EVEN -- MICHELLE

8874
05:54:58,577 --> 05:55:01,046
DIDN'T KNOW WHAT A CAR WAS, SHE

8875
05:55:01,046 --> 05:55:05,117
WAS A NEUROBIOLOGIST.

8876
05:55:05,117 --> 05:55:06,519
TRUTH BE TOLD IT'S NOT A GOOD

8877
05:55:06,519 --> 05:55:08,254
CAR BECAUSE WE LEARNED UNLIKE

8878
05:55:08,254 --> 05:55:09,789
THE CD19 CAR THAT JIM JUST

8879
05:55:09,789 --> 05:55:13,959
TALKED ABOUT, WHICH HAS SUCH

8880
05:55:13,959 --> 05:55:14,593
ASTOUNDING EFFICACY, THIS CD19

8881
05:55:14,593 --> 05:55:17,563
WHEN YOU MAKE IT A FLUORESCENT

8882
05:55:17,563 --> 05:55:19,098
CORRECTIONER YOU SEE IT

8883
05:55:19,098 --> 05:55:19,765
DISTRIBUTE IN THE CELL MEMBRANE

8884
05:55:19,765 --> 05:55:23,135
US A IMAGINE IT SHOULD BUT FOR

8885
05:55:23,135 --> 05:55:24,804
WHATEVER REASON THE GD2 CAR

8886
05:55:24,804 --> 05:55:26,539
USING THE ANTIBODY THAT IS

8887
05:55:26,539 --> 05:55:29,708
REALLY THE GOLD STANDARD

8888
05:55:29,708 --> 05:55:30,676
ANTIBODY TARGETING THIS MOLECULE

8889
05:55:30,676 --> 05:55:33,312
IN THE MEMBRANE LEADS TO

8890
05:55:33,312 --> 05:55:35,281
ACTIVATION, EVEN IN THE ABSENCE

8891
05:55:35,281 --> 05:55:35,948
OF ANTIGEN.

8892
05:55:35,948 --> 05:55:38,450
I WAS HERE AT NIH BEFORE

8893
05:55:38,450 --> 05:55:43,389
STANFORD IN 2016 A TALENTED

8894
05:55:43,389 --> 05:55:45,558
MD/PHD STUDENT WAS TRYING TO

8895
05:55:45,558 --> 05:55:47,560
MAKE THE CAR WORK BETTER, WE

8896
05:55:47,560 --> 05:55:50,596
TRIED TO USE IT FOR

8897
05:55:50,596 --> 05:55:52,531
NEUROBLASTOMA BUT IT SIGNALED IN

8898
05:55:52,531 --> 05:55:55,100
ABSENCE OF ANTIGEN, CAN YOU SEE

8899
05:55:55,100 --> 05:55:59,471
IT HERE, IT'S ALREADY

8900
05:55:59,471 --> 05:56:00,673
PHOSPHORYLATED, EVEN WITHOUT

8901
05:56:00,673 --> 05:56:02,107
CROSS-LINKING, DIFFERENT THAN

8902
05:56:02,107 --> 05:56:04,376
CD19, CELLS RAPIDLY UNDERWENT

8903
05:56:04,376 --> 05:56:05,277
EXHAUSTION.

8904
05:56:05,277 --> 05:56:06,278
THEY EXPRESSED CHECKPOINT

8905
05:56:06,278 --> 05:56:07,346
MOLECULES, DIDN'T WORK VERY

8906
05:56:07,346 --> 05:56:07,813
WELL.

8907
05:56:07,813 --> 05:56:12,051
WHEN WE USED THEM IN THE 28Z

8908
05:56:12,051 --> 05:56:12,384
CONFIGURATION.

8909
05:56:12,384 --> 05:56:15,554
WE USED THAT BECAUSE THAT'S THE

8910
05:56:15,554 --> 05:56:16,889
CONFIGURATION SURGERY BRANCH

8911
05:56:16,889 --> 05:56:17,156
UTILIZED.

8912
05:56:17,156 --> 05:56:20,259
BUT WE LEARNED IF YOU CHANGE

8913
05:56:20,259 --> 05:56:23,963
THAT UP, INSTEAD USE 4-1BB, A

8914
05:56:23,963 --> 05:56:26,599
MUTED SIGNAL, YOU COULD ACTUALLY

8915
05:56:26,599 --> 05:56:28,133
TURN THIS CAR FROM SOMETHING

8916
05:56:28,133 --> 05:56:30,769
THAT DIDN'T WORK WELL TO

8917
05:56:30,769 --> 05:56:32,071
SOMETHING THAT WORKED OKAY.

8918
05:56:32,071 --> 05:56:33,872
AND SO THIS WAS OUR OPTIMIZED

8919
05:56:33,872 --> 05:56:35,708
CAR THAT WE WERE WORKING WITH

8920
05:56:35,708 --> 05:56:39,979
WHEN I LEARNED ABOUT THE GD2

8921
05:56:39,979 --> 05:56:44,250
EXPRESSION AND DIFFUSE MIDLINE

8922
05:56:44,250 --> 05:56:45,451
GLIOMA.

8923
05:56:45,451 --> 05:56:47,620
USING THIS OPTIMIZED CAR, IN

8924
05:56:47,620 --> 05:56:51,690
NEONATAL MICE FOR WHOM THEY

8925
05:56:51,690 --> 05:56:52,791
RECEIVED IMPLANT INTO THE PONS

8926
05:56:52,791 --> 05:56:58,030
WE  CURED WITH ONE IV INJECTION

8927
05:56:58,030 --> 05:57:00,432
OF A SMALL NUMBER OF CAR-T

8928
05:57:00,432 --> 05:57:01,000
CELLS, SIMILAR TO LEUKEMIA.

8929
05:57:01,000 --> 05:57:05,471
IT WAS SORT OF WHAT WE WERE USED

8930
05:57:05,471 --> 05:57:07,873
TO SEEING BUT DR. MANJAY HAD

8931
05:57:07,873 --> 05:57:09,408
NEVER SEEN THIS WORKED IN THIS

8932
05:57:09,408 --> 05:57:11,911
SPACE FOR A DECADE TRYING TO USE

8933
05:57:11,911 --> 05:57:13,679
SMALL MOLECULES TO CURE THIS

8934
05:57:13,679 --> 05:57:14,113
DISEASE.

8935
05:57:14,113 --> 05:57:15,547
THESE RESPONSES WERE LONG

8936
05:57:15,547 --> 05:57:15,915
LASTING.

8937
05:57:15,915 --> 05:57:17,750
THERE WAS A NOTE OF CAUTION

8938
05:57:17,750 --> 05:57:19,151
BECAUSE SMALL FRACTION OF MICE

8939
05:57:19,151 --> 05:57:19,818
DIED EARLY.

8940
05:57:19,818 --> 05:57:27,026
THIS WAS NOT DUE TO ON-TARGET

8941
05:57:27,026 --> 05:57:30,429
OFF-TUMOR TOXICITY BUT RATHER

8942
05:57:30,429 --> 05:57:31,297
HYDROCEPHALUS.

8943
05:57:31,297 --> 05:57:33,165
TUMORS IN THE PONS CELLS,

8944
05:57:33,165 --> 05:57:35,134
LEADING TO HYDROCEPHALUS AND

8945
05:57:35,134 --> 05:57:36,535
DIDN'T HAVE SUPPORTIVE CARE TO

8946
05:57:36,535 --> 05:57:36,902
OFFER.

8947
05:57:36,902 --> 05:57:38,771
WE LEARNED WE COULD FURTHER

8948
05:57:38,771 --> 05:57:41,507
ENHANCE THE FUNCTION OF THESE

8949
05:57:41,507 --> 05:57:42,508
TONICALLY SIGNALING GD2 CAR-T

8950
05:57:42,508 --> 05:57:44,610
CELLS IF WE MANUFACTURED THEM IN

8951
05:57:44,610 --> 05:57:48,847
THE PRESENCE OF A SMALL MOLECULE

8952
05:57:48,847 --> 05:57:52,151
INHIBITOR THAT BASICALLY

8953
05:57:52,151 --> 05:57:56,288
INHIBITED CAR SIGNAL, THIS BEING

8954
05:57:56,288 --> 05:57:56,555
DASATINIB.

8955
05:57:56,555 --> 05:57:59,458
SO YOU CAN SEE HERE WHEN WE

8956
05:57:59,458 --> 05:58:00,359
MANUFACTURED CELLS IN DASATINIB

8957
05:58:00,359 --> 05:58:03,429
WE WERE ABLE TO GET MORE POTENT

8958
05:58:03,429 --> 05:58:06,532
CELLS THAN WHEN WE ONLY USED

8959
05:58:06,532 --> 05:58:06,999
VEHICLE.

8960
05:58:06,999 --> 05:58:08,600
AND THEN FINALLY BEFORE WE TOOK

8961
05:58:08,600 --> 05:58:09,902
THIS TO THE CLINIC BECAUSE WE

8962
05:58:09,902 --> 05:58:11,870
WERE GOING TO BE TREATING A

8963
05:58:11,870 --> 05:58:13,739
TUMOR IN THE MIDDLE OF THE

8964
05:58:13,739 --> 05:58:14,606
BRAINSTEM WE KNEW THERE WERE

8965
05:58:14,606 --> 05:58:16,575
GOING TO BE RISKS, INCORPORATED

8966
05:58:16,575 --> 05:58:19,978
WHAT WE THOUGHT WAS BEST IN

8967
05:58:19,978 --> 05:58:22,047
CLASS SUICIDE DOMAIN, INDUCED

8968
05:58:22,047 --> 05:58:23,349
CASPASE 9 DEVELOPED AT BAYLOR

8969
05:58:23,349 --> 05:58:26,085
AND COULD BE ACTIVATED WITH

8970
05:58:26,085 --> 05:58:28,187
OTHERWISE INERT SMALL MOLECULE

8971
05:58:28,187 --> 05:58:29,688
AP 1903.

8972
05:58:29,688 --> 05:58:31,357
THIS WAS ABOUT 2018.

8973
05:58:31,357 --> 05:58:32,925
WE PUBLISHED THOSE RESULTS.

8974
05:58:32,925 --> 05:58:36,695
AT THE SAME TIME WHILE GETTING

8975
05:58:36,695 --> 05:58:38,897
CLINICAL TRIAL READY WE STARTED

8976
05:58:38,897 --> 05:58:40,833
TO WANT TO REALLY START TO THINK

8977
05:58:40,833 --> 05:58:42,735
ABOUT DIRECT DELIVERY OF THE CAR

8978
05:58:42,735 --> 05:58:44,737
T CELLS, BASED ON WORK COMING

8979
05:58:44,737 --> 05:58:48,307
OUT OF THE CITY OF HOPE WHERE

8980
05:58:48,307 --> 05:58:50,609
THEY WERE USING BASICALLY

8981
05:58:50,609 --> 05:58:51,176
INTRACEREBRAL ADMINISTRATION

8982
05:58:51,176 --> 05:58:54,546
INTO A CATHETER INTO THE LATERAL

8983
05:58:54,546 --> 05:58:54,980
VENTRICLES.

8984
05:58:54,980 --> 05:58:56,949
INDEED WE REPLICATED RESULTS,

8985
05:58:56,949 --> 05:58:58,917
QUITE REMARKABLE, IF YOU TREATED

8986
05:58:58,917 --> 05:59:00,152
LOCAL REGIONALLY YOU ONLY NEEDED

8987
05:59:00,152 --> 05:59:01,987
ABOUT A TENTH OF THE DOSE TO

8988
05:59:01,987 --> 05:59:04,723
CURE THE MICE AS YOU NEEDED IF

8989
05:59:04,723 --> 05:59:05,524
YOU TREATED INTRAVENOUSLY.

8990
05:59:05,524 --> 05:59:08,861
NOT ONLY DID YOU GET A MORE

8991
05:59:08,861 --> 05:59:10,429
POTENT ANTITUMOR EFFECT, BUT YOU

8992
05:59:10,429 --> 05:59:12,498
DID SO WITH LESS SYSTEMIC

8993
05:59:12,498 --> 05:59:14,466
INFLAMMATION, SO LOOKING AT YOUR

8994
05:59:14,466 --> 05:59:16,335
SYSTEMIC CYTOKINE LEVELS AGAIN

8995
05:59:16,335 --> 05:59:18,203
IN MICE NOW, IF YOU GIVE ICV

8996
05:59:18,203 --> 05:59:19,938
ADMINISTRATION YOU DIDN'T GET

8997
05:59:19,938 --> 05:59:21,807
THE SERUM CYTOKINES BUT GOT

8998
05:59:21,807 --> 05:59:24,309
SIMILAR LEVELS OF CSF CYTOKINES.

8999
05:59:24,309 --> 05:59:26,945
PEOPLE SOMETIMES ASK IF YOU PUT

9000
05:59:26,945 --> 05:59:28,147
CELLS INTO THE CSF DO THEY DIVE

9001
05:59:28,147 --> 05:59:29,014
INTO THE BRAIN?

9002
05:59:29,014 --> 05:59:30,115
THE ANSWER IS YES.

9003
05:59:30,115 --> 05:59:32,184
WE'VE SEEN THIS NOW BOTH IN MICE

9004
05:59:32,184 --> 05:59:34,586
HERE, CAN YOU SEE BY DAY 2 THE

9005
05:59:34,586 --> 05:59:36,655
CELLS GOING DEEPLY INTO THE

9006
05:59:36,655 --> 05:59:38,557
BRAIN, GREEN CELLS THERE BEING

9007
05:59:38,557 --> 05:59:41,093
CAR T, RED BEING TUMOR.

9008
05:59:41,093 --> 05:59:44,530
WE'VE ALSO NOW SEEN THIS IN

9009
05:59:44,530 --> 05:59:45,898
PRACTICE IN THE CLINIC.

9010
05:59:45,898 --> 05:59:49,601
AND SO THIS WAS WHERE WE STOOD.

9011
05:59:49,601 --> 05:59:50,502
WE KNEW INTRAVENOUS DELIVERY

9012
05:59:50,502 --> 05:59:52,905
DOING IT A SIMILAR WAY TO HOW WE

9013
05:59:52,905 --> 05:59:55,340
DID IT FOR LEUKEMIA OR LYMPHOMA

9014
05:59:55,340 --> 05:59:58,710
HAD ACTIVITY IN THE MICE BUT

9015
05:59:58,710 --> 06:00:00,979
ALSO HAD EARLY RESULTS

9016
06:00:00,979 --> 06:00:04,183
SUGGESTING DELIVERY INTO THE CNS

9017
06:00:04,183 --> 06:00:06,051
COULD BE USEFUL.

9018
06:00:06,051 --> 06:00:12,057
WE LAUNCHED A PHASE 1 CLINICAL

9019
06:00:12,057 --> 06:00:17,563
TRIAL, IV INFUSION CHEMOTHERAPY,

9020
06:00:17,563 --> 06:00:19,131
THREE DOSE ESCALATION, AFTER THE

9021
06:00:19,131 --> 06:00:21,033
PERIOD WAS OVER 28 DAYS WE WOULD

9022
06:00:21,033 --> 06:00:24,203
THEN ALLOW THE PATIENTS TO

9023
06:00:24,203 --> 06:00:25,671
POTENTIALLY RECEIVE A SUBSEQUENT

9024
06:00:25,671 --> 06:00:27,606
ICV INFUSION IN THE PATIENT

9025
06:00:27,606 --> 06:00:30,476
BENEFITED AND NOT HAD

9026
06:00:30,476 --> 06:00:31,643
DOSE-LIMITING TOXICITY.

9027
06:00:31,643 --> 06:00:34,947
I WANT TO CALL OUT STEVE FELDMAN

9028
06:00:34,947 --> 06:00:36,148
AT STANFORD, BECAUSE WE HAD

9029
06:00:36,148 --> 06:00:41,086
STEVE WE WERE ABLE TO GET THIS

9030
06:00:41,086 --> 06:00:43,689
DONE QUICKLY USING THE PRODIGY

9031
06:00:43,689 --> 06:00:45,557
PLATFORM, CELLS ARE READY, SEVEN

9032
06:00:45,557 --> 06:00:46,758
DAYS OF MANUFACTURING, MEDIAN

9033
06:00:46,758 --> 06:00:49,695
TIME FROM ENROLLMENT TO INFUSION

9034
06:00:49,695 --> 06:00:50,929
WAS 15 DAYS.

9035
06:00:50,929 --> 06:00:52,998
THIS WAS THE SECOND PATIENT

9036
06:00:52,998 --> 06:00:55,067
ENROLLED, THE FIRST WE DIDN'T

9037
06:00:55,067 --> 06:00:55,300
BENEFIT.

9038
06:00:55,300 --> 06:01:00,005
BUT THIS SECOND PATIENT CAME TO

9039
06:01:00,005 --> 06:01:06,011
US, MIDDLE OF THE PANDEMIC, JUNE

9040
06:01:06,011 --> 06:01:07,546
2020, A MEDICAL STUDENT DROVE

9041
06:01:07,546 --> 06:01:08,547
FROM FLORIDA TO CALIFORNIA, WAS

9042
06:01:08,547 --> 06:01:10,148
ABLE TO WALK WHEN THE DRIVE

9043
06:01:10,148 --> 06:01:11,683
STARTED BUT TUMOR IN THE SPINAL

9044
06:01:11,683 --> 06:01:13,552
CORD, NOT ABLE TO WALK BY THE

9045
06:01:13,552 --> 06:01:16,722
TIME SHE ARRIVED.

9046
06:01:16,722 --> 06:01:19,157
SHE HAD RAPIDLY PROGRESSING

9047
06:01:19,157 --> 06:01:19,992
TUMOR.

9048
06:01:19,992 --> 06:01:23,962
BECAUSE OF RAPID PROGRESSION

9049
06:01:23,962 --> 06:01:25,030
RETREATED HER ON COMPASSIONATE

9050
06:01:25,030 --> 06:01:27,900
EXEMPTION, WOULDN'T BE ABLE TO

9051
06:01:27,900 --> 06:01:29,201
DISTINGUISH TOXICITY FROM

9052
06:01:29,201 --> 06:01:29,501
PROGRESSION.

9053
06:01:29,501 --> 06:01:30,369
NONETHELESS SHE RECEIVED THE

9054
06:01:30,369 --> 06:01:33,605
THERAPY AS DIRECTED IN THE

9055
06:01:33,605 --> 06:01:34,806
PROTOCOL, WE SAW DRAMATIC

9056
06:01:34,806 --> 06:01:37,442
SHRINKAGE OF THE LARGE SPINAL

9057
06:01:37,442 --> 06:01:39,411
TUMOR, ASSOCIATED WITH CLINICAL

9058
06:01:39,411 --> 06:01:40,512
IMPROVEMENT.

9059
06:01:40,512 --> 06:01:41,113
SHE WAS COMPLETELY PARALYZED

9060
06:01:41,113 --> 06:01:42,915
WHEN SHE WENT ON WITH THIS

9061
06:01:42,915 --> 06:01:44,783
REDUCTION WAS ABLE TO WALK WITH

9062
06:01:44,783 --> 06:01:47,286
A LOT OF ASSISTANCE BUT ALSO

9063
06:01:47,286 --> 06:01:49,288
WENT FROM HAVING COMPLETE LOSS

9064
06:01:49,288 --> 06:01:53,191
OF BOWEL BLADDER FUNCTION TO

9065
06:01:53,191 --> 06:01:54,092
RETRIEVING BLADDER FUNCTION, THE

9066
06:01:54,092 --> 06:01:56,461
FIRST SIGNAL THAT MAYBE WE HAVE

9067
06:01:56,461 --> 06:01:57,462
SOMETHING HERE.

9068
06:01:57,462 --> 06:02:01,867
HERE'S THE THIRD PATIENT, A

9069
06:02:01,867 --> 06:02:08,273
YOUNG ADULT WITH SOMEWHAT

9070
06:02:08,273 --> 06:02:10,809
UNUSUAL, PONTINE TUMOR HAD A

9071
06:02:10,809 --> 06:02:16,815
CYST IN THE MIDDLE, COMPRESSED

9072
06:02:16,815 --> 06:02:18,350
FOURTH VENTRICLE, CAUSING

9073
06:02:18,350 --> 06:02:19,351
MASSIVE PRESSURE, GAVE

9074
06:02:19,351 --> 06:02:20,385
INTRAVENOUS INFUSION.

9075
06:02:20,385 --> 06:02:22,387
SYMPTOMS WERE MAINLY TROUBLE

9076
06:02:22,387 --> 06:02:24,823
OPENING HIS MOUTH, HE COULD OPEN

9077
06:02:24,823 --> 06:02:26,358
MIDWAY BUT NOT NORMALLY.

9078
06:02:26,358 --> 06:02:28,427
AND SEVEN DAYS AFTER INFUSION HE

9079
06:02:28,427 --> 06:02:30,729
HAD GONE FROM BEING ABLE TO OPEN

9080
06:02:30,729 --> 06:02:31,930
MIDWAY TO BASICALLY NOT BEING

9081
06:02:31,930 --> 06:02:33,332
ABLE TO OPEN AT ALL.

9082
06:02:33,332 --> 06:02:36,201
THIS WAS AT THE TIME OF A PEAK

9083
06:02:36,201 --> 06:02:37,569
CYTOKINE RELEASE SYNDROME.

9084
06:02:37,569 --> 06:02:38,537
SYMPTOMS WERE GETTING WORSE.

9085
06:02:38,537 --> 06:02:40,839
THIS WAS EXACTLY WHAT WE

9086
06:02:40,839 --> 06:02:42,040
ANTICIPATED BASED ON WHAT WE

9087
06:02:42,040 --> 06:02:44,109
LEARNED IN THE MOUSE, THE TUMOR

9088
06:02:44,109 --> 06:02:46,645
WAS SWELLING, SO HE USED A STRAW

9089
06:02:46,645 --> 06:02:48,180
TO DRINK, BY DAY 14 WAS NOW

9090
06:02:48,180 --> 06:02:50,048
STARTING TO BE ABLE TO USE HIS

9091
06:02:50,048 --> 06:02:52,217
MOUTH AGAIN, WE SAW SOME OPENING

9092
06:02:52,217 --> 06:02:54,720
UP OF THIS FOURTH VENTRICLE, NOW

9093
06:02:54,720 --> 06:02:56,955
STARTS TO HAVE A NORMAL SHAPE,

9094
06:02:56,955 --> 06:02:59,658
NUMBNESS ON THE LEFT SIDE OF HIS

9095
06:02:59,658 --> 06:03:02,160
FACE IMPROVING, BY DAY 21

9096
06:03:02,160 --> 06:03:03,695
SYMPTOMS ON FACE HAD RESOLVED.

9097
06:03:03,695 --> 06:03:06,231
HE WAS ABLE TO EAT A LARGE

9098
06:03:06,231 --> 06:03:08,400
CHEESEBURGER AND BOY, WAS HE

9099
06:03:08,400 --> 06:03:08,634
HAPPY.

9100
06:03:08,634 --> 06:03:11,169
SO IT REALLY WAS QUITE

9101
06:03:11,169 --> 06:03:14,006
REMARKABLE TO SEE THIS TOXICITY

9102
06:03:14,006 --> 06:03:16,742
SYNDROME WHICH WE'VE NOW CALLED

9103
06:03:16,742 --> 06:03:17,843
TUMOR INFLAMMATION ASSOCIATED

9104
06:03:17,843 --> 06:03:22,214
TOXICITY, REMINED ME BACK IN THE

9105
06:03:22,214 --> 06:03:22,848
DAYS WHEN CYTOKINE RELEASE

9106
06:03:22,848 --> 06:03:24,716
SYNDROME WAS DESCRIBED WE NEEDED

9107
06:03:24,716 --> 06:03:26,351
TO UNDERSTAND TOXICITY, TO GRADE

9108
06:03:26,351 --> 06:03:28,987
IT, AND TO BE ABLE TO REPORT THE

9109
06:03:28,987 --> 06:03:32,858
TOXICITY AND ALSO MANAGE IT IN A

9110
06:03:32,858 --> 06:03:34,660
GRADE-DIRECTED WAY.

9111
06:03:34,660 --> 06:03:36,228
WE WORKED WITH INVESTIGATORS

9112
06:03:36,228 --> 06:03:38,096
ACROSS THE COUNTRY TREATING

9113
06:03:38,096 --> 06:03:40,265
BRAIN TUMORS WITH VARIOUS TYPES

9114
06:03:40,265 --> 06:03:45,437
OF CELL THERAPIES INCLUDING CD19

9115
06:03:45,437 --> 06:03:46,838
CAR FOR CD19 POSITIVE TUMORS IN

9116
06:03:46,838 --> 06:03:54,746
THE BRAIN, COINED THIS TOXICITY

9117
06:03:54,746 --> 06:03:56,615
SYNDROME DISTINCT FROM CRS,

9118
06:03:56,615 --> 06:03:57,582
CAUSING LOCAL NEUROLOGIC

9119
06:03:57,582 --> 06:04:00,218
DYSFUNCTION OR MORE SEVERE CASES

9120
06:04:00,218 --> 06:04:02,954
HYDROCEPHALUS WHICH WOULD

9121
06:04:02,954 --> 06:04:03,822
REQUIRE URGENT INTERVENTION.

9122
06:04:03,822 --> 06:04:06,491
WE LAID OUT THE MANAGEMENT.

9123
06:04:06,491 --> 06:04:07,926
COULD BE OBSERVATION AND

9124
06:04:07,926 --> 06:04:10,662
SUPPORTIVE CARE ONLY TO RAPID

9125
06:04:10,662 --> 06:04:11,329
INTERVENTION TO LOWER

9126
06:04:11,329 --> 06:04:14,032
INTRACRANIAL PRESSURE.

9127
06:04:14,032 --> 06:04:14,933
BY UNDERSTANDING THE

9128
06:04:14,933 --> 06:04:17,235
PATHOPHYSIOLOGY, AND GRADING IT,

9129
06:04:17,235 --> 06:04:19,504
WE WERE ABLE TO BASICALLY KEEP

9130
06:04:19,504 --> 06:04:22,808
OUR TRIAL OPEN, NOT BE SHUT DOWN

9131
06:04:22,808 --> 06:04:24,009
FOR TOXICITY WE DIDN'T

9132
06:04:24,009 --> 06:04:25,077
UNDERSTAND, AND IMPORTANTLY WERE

9133
06:04:25,077 --> 06:04:26,978
ABLE TO KEEP ALL THESE PATIENTS

9134
06:04:26,978 --> 06:04:27,179
SAFE.

9135
06:04:27,179 --> 06:04:30,449
I THINK THIS IS PART OF THE WAY

9136
06:04:30,449 --> 06:04:31,349
WE DEVELOPED NEW THERAPIES, BY

9137
06:04:31,349 --> 06:04:33,085
NOT SHYING AWAY FROM TOXICITY

9138
06:04:33,085 --> 06:04:35,187
BUT LEANING IN AND REALLY

9139
06:04:35,187 --> 06:04:36,154
UNDERSTANDING WHAT IS HAPPENING

9140
06:04:36,154 --> 06:04:37,889
AND CAN WE MANAGE OUR WAY

9141
06:04:37,889 --> 06:04:38,457
THROUGH IT.

9142
06:04:38,457 --> 06:04:41,860
SO AT THE END OF ARM A, ARM A IS

9143
06:04:41,860 --> 06:04:44,362
THIS IV INFUSION FOLLOWED BY ICV

9144
06:04:44,362 --> 06:04:46,898
GIVEN AS EARLY AS EVERY MONTH,

9145
06:04:46,898 --> 06:04:49,000
WE SAW THAT THE FIRST INFUSION

9146
06:04:49,000 --> 06:04:51,837
WAS THE MOST TOXIC ONE, IT WAS

9147
06:04:51,837 --> 06:04:55,307
THE IV ONE, SAW SIGNIFICANT

9148
06:04:55,307 --> 06:04:58,176
CYTOKINE RELEASE SYNDROME,

9149
06:04:58,176 --> 06:05:00,512
DOSE-LIMITING TOXICITY DUE TO

9150
06:05:00,512 --> 06:05:04,516
CRS  AND PATIENTS DON'T TOLERATE

9151
06:05:04,516 --> 06:05:08,019
THAT WELL.

9152
06:05:08,019 --> 06:05:13,692
WE SAW VERY LITTLE ICAN

9153
06:05:13,692 --> 06:05:14,893
SURPRISING.

9154
06:05:14,893 --> 06:05:16,528
WE SAW TUMOR ASSOCIATED

9155
06:05:16,528 --> 06:05:17,529
TOXICITY, NEUROTOXICITY, MORE

9156
06:05:17,529 --> 06:05:19,931
COMMON EARLY ON, AND GRADUALLY

9157
06:05:19,931 --> 06:05:21,133
DIMINISHED LIKELY BECAUSE THERE

9158
06:05:21,133 --> 06:05:24,503
WAS MORE SPACE AS THE TUMOR WAS

9159
06:05:24,503 --> 06:05:24,803
RESPONDING.

9160
06:05:24,803 --> 06:05:34,946
WE NEVER SAW A DLT AFTER THE ICV

9161
06:05:34,946 --> 06:05:37,215
INFUSION, REMARKABLY SAFE.

9162
06:05:37,215 --> 06:05:44,356
THIS IS A WATERFALL PLOT, A

9163
06:05:44,356 --> 06:05:47,092
TUMOR FOR WHICH WE'VE HAD NOT

9164
06:05:47,092 --> 06:05:52,330
THERAPY, NOW FOUR PATIENTS WITH

9165
06:05:52,330 --> 06:05:53,698
50% VOLUMETRIC REDUCTION, ALL

9166
06:05:53,698 --> 06:05:55,400
PROGRESSING AT THE TIME OF

9167
06:05:55,400 --> 06:05:55,700
ENROLLMENT.

9168
06:05:55,700 --> 06:05:57,702
THIS PATIENT HAD A COMPLETE AND

9169
06:05:57,702 --> 06:06:00,338
DURABLE RESPONSE, I'LL TALK

9170
06:06:00,338 --> 06:06:00,806
ABOUT HIM.

9171
06:06:00,806 --> 06:06:02,340
SOME HAVE WONDERED IS HE AN

9172
06:06:02,340 --> 06:06:02,574
OUTLIER.

9173
06:06:02,574 --> 06:06:03,542
HE'S NOT AN OUTLIER.

9174
06:06:03,542 --> 06:06:05,710
IN FACT IF YOU LOOK AT THE

9175
06:06:05,710 --> 06:06:08,580
OVERALL RESPONSE FROM THE

9176
06:06:08,580 --> 06:06:11,082
VOLUMETRIC CHANGE, WE HAVE

9177
06:06:11,082 --> 06:06:14,252
GAUSSIAN DISTRIBUTION, A BROADLY

9178
06:06:14,252 --> 06:06:17,522
ACTIVE THERAPEUTIC THAT IS, YOU

9179
06:06:17,522 --> 06:06:18,089
KNOW, REALLY SHOWING

9180
06:06:18,089 --> 06:06:19,825
REPRODUCIBLE AND IN SOME CASES

9181
06:06:19,825 --> 06:06:21,459
DURABLE ACTIVITY.

9182
06:06:21,459 --> 06:06:22,894
THE MEDIAN OVERALL SURVIVAL,

9183
06:06:22,894 --> 06:06:24,863
REMEMBER I TOLD YOU 9 TO 11

9184
06:06:24,863 --> 06:06:26,064
MONTHS FOR THESE PATIENTS, IT

9185
06:06:26,064 --> 06:06:29,367
WAS 17 MONTHS FOR THE DIPG

9186
06:06:29,367 --> 06:06:32,737
PATIENTS, IF YOU INCLUDE SPINAL

9187
06:06:32,737 --> 06:06:34,940
DMGs, 20.6 MONTHS.

9188
06:06:34,940 --> 06:06:36,374
SO, MOST OF THESE PATIENTS WENT

9189
06:06:36,374 --> 06:06:39,411
ON TO DIE EXCEPT FOR THE PATIENT

9190
06:06:39,411 --> 06:06:44,783
10, I'LL TELL YOU ABOUT, BUT FOR

9191
06:06:44,783 --> 06:06:49,154
THIS DISEASE SEEING SIGNIFICANT

9192
06:06:49,154 --> 06:06:49,921
CLINICALLY RELEVANT ACTIVITY AND

9193
06:06:49,921 --> 06:06:52,324
CHANGES IN SURVIVAL WAS VERY

9194
06:06:52,324 --> 06:06:52,657
ENCOURAGING.

9195
06:06:52,657 --> 06:06:55,393
HERE'S PATIENT NUMBER 3, WHO HAD

9196
06:06:55,393 --> 06:06:56,695
THAT ORIGINAL NICE RESPONSE,

9197
06:06:56,695 --> 06:06:58,363
LASTED ABOUT THREE MONTHS.

9198
06:06:58,363 --> 06:07:00,765
HE THEN CAME BACK WITH

9199
06:07:00,765 --> 06:07:01,233
DIFFICULTY SMILING.

9200
06:07:01,233 --> 06:07:03,602
AGAIN HIS SYMPTOMS ON THE LEFT

9201
06:07:03,602 --> 06:07:05,237
SIDE OF HIS FACE WERE RECURRENT.

9202
06:07:05,237 --> 06:07:07,639
IN THIS TIME WE GAVE HIM ICV

9203
06:07:07,639 --> 06:07:10,308
INFUSION, YOU CAN SEE IT MADE

9204
06:07:10,308 --> 06:07:12,010
HIS FACIAL MUSCLES ABLE TO SMILE

9205
06:07:12,010 --> 06:07:14,646
AGAIN, HERE HE IS WHEN HE CAME

9206
06:07:14,646 --> 06:07:19,050
BACK WITH REALLY MORE

9207
06:07:19,050 --> 06:07:20,352
RIGHT-SIDED STIFFNESS, AND

9208
06:07:20,352 --> 06:07:21,119
SPASTICITY, DIFFICULTY WITH

9209
06:07:21,119 --> 06:07:24,022
BALANCE, WE GAVE HIM THE ICV

9210
06:07:24,022 --> 06:07:26,157
INFUSION, HERE IS HE IN CLINIC,

9211
06:07:26,157 --> 06:07:29,761
A FEW DAYS LATER ABLE TO WALK

9212
06:07:29,761 --> 06:07:32,063
REALLY QUITE WELL, TOOK A DAY

9213
06:07:32,063 --> 06:07:34,266
HIKE WITH HIS SISTER.

9214
06:07:34,266 --> 06:07:35,567
EVENTUALLY ABOUT A YEAR AND A

9215
06:07:35,567 --> 06:07:37,202
HALF IN HE DIED OF A HEMORRHAGE

9216
06:07:37,202 --> 06:07:39,070
IN HIS TUMOR WHICH IS SEEN WITH

9217
06:07:39,070 --> 06:07:40,272
THESE TUMORS.

9218
06:07:40,272 --> 06:07:42,007
BUT WE CLEARLY GAVE HIM ABOUT A

9219
06:07:42,007 --> 06:07:46,745
YEAR AND A HALF OF GOOD TIME.

9220
06:07:46,745 --> 06:07:47,646
HERE'S PATIENT NUMBER 10, A

9221
06:07:47,646 --> 06:07:49,014
17-YEAR-OLD WHO CAME TO US WHEN

9222
06:07:49,014 --> 06:07:51,616
HE WAS A JUNIOR IN HIGH SCHOOL

9223
06:07:51,616 --> 06:07:57,322
WITH I HAD NASTY-LOOKING LARGE

9224
06:07:57,322 --> 06:07:58,323
PONTINE TUMOR, FOURTH VENTRICLE,

9225
06:07:58,323 --> 06:08:00,191
COMPLETE RESPONSE OVER ABOUT

9226
06:08:00,191 --> 06:08:01,927
FIVE MONTHS.

9227
06:08:01,927 --> 06:08:03,428
NOW SUSTAINED FOR MORE THAN 3

9228
06:08:03,428 --> 06:08:04,863
1/2 YEARS.

9229
06:08:04,863 --> 06:08:06,364
WHEN HE CAME, HE WAS ABLE TO

9230
06:08:06,364 --> 06:08:09,367
WALK BUT IF HAD HE TO GO TOO FAR

9231
06:08:09,367 --> 06:08:11,269
WAS IN A WHEELCHAIR, COULDN'T

9232
06:08:11,269 --> 06:08:14,973
ATTEND HIGH SCHOOL, HE IS NOW

9233
06:08:14,973 --> 06:08:17,042
STARTING ACTUALLY A SENIOR IN

9234
06:08:17,042 --> 06:08:18,677
COLLEGE NOW, SPENT THE SUMMER

9235
06:08:18,677 --> 06:08:20,412
TRAVELING EUROPE WITH HIS

9236
06:08:20,412 --> 06:08:20,645
FAMILY.

9237
06:08:20,645 --> 06:08:23,381
HERE HE IS A MONTH AFTER HIS

9238
06:08:23,381 --> 06:08:25,250
FIRST INFUSION, YOU CAN SEE HE'S

9239
06:08:25,250 --> 06:08:27,185
WITH HIS FATHER, WHO IS HELPING

9240
06:08:27,185 --> 06:08:29,287
HIM WALK BECAUSE HE CAN WALK,

9241
06:08:29,287 --> 06:08:31,122
BUT NOT VERY WELL.

9242
06:08:31,122 --> 06:08:33,124
AND HERE HE IS EIGHT MONTHS

9243
06:08:33,124 --> 06:08:40,098
AFTER FIRST INFUSION.

9244
06:08:40,098 --> 06:08:41,533
SO DRAMATIC REALIZATION FROM THE

9245
06:08:41,533 --> 06:08:44,536
TRIAL MUCH OF THE NEUROLOGIC

9246
06:08:44,536 --> 06:08:46,304
FUNCTION LOST IS POTENTIALLY

9247
06:08:46,304 --> 06:08:47,672
RECOVERABLE, AND HE'S NOW ABLE

9248
06:08:47,672 --> 06:08:48,873
TO RUN.

9249
06:08:48,873 --> 06:08:50,575
HERE IS LOOKING AT CLINICAL

9250
06:08:50,575 --> 06:08:52,277
BENEFIT IN BLUE, CAN YOU SEE

9251
06:08:52,277 --> 06:08:54,879
MANY OF THESE PATIENTS HAD

9252
06:08:54,879 --> 06:08:55,647
SIGNIFICANT CLINICAL BENEFIT,

9253
06:08:55,647 --> 06:08:57,615
AND SOME PATIENTS WHO DIDN'T

9254
06:08:57,615 --> 06:08:58,950
EVEN HAVE SHRINKAGE OF TUMOR ON

9255
06:08:58,950 --> 06:09:00,485
THE SCANS IT'S VERY HARD TO KNOW

9256
06:09:00,485 --> 06:09:03,655
WHAT'S TUMOR AND WHAT'S THE PONS

9257
06:09:03,655 --> 06:09:07,726
BECAUSE IT'S  INFILTRATIVE BY

9258
06:09:07,726 --> 06:09:10,795
NATURE BUT THIS GIRL WAS 3 WHEN

9259
06:09:10,795 --> 06:09:12,430
SHE WENT ON, HAVING TROUBLE

9260
06:09:12,430 --> 06:09:14,065
COLORING BECAUSE OF THE

9261
06:09:14,065 --> 06:09:16,134
DYSFUNCTION, AND EVEN FOUR WEEKS

9262
06:09:16,134 --> 06:09:18,436
IN WAS ABLE TO REALLY HAVE MUCH

9263
06:09:18,436 --> 06:09:19,971
BETTER FINE MOTOR COORDINATION

9264
06:09:19,971 --> 06:09:22,807
AND SHE ENDED UP LIVING FOR OVER

9265
06:09:22,807 --> 06:09:24,509
TWO YEARS ON TRIAL WITH

9266
06:09:24,509 --> 06:09:30,915
GENERALLY GOOD QUALITY OF LIFE.

9267
06:09:30,915 --> 06:09:32,550
WHY DID SOME RESPOND AND NOT

9268
06:09:32,550 --> 06:09:33,651
OTHERS IN THE MILLION DOLLAR

9269
06:09:33,651 --> 06:09:34,552
QUESTION.

9270
06:09:34,552 --> 06:09:36,354
THIS IS THE DURABLE COMPLETE

9271
06:09:36,354 --> 06:09:39,891
RESPONSE, TUMOR VOLUME GOES TO

9272
06:09:39,891 --> 06:09:42,060
ZERO. 

9273
06:09:42,060 --> 06:09:45,130
HIS CELL-FREE DNA AND CNS GOES

9274
06:09:45,130 --> 06:09:46,765
TO ZERO, PERSISTING IN

9275
06:09:46,765 --> 06:09:48,199
BLOODSTREAM OVER A YEAR OUT.

9276
06:09:48,199 --> 06:09:50,368
WE DON'T KNOW IF THESE ARE THE

9277
06:09:50,368 --> 06:09:54,339
CELLS HE GOT IV OR CELLS WE GAVE

9278
06:09:54,339 --> 06:09:57,275
ICV, WE KNOW ADMINISTRATION ICV

9279
06:09:57,275 --> 06:09:59,244
CAN LEAD TO TRAFFICKING IN THE

9280
06:09:59,244 --> 06:10:01,780
BLOOD BUT HE HAD THE MOST

9281
06:10:01,780 --> 06:10:02,547
DURABLE PERSISTENCE OF CAR-T

9282
06:10:02,547 --> 06:10:02,814
CELLS.

9283
06:10:02,814 --> 06:10:05,283
WE ALSO KNOW THAT EVERY TIME WE

9284
06:10:05,283 --> 06:10:07,585
GAVE HIM AN INTRACRANIAL

9285
06:10:07,585 --> 06:10:09,454
INFUSION WE COULD HAVE

9286
06:10:09,454 --> 06:10:12,524
INFLAMMATORY SIGNATURE IN HIS

9287
06:10:12,524 --> 06:10:14,492
CSF, LARGELY DRIVEN BY

9288
06:10:14,492 --> 06:10:15,460
INTERFERON GAMMA AND INDUCED

9289
06:10:15,460 --> 06:10:15,960
CYTOKINES.

9290
06:10:15,960 --> 06:10:17,762
HERE IS PATIENT NUMBER 10 WITH

9291
06:10:17,762 --> 06:10:19,831
THAT DURABLE PERSISTENCE OF CAR

9292
06:10:19,831 --> 06:10:23,435
Ts, ANOTHER YOUNG WOMAN SHE

9293
06:10:23,435 --> 06:10:25,203
HAD A 99% RESPONSE, TUMOR

9294
06:10:25,203 --> 06:10:26,738
COMPLETELY DISAPPEARED EXCEPT

9295
06:10:26,738 --> 06:10:28,273
FOR ONE TEENY SPOT, AND THEN

9296
06:10:28,273 --> 06:10:30,442
WOULDN'T YOU KNOW IT, EVENTUALLY

9297
06:10:30,442 --> 06:10:31,242
STARTED TO REGROW.

9298
06:10:31,242 --> 06:10:33,411
AND WE DON'T KNOW WHY BUT WE DO

9299
06:10:33,411 --> 06:10:35,380
KNOW THE TIME OF REGROWTH

9300
06:10:35,380 --> 06:10:38,883
COINCIDED WITH LOSS OF HER CAR T

9301
06:10:38,883 --> 06:10:40,985
CELL PERSISTENCE.

9302
06:10:40,985 --> 06:10:42,487
WE HAVE SEEN SOME -- BEEN ABLE

9303
06:10:42,487 --> 06:10:43,855
TO LOOK AT SOME TUMORS AT THE

9304
06:10:43,855 --> 06:10:45,890
TIME OF PROGRESSION AND SO FAR

9305
06:10:45,890 --> 06:10:50,295
WE'VE NOT SEEN LOSS OF TARGET.

9306
06:10:50,295 --> 06:10:51,796
WE KNOW RESISTANCE CAN HAPPEN

9307
06:10:51,796 --> 06:10:52,997
WITHOUT TARGET LOSS.

9308
06:10:52,997 --> 06:10:55,100
THAT DOESN'T MEAN NO ONE HAS

9309
06:10:55,100 --> 06:10:55,533
LOST TARGET.

9310
06:10:55,533 --> 06:10:57,402
WHEN YOU LOOK AT WHAT'S GOING ON

9311
06:10:57,402 --> 06:11:01,339
IN THE CSF IT'S REALLY

9312
06:11:01,339 --> 06:11:02,941
REMARKABLE WE'VE BEEN LEVERAGING

9313
06:11:02,941 --> 06:11:05,376
SINGLE CELL RNAseq IN THE

9314
06:11:05,376 --> 06:11:06,344
RESERVOIR, ACCESSING THE CELLS,

9315
06:11:06,344 --> 06:11:07,779
MANY OF THEM ARE T CELLS BUT

9316
06:11:07,779 --> 06:11:09,981
MANY OF THESE ARE MYELOID CELLS

9317
06:11:09,981 --> 06:11:11,516
IN THE CSF.

9318
06:11:11,516 --> 06:11:13,017
MYELOID CELLS COME IN MANY

9319
06:11:13,017 --> 06:11:15,220
SHAPES AN SIZES.

9320
06:11:15,220 --> 06:11:16,855
SOME ARE DERIVED FROM THE

9321
06:11:16,855 --> 06:11:19,891
MONOCYTES IN THE BLOOD.

9322
06:11:19,891 --> 06:11:23,528
SOME DERIVED FROM MICROGLIA,

9323
06:11:23,528 --> 06:11:24,529
SOME IMMUNE ACTIVATING, SOME

9324
06:11:24,529 --> 06:11:28,133
IMMUNE SUPPRESSIVE.

9325
06:11:28,133 --> 06:11:29,467
A TEMPORAL COURSE SEEMS TO WORK

9326
06:11:29,467 --> 06:11:30,869
WITH EACH PATIENT FOLLOWING A

9327
06:11:30,869 --> 06:11:38,543
SIMILAR TEMPORAL COURSE WITH

9328
06:11:38,543 --> 06:11:39,978
INFLUX OF MYELOID CELLS, COULD

9329
06:11:39,978 --> 06:11:41,379
BE WHY WE'RE SEEING RESISTANCE,

9330
06:11:41,379 --> 06:11:42,914
WE DON'T KNOW.

9331
06:11:42,914 --> 06:11:51,556
WE HAVE A CLEAR SIG AND  -- SIG.

9332
06:11:51,556 --> 06:11:53,658
NOT A HOME RUN BUT WE'RE ON

9333
06:11:53,658 --> 06:11:53,958
BASE.

9334
06:11:53,958 --> 06:11:56,694
WE CONTINUE TO ACCRUE TO PHASE 1

9335
06:11:56,694 --> 06:11:57,795
TRIAL.

9336
06:11:57,795 --> 06:12:00,198
I SHARED RESULTS FROM ARM A.

9337
06:12:00,198 --> 06:12:02,734
WE ENROLLED PATIENTS ON ARM B

9338
06:12:02,734 --> 06:12:06,437
WHERE WE USE NO LYMPHODEPLETION,

9339
06:12:06,437 --> 06:12:07,272
ICV ADMINISTRATION ONLY, HIGH

9340
06:12:07,272 --> 06:12:09,340
RATES OF RESPONSE BUT RESPONSE

9341
06:12:09,340 --> 06:12:11,776
WAS NOT DURABLE.

9342
06:12:11,776 --> 06:12:13,278
WE'RE WORRIED MAYBE THESE

9343
06:12:13,278 --> 06:12:14,379
PATIENTS WERE REJECTING CAR-T

9344
06:12:14,379 --> 06:12:16,247
CELLS BUT DON'T HAVE PROOF AS

9345
06:12:16,247 --> 06:12:16,581
YET.

9346
06:12:16,581 --> 06:12:22,153
WE'RE NOW TREATING ON ARM C, WE

9347
06:12:22,153 --> 06:12:27,759
GIVE ICV DELIVERY AND PERIODIC

9348
06:12:27,759 --> 06:12:28,159
DEPLETION.

9349
06:12:28,159 --> 06:12:29,727
WE'VE SEEN IMPRESSIVE RESPONSES

9350
06:12:29,727 --> 06:12:30,728
WITH DURABILITY, MAYBE THAT'S

9351
06:12:30,728 --> 06:12:34,866
GOING TO BE THE FINAL DOSE ROUTE

9352
06:12:34,866 --> 06:12:36,834
AND SCHEDULE FOR FORMAL EFFICACY

9353
06:12:36,834 --> 06:12:37,068
TESTING.

9354
06:12:37,068 --> 06:12:39,938
I DIDN'T TALK ABOUT SAFETY

9355
06:12:39,938 --> 06:12:40,772
MANAGEMENT BUT IT'S EVOLVES

9356
06:12:40,772 --> 06:12:41,573
SUBSTANTIALLY, WE'RE CONFIDENT

9357
06:12:41,573 --> 06:12:43,374
IN OUR APPROACH AT THE SINGLE

9358
06:12:43,374 --> 06:12:45,243
INSTITUTION LEVEL BUT IMPORTANT

9359
06:12:45,243 --> 06:12:46,878
NEXT STEPS TO EXPORT TO OTHER

9360
06:12:46,878 --> 06:12:48,179
PEDIATRIC HOSPITALS TO BE SURE

9361
06:12:48,179 --> 06:12:50,515
OTHERS CAN DELIVER IT SAFELY AND

9362
06:12:50,515 --> 06:12:54,652
WE'RE NOW EASING OUR ELIGIBILITY

9363
06:12:54,652 --> 06:13:01,793
CRITERIA TO SOME MORE HIGH RISK

9364
06:13:01,793 --> 06:13:04,529
CEREBELLAR AND THYLAMIC

9365
06:13:04,529 --> 06:13:05,063
PATIENTS.

9366
06:13:05,063 --> 06:13:06,598
WE'RE PROPOSING MULTI-CENTER

9367
06:13:06,598 --> 06:13:07,565
POTENTIALLY PIVOTALL PHASE 2

9368
06:13:07,565 --> 06:13:16,541
PRIAL, -- TRIAL, ENPOINTS COULD

9369
06:13:16,541 --> 06:13:19,944
BE RESPONSE RATE, OR SURVIVAL.

9370
06:13:19,944 --> 06:13:23,448
A DRUG WAS APPROVED FOR

9371
06:13:23,448 --> 06:13:24,315
NEUROFIBROMATOSIS PATIENT ON

9372
06:13:24,315 --> 06:13:25,416
PATIENT-REPORTED OUTCOMES SO

9373
06:13:25,416 --> 06:13:26,751
WE'RE INCORPORATING PATIENT

9374
06:13:26,751 --> 06:13:28,052
OUTCOMES INTO THE TRIAL NOW BUT

9375
06:13:28,052 --> 06:13:29,687
THE BIGGEST PROBLEM THAT KEEPS

9376
06:13:29,687 --> 06:13:32,357
ME UP AT NIGHT WE HAVE NO WAY TO

9377
06:13:32,357 --> 06:13:35,793
DEVELOP THIS THROUGH THE

9378
06:13:35,793 --> 06:13:36,261
COMMERCIAL MODEL.

9379
06:13:36,261 --> 06:13:37,562
BIOPHARMA WILL NOT DEVELOP CELL

9380
06:13:37,562 --> 06:13:39,297
AND GENE THERAPIES FOR

9381
06:13:39,297 --> 06:13:39,597
PEDIATRICS.

9382
06:13:39,597 --> 06:13:40,632
SO WE NEED NEW BUSINESS MODELS

9383
06:13:40,632 --> 06:13:44,035
TO BE ABLE TO DELIVER THIS TO

9384
06:13:44,035 --> 06:13:46,004
PATIENTS, IN A WAY THAT ENSURES

9385
06:13:46,004 --> 06:13:48,006
ACCESS TO EVERY PATIENT WHO

9386
06:13:48,006 --> 06:13:48,439
NEEDS IT.

9387
06:13:48,439 --> 06:13:50,908
AND SO THAT'S WHAT I FIND MYSELF

9388
06:13:50,908 --> 06:13:52,210
WORKING ON TODAY.

9389
06:13:52,210 --> 06:13:54,178
A NEW BUSINESS MODEL.

9390
06:13:54,178 --> 06:13:56,180
SCIENTIFIC WORK IS ONGOING, WE

9391
06:13:56,180 --> 06:13:57,482
NEED NEXT GENERATION APPROACHES,

9392
06:13:57,482 --> 06:13:59,284
WE'RE DOING THAT IN PARALLEL.

9393
06:13:59,284 --> 06:14:01,419
WHY THIS DISEASE?

9394
06:14:01,419 --> 06:14:04,155
WE HAVE AN ONCOGENE-DRIVEN

9395
06:14:04,155 --> 06:14:07,258
DRIVER, THIS MUTATION DRIVES GD2

9396
06:14:07,258 --> 06:14:07,792
EXPRESSION.

9397
06:14:07,792 --> 06:14:10,295
WE HAVE AN OPTIMIZED CAR.

9398
06:14:10,295 --> 06:14:11,596
WE HAVE LOCAL REGIONAL

9399
06:14:11,596 --> 06:14:12,931
ADMINISTRATION THAT COULD

9400
06:14:12,931 --> 06:14:14,332
POTENTIALLY OVERCOME TRAFFICKING

9401
06:14:14,332 --> 06:14:15,266
PROBLEMS.

9402
06:14:15,266 --> 06:14:16,634
BUT IF WE HAD HAD ONLY THE

9403
06:14:16,634 --> 06:14:18,403
ABILITY TO GIVE ONE DOSE I THINK

9404
06:14:18,403 --> 06:14:20,338
WE WOULD HAVE SEEN HIGH RESPONSE

9405
06:14:20,338 --> 06:14:21,673
RATES AND HIGH RECURRENCE RATES.

9406
06:14:21,673 --> 06:14:24,409
THE FACT THAT WE'RE ABLE TO GIVE

9407
06:14:24,409 --> 06:14:25,376
REPEATED DOSING IN THESE

9408
06:14:25,376 --> 06:14:26,811
DISEASES THAT ARE VERY STEM-LIKE

9409
06:14:26,811 --> 06:14:28,246
I THINK ARE VERY IMPORTANT.

9410
06:14:28,246 --> 06:14:29,347
I DON'T KNOW IF SOLID TUMORS

9411
06:14:29,347 --> 06:14:32,817
WILL BE ABLE TO BE CURED WITH A

9412
06:14:32,817 --> 06:14:34,585
ONE AND DONE APPROACH LIKE

9413
06:14:34,585 --> 06:14:35,353
LIQUID TUMORS.

9414
06:14:35,353 --> 06:14:45,697
IT TAKES AN ARMY. . 

9415
06:14:46,898 --> 06:14:48,933
I'VE HIGHLIGHTED THE WORK.

9416
06:14:48,933 --> 06:14:50,802
THE ENTIRE TEAM AT STANFORD AND

9417
06:14:50,802 --> 06:14:52,003
PATIENTS AND FAMILIES, AND HERE

9418
06:14:52,003 --> 06:14:53,104
ARE OUR FUNDERS.

9419
06:14:53,104 --> 06:14:53,638
THANK YOU VERY MUCH.

9420
06:14:53,638 --> 06:14:56,541
[APPLAUSE]

9421
06:14:56,541 --> 06:15:01,846
 

9422
06:15:01,846 --> 06:15:08,419
 

9423
06:15:08,419 --> 06:15:10,188
>> IF WE DON'T HAVE
QUESTIONS I

9424
06:15:10,188 --> 06:15:12,023
WOULD LIKE TO THANK AGAIN

9425
06:15:12,023 --> 06:15:13,358
EVERYONE FOR PARTICIPATING IN

9426
06:15:13,358 --> 06:15:15,093
DAY 1.

9427
06:15:15,093 --> 06:15:16,561
WE WILL ADJOURN.

9428
06:15:16,561 --> 06:15:18,463
REMINDER FOR THOSE THAT ARE

9429
06:15:18,463 --> 06:15:19,797
SURGERY BRANCH ALUMNI, WE'RE

9430
06:15:19,797 --> 06:15:23,634
GOING TO GATHER ON THE FAES

9431
06:15:23,634 --> 06:15:24,836
TERRACE WHERE POSTER SESSION WAS

9432
06:15:24,836 --> 06:15:28,906
AT AN ATTEMPT AT GROUP PHOTO.

9433
06:15:28,906 --> 06:15:38,906