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>>I'M DELIGHTED TODAY AND

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HONORED, REALLY, TO INTRODUCE

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DR. TONI RIBAS.

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HE IS A PROFESSOR OF MEDICINE

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WITH TENURE, PROFESSOR OF

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SURGERY IN MOLECULAR AND MEDICAL

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PHARMACOLOGY AT UCLA AND THE

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DIRECTOR OF THE TUMOR IMMUNOLOGY

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PROGRAM AT THE JONSSON

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COMPREHENSIVE CANCER CENTER, AND

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DIRECTOR OF THE PARKER INSTITUTE

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FOR CANCER IMMUNOTHERAPY AT

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UCLA.

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TONY DID HIS MD PH.D. AT THE

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UNIVERSITY OF BARCELONA AND

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STAYED ON AS A CLINICAL

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INSTRUCTOR BEFORE GOING TO UCLA

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IN 1996 AND DOING HIS POSTDOC

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THERE.

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SINCE THAT TIME, HE STAYED AT

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UCLA IN MULTIPLE DIFFERENT ROLES

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AND HE REALLY IS A TRUE

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PHYSICIAN SCIENTIST.

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HIS RESEARCH IS FOCUSED ON

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LABORATORY AND CLINICAL STUDIES

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TO ADDRESS PRIMARY AND ACQUIRED

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RESISTANCE FOR IMMUNOTHERAPY AND

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TARGETED THERAPIES AND ALSO THE

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DEVELOPMENT OF GENE ENGINEERED

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ADOPTIVE T-CELL TRANSFER

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THERAPIES FOR OTHER CANCERS.

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HE'S BEEN INSTRUMENTAL IN THE

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CLINICAL DEVELOPMENT OF SEVERAL

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DIFFERENT AGENTS THAT HAVE LED

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TO FDA APPROVAL, INCLUDING

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PEMBROLIZUMAB, THE FIRST PD-1

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INHIBITOR APPROVED BY THE FDA,

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TWO COMBINATIONS OF BRAF AND MEK

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INHIBITORS AND WAS ALSO INVOLVED

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IN THE INITIAL CD-19 CAR T FOR

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LYMPHOTHAT AXI CELL.

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HE'S A PAST PRESIDENT OF THE

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AACR AND ELECTED FELLOW IN THE

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AACR ACADEMY, THE ROYAL ACADEMY

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OF MEDICINE OF CATALONIA, THE

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AMERICAN SOCIETY OF CLINICAL

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INVESTIGATION AND THE NATIONAL

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ACADEMY OF MEDICINE.

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YOU KNOW, MY FIRST INTRODUCTION

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TO TONY REALLY WAS WHEN I HAD

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THE PRIVILEGE OF BEING

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ASSOCIATED WITH HIM AS HE WAS

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THE CO-LEADER OF THE STAND UP TO

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CANCER IMMUNOTHERAPY DREAM TEAM,

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ALONG WITH DR. JIM ALISON.

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AND YOU KNOW, I WAS REALLY

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IMPRESSED BY HIS LEADERSHIP AND

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HIS SCIENTIFIC INSIGHTS THERE.

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I ALSO HAD THE DISTINCT -- AND I

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WOULD GO AND VISIT WITH THE

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REVIEW TEAM EVERY SIX MONTHS FOR

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ABOUT FIVE YEARS, AND THEY MADE

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SOME AMAZING PROGRESS, HAD SOME

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AMAZING SCIENCE THAT CAME OUT OF

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THAT TEAM.

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IN ADDITION, I HAD THE DISTINCT

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PLEASURE OF WORKING WITH HIM ON

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THE AACR NCI EURTC TRIPLE

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MEETING FOR TWO YEARS AND

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REALLY, I JUST WANT TO SAY THAT

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HE'S AN INCREDIBLY BRIGHT AND

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THOUGHT-PROVOKING LEADER, HE'S A

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DYNAMIC SPEAKER, AND HE'S A

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SINCERE PERSONAL FRIEND.

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SO PLEASE JOIN ME IN WELCOMING

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DR. TONY RIBAS.

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[APPLAUSE]

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>>THIS IS WHAT HAPPEN
WHEN IS A

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FRIEND INTRODUCES YOU AND MAKES

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YOU LOOK GOOD.

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SO I WISH MY MOM WAS HERE AND

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SHE COULD HEAR THIS.

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[LAUGHTER]

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I'LL START WITH MY DISCLOSURES.

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WHAT I'M TRYING TO TALK ABOUT IS

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PERSONALIZED CELLULAR THERAPIES

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FOR CANCER.

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I'VE BEEN INVOLVED WITH SEVERAL

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COMPANIES.

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THERE'S ONE THAT HAS A

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PARTICULAR RELEVANCE, WHICH IS

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THIS 1PACPHARMA, BECAUSE ALL OF

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THE WORK I'M GOING TO BE TALKING

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ABOUT IS IN COLLABORATION WITH

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THEM.

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SO PLEASE TAKE THAT INTO ACCOUNT

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ON WHAT I'M TALKING ABOUT.

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AND I'M GOING TO BE TALKING

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ABOUT ANALYSIS OF ANTIGEN

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SPECIFIC -- BY TAKING SAMPLES

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FROM PATIENTS, ANALYZING THIS

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FIELD OF RARE CELLS THAT HAVE

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ANTIGEN SPECIFICITY FOR THE

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CANCER.

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AND THEN THE ABILITY TO

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RECOGNIZE THOSE CELLS ALLOWS US

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TO THINK ABOUT THE THERAPEUT%C

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WHERE WE ENGINEER CELLS TO

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EXPRESS THE RECEPTORS AND GIVE

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THEM TO PATIENTS WITH CANCER.

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I KNOW IT TAKES A LOT OF COURAGE

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TO GO TO THIS BUILDING AND TALK

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ABOUT TARGETING NEOANTIGENS, AND

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IT PROBABLY WHY JAMES HAS

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INVITED ME ON A DAY THAT --

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ROSENBERG, IT'S ONE OF THE FEW

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DAYS HE'S NOT IN TOWN.

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STEVE TOLD ME I'M ON VACATION IN

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LOS ANGELES AND YOU'RE COMING

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HERE, SO IT GIVES ME A LITTLE

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BIT MORE CONFIDENCE OF WHAT I'M

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TALKING ABOUT, BECAUSE WE'VE

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STUDIED ALL OF THESE BECAUSE OF

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THE PIONEERING WORK THAT HAS

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BEEN DONE IN THIS BUILDING,

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ABOUT HOW TILLS RECOGNIZE

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CANCER -- AT THE CORE OF HOW THE

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IMMUNE SYSTEM CAN DIFFERENTIATE

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CANCER CELLS FROM NORMAL CELLS.

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OUR THOUGHT WAS, WELL, IF THAT'S

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THE CASE AND WE KNOW THERE'S THE

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ALPHA AND BETA T-CELL RECEPTOR,

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CAN WE CLONE THOSE T-CELL

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RECEPTORS AND ENGINEER OTHER

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CELLS IN A WAY OF MAKING

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SYNTHETIC TILL THERAPIES.

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SO TO DO THAT, WE HAD TO COME UP

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WITH A SERIES OF NEW

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TECHNOLOGIES TO BE ABLE TO STUDY

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THE LANDSCAPE OF RESPONSES TO

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NEW ANTIGENS, CLONE THOSE T-CELL

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RECEPTORS AND ENGINEER THEM

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BACK.

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ONE OF THE NEW TECHNOLOGIES THAT

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NEEDED TO BE GENERATED IS TO BE

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ABLE TO ISOLATE PERSONALIZED

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T-CELL RECEPTORS BY DIRECT

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MISSION OF THE NEOANTIGENS, BUT

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WE WANT TO NOT DO IT ONLY ON

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HLA2.1, WE WANT TO BE ABLE TO

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COVER THE MAJORITY OF THE

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POPULATION, AND TO DO THAT, WE

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WANTED TO HAVE A PLATFORM THAT

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WOULD ALLOW US TO DO AS MANY

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HLAs CLASS Is AS WE COULD,

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ENDED UP 64 C CLASS Is, AND BE

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ABLE TO TAKE THOSE T-CELL

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RECEPTORS AND ENGINEER THEM BACK

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INTO THE PATIENT'S OWN T-CELLS,

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AND IF WE TRIED TO DO THAT WITH

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RETROVIRUS AND LENTIVIRUSES, WE

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COULD TREAT ONE PATIENT, I DON'T

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KNOW HOW MANY -- IN HOW MANY

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YEARS, AND THEN DO ANOTHER ONE,

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WE WANTED TO DO THIS IN AN

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EFFICIENT WAY SO WE HAD TO

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CREATE THOSE TECHNOLOGIES.

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SO I'LL WALK YOU THROUGH THE

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FIRST GENERATION OF THE

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TECHNOLOGIES AND THEN I'LL WALK

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YOU THROUGH WHAT EVENTUALLY WAS

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DONE WHEN THE TECHNOLOGIES WERE

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INDUSTRIALIZED AND PUT INTO

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CLINICAL -- THE FIRST WAS A

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POSTDOC IN JIM KEITH'S LAB,

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POSTDOC IN DAVID BALTIMORE'S LAB

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AND A GRADUATE STUDENT IN MY LAB

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WHO WORKED ON THIS SOLUBLE

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COMPLEXES OF -- PEPTIDE FROM DON

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SCHUMACHER'S APPROACH AND LOAD

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IT WITH A MUTATIONAL PEPTIDE,

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PUT IT INTO A NANOPARTICLE AND

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SORTED THEM OUT.

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THAT'S NOT WHAT WE DID IN THE

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CLINIC.

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THIS WAS THE FIRST ITERATION, IT

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NEEDED TO BE MORE SOLID THAN

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WHAT WE DESCRIBED IN THIS PAPER.

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AND THEN IF WE DO THAT, WE

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ISOLATE T-CELLS WITH THAT --

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THAT RECOGNIZE TUMOR ANTIGENS BY

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THIS SORTING WITH THE HLA

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PEPTIDE COMPLEXES, THEN WE NEED

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TO GET THOSE T-CELL RECEPTORS

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BACK.

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AND TO DO THAT, WE HAVE TO ALSO

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GENERATE THE NEW TECHNOLOGY, AND

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THAT WAS ENABLED BY THE CRISPR

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EDITING WHERE YOU CAN ONE STEP,

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YOU CAN -- CAS9 ON A DNA PLASMIC

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WITH HOMOLOGY ENDS THAT WOULD

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00:07:17,720 --> 00:07:19,360
BIND TO WHERE YOU CUT IT AND YOU

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COULD EFFICIENTLY KNOCK OUT THE

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GENE AND KNOCK IN ANOTHER GENE.

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AND THIS WOULD BE THE T-CELL

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RECEPTOR.

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THE FIRST ITERATION OF THIS WAS

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DONE BY A GRADUATE STUDENT IN

209
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ALEX MARSON'S LAB AND A POSTDOC

210
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IN MY LAB, AND YOU'LL SEE MORE

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WORK FROM CHRIS THAT COMES FROM

212
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THIS ABILITY TO --

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SPECIFICALLY -- IN AN EFFICIENT

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MANNER.

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SO THEN WE'VE DONE ALL OF THIS,

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THEN I'M GOING TO SHOW YOU IF

217
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THE TECHNOLOGIES WORK, WHAT DO

218
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THESE T-CELL RECEPTORS DO, CAN

219
00:07:54,840 --> 00:07:56,760
WE GET THESE T-CELLS THAT ARE

220
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GENE-ENGINEERED WITH A NEO --

221
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THAT WE SORTED FROM PATIENTS,

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CAN WE GET THEM TO SHOW THEY

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RECOGNIZE AND KILL TUMOR CELLS.

224
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SO I'M GOING TO GO THROUGH DATA

225
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PRESENTED BY CRIS THAT PAST FALL

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THAT'S NOW BEEN WRITTEN UP AND

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IT WILL COME OUT IN PUBLICATION.

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THIS IS THE ABILITY TO USE THESE

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TECHNOLOGIES TO STUDY AN IMMUNE

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RESPONSE IN THA HUMANS.

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WE'LL TALK AFTERWARDS HOW TO USE

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THE T-CELL RECEPTORS AS

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THERAPEUTICS.

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WHAT WE WANTED TO DO WAS HAVE A

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LANDSCAPE ANALYSIS OF

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NEOANTIGEN-SPECIFIC T-CELL

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RESPONSES INDUCED BY IMMUNE

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CHECKPOINT BLOCKADE.

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AND TO DO THIS, WE TOOK 11

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PATIENTS, ALL OF THEM FROM MY

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CLINIC AT UCLA, THAT HAD

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RECEIVED ANTI-PD-1-BASED THERAPY

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IN SOME FORM, DIFFERENT

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ANTI-PD-1s, MOST OF THEM

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SINGLE AGENTS, SOME OF THEM IN

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COMBINATION.

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OF THESE 11 PATIENTS, THE FIRST

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SEVEN PATIENTS HAD OBJECTIVE

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RESPONSES TO THERAPY.

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AND THE LAST FOUR HAD NO

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RESPONSES TO THERAPY.

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SO WE WANTED TO COMPARE THE

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T-CELLS THAT WE ISOLATED FROM

254
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THESE PATIENTS FROM T-CELLS THAT

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WE ISOLATED FROM THESE PATIENTS.

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AND IN SOME OF THEM, IN FIVE OF

257
00:09:14,560 --> 00:09:19,840
THESE 11 PATIENTS, WE HAD

258
00:09:19,840 --> 00:09:23,560
STUDIED A PATIENT

259
00:09:23,560 --> 00:09:26,840
MELANOMA-SPECIFIC CELL LINE,

260
00:09:26,840 --> 00:09:27,720
TESTING IN VITRO AGAINST THE

261
00:09:27,720 --> 00:09:29,600
PATIENT'S OWN CELL LAN

262
00:09:29,600 --> 00:09:32,560
IRRESPECTIVE OF WHAT HLA WAS

263
00:09:32,560 --> 00:09:34,600
RESTRICTED BECAUSE THEY WERE ALL

264
00:09:34,600 --> 00:09:36,240
ENDOGENOUS HLAs.

265
00:09:36,240 --> 00:09:38,080
SO NOW THE TECHNOLOGY AS IT

266
00:09:38,080 --> 00:09:41,040
EVOLVED WHEN PACPHARMA PUT OVER

267
00:09:41,040 --> 00:09:44,600
100 PEOPLE TO WORK ON IT, WAS

268
00:09:44,600 --> 00:09:47,520
THAT WE WOULD TAKE A TUMOR AND

269
00:09:47,520 --> 00:09:51,040
CELL LINE INITIALLY, ANY TUMOR

270
00:09:51,040 --> 00:09:52,800
BIOPSY, AND DO DNA TO LOOK FOR

271
00:09:52,800 --> 00:09:54,520
MUTATIONS, RNA TO LOOK FOR

272
00:09:54,520 --> 00:09:56,520
EXPRESS GENE, AND THEN I COMPARE

273
00:09:56,520 --> 00:09:59,080
IT WITH A PERIPHERAL BLOCK MONO

274
00:09:59,080 --> 00:10:00,640
NUCLEAR CELLS, SO YOU COULD HAVE

275
00:10:00,640 --> 00:10:03,760
A PREDICTED LIST OF MUTATIONS

276
00:10:03,760 --> 00:10:04,920
THAT COULD -- THAT WOULD BE

277
00:10:04,920 --> 00:10:08,760
PRESENTED BY DIFFERENT HLAs

278
00:10:08,760 --> 00:10:11,920
AND THE SEQUENCING WOULD GIVE US

279
00:10:11,920 --> 00:10:13,720
THE SIX HLAs OF THE PATIENT,

280
00:10:13,720 --> 00:10:16,920
AND THEN WE'D HAVE THIS ABILITY

281
00:10:16,920 --> 00:10:18,200
TO MAKE PROTEINS THAT HAVE --

282
00:10:18,200 --> 00:10:20,600
THAT ARE A SINGLE CHAIN TRIMER

283
00:10:20,600 --> 00:10:24,080
OF HLA BETA TO MICRO GLOBULIN ON

284
00:10:24,080 --> 00:10:26,120
THE MUTATED PEPTIDE ALL IN A

285
00:10:26,120 --> 00:10:27,600
SEQUENCE OF NUCLEOTIDES THAT

286
00:10:27,600 --> 00:10:29,880
THEN WOULD MAKE THE PROTEIN IN

287
00:10:29,880 --> 00:10:33,040
293 CELLS, AND THOSE PROTEINS

288
00:10:33,040 --> 00:10:35,280
WOULD SELF-ASSEMBLE IF THE

289
00:10:35,280 --> 00:10:39,960
PEPTIDE STABILIZES, IT

290
00:10:39,960 --> 00:10:42,040
STABILIZES THIS SINGLE CHAIN

291
00:10:42,040 --> 00:10:46,760
TRIMER WITH BIOTIN LAITION AND

292
00:10:46,760 --> 00:10:49,560
THEN YOU HAVE THE AFFINITY, DNA

293
00:10:49,560 --> 00:10:50,800
BARCODING TO HAVE HUNDREDS OF

294
00:10:50,800 --> 00:10:54,080
THESE PER PATIENT, FLUORESCENTLY

295
00:10:54,080 --> 00:10:55,720
LABELED AND COCULTURED WITH

296
00:10:55,720 --> 00:10:57,760
T-CELLS THAT WE OBTAIN FROM THE

297
00:10:57,760 --> 00:11:00,640
PATIENT'S BLOOD OF THE PATIENTS'

298
00:11:00,640 --> 00:11:01,080
TUMORS.

299
00:11:01,080 --> 00:11:02,480
I KNOW I'M GOING FAST ON ALL OF

300
00:11:02,480 --> 00:11:04,560
THIS, BUT IT A COMPLICATED

301
00:11:04,560 --> 00:11:05,320
TECHNOLOGY, BUT THE WHOLE THING

302
00:11:05,320 --> 00:11:09,000
IS THAT WE CAN MAKE THESE

303
00:11:09,000 --> 00:11:12,120
BARCODED HLA MUTATED PEPTIDE

304
00:11:12,120 --> 00:11:14,480
COMPLEXES THAT COULD BE USED

305
00:11:14,480 --> 00:11:17,240
THROUGH MULTIPLE HLAs, THE SIX

306
00:11:17,240 --> 00:11:25,400
HIGH PRESSUHLAs FROM EVERY PATI.

307
00:11:25,400 --> 00:11:26,680
SO HERE ARE THE 11 PATIENTS, AND

308
00:11:26,680 --> 00:11:28,280
THIS IS THE NUMBER OF MUTATIONS.

309
00:11:28,280 --> 00:11:29,440
HERE ARE THE PATIENTS WHO HAVE

310
00:11:29,440 --> 00:11:31,320
RESPONDED TO ANTIPD-1 THERAPY,

311
00:11:31,320 --> 00:11:34,040
AND HERE ARE PATIENTS WHO DID

312
00:11:34,040 --> 00:11:36,920
NOT RESPOND TO ANTIPD-# THERAPY.

313
00:11:36,920 --> 00:11:39,080
THESE ARE ALL PATIENTS WITH

314
00:11:39,080 --> 00:11:39,320
MELANOMA.

315
00:11:39,320 --> 00:11:40,760
THE PATIENTS WITH CLINICAL

316
00:11:40,760 --> 00:11:41,960
RESPONSE TEND TO HAVE MORE

317
00:11:41,960 --> 00:11:46,560
MUTATIONS BULL I BUT IT'S NOT L.

318
00:11:46,560 --> 00:11:48,320
THESE HAD 977 NON-SYNONYMOUS

319
00:11:48,320 --> 00:11:48,920
MUTATIONS.

320
00:11:48,920 --> 00:11:52,160
FROM THERE, WE LOOKED AT THE

321
00:11:52,160 --> 00:11:53,000
MUTATIONS THAT COULD BE SCREENED

322
00:11:53,000 --> 00:11:54,440
BECAUSE WE HAD THE PREDICTION

323
00:11:54,440 --> 00:11:55,520
ALGORITHMS TO PRESENT WITH ONE

324
00:11:55,520 --> 00:12:00,920
OF THESE 64 HLA CLASS 1s THAT

325
00:12:00,920 --> 00:12:03,080
IN THE PACKPHARMA REPOSITORY,

326
00:12:03,080 --> 00:12:05,840
THEN THEY MADE EIGHT OF THESE

327
00:12:05,840 --> 00:12:08,120
SINGLE CHAIN TRIMERS THAT ARE

328
00:12:08,120 --> 00:12:10,080
MULTI-MERRIZED OF NEOANTIGEN

329
00:12:10,080 --> 00:12:10,680
HLAs.

330
00:12:10,680 --> 00:12:16,760
SO FROM THIS FIRST PATIENT THAT

331
00:12:16,760 --> 00:12:19,240
THAT -- MADE IT INTO 243 LIBRARY

332
00:12:19,240 --> 00:12:23,000
OF HLA PEPTIDE -- BETA PEPTIDE

333
00:12:23,000 --> 00:12:24,160
COMPLEXES BECAUSE FOR SOME

334
00:12:24,160 --> 00:12:25,960
MUTATIONS, YOU COULD HAVE A

335
00:12:25,960 --> 00:12:27,040
PRESENTATION BY DIFFERENT

336
00:12:27,040 --> 00:12:27,560
HLAs.

337
00:12:27,560 --> 00:12:28,800
WE CAN GO DOWN, THIS IS THE

338
00:12:28,800 --> 00:12:32,640
MAXIMUM THAT WE DID IS 243.

339
00:12:32,640 --> 00:12:38,520
THIS TUMOR THAT HAD MUTATION, WE

340
00:12:38,520 --> 00:12:41,080
COULD ONLY MAKE 17 SOLID

341
00:12:41,080 --> 00:12:43,080
COMPLEXES OF PEPTIDE HLA.

342
00:12:43,080 --> 00:12:44,920
SO WE SEE HOW MANY OF THESE

343
00:12:44,920 --> 00:12:47,320
COMPLEXES BOUND TO T-CELLS IN

344
00:12:47,320 --> 00:12:49,320
PATIENTS' BLOOD THAT MADE THE

345
00:12:49,320 --> 00:12:51,120
CUTOFF TO SAY THAT THEY'RE

346
00:12:51,120 --> 00:12:53,880
ANTIGEN-SPECIFIC T-CELLS.

347
00:12:53,880 --> 00:12:55,040
WE CAN SEE THAT NOW THE NUMBER

348
00:12:55,040 --> 00:12:56,400
OF MUTATIONS THAT ARE TARGETED

349
00:12:56,400 --> 00:12:58,760
AND RECOGNIZED BY T-CELLS ARE

350
00:12:58,760 --> 00:12:59,600
VERY FEW.

351
00:12:59,600 --> 00:13:02,400
SO EVEN IF YOU START WITH 3,000,

352
00:13:02,400 --> 00:13:04,560
THERE WERE ONLY -- WE MADE A

353
00:13:04,560 --> 00:13:08,440
LIBRARY OF 243 HLA PEPTIDE

354
00:13:08,440 --> 00:13:09,800
COMPLEXES, ONLY 11 OF THEM WERE

355
00:13:09,800 --> 00:13:10,120
RECOGNIZED.

356
00:13:10,120 --> 00:13:13,960
LET GO DOWN HERE FROM 17 PEPTIDE

357
00:13:13,960 --> 00:13:15,560
HLA COMPLEXES, FIVE WERE

358
00:13:15,560 --> 00:13:16,000
RECOGNIZED.

359
00:13:16,000 --> 00:13:17,880
TELLING US THAT THERE'S

360
00:13:17,880 --> 00:13:21,840
SOMETHING CONSTANT HERE WHERE

361
00:13:21,840 --> 00:13:22,800
THE IMMUNE SYSTEM RECOGNIZES

362
00:13:22,800 --> 00:13:24,920
SOME MUTATIONS IN AN

363
00:13:24,920 --> 00:13:26,440
IMMUNODOMINANT WAY, AND SEEMS TO

364
00:13:26,440 --> 00:13:28,280
IGNORE MANY OTHERS, AND IT'S NOT

365
00:13:28,280 --> 00:13:33,360
LINEAR LIQUOR LALY CORRELATED, R

366
00:13:33,360 --> 00:13:34,760
THAT THE TUMOR HAS AND THE

367
00:13:34,760 --> 00:13:36,720
NUMBER OF T-CELLS THE PATIENT

368
00:13:36,720 --> 00:13:37,920
RECOGNIZES.

369
00:13:37,920 --> 00:13:39,800
THESE DID NOT SEPARATE PATIENTS

370
00:13:39,800 --> 00:13:41,560
WITH RESPONSE OR NO RESPONSE TO

371
00:13:41,560 --> 00:13:41,960
THERAPY.

372
00:13:41,960 --> 00:13:43,640
JUST THE METRIC OF THE NUMBER OF

373
00:13:43,640 --> 00:13:45,160
T-CELLS RECOGNIZING THESE

374
00:13:45,160 --> 00:13:45,880
COMPLEXES.

375
00:13:45,880 --> 00:13:50,400
BUT IF WE LOOK AT THE NUMBER OF

376
00:13:50,400 --> 00:13:51,680
P CELL RECEPTOR CHRONOTYPES THAT

377
00:13:51,680 --> 00:13:53,120
RECOGNIZE THESE MUTATIONS, THEN

378
00:13:53,120 --> 00:13:54,240
THERE'S A SPREAD.

379
00:13:54,240 --> 00:13:56,200
THE PATIENTS WHO HAD CLINICAL

380
00:13:56,200 --> 00:13:59,840
RESPONSE TO THERAPY, THEY HAD A

381
00:13:59,840 --> 00:14:02,120
LOT MORE CLONAL TYPES FOR EVERY

382
00:14:02,120 --> 00:14:07,560
KNEW TAITIONEVERYMUTATION THAT'.

383
00:14:07,560 --> 00:14:11,000
SO SAY THERE'S THREE RECOGNITION

384
00:14:11,000 --> 00:14:12,160
BUT 24 DIFFERENT T-CELL

385
00:14:12,160 --> 00:14:14,720
RECEPTORS THAT RECOGNIZE THOSE

386
00:14:14,720 --> 00:14:16,800
THREE HLA PEPTIDE COMPLEXES.

387
00:14:16,800 --> 00:14:18,320
IN PATIENTS WITHOUT RESPONSE TO

388
00:14:18,320 --> 00:14:19,720
THERAPY, THERE WAS SOME

389
00:14:19,720 --> 00:14:20,720
DISCREPANCY BUT THE MAJORITY OF

390
00:14:20,720 --> 00:14:25,000
THEM HAD A LOT LESS TCR CLOA

391
00:14:25,000 --> 00:14:27,880
KNOW TYPES RECOGNIZING SIMILAR

392
00:14:27,880 --> 00:14:35,520
NUMBERS OF MUTATIONS.

393
00:14:35,520 --> 00:14:38,360
THE DATA I'M SHOWING YOU, I'M

394
00:14:38,360 --> 00:14:39,760
GOING TO WALK YOU THROUGH HERE.

395
00:14:39,760 --> 00:14:41,760
THIS IS A PATIENT WITH A LUNG

396
00:14:41,760 --> 00:14:44,040
METASTASES RESPONDING TO

397
00:14:44,040 --> 00:14:44,640
ANTI-PD-1.

398
00:14:44,640 --> 00:14:50,440
THIS IS PRUF RAL BLOOD MONO --

399
00:14:50,440 --> 00:14:51,080
BASELINE AT DAY 14.

400
00:14:51,080 --> 00:14:52,240
HERE FROM THIS PATIENT NUMBER

401
00:14:52,240 --> 00:14:58,000
TWO, WE HAD MET A LIBRARY OF 24A

402
00:14:58,000 --> 00:15:00,400
COMPLEXES, I THINK IT WAS OVER

403
00:15:00,400 --> 00:15:05,000
FOUR OF THE SIX, AND THEY WERE

404
00:15:05,000 --> 00:15:07,320
ORGANIZED BY LOW AFFINITY TO

405
00:15:07,320 --> 00:15:08,280
HIGH AFFINITY.

406
00:15:08,280 --> 00:15:10,800
AND THIS IS THE RECOGNITION OF

407
00:15:10,800 --> 00:15:14,080
T-CELLS, SO EACH BOX IS ONE

408
00:15:14,080 --> 00:15:16,080
T-CELL.

409
00:15:16,080 --> 00:15:20,000
AND X IS 10 T-CELLS SO WE DON'T

410
00:15:20,000 --> 00:15:21,000
DWARF ALL OF THESE.

411
00:15:21,000 --> 00:15:22,200
THERE'S ACTUALLY THREE MUTATIONS

412
00:15:22,200 --> 00:15:25,240
THAT ARE RECOGNIZE DOLLARS.

413
00:15:25,240 --> 00:15:30,720
IL-18 PRESENT BY HLA2.4 OR HLA

414
00:15:30,720 --> 00:15:33,280
A03 IS RECOGNIZED BY SEVERAL

415
00:15:33,280 --> 00:15:35,000
T-CELLS, EACH CLONE OF T-CELL

416
00:15:35,000 --> 00:15:36,200
RECEPTOR IS ONE COLOR.

417
00:15:36,200 --> 00:15:39,560
SO THERE'S TWO T-CELLS WITH A

418
00:15:39,560 --> 00:15:40,920
T-CELL RECEPTOR THAT'S THE

419
00:15:40,920 --> 00:15:42,000
SEQUENCE OF THIS BLUE AND

420
00:15:42,000 --> 00:15:46,360
THERE'S THE RED T-CELL RECEPTOR,

421
00:15:46,360 --> 00:15:49,560
THERE'S 14, 10 PLUS FOUR HERE.

422
00:15:49,560 --> 00:15:50,880
THERE'S THESE OTHER TWO ANTIGENS

423
00:15:50,880 --> 00:15:52,400
THAT ARE RECOGNIZED WITH JUST A

424
00:15:52,400 --> 00:15:54,800
COUPLE OF CELLS THAT MADE THE

425
00:15:54,800 --> 00:15:59,560
CUTOFF TO BE ABLE TO RECOGNIZE.

426
00:15:59,560 --> 00:16:01,120
AND WITH NOT ONLY THIS ONE TIME,

427
00:16:01,120 --> 00:16:03,160
WE DID IT OVER TIME, SO NOW I'M

428
00:16:03,160 --> 00:16:06,000
GOING TO ADD THE DIFFERENT TIME

429
00:16:06,000 --> 00:16:06,440
POINTS.

430
00:16:06,440 --> 00:16:08,440
AT BASELINE WE HAD A BIOPSY,

431
00:16:08,440 --> 00:16:10,440
WHICH IS JUST A CORE BIOPSY AND

432
00:16:10,440 --> 00:16:11,920
WE EXPANDED T-CELLS FROM THERE,

433
00:16:11,920 --> 00:16:15,160
SO IT'S A SKEWED READOUT.

434
00:16:15,160 --> 00:16:17,320
HERE'S PBMCs AT DIFFERENT TIME

435
00:16:17,320 --> 00:16:18,040
POINTS, AND THEN WHEN THE

436
00:16:18,040 --> 00:16:19,680
PATIENT WAS RESPONDING, THERE

437
00:16:19,680 --> 00:16:21,120
WAS ANOTHER CORE BIOPSY FROM

438
00:16:21,120 --> 00:16:23,000
THIS LUNG METASTASES ON

439
00:16:23,000 --> 00:16:24,720
EXPANDING THE T-CELLS.

440
00:16:24,720 --> 00:16:28,200
IF WE LOOK AT THIS, AGAIN, IT'S

441
00:16:28,200 --> 00:16:32,680
NON-RANDOM DATA.

442
00:16:32,680 --> 00:16:35,120
IT THE SAME FOUR MUTATED

443
00:16:35,120 --> 00:16:36,880
PEPTIDES, ONE OF THEM

444
00:16:36,880 --> 00:16:38,000
PRESENTED -- THE SAME PEPTIDE

445
00:16:38,000 --> 00:16:39,960
PRESENTED BY TWO HLAs, SO

446
00:16:39,960 --> 00:16:40,840
THERE'S ONLY THREE MUTATIONS

447
00:16:40,840 --> 00:16:43,040
THAT ARE BEING RECOGNIZED OVER

448
00:16:43,040 --> 00:16:45,920
TIME, WHEN WE HAD A LIBRARY OF

449
00:16:45,920 --> 00:16:50,240
243 PUTATIVE HLA NEOANTIGEN

450
00:16:50,240 --> 00:16:52,560
COMPLEXES.

451
00:16:52,560 --> 00:16:54,080
AND THERE'S THESE CLONOTYPES

452
00:16:54,080 --> 00:16:55,840
THAT APPEAR AND DISAPPEAR, SO

453
00:16:55,840 --> 00:16:57,680
THIS ONE IS THE SAME ONE ALL OF

454
00:16:57,680 --> 00:16:59,520
THE TIME, THIS ONE IS THE SAME

455
00:16:59,520 --> 00:17:01,040
ONE ALL THE TIME BUT HERE WE SEE

456
00:17:01,040 --> 00:17:03,040
THIS ANTIGEN HAS MULTIPLE T-CELL

457
00:17:03,040 --> 00:17:04,120
RECEPTORS OF DIFFERENT COLORS

458
00:17:04,120 --> 00:17:05,040
THAT EXPAND AT DIFFERENT TIME

459
00:17:05,040 --> 00:17:06,120
POINTS.

460
00:17:06,120 --> 00:17:07,640
I DON'T THINK THIS TELLS US

461
00:17:07,640 --> 00:17:09,680
ANYTHING ABOUT THE CLONAL

462
00:17:09,680 --> 00:17:10,480
REPOPULATION.

463
00:17:10,480 --> 00:17:12,160
I THINK IT'S SAMPLING ERROR.

464
00:17:12,160 --> 00:17:16,040
WE HAD 10 MLs OF BLOOD IN A

465
00:17:16,040 --> 00:17:18,000
CORE BIOPSY SO THERE'S A LOT OF

466
00:17:18,000 --> 00:17:18,960
SAMPLING ERROR OF THIS BUT WHAT

467
00:17:18,960 --> 00:17:21,640
IT TELLS US IS THAT THE SAME

468
00:17:21,640 --> 00:17:24,040
MUTATIONS KEEP BEING RECOGNIZED

469
00:17:24,040 --> 00:17:26,680
OVER TIME, IN THIS PATIENT

470
00:17:26,680 --> 00:17:28,720
RESPONDING TO ANTIPD-1.

471
00:17:28,720 --> 00:17:30,000
THAT'S PATIENT NUMBER 2, I'LL

472
00:17:30,000 --> 00:17:31,080
SHOW YOU THE SAME GRAPH.

473
00:17:31,080 --> 00:17:32,920
THERE WERE FOUR MUTATIONS,

474
00:17:32,920 --> 00:17:34,880
ACTUALLY THREE MUTATIONS

475
00:17:34,880 --> 00:17:36,080
PRESENTED BY -- ONE OF THEM

476
00:17:36,080 --> 00:17:42,880
PRESENTED BY TWO HLAs AND

477
00:17:42,880 --> 00:17:43,680
21 NEOANTIGEN PCRs.

478
00:17:43,680 --> 00:17:47,960
HERE WE HAVE A LIBRARY OF

479
00:17:47,960 --> 00:17:49,480
243 NEOANTIGEN HLA COMPLEXES ALL

480
00:17:49,480 --> 00:17:50,120
ORGANIZED.

481
00:17:50,120 --> 00:17:51,120
THE ONE IN COLOR ARE THE ONES

482
00:17:51,120 --> 00:17:53,320
THAT HAVE AT LEAST ONE T-CELL

483
00:17:53,320 --> 00:17:55,000
THAT RECOGNIZE IT, SO LET'S SAY

484
00:17:55,000 --> 00:17:59,480
THIS ONE, PLA2GA PRESENTED BY

485
00:17:59,480 --> 00:18:01,480
HLA2.1, THERE'S A SINGLE T-CELL

486
00:18:01,480 --> 00:18:04,200
THAT RECOGNIZES THIS MUTATION AT

487
00:18:04,200 --> 00:18:09,160
ONE TIME POINT, AS OPPOSED TO

488
00:18:09,160 --> 00:18:13,240
THIS NON188, RECOGNIZING IT

489
00:18:13,240 --> 00:18:16,280
MULTIPLE TIMES OR WDR1 THAT HAS

490
00:18:16,280 --> 00:18:19,320
ONLY TWO CLONOTYPES BUT MULTIPLE

491
00:18:19,320 --> 00:18:20,440
T-CELLS EXPANDED IN DIFFERENT

492
00:18:20,440 --> 00:18:20,920
TIMES.

493
00:18:20,920 --> 00:18:22,840
SO HERE THERE WERE 11 MUTATIONS

494
00:18:22,840 --> 00:18:25,240
RECOGNIZED BY 41 DISTINCT T-CELL

495
00:18:25,240 --> 00:18:27,120
RECEPTORS.

496
00:18:27,120 --> 00:18:29,640
SO HOW CAN I CONVINCE THAT THESE

497
00:18:29,640 --> 00:18:30,920
T-CELL RECEPTORS ARE THE RIGHT

498
00:18:30,920 --> 00:18:33,560
ONES AND NOT JUST NOISE OR

499
00:18:33,560 --> 00:18:34,800
BINDING -- NONSPECIFIC BINDING

500
00:18:34,800 --> 00:18:36,320
WHEN WE HAD CELL LINES FROM

501
00:18:36,320 --> 00:18:40,200
THESE PATIENTS, WE CAN GET THESE

502
00:18:40,200 --> 00:18:42,000
T-CELL RECEPTORS, CLONE THEM,

503
00:18:42,000 --> 00:18:43,640
CRISPR EDITING THEM INTO DONOR

504
00:18:43,640 --> 00:18:45,000
T-CELLS AND THEN COCULTURE THEM

505
00:18:45,000 --> 00:18:46,920
WITH THE MELANOMA CELL LINE FROM

506
00:18:46,920 --> 00:18:49,600
THE PATIENT.

507
00:18:49,600 --> 00:18:52,040
SO HERE WE GO BACK TO PATIENT

508
00:18:52,040 --> 00:18:57,280
NUMBER 2, THE ONE THAT HAD TWO

509
00:18:57,280 --> 00:19:00,480
MUTATIONS, PRESENTED BY HLA

510
00:19:00,480 --> 00:19:03,520
2.1 SO T-CELLS EXPRESSING THIS

511
00:19:03,520 --> 00:19:04,840
T-CELL RECEPTOR RECOGNIZING THIS

512
00:19:04,840 --> 00:19:06,000
MUTATION KILLED THE TUMOR, THE

513
00:19:06,000 --> 00:19:08,360
TUMOR IS IN RED, THE T-CELLS

514
00:19:08,360 --> 00:19:09,800
EXPAND AND THAT'S WHY THERE'S

515
00:19:09,800 --> 00:19:11,280
ALL THESE VERY DARK -- THOSE ARE

516
00:19:11,280 --> 00:19:15,000
THE T-CELLS, AND HERE'S A

517
00:19:15,000 --> 00:19:18,640
CONTROL NEOANTIGEN TCR,

518
00:19:18,640 --> 00:19:20,160
ENGINEERED -- WITH CRISPR

519
00:19:20,160 --> 00:19:22,200
EDITING, THE MELANOMA CELLS GROW

520
00:19:22,200 --> 00:19:26,080
PRPROGRESSIVELY.

521
00:19:26,080 --> 00:19:31,880
WE TREAT WITH -- THIS TCR NUMBER

522
00:19:31,880 --> 00:19:33,200
2 KILLED THE TUMOR.

523
00:19:33,200 --> 00:19:35,520
THAT'S ONE OF THE TCRs THAT

524
00:19:35,520 --> 00:19:37,040
I'LL SHOW YOU FROM THAT PLOT BUT

525
00:19:37,040 --> 00:19:37,440
THERE'S 20 OTHERS.

526
00:19:37,440 --> 00:19:39,160
WHAT HAPPENED WITH THE 2 20

527
00:19:39,160 --> 00:19:39,560
OTHERS?

528
00:19:39,560 --> 00:19:40,480
WE DID THE SAME EXPERIMENT AND

529
00:19:40,480 --> 00:19:43,480
ALL OF THEM, ALL 21 OF THEM,

530
00:19:43,480 --> 00:19:48,640
KILLED THE ANTIGEN MATCHED

531
00:19:48,640 --> 00:19:49,440
TUMOR.

532
00:19:49,440 --> 00:19:50,640
TELLING US ASSORTING THESE

533
00:19:50,640 --> 00:19:54,880
CELLS, CLONING THE TCRs AND

534
00:19:54,880 --> 00:19:56,960
GENE EDITING THEM BACK CAN GET

535
00:19:56,960 --> 00:19:59,040
THEM IN SOME CASES AS EFFICIENT

536
00:19:59,040 --> 00:20:00,960
AS THESE ARE, EVERY SINGLE ONE

537
00:20:00,960 --> 00:20:02,680
SELECTED THIS WAY LED TO

538
00:20:02,680 --> 00:20:04,520
CYTOTOXIC ACTIVITY TO THE SAME

539
00:20:04,520 --> 00:20:06,360
CANCER CELL.

540
00:20:06,360 --> 00:20:08,320
THAT'S NOT IN ALL, BUT IT

541
00:20:08,320 --> 00:20:09,440
ACTUALLY WAS THE MAJORITY.

542
00:20:09,440 --> 00:20:11,240
LET'S LOOK AT PATIENT NUMBER ONE

543
00:20:11,240 --> 00:20:16,400
THAT HAD, I THINK, 41 TCRs,

544
00:20:16,400 --> 00:20:20,000
TARGETING 11 MUTATIONS.

545
00:20:20,000 --> 00:20:21,240
NON-NEOANTIGEN -- BY DIFFERENT

546
00:20:21,240 --> 00:20:23,440
HLAs SO HERE ARE ALL OF THE

547
00:20:23,440 --> 00:20:23,720
NEOANTIGENS.

548
00:20:23,720 --> 00:20:25,040
IN THIS CASE IT WAS A LITTLE BIT

549
00:20:25,040 --> 00:20:25,280
DIFFERENT.

550
00:20:25,280 --> 00:20:26,920
THE CELL LINE FROM THIS PATIENT

551
00:20:26,920 --> 00:20:33,080
WERE CALLED MR495, HERE WE'RE

552
00:20:33,080 --> 00:20:34,720
TESTING A SET OF TCRs, ANOTHER

553
00:20:34,720 --> 00:20:37,800
SET OF TCRs, ANOTHER SET OF

554
00:20:37,800 --> 00:20:39,120
TCRs, AND THEY'RE ORGANIZED

555
00:20:39,120 --> 00:20:41,520
LOGICALLY WHERE ALL OF THESE TCR

556
00:20:41,520 --> 00:20:43,720
KILL THE AUTOLOGOUS CELL, NOT

557
00:20:43,720 --> 00:20:46,200
THE MISMATCH.

558
00:20:46,200 --> 00:20:49,280
THIS ONE HAD INTERMEDIATE

559
00:20:49,280 --> 00:20:50,280
KILLING, THESE ONES HAD NO

560
00:20:50,280 --> 00:20:51,400
KILLING AT ALL.

561
00:20:51,400 --> 00:20:52,600
WHEN WE WENT THROUGH THE DATA OF

562
00:20:52,600 --> 00:20:53,640
THIS PATIENT, IT WAS SAID THAT

563
00:20:53,640 --> 00:20:59,360
THE NUP P188 HAD MULTIPLE TCRs

564
00:20:59,360 --> 00:21:00,640
AT MULTIPLE TIME POINTS, THAT

565
00:21:00,640 --> 00:21:02,120
WAS ONE OF THE GOOD KILLERS, AS

566
00:21:02,120 --> 00:21:04,480
OPPOSED TO THE 2GA 4-RBGS THERE

567
00:21:04,480 --> 00:21:06,760
WAS ONLY ONE T-CELL AND THAT WAS

568
00:21:06,760 --> 00:21:07,800
ONLY ONE TIME POINT AND THAT

569
00:21:07,800 --> 00:21:09,320
DIDN'T KILL AT ALL, THEN THERE'S

570
00:21:09,320 --> 00:21:13,360
THE INTERMEDIATE TCRs, ALSO

571
00:21:13,360 --> 00:21:16,120
HAD A PAUCITY OF CLONAL TYPES

572
00:21:16,120 --> 00:21:20,480
RECOGNIZING THESE MUTATIONS.

573
00:21:20,480 --> 00:21:21,920
SO THIS IS PATIENTS WHO HAD

574
00:21:21,920 --> 00:21:24,560
CLINICAL RESPONSES TO ANTI-PD-1

575
00:21:24,560 --> 00:21:25,360
THERAPY THAT MAKES SENSE THAT

576
00:21:25,360 --> 00:21:26,760
THOSE T-CELLS WERE STRONG ENOUGH

577
00:21:26,760 --> 00:21:29,080
TO GET AN IMMUNE RESPONSE THAT

578
00:21:29,080 --> 00:21:30,840
SHRINK THE CANCER AND LED TO

579
00:21:30,840 --> 00:21:31,920
LONG TERM BENEFIT.

580
00:21:31,920 --> 00:21:38,200
SO WHAT HAPPENED IN PATIENTS

581
00:21:38,200 --> 00:21:39,800
WHERE WITH PULL T-CELLS WITH

582
00:21:39,800 --> 00:21:41,880
THIS APPROACH BUT TCRs FROM

583
00:21:41,880 --> 00:21:43,080
PATIENTS THAT DID NOT HAVE

584
00:21:43,080 --> 00:21:43,840
CLINICAL RESPONSE TO THERAPY.

585
00:21:43,840 --> 00:21:45,120
SO WE HAD THREE OF THESE

586
00:21:45,120 --> 00:21:46,120
PATIENTS WHERE WE HAD NO

587
00:21:46,120 --> 00:21:48,880
RESPONSE TO THERAPY, BUT WE GOT

588
00:21:48,880 --> 00:21:51,360
THE CELL LINE AND WE GOT PULLED

589
00:21:51,360 --> 00:21:52,160
TCRs.

590
00:21:52,160 --> 00:21:53,760
WE PULLED A LOT LESS TCRs, SO

591
00:21:53,760 --> 00:21:55,440
FROM PATIENT NUMBER ONE, THERE'S

592
00:21:55,440 --> 00:21:56,960
ONLY ONE CELL THAT RECOGNIZES

593
00:21:56,960 --> 00:22:00,560
ONE MUTATION.

594
00:22:00,560 --> 00:22:01,440
PATIENT NUMBER 9.

595
00:22:01,440 --> 00:22:05,600
PATIENT NUMBER 10, THERE'S THREE

596
00:22:05,600 --> 00:22:07,040
CELLS FROM TWO CLONAL TYPES THAT

597
00:22:07,040 --> 00:22:08,320
RECOGNIZE THE SAME MUTATION.

598
00:22:08,320 --> 00:22:09,520
PATIENT 11, THERE'S TWO CELLS

599
00:22:09,520 --> 00:22:14,080
THAT RECOGNIZE TWO MUTATIONS.

600
00:22:14,080 --> 00:22:16,560
FIVE TCRs ON TOTAL FROM THESE

601
00:22:16,560 --> 00:22:17,600
THREE PATIENTS WITHOUT CLINICAL

602
00:22:17,600 --> 00:22:18,560
RESPONSE TO THERAPY.

603
00:22:18,560 --> 00:22:20,840
SO HOW MANY OF THESE 5TCRs DO

604
00:22:20,840 --> 00:22:22,400
YOU THINK WILL RECOGNIZE AND

605
00:22:22,400 --> 00:22:26,440
KILL THE MATCHED CELL LINE?

606
00:22:26,440 --> 00:22:28,040
ACTUALLY ALL OF THEM.

607
00:22:28,040 --> 00:22:30,160
HERE'S THE TWO TCRs FROM

608
00:22:30,160 --> 00:22:33,200
PATIENT 11, THE ONE ACTUALLY TWO

609
00:22:33,200 --> 00:22:36,200
TCRs FROM PATIENT 10, AND ONE

610
00:22:36,200 --> 00:22:36,840
TCR FROM PATIENT NINE.

611
00:22:36,840 --> 00:22:38,880
ALL OF THEM HAD CYTOTOXICITY TO

612
00:22:38,880 --> 00:22:42,080
THE MATCHED CELL LINE.

613
00:22:42,080 --> 00:22:44,160
SO THESE ARE PATIENTS WHO HAD NO

614
00:22:44,160 --> 00:22:45,880
CLINICAL RESPONSE TO ANTI-PD-1

615
00:22:45,880 --> 00:22:47,680
BUT WE CAN STILL PULL RARE

616
00:22:47,680 --> 00:22:50,600
T-CELLS FROM BLOOD OR THE TUMOR

617
00:22:50,600 --> 00:22:53,160
AND ISOLATE BASED ON THEIR

618
00:22:53,160 --> 00:22:54,880
ANTIGEN SPECIFICITY AND GENE

619
00:22:54,880 --> 00:23:00,040
ENGINEER THEM AND SHOW THIS

620
00:23:00,040 --> 00:23:00,320
ACTIVITY.

621
00:23:00,320 --> 00:23:01,480
SO FROM THIS PART OF THE TALK,

622
00:23:01,480 --> 00:23:04,080
WE CAN CONCLUDE THAT NEOANTIJET

623
00:23:04,080 --> 00:23:05,400
SPECIFIC T-CELLS CAN BE

624
00:23:05,400 --> 00:23:07,600
IDENTIFIED FROM PATIENTS WITH

625
00:23:07,600 --> 00:23:08,640
METASTATIC MELANOMA THAT HAVE OR

626
00:23:08,640 --> 00:23:11,360
DO NOT HAVE CLINICAL RESPONSES

627
00:23:11,360 --> 00:23:13,440
ENDUED BY PD-1 BLOCKADE-BASED

628
00:23:13,440 --> 00:23:15,720
THERAPY.

629
00:23:15,720 --> 00:23:19,920
BUT THESE NEOANTIGEN-SPECIFIC

630
00:23:19,920 --> 00:23:22,080
TCRs WHEN -- ONE STEP OF

631
00:23:22,080 --> 00:23:23,720
CYTOSPECIFIC JEAN ENGINEERING

632
00:23:23,720 --> 00:23:26,480
WHERE WE KNOCK OUT ENDOGENOUS

633
00:23:26,480 --> 00:23:29,320
T-CELL RECEPTOR ALPHA BETA --

634
00:23:29,320 --> 00:23:31,160
THAT WE CAN GET THEM TO HAVE

635
00:23:31,160 --> 00:23:32,360
REACTIVITY AGAINST MELANOMA

636
00:23:32,360 --> 00:23:32,920
CELLS.

637
00:23:32,920 --> 00:23:37,120
AND THAT THIS IS THE -- THESE

638
00:23:37,120 --> 00:23:37,840
NEOANTIGEN-SPECIFIC T-CELL

639
00:23:37,840 --> 00:23:39,240
RESPONSES ARE NON-RANDOM,

640
00:23:39,240 --> 00:23:45,960
THEY'RE NOT MORE MUTATIONS, MORE

641
00:23:45,960 --> 00:23:49,240
T-CELLS ARE RECOGNIZED IN MORE

642
00:23:49,240 --> 00:23:50,520
MUTATIONS, BUT THERE'S

643
00:23:50,520 --> 00:23:51,440
IMMUNODOMINANCE INTO THE

644
00:23:51,440 --> 00:23:53,720
RECOGNITION, BUT TO THOSE

645
00:23:53,720 --> 00:23:55,360
IMMUNODOMINANT MUTATIONS

646
00:23:55,360 --> 00:23:56,920
PRESENTED BY -- HLA, THE

647
00:23:56,920 --> 00:23:58,200
CLINICAL RESPONSE, PATIENTS WITH

648
00:23:58,200 --> 00:23:59,880
CLINICAL RESPONSE HAVE A

649
00:23:59,880 --> 00:24:01,160
DIVERSITY OF CLONOTYPES

650
00:24:01,160 --> 00:24:04,360
RECOGNIZED IN THOSE FEW

651
00:24:04,360 --> 00:24:06,120
MUTATIONS.

652
00:24:06,120 --> 00:24:08,280
WHICH IS ALL GREAT DESCRIPTIVE

653
00:24:08,280 --> 00:24:11,000
SCIENCE, I THINK, BUT WHAT DO WE

654
00:24:11,000 --> 00:24:11,600
DO WITH IT?

655
00:24:11,600 --> 00:24:13,640
WHAT WE DO WITH IT IS WE WANT TO

656
00:24:13,640 --> 00:24:15,960
TAKE THESE AND MAKE THEM INTO

657
00:24:15,960 --> 00:24:17,880
THERAPEUTIC BECAUSE THOSE T-CELL

658
00:24:17,880 --> 00:24:19,560
RECEPTORS FROM PATIENTS WHO

659
00:24:19,560 --> 00:24:22,480
DON'T RESPOND TO ANTIPD-1 CAN

660
00:24:22,480 --> 00:24:24,480
STILL KILL IN VITRO, WE DON'T WE

661
00:24:24,480 --> 00:24:26,320
DO THIS IN HUMANS?  WE ALL KNOW

662
00:24:26,320 --> 00:24:27,880
WHEN WE DO THINGS IN HUMANS, IT

663
00:24:27,880 --> 00:24:29,080
TAKES A LITTLE MORE EFFORT BUT

664
00:24:29,080 --> 00:24:30,600
AT LEAST WE MADE AN ATTEMPT AND

665
00:24:30,600 --> 00:24:33,000
THIS IS THE SECOND PART OF THIS

666
00:24:33,000 --> 00:24:34,440
PRESENTATION THAT WAS

667
00:24:34,440 --> 00:24:35,080
PRESENTED -- THAT WAS MOST OF

668
00:24:35,080 --> 00:24:39,000
THE DATA PRESENTED BY STEPHANIE

669
00:24:39,000 --> 00:24:42,120
MANDELL AND WE HAVE AN ARTICLE

670
00:24:42,120 --> 00:24:43,280
ALREADY IN NATURE THAT SOME OF

671
00:24:43,280 --> 00:24:45,920
YOU HAVE COMMENTED ON.

672
00:24:45,920 --> 00:24:49,200
HERE WE'RE DOING THE SAME PART

673
00:24:49,200 --> 00:24:50,680
WE DID BEFORE, THE TUMOR

674
00:24:50,680 --> 00:24:52,320
SEQUENCING COMPARED TO BLOT,

675
00:24:52,320 --> 00:24:54,240
MAKE THE LIBRARY OF THE HLA

676
00:24:54,240 --> 00:24:58,680
PEPTIDES WITH THE SINGLE CHAIN

677
00:24:58,680 --> 00:25:01,120
TRIMERS, MULTI-MERRIZED TO

678
00:25:01,120 --> 00:25:02,240
T-CELLS FROM BLOOD IN THIS CASE

679
00:25:02,240 --> 00:25:03,840
AND CLONE THE T-CELL RECEPTORS

680
00:25:03,840 --> 00:25:06,520
FROM SINGLE CELLS AND THEN

681
00:25:06,520 --> 00:25:11,520
PRODUCE T-CELLS BY GENE

682
00:25:11,520 --> 00:25:15,440
ENGINEERING, BY THIS CRISPR

683
00:25:15,440 --> 00:25:19,360
BASE -- OF CAS9 GUIDE RNA AND ON

684
00:25:19,360 --> 00:25:23,960
THE PEPTIDE -- AND THEN WE DID

685
00:25:23,960 --> 00:25:25,960
THIS FOR PATIENTS, WE DID UP TO

686
00:25:25,960 --> 00:25:27,960
THREE T-CELL RECEPTOR PER

687
00:25:27,960 --> 00:25:29,440
PATIENT BECAUSE FROM THE START,

688
00:25:29,440 --> 00:25:31,440
WE DON'T WANT TO DO ONE AND HAVE

689
00:25:31,440 --> 00:25:33,720
THE TUMOR ESCAPE TO ONE T-CELL

690
00:25:33,720 --> 00:25:35,040
RECEPTOR SO WE MADE IT EVEN

691
00:25:35,040 --> 00:25:36,680
HARDER FOR OUR CELLS AND START

692
00:25:36,680 --> 00:25:38,440
WITH THE T-CELL RECEPTOR

693
00:25:38,440 --> 00:25:39,200
PRODUCT.

694
00:25:39,200 --> 00:25:41,480
IF WE LOOK AT FROM THE PATIENT

695
00:25:41,480 --> 00:25:47,760
PERSPECTIVE, PATIENTS WHO WERE

696
00:25:47,760 --> 00:25:49,720
ENROLLED TO LOOK FOR ARCHIVAL

697
00:25:49,720 --> 00:25:51,360
TISSUE TO DO THE SEQUENCING, AND

698
00:25:51,360 --> 00:25:53,200
THEN ONCE WE HAD THE T-CELL

699
00:25:53,200 --> 00:26:00,760
RECEPTORS SH PATIENTS, PATIENTS,

700
00:26:00,760 --> 00:26:02,400
TESTING, THEN THE PATIENTS WOULD

701
00:26:02,400 --> 00:26:08,640
COME IN, CHEMOTHERAPY, THE THREE

702
00:26:08,640 --> 00:26:10,520
T-CELL RECEPTOR AND HAVE AN

703
00:26:10,520 --> 00:26:14,360
EARLY BIOPSY, AND THEN A LOOK AT

704
00:26:14,360 --> 00:26:15,760
ANY POTENTIAL OF TUMOR

705
00:26:15,760 --> 00:26:16,800
RESPONSES.

706
00:26:16,800 --> 00:26:18,800
IT WAS A DOSE ESCALATION PHASE

707
00:26:18,800 --> 00:26:21,160
ONE TRIAL.

708
00:26:21,160 --> 00:26:25,480
WE STARTED ON -- GOING UP TO

709
00:26:25,480 --> 00:26:27,720
FOUR TIMES 10 TO THE 9.

710
00:26:27,720 --> 00:26:30,120
AND THEN THIS PROTOCOL, DESPITE

711
00:26:30,120 --> 00:26:33,920
MY COMPLAINING, DIDN'T HAVE

712
00:26:33,920 --> 00:26:34,680
IL2 AS A COMPONENT FROM THE

713
00:26:34,680 --> 00:26:36,640
START BUT THEY WERE COHORTS THAT

714
00:26:36,640 --> 00:26:42,480
WERE ALLOWED TO GIVE

715
00:26:42,480 --> 00:26:43,320
IL2 AFTERWARDS.

716
00:26:43,320 --> 00:26:45,120
WE ENROLLED 189 PATIENTS, AND WE

717
00:26:45,120 --> 00:26:50,480
LOOKED FOR T-CELL REACCEPT PO RM

718
00:26:50,480 --> 00:26:51,000
89 PATIENTS.

719
00:26:51,000 --> 00:26:52,560
FROM THE FIRST 88 PATIENTS WITH

720
00:26:52,560 --> 00:26:56,840
A LIBRARY OF 64 HLAs, WE

721
00:26:56,840 --> 00:26:59,680
PREDICTED OVER 50,000

722
00:26:59,680 --> 00:27:01,080
NEOANTIGENS, AND HERE THEY'RE

723
00:27:01,080 --> 00:27:02,560
ORGANIZED BY LOW AFFINITY TO

724
00:27:02,560 --> 00:27:04,520
HIGH AFFINITY.

725
00:27:04,520 --> 00:27:09,680
EACH DOT WOULD BE PREDICTED

726
00:27:09,680 --> 00:27:10,480
NEOANTIGEN PRESENTED BY ONE OF

727
00:27:10,480 --> 00:27:14,040
THE HLAs OF THAT PATIENT.

728
00:27:14,040 --> 00:27:17,760
THAT LED TO PACPHARMA MAKING

729
00:27:17,760 --> 00:27:22,320
12,000 DISTINCT NEW ANTIGEN

730
00:27:22,320 --> 00:27:23,960
REACTIONS, COCULTURED WITH THE

731
00:27:23,960 --> 00:27:24,200
T-CELLS.

732
00:27:24,200 --> 00:27:26,960
WE CAN SEE THAT THESE ARE THE

733
00:27:26,960 --> 00:27:31,880
GREEN DOTS AND IT'S SKEWED OVER

734
00:27:31,880 --> 00:27:33,200
HERE BECAUSE ONLY THE HIGHER

735
00:27:33,200 --> 00:27:34,400
AFFINITY PEPTIDES WOULD

736
00:27:34,400 --> 00:27:36,280
STABILIZE THE SINGLE CHAIN

737
00:27:36,280 --> 00:27:38,640
TRIMER, IF IT'S LOW AFFINITY, IT

738
00:27:38,640 --> 00:27:41,280
FALSE OFF.

739
00:27:41,280 --> 00:27:44,040
AND THEN HOW MANY T-CELL

740
00:27:44,040 --> 00:27:47,000
RECEPTORS WERE PULLED, THERE ARE

741
00:27:47,000 --> 00:27:49,160
OVER 900 UNIQUE NEOANTIGEN

742
00:27:49,160 --> 00:27:51,600
RECEPTORS, PROBABLY THE HIGHEST

743
00:27:51,600 --> 00:27:55,920
SO FAR THAT ANYBODY HAS CLONED,

744
00:27:55,920 --> 00:27:57,040
COULD BE ISOLATED FROM ALL OF

745
00:27:57,040 --> 00:27:57,960
THESE SAMPLES.

746
00:27:57,960 --> 00:27:59,480
AGAIN, THERE'S A SKEWING TO THE

747
00:27:59,480 --> 00:28:00,640
HIGHER AFFINITY, BUT THERE'S

748
00:28:00,640 --> 00:28:02,320
ALSO LOWER AFFINITY T-CELL

749
00:28:02,320 --> 00:28:05,480
RECEPTORS THAT WOULD DISTINCTLY

750
00:28:05,480 --> 00:28:06,560
BIND WITH ALL OF THE CUTOFFS

751
00:28:06,560 --> 00:28:11,280
THAT WE HAD TO GET OUT FROM

752
00:28:11,280 --> 00:28:11,840
BACKGROUND.

753
00:28:11,840 --> 00:28:13,720
THE DATA FROM THESE PATIENTS IS

754
00:28:13,720 --> 00:28:16,440
LIKE YOU SAW BEFORE, WITH THE

755
00:28:16,440 --> 00:28:19,000
PATIENTS WITH MELANOMA, SO HERE

756
00:28:19,000 --> 00:28:24,720
IS A LIBRARY OF 26 262 PIP TIED

757
00:28:24,720 --> 00:28:26,600
LIBRARY COVERING MUTATIONS FROM

758
00:28:26,600 --> 00:28:28,280
LOW AFFINITY TO HIGH AFFINITY.

759
00:28:28,280 --> 00:28:30,360
THERE'S ONLY ONE, TWO, THREE AND

760
00:28:30,360 --> 00:28:32,840
FOUR MUTATIONS BEING RECOGNIZED,

761
00:28:32,840 --> 00:28:34,000
THIS ONE PRESENTED BY THREE OF

762
00:28:34,000 --> 00:28:39,320
THE HLA -- SO THIS MUST BE TWO

763
00:28:39,320 --> 00:28:40,320
MUTATIONS, I'M SORRY, AND THIS

764
00:28:40,320 --> 00:28:45,160
IS ONE OF THEM.

765
00:28:45,160 --> 00:28:48,200
HERE THERE'S MULTIPLE -- I'M

766
00:28:48,200 --> 00:28:49,520
SORRY IT'S NOT LABELED

767
00:28:49,520 --> 00:28:51,160
COMPLETELY WITH THE MUTATIONS

768
00:28:51,160 --> 00:28:52,880
BUT IN THE PAPER, THERE'S A

769
00:28:52,880 --> 00:28:55,440
TABLE WITH ALL OF THE HLAs,

770
00:28:55,440 --> 00:28:56,320
THE SEQUENCES OF THE MUTATIONS

771
00:28:56,320 --> 00:28:58,400
AND THE SEQUENCES OF THE T-CELL

772
00:28:58,400 --> 00:28:59,360
RECEPTORS, IF ANYBODY IS

773
00:28:59,360 --> 00:29:02,760
INTERESTED ON THAT.

774
00:29:02,760 --> 00:29:04,560
FROM CLONING THE T-CELL

775
00:29:04,560 --> 00:29:06,160
RECEPTORS, THEY HAVE TO BE GENE

776
00:29:06,160 --> 00:29:09,440
EDITED AND THIS IS -- THESE

777
00:29:09,440 --> 00:29:12,120
PRECISION CAS9-BASED GENE

778
00:29:12,120 --> 00:29:14,240
EDITING KNOCKING OUT THE T-CELL

779
00:29:14,240 --> 00:29:16,200
RECEPTOR ALPHA AND BETA, AND

780
00:29:16,200 --> 00:29:18,320
THEN KNOCKING INTO THE T-CELL

781
00:29:18,320 --> 00:29:21,480
RECEPTOR ALPHA, THE TWO -- THIS

782
00:29:21,480 --> 00:29:24,640
PEPTIDE THAT HAS -- THE PLASMID

783
00:29:24,640 --> 00:29:26,840
THAT HAS THE TRANSGENIC TCR

784
00:29:26,840 --> 00:29:29,560
ALPHA AND PART OF THE BETA --

785
00:29:29,560 --> 00:29:31,320
THE BETA AND PART OF THE ALPHA,

786
00:29:31,320 --> 00:29:35,280
AND THEN EXPAND THE CELLS AND

787
00:29:35,280 --> 00:29:36,480
GIVE THEM TO PATIENTS.

788
00:29:36,480 --> 00:29:38,960
HERE'S THE SCHEMATIC OF THE

789
00:29:38,960 --> 00:29:41,840
PEPTIDE, SO IT'S THE FULL

790
00:29:41,840 --> 00:29:44,400
SEQUENCE TCR BETA WITH 2A AND

791
00:29:44,400 --> 00:29:46,000
THE VARIABLE PART OF THE TCR

792
00:29:46,000 --> 00:29:47,320
ALPHA BECAUSE WE'RE PUTTING

793
00:29:47,320 --> 00:29:50,160
UNDER TRACK LOCUS DOUBLE LATE TO

794
00:29:50,160 --> 00:29:52,240
EXPRESSION OF THE TRANSGENIC TCR

795
00:29:52,240 --> 00:29:54,120
ALPHA AND BETA.

796
00:29:54,120 --> 00:29:55,280
THAT WENT INTO MANUFACTURING OF

797
00:29:55,280 --> 00:29:58,280
THE T-CELLS, AND WITH TIME, AS

798
00:29:58,280 --> 00:29:59,600
WE'RE RUNNING THE CLINICAL

799
00:29:59,600 --> 00:30:03,960
TRIAL, THE MANUFACTURING KEEPING

800
00:30:03,960 --> 00:30:06,600
PROBING, TO THIS IS THE VERSION

801
00:30:06,600 --> 00:30:09,960
1.1 ONLY HAD 10 KNOCK-IN -- 10%

802
00:30:09,960 --> 00:30:13,280
KNOCK-IN AND VARIABLE KNOCK-OUT,

803
00:30:13,280 --> 00:30:15,000
VERSION TWO HAD INCREASED AND

804
00:30:15,000 --> 00:30:18,000
VERSION THREE WENT UP TO 90%

805
00:30:18,000 --> 00:30:19,760
KNOCKOUT AND 40% KNOCK-IN WITH

806
00:30:19,760 --> 00:30:21,040
THE CRISPR BASE, WHICH IS

807
00:30:21,040 --> 00:30:22,760
GETTING CLOSE TO WHAT YOU CAN

808
00:30:22,760 --> 00:30:26,720
GET WITH A RETROVIRUS.

809
00:30:26,720 --> 00:30:29,600
AND WITH THE NUMBER OF CELLS

810
00:30:29,600 --> 00:30:30,800
PRODUCED WITH THE VERSION THREE

811
00:30:30,800 --> 00:30:32,000
WAS ALREADY AT THE LEVELS WE

812
00:30:32,000 --> 00:30:33,080
COULD GO UP IN THE DOSE

813
00:30:33,080 --> 00:30:38,120
ESCALATION.

814
00:30:38,120 --> 00:30:39,680
I'LL SHOW YOU THE DETAILS OF THE

815
00:30:39,680 --> 00:30:40,520
GENE EDITING.

816
00:30:40,520 --> 00:30:43,120
SO HERE IS CD8 T-CELLS AND

817
00:30:43,120 --> 00:30:44,040
CD4s.

818
00:30:44,040 --> 00:30:45,120
HERE'S UNEDITED CELLS, AND

819
00:30:45,120 --> 00:30:47,640
HERE'S WITH THE T-CELL RECEPTOR.

820
00:30:47,640 --> 00:30:49,520
THIS PATIENT RECEIVED T-CELL --

821
00:30:49,520 --> 00:30:52,640
THREE T-CELL RECEPTORS, 1036,

822
00:30:52,640 --> 00:30:55,760
1033, AND 1037.

823
00:30:55,760 --> 00:31:00,880
THIS FIRST T-CELL RECEPTOR IS ON

824
00:31:00,880 --> 00:31:05,320
CD8s AND CD4s, SO IT'S A

825
00:31:05,320 --> 00:31:07,160
CD8 -- TRANSGENIC T-CELL

826
00:31:07,160 --> 00:31:08,000
RECEPTOR.

827
00:31:08,000 --> 00:31:09,160
THESE TWO OTHER T-CELL RECEPTORS

828
00:31:09,160 --> 00:31:10,920
ARE ONLY EXPRESSED IN CD #s

829
00:31:10,920 --> 00:31:18,160
CD8s ANDNOT IN CD4s SO THEY ARE

830
00:31:18,160 --> 00:31:19,360
CD8 DEPENDENT SO THEY NEED THE

831
00:31:19,360 --> 00:31:21,560
CORE RECEPTOR TO BE EXPRESSED ON

832
00:31:21,560 --> 00:31:24,000
THIS SURFACE AND THEN BIND TO

833
00:31:24,000 --> 00:31:25,880
THE COMPLEXES THAT THE

834
00:31:25,880 --> 00:31:27,440
MULTI-MERES THAT WE HAVE THAT WE

835
00:31:27,440 --> 00:31:29,040
USE FOR SELECTING AND ALSO WE

836
00:31:29,040 --> 00:31:32,160
USE FOR VALIDATION.

837
00:31:32,160 --> 00:31:33,840
NOT ONLY WE VALIDATED THE

838
00:31:33,840 --> 00:31:38,320
EXPRESSION BUT THE POTENCY ASSAY

839
00:31:38,320 --> 00:31:41,680
WAS IF WE GIVE THESE SOLUBLE HLA

840
00:31:41,680 --> 00:31:45,960
PEPTIDE COMPLEXES THAT WE CALL

841
00:31:45,960 --> 00:31:47,360
COMPACTS, WOULD THAT INDUCE

842
00:31:47,360 --> 00:31:48,600
PROLIFERATION OF DONOR T-CELLS

843
00:31:48,600 --> 00:31:50,040
THAT EXPRESS THE T-CELL RECEPTOR

844
00:31:50,040 --> 00:31:52,320
THAT WAS PART OF THE TESTING.

845
00:31:52,320 --> 00:31:54,560
WE CAN SEE THAT THE GENE

846
00:31:54,560 --> 00:31:59,640
EDITED -- THEY ALL HAVE DILUTION

847
00:31:59,640 --> 00:32:03,160
OF CFSC SHOWING PROLIFERATION.

848
00:32:03,160 --> 00:32:05,000
THE CELLS THAT HAVE ONLY

849
00:32:05,000 --> 00:32:06,440
KNOCKOUT AND NO -- DO NOT

850
00:32:06,440 --> 00:32:07,680
PROLIFERATE AND THE WILD TYPE

851
00:32:07,680 --> 00:32:09,920
CELLS WITHOUT THE KNOCK-OUT OR

852
00:32:09,920 --> 00:32:11,360
KNOCK-IN DO NOT PROLIFERATE SO

853
00:32:11,360 --> 00:32:13,120
IT'S TRUANT GENERAL-SPECIFIC

854
00:32:13,120 --> 00:32:14,200
PROLIFERATION.

855
00:32:14,200 --> 00:32:16,400
SO GOING BACK TO THE PATIENTS,

856
00:32:16,400 --> 00:32:20,560
WE ENROLLED 187 PATIENTS THAT

857
00:32:20,560 --> 00:32:21,640
WENT THROUGH DIFFERENT PHASES OF

858
00:32:21,640 --> 00:32:24,160
THE SCREENING.

859
00:32:24,160 --> 00:32:26,240
88 PATIENTS HAD ENOUGH OF THE

860
00:32:26,240 --> 00:32:27,880
TISSUE AND DATA THAT WE COULD DO

861
00:32:27,880 --> 00:32:29,600
THE SCREENING OF T-CELL

862
00:32:29,600 --> 00:32:29,880
RECEPTORS.

863
00:32:29,880 --> 00:32:30,720
THAT'S THE DATA I SHOWED YOU

864
00:32:30,720 --> 00:32:32,720
BEFORE.

865
00:32:32,720 --> 00:32:37,560
28 MADE TO LOU KA PHORESIS AND

866
00:32:37,560 --> 00:32:38,560
16 PATIENTS WERE DOSED OVER A

867
00:32:38,560 --> 00:32:42,040
PERIOD OF TIME.

868
00:32:42,040 --> 00:32:46,480
THESE 16 PATIENTS HAD DIFFERENT

869
00:32:46,480 --> 00:32:46,680
CANCERS.

870
00:32:46,680 --> 00:32:48,400
THERE WAS NO RESTRICTION -- THIS

871
00:32:48,400 --> 00:32:49,920
WAS A PHASE ONE TRIAL THAT

872
00:32:49,920 --> 00:32:51,240
ALLOWED PATIENTS WITH MULTIPLE

873
00:32:51,240 --> 00:32:53,120
CANCERS TO COME IN.

874
00:32:53,120 --> 00:32:54,280
IT TURNED OUT THAT ONE SIDE PUT

875
00:32:54,280 --> 00:32:56,160
A LOT OF PATIENTS WITH

876
00:32:56,160 --> 00:32:56,960
COLORECTAL CANCER AND THOSE

877
00:32:56,960 --> 00:32:58,760
COVERED THE FIRST COHORT, SO

878
00:32:58,760 --> 00:33:01,800
THAT WAS THE PREDOMINANT NUMBER

879
00:33:01,800 --> 00:33:05,760
OF PATIENTS THAT WERE INVOLVED.

880
00:33:05,760 --> 00:33:06,600
THIS IS A SLIDE THAT'S PAINFUL

881
00:33:06,600 --> 00:33:09,480
BECAUSE IT SHOWS THE TIME THAT

882
00:33:09,480 --> 00:33:13,520
IT TOOK FROM BASELINE TO GETTING

883
00:33:13,520 --> 00:33:14,960
THE INFUSION IN THESE 16

884
00:33:14,960 --> 00:33:15,240
PATIENTS.

885
00:33:15,240 --> 00:33:18,080
AND HERE WE HAVE ONE YEAR.

886
00:33:18,080 --> 00:33:19,240
SO MAJORITY OF THE PATIENTS TOOK

887
00:33:19,240 --> 00:33:24,160
UP TO A YEAR.

888
00:33:24,160 --> 00:33:25,720
BUT IT WAS NOT THAT ONE STEP WAS

889
00:33:25,720 --> 00:33:26,480
MORE LENGTHY.

890
00:33:26,480 --> 00:33:32,360
HERE IS COLOR-CODED INFORMED

891
00:33:32,360 --> 00:33:33,480
CONSENT, BIOINFORMA TICKETS,

892
00:33:33,480 --> 00:33:36,080
IMPACT ISOLATION, YOU CAN SEE

893
00:33:36,080 --> 00:33:37,520
THE GREY BARS ARE LONG SO JUST

894
00:33:37,520 --> 00:33:38,960
GETTING THE PATIENTS IN AND

895
00:33:38,960 --> 00:33:40,600
START THE PROCESS TOOK QUITE A

896
00:33:40,600 --> 00:33:44,280
WHILE AT MULTIPLE SITES.

897
00:33:44,280 --> 00:33:45,400
THESE ORANGE ONE MAY TAKE LONG

898
00:33:45,400 --> 00:33:49,760
SO THE ISOLATION OF THE --

899
00:33:49,760 --> 00:33:51,920
MAKING THE HLA COMPLEXES, BUT

900
00:33:51,920 --> 00:33:53,080
ONCE WE HAD THE CELL

901
00:33:53,080 --> 00:33:54,480
MANUFACTURING TO DOSING, IT ALL

902
00:33:54,480 --> 00:33:56,640
BECAME MUCH SHORTER.

903
00:33:56,640 --> 00:33:58,120
SO IT'S -- THE LATER PART WAS

904
00:33:58,120 --> 00:34:01,800
MORE CONTROLLABLE.

905
00:34:01,800 --> 00:34:02,480
BUT WHY THAT?

906
00:34:02,480 --> 00:34:06,200
WELL, IF WE 50 BACK GO BACK TO S

907
00:34:06,200 --> 00:34:07,600
CARTOON, WE SCREENED

908
00:34:07,600 --> 00:34:09,920
187 PATIENTS, WE TREATED 16, AND

909
00:34:09,920 --> 00:34:11,800
IN BETWEEN, WE MADE THE MEDIAN

910
00:34:11,800 --> 00:34:14,960
OF 35 -- WE TARGETED A MEDIAN OF

911
00:34:14,960 --> 00:34:18,680
35, RANGE OF 20 TO 236 EXPRESS

912
00:34:18,680 --> 00:34:19,880
MUTATIONS PER PATIENT.

913
00:34:19,880 --> 00:34:23,840
A MEDIAN OF 104 PEPTIDE HLA

914
00:34:23,840 --> 00:34:24,600
LIBRARIES WERE MADE.

915
00:34:24,600 --> 00:34:34,720
THE MAJORITY WENT FROM 49 TO 26F

916
00:34:34,720 --> 00:34:37,280
1,841 PEPTIDE-HLA PROTEINS WERE

917
00:34:37,280 --> 00:34:40,120
PRODUCED TO TREAT THESE 16

918
00:34:40,120 --> 00:34:43,640
PATIENTS WITH A MEDIAN OF SIX

919
00:34:43,640 --> 00:34:44,760
HLAs TARGET PER PATIENT SO

920
00:34:44,760 --> 00:34:46,320
COVERING MOST OF THE HLA

921
00:34:46,320 --> 00:34:47,400
CLASS I.

922
00:34:47,400 --> 00:34:51,080
WE HAD THE MEDIAN OF EIGHT

923
00:34:51,080 --> 00:34:51,960
NEOTCRs FOR PATIENT FOR A

924
00:34:51,960 --> 00:34:54,960
TOTAL OF 175 TCRs IN THE GROUP

925
00:34:54,960 --> 00:34:57,920
OF 16 PATIENTS, AND AT 37

926
00:34:57,920 --> 00:35:00,080
NEOANTIGEN TCRs WERE INFUSED

927
00:35:00,080 --> 00:35:01,520
BACK TO THE 16 PATIENT.

928
00:35:01,520 --> 00:35:04,040
THEY HAD DIFFERENT EC50s FROM

929
00:35:04,040 --> 00:35:06,240
LOW AFFINITY TO VERY HIGH

930
00:35:06,240 --> 00:35:09,520
AFFINITY.

931
00:35:09,520 --> 00:35:11,160
HERE'S THE CLINICAL RESULTS.

932
00:35:11,160 --> 00:35:14,440
THERE WERE NO OBJECTIVE

933
00:35:14,440 --> 00:35:15,200
RESPONSES, FIVE PATIENTS WITH

934
00:35:15,200 --> 00:35:15,760
STABLE DISEASE.

935
00:35:15,760 --> 00:35:16,960
SOME OF THEM, IT COULD BE FROM

936
00:35:16,960 --> 00:35:19,200
THE CONDITIONING CHEMOTHERAPY.

937
00:35:19,200 --> 00:35:20,960
I'LL SHOW YOU THE ONE PATIENT WE

938
00:35:20,960 --> 00:35:23,280
THINK THAT WAS NOT THE

939
00:35:23,280 --> 00:35:24,200
CONDITIONING CHEMOTHERAPY.

940
00:35:24,200 --> 00:35:25,280
I'M SORRY, I'LL GO BACK.

941
00:35:25,280 --> 00:35:27,680
AND THE TOXICITIES WERE MOSTLY

942
00:35:27,680 --> 00:35:29,520
THAT THE CONDITIONING THERAPY,

943
00:35:29,520 --> 00:35:32,880
THERE WAS ONE PATIENT WITH

944
00:35:32,880 --> 00:35:34,280
HISTORY OF BRAIN METASTASES THAT

945
00:35:34,280 --> 00:35:36,920
HAD SOME KIND OF ENCEPHALOPATHY

946
00:35:36,920 --> 00:35:38,560
FOR ONE DAY AND WAS GIVEN

947
00:35:38,560 --> 00:35:39,280
CORTICOSTEROIDS.

948
00:35:39,280 --> 00:35:40,520
WE'LL NEVER BE SURE WHAT THAT

949
00:35:40,520 --> 00:35:44,720
WAS, BUT IT SEEMED TO BE THAT

950
00:35:44,720 --> 00:35:45,920
THIS NEOANTIGEN T-CELLS, THE

951
00:35:45,920 --> 00:35:48,840
MAJORITY OF THEM, PATIENTS HAD

952
00:35:48,840 --> 00:35:50,720
NO DISCERNING TOXICITIES EVEN

953
00:35:50,720 --> 00:35:52,800
THOUGH WE CLONED THEM IN LARGE

954
00:35:52,800 --> 00:35:53,800
NUMBERS OF THEM.

955
00:35:53,800 --> 00:35:59,160
SIMILAR TO YOUR EXPERIENCE WITH

956
00:35:59,160 --> 00:36:00,880
TIL CULTURES.

957
00:36:00,880 --> 00:36:02,080
SO HERE ARE THE THREE DOSE

958
00:36:02,080 --> 00:36:03,520
LEVELS.

959
00:36:03,520 --> 00:36:05,280
DOSE LEVEL ONE, DOSE LEVEL TWO,

960
00:36:05,280 --> 00:36:06,280
DOSE LEVEL THREE.

961
00:36:06,280 --> 00:36:07,360
DOSE LEVEL ONE, THERE WAS VERY

962
00:36:07,360 --> 00:36:09,440
LOW EXPOSURE, SO VERY FEW

963
00:36:09,440 --> 00:36:11,120
T-CELLS EXPANDED AND STAYED

964
00:36:11,120 --> 00:36:11,320
AROUND.

965
00:36:11,320 --> 00:36:13,080
THAT WAS WITH LOW DOSES OF

966
00:36:13,080 --> 00:36:14,800
CONDITIONING CHEMOTHERAPY AND

967
00:36:14,800 --> 00:36:16,000
WITHOUT IL-2.

968
00:36:16,000 --> 00:36:17,360
DOSE LEVEL TWO WAS HIGHER DOSES

969
00:36:17,360 --> 00:36:18,640
BUT ALSO WE CHANGED THE

970
00:36:18,640 --> 00:36:19,440
CONDITIONING BECAUSE WE THOUGHT

971
00:36:19,440 --> 00:36:23,000
THERE WAS NO -- NOT ENOUGH

972
00:36:23,000 --> 00:36:24,800
LYMPHODEPLETION AND THAT LED TO

973
00:36:24,800 --> 00:36:25,560
MORE EXPOSURE.

974
00:36:25,560 --> 00:36:27,200
THOSE LEVEL THREE, SOME PATIENTS

975
00:36:27,200 --> 00:36:29,800
REALLY HAD GOOD EXPOSURE LIKE

976
00:36:29,800 --> 00:36:32,120
THIS LAST ONE, WHERE 40% OF THE

977
00:36:32,120 --> 00:36:33,840
T-CELLS AT ONE POINT CIRCULATING

978
00:36:33,840 --> 00:36:36,360
IN BLOOD WHERE ANTIGEN -- WHERE

979
00:36:36,360 --> 00:36:37,720
TCR TRANSGENIC T-CELLS.

980
00:36:37,720 --> 00:36:39,880
BUT HERE WE HAVE HIGH EXPOSURE.

981
00:36:39,880 --> 00:36:42,200
WITH IL-2, THERE SEEMS TO BE

982
00:36:42,200 --> 00:36:44,760
HIGH EXPANSION INITIALLY THAN

983
00:36:44,760 --> 00:36:49,840
THE ONES WITHOUT THE IL-2.

984
00:36:49,840 --> 00:36:52,680
THE KEY POINT OF ALL OF THIS IS

985
00:36:52,680 --> 00:36:53,920
DID WE REDISTRICT IMMUNE SYSTEM

986
00:36:53,920 --> 00:36:55,360
TO THE CANCER BECAUSE THERE WERE

987
00:36:55,360 --> 00:36:58,480
THE MUTATIONS ALLOWED THE

988
00:36:58,480 --> 00:37:01,720
T-CELLS TO GET THEM -- TO GET

989
00:37:01,720 --> 00:37:03,920
THOSE T-CELL RECEPTORS TO

990
00:37:03,920 --> 00:37:04,680
RECOGNIZE CANCER CELLS.

991
00:37:04,680 --> 00:37:06,440
AND HERE WE HAVE A SERIES OF

992
00:37:06,440 --> 00:37:08,440
PATIENTS ON DOSE LEVEL ONE, DOSE

993
00:37:08,440 --> 00:37:09,680
LEVEL TWO AND DOSE LEVEL THREE

994
00:37:09,680 --> 00:37:13,680
WITH A BASELINE AND A

995
00:37:13,680 --> 00:37:14,600
NON-THERAPY BIOPSY AND THIS

996
00:37:14,600 --> 00:37:17,040
PATIENT RECEIVED THREE T-CELL

997
00:37:17,040 --> 00:37:18,120
RECEPTORS, ONLY ONE WAS

998
00:37:18,120 --> 00:37:19,160
RECOGNIZED AT BASELINE.

999
00:37:19,160 --> 00:37:21,360
THIS IS A LOGARITHMIC SCALE ON

1000
00:37:21,360 --> 00:37:21,920
THE Y AXIS.

1001
00:37:21,920 --> 00:37:24,120
YOU CAN SEE THAT THE THREE

1002
00:37:24,120 --> 00:37:25,560
T-CELL RECEPTORS NOW BECAME

1003
00:37:25,560 --> 00:37:27,720
PRESENT IN THE TE TUMOR.

1004
00:37:27,720 --> 00:37:30,520
HERE THERE'S 1 T-CELL RECEPTOR

1005
00:37:30,520 --> 00:37:32,880
THAT SPANNED HERE, THREE T-CELL

1006
00:37:32,880 --> 00:37:34,000
RECEPTORS EXPANDED AND HERE YOU

1007
00:37:34,000 --> 00:37:35,480
CAN SEE THE DATA FROM ALL OF

1008
00:37:35,480 --> 00:37:37,680
THESE PLOTS WOULD COME SO

1009
00:37:37,680 --> 00:37:39,320
PATIENT 612, SO THIS ONE HERE

1010
00:37:39,320 --> 00:37:40,520
FROM DOSE LEVEL THREE, AT

1011
00:37:40,520 --> 00:37:42,040
BASELINE WE COULD NOT DETECT ANY

1012
00:37:42,040 --> 00:37:45,280
OF THE T-CELL RECEPTORS AMONG

1013
00:37:45,280 --> 00:37:49,480
THE MOST EXPRESSED T-CELL

1014
00:37:49,480 --> 00:37:51,320
RECEPTORS, AND POST DOSING,

1015
00:37:51,320 --> 00:37:52,720
THOSE THREE T-CELL RECEPTORS

1016
00:37:52,720 --> 00:37:56,240
WERE 6%, 1.4% AND 1.1% OF THE

1017
00:37:56,240 --> 00:37:57,200
T-CELL RECEPTORS THAT WERE

1018
00:37:57,200 --> 00:37:58,640
PRESENT IN THE TUMOR.

1019
00:37:58,640 --> 00:38:00,880
TELLING US THAT WE COULD

1020
00:38:00,880 --> 00:38:02,720
EFFICIENTLY REDIRECT T-CELLS TO

1021
00:38:02,720 --> 00:38:05,680
TUMORS BY GIVING THEM THESE

1022
00:38:05,680 --> 00:38:08,400
TRANSGENIC T-CELL RECEPTORS.

1023
00:38:08,400 --> 00:38:10,400
THIS ONE PATIENT THAT WE THINK

1024
00:38:10,400 --> 00:38:11,480
THAT WAS LITTLE EVIDENCE OF

1025
00:38:11,480 --> 00:38:13,440
RESPONSE BUT SOME IS A PATIENT

1026
00:38:13,440 --> 00:38:18,720
WHO HAD RECEIVED -- WHO HAD

1027
00:38:18,720 --> 00:38:21,360
LUNG -- METASTATIC LUNG CANCER

1028
00:38:21,360 --> 00:38:23,880
WITH SIX -- LINES OF THERAPY AT

1029
00:38:23,880 --> 00:38:25,520
THE TIME OF SCREENING, WENT UP

1030
00:38:25,520 --> 00:38:26,840
TO NINE AT THE TIME OF DOSING,

1031
00:38:26,840 --> 00:38:28,720
HAD ONLY ONE T-CELL RECEPTOR

1032
00:38:28,720 --> 00:38:30,960
PRODUCT AND HAD IL-2 FOR 6 DAYS

1033
00:38:30,960 --> 00:38:35,360
AND WE CAN SEE TWO OF THE

1034
00:38:35,360 --> 00:38:36,800
METASTASES RETROPERITONEAL AND

1035
00:38:36,800 --> 00:38:38,680
OVARIAN MASS THAT SLIGHTLY

1036
00:38:38,680 --> 00:38:40,000
DECREASED IN SIZE.

1037
00:38:40,000 --> 00:38:41,440
OTHERS INCREASED IN SIZE.

1038
00:38:41,440 --> 00:38:43,480
SO THIS IS -- I'M NOT SAYING

1039
00:38:43,480 --> 00:38:44,920
THIS IS THERAPEUTIC BUT AT LEAST

1040
00:38:44,920 --> 00:38:46,600
THERE WAS A HINT THAT THESE

1041
00:38:46,600 --> 00:38:48,240
T-CELL RECEPTORS, EVEN THOUGH

1042
00:38:48,240 --> 00:38:49,720
THEY WERE PROBABLY TOO FEW AND

1043
00:38:49,720 --> 00:38:50,720
TOO LATE FOR THIS PATIENT, HAD

1044
00:38:50,720 --> 00:38:55,120
SOME EFFECT.

1045
00:38:55,120 --> 00:38:56,680
AND IF YOU WOULD SAY, WELL, WHY

1046
00:38:56,680 --> 00:38:58,000
DEPARTMENT YOU HAVE BETTER

1047
00:38:58,000 --> 00:38:59,440
RESPONSES, THESE T-CELL

1048
00:38:59,440 --> 00:39:01,160
RECEPTORS KILL CANCER CELLS IN

1049
00:39:01,160 --> 00:39:04,280
VITRO, WHY DIDN'T YOU GET BETTER

1050
00:39:04,280 --> 00:39:04,960
RESPONSES IN THIS CLINICAL

1051
00:39:04,960 --> 00:39:05,600
TRIAL?

1052
00:39:05,600 --> 00:39:06,800
WELL, WE'VE DONE A WHOLE BUNCH

1053
00:39:06,800 --> 00:39:08,440
OF STUDIES GOING BACK, SO HERE

1054
00:39:08,440 --> 00:39:10,560
IS LOOKING AT THE POTENCY OF THE

1055
00:39:10,560 --> 00:39:16,240
T-CELL RECEPTORS, HERE THE 37

1056
00:39:16,240 --> 00:39:19,080
T-CELL RECEPTORS GIVEN TO

1057
00:39:19,080 --> 00:39:20,920
PATIENTS IN THE SEMI LOGARITHMIC

1058
00:39:20,920 --> 00:39:22,240
SCALE AND HERE ARE T-CELL

1059
00:39:22,240 --> 00:39:23,240
RECEPTORS THAT MANY OF YOU GUYS

1060
00:39:23,240 --> 00:39:25,760
HAVE DEVELOPED, THE DMF5, WHICH

1061
00:39:25,760 --> 00:39:27,640
IS A HIGH AFFINITY T-CELL

1062
00:39:27,640 --> 00:39:32,240
RECEPTOR HERE, AND A PAUL

1063
00:39:32,240 --> 00:39:33,960
ROBBINS ENGINEERED T-CELL

1064
00:39:33,960 --> 00:39:39,840
RECEPTOR IS HERE, THEY'RE ALL

1065
00:39:39,840 --> 00:39:41,520
HIGHER AFFINITY THAN THE MEDIAN

1066
00:39:41,520 --> 00:39:47,240
OF THE PAC T-CELL RE ACCE ACCEPS

1067
00:39:47,240 --> 00:39:48,720
AT LEAST WITH THESE PATIENTS

1068
00:39:48,720 --> 00:39:50,720
WITH EPITHELIAL CANCERS.

1069
00:39:50,720 --> 00:39:51,920
NOT ONLY -- BUT THE EXPRESSION

1070
00:39:51,920 --> 00:39:55,120
OF THE ANTIGEN, WE CAN SEE THAT

1071
00:39:55,120 --> 00:39:57,120
THE PACKED NEOANTIGENS WERE IN

1072
00:39:57,120 --> 00:40:01,480
MEDIAN LOW EXPRESSION LIKE KRAS,

1073
00:40:01,480 --> 00:40:03,160
AS EXPOSED TO HIGHLY EXPRESSED

1074
00:40:03,160 --> 00:40:04,880
TARGETS IN THE CANCER CELLS THAT

1075
00:40:04,880 --> 00:40:06,240
MAKE IT BETTER TARGETS FOR

1076
00:40:06,240 --> 00:40:07,280
T-CELLS.

1077
00:40:07,280 --> 00:40:10,160
THE LAST THING IS, ARE WE DOING

1078
00:40:10,160 --> 00:40:11,960
THIS TOO LATE AND TOO LITTLE.

1079
00:40:11,960 --> 00:40:18,200
AND WE LOOKED FOR HLA LAWS OF

1080
00:40:18,200 --> 00:40:18,800
HETEROZYGOSITY RETROSPECTIVELY

1081
00:40:18,800 --> 00:40:19,480
AND THESE ARE ALL OF THE

1082
00:40:19,480 --> 00:40:20,880
BIOPSIES WE LOOKED FOR THESE

1083
00:40:20,880 --> 00:40:22,760
DIFFERENT PATIENTS.

1084
00:40:22,760 --> 00:40:24,440
WHEN WE SEE AN HLA WITH GREEN,

1085
00:40:24,440 --> 00:40:26,680
THAT MEANS THIS T-CELL RECEPTOR

1086
00:40:26,680 --> 00:40:28,480
RECOGNIZED A B ALLELE, AND THAT

1087
00:40:28,480 --> 00:40:29,600
B ALLELE WAS EXPRESSED.

1088
00:40:29,600 --> 00:40:32,240
BUT IF THERE'S A RED, IT MEANS

1089
00:40:32,240 --> 00:40:33,880
THAT THIS T-CELL RECEPTOR FROM

1090
00:40:33,880 --> 00:40:36,320
THE PATIENT THAT RECEIVED THE

1091
00:40:36,320 --> 00:40:38,560
THREE T-CELL RECEPTOR PRODUCT

1092
00:40:38,560 --> 00:40:40,280
HAD LOSS OF HETEROZYGOSITY.

1093
00:40:40,280 --> 00:40:42,680
SO WE GAVE TO THIS PATIENT ONE

1094
00:40:42,680 --> 00:40:43,760
T-CELL RECEPTOR THAT THE TUMOR

1095
00:40:43,760 --> 00:40:47,400
NO LONGER EXPRESSED BECAUSE OF

1096
00:40:47,400 --> 00:40:49,240
LOSS OF HETEROZYGOSITY SO THAT

1097
00:40:49,240 --> 00:40:50,920
HAPPENED IN ONE, TWO, THREE

1098
00:40:50,920 --> 00:40:52,840
PATIENTS, THIS ONE HAD TWO FROM

1099
00:40:52,840 --> 00:40:54,120
THE C ALLELE THAT HAD LOST

1100
00:40:54,120 --> 00:40:55,200
EXPRESSION, SO THE PEPTIDE WAS

1101
00:40:55,200 --> 00:40:57,400
NO LONGER EXPRESSED BY THE TIME

1102
00:40:57,400 --> 00:40:58,920
WE HAD DONE ALL OF THESE AND

1103
00:40:58,920 --> 00:41:03,320
MADE IT INTO THE CLINIC.

1104
00:41:03,320 --> 00:41:04,880
SO WHAT I WANT TO CONVEY WITH

1105
00:41:04,880 --> 00:41:06,720
THIS IS THAT ACTUALLY WE CAN DO

1106
00:41:06,720 --> 00:41:07,400
IT.

1107
00:41:07,400 --> 00:41:08,680
I'M NOT SAYING THAT IT'S EASY OR

1108
00:41:08,680 --> 00:41:10,560
THAT IT'S GOING TO BE

1109
00:41:10,560 --> 00:41:14,320
THERAPEUTIC ANY TIME SOON, BUT

1110
00:41:14,320 --> 00:41:16,280
WE CAN ISOLATE AND CLONE T-CELL

1111
00:41:16,280 --> 00:41:17,800
RECEPTORS THAT CAN RECOGNIZE

1112
00:41:17,800 --> 00:41:19,160
PATIENT-SPECIFIC MUTATIONAL KNEW

1113
00:41:19,160 --> 00:41:21,560
OWE AT GENERALS, WE CAN USE THIS

1114
00:41:21,560 --> 00:41:24,280
ONE STEP SINGLE NON-VIRAL PREER

1115
00:41:24,280 --> 00:41:26,280
SITION GENE EDITING TO INSERT

1116
00:41:26,280 --> 00:41:28,200
THE KNOCK-IN THE T-CELL RECEPTOR

1117
00:41:28,200 --> 00:41:30,400
AND KNOCK OUT THE ENDOGENOUS

1118
00:41:30,400 --> 00:41:33,080
T-CELL RECEPTORS, THAT WE CAN DO

1119
00:41:33,080 --> 00:41:35,480
THIS IN -- AND MAKE UP TO

1120
00:41:35,480 --> 00:41:36,920
THREE -- PER PATIENTS, WE CAN

1121
00:41:36,920 --> 00:41:38,080
SAFELY REINFUSE THEM TO PATIENTS

1122
00:41:38,080 --> 00:41:40,360
AND WE CAN DEMONSTRATE THAT THAT

1123
00:41:40,360 --> 00:41:42,760
REDIRECTS T-CELLS TO ACCUMULATE

1124
00:41:42,760 --> 00:41:45,320
IN THE TUMOR BECAUSE AFTERWARDS

1125
00:41:45,320 --> 00:41:48,600
THOSE T-CELL CLONOTYPES THAT --

1126
00:41:48,600 --> 00:41:50,840
TCRs WERE THE MOST EXPRESSED

1127
00:41:50,840 --> 00:41:53,040
OF THE TCRs IN THE TUMORS.

1128
00:41:53,040 --> 00:41:55,240
AND RETROSPECTIVE ANALYSIS TELLS

1129
00:41:55,240 --> 00:41:56,440
US SOME PLACES WE HAVE TO

1130
00:41:56,440 --> 00:41:57,520
IMPROVE, WE SHOULD GET THE

1131
00:41:57,520 --> 00:41:59,120
HIGHER AFFINITY T-CELL

1132
00:41:59,120 --> 00:42:00,360
RECEPTORS, HIGH EXPRESSION OF

1133
00:42:00,360 --> 00:42:02,400
THE ANTIGENS, AND FOR SURE MAKE

1134
00:42:02,400 --> 00:42:03,840
SURE THAT THAT TUMOR BY THE TIME

1135
00:42:03,840 --> 00:42:06,680
WE TREAT THE PATIENT HAS NOT

1136
00:42:06,680 --> 00:42:13,680
DONE IMMUNOEDITING APPROACHES

1137
00:42:13,680 --> 00:42:14,280
THAT -- EXPRESSION.

1138
00:42:14,280 --> 00:42:15,480
THE DATA I PRESENTED TO YOU IS

1139
00:42:15,480 --> 00:42:19,520
WORK FROM MANY PEOPLE.

1140
00:42:19,520 --> 00:42:21,400
PROBABLY THE PAC LIST SHOULD GO

1141
00:42:21,400 --> 00:42:21,880
TO 200 PEOPLE.

1142
00:42:21,880 --> 00:42:22,720
THESE ARE THE PEOPLE FROM MY

1143
00:42:22,720 --> 00:42:23,160
LAB.

1144
00:42:23,160 --> 00:42:26,920
I TALKED ABOUT CRIS PUIG-SAUS,

1145
00:42:26,920 --> 00:42:29,120
NOW FACULTY MEMBER AT UCLA

1146
00:42:29,120 --> 00:42:30,400
PROCEEDING TO THE

1147
00:42:30,400 --> 00:42:32,000
CHARACTERIZATION OF THESE

1148
00:42:32,000 --> 00:42:33,280
NEOANTIGEN SPECIFIC TCRs THAT

1149
00:42:33,280 --> 00:42:40,640
WE DESCRIBED.

1150
00:42:40,640 --> 00:42:42,120
ELENA GROSS TRAINED IN SPAIN,

1151
00:42:42,120 --> 00:42:43,800
HELPED US A LOT IN SETTING UP

1152
00:42:43,800 --> 00:42:45,880
THE FIRST CULTURES, THE

1153
00:42:45,880 --> 00:42:47,040
TECHNOLOGIES WERE DEVELOPED WITH

1154
00:42:47,040 --> 00:42:48,880
JIM KEITH AND DAVID BALTIMORE,

1155
00:42:48,880 --> 00:42:56,760
WITH MULTIPLE FUNDING SOURCES,

1156
00:42:56,760 --> 00:42:57,760
NIH -- SO I'D BE HAPPY TO TAKE

1157
00:42:57,760 --> 00:43:00,080
ANY QUESTIONS OR COMMENTS.

1158
00:43:00,080 --> 00:43:10,240
[APPLAUSE]

1159
00:43:13,320 --> 00:43:14,520
>>HI.

1160
00:43:14,520 --> 00:43:15,880
THIS IS A TOUR DEFORCE.

1161
00:43:15,880 --> 00:43:16,280
THANK YOU.

1162
00:43:16,280 --> 00:43:17,600
I THINK IT'S IMPORTANT FOR

1163
00:43:17,600 --> 00:43:18,640
EVERYONE HERE TO SEE THIS TYPE

1164
00:43:18,640 --> 00:43:22,440
OF STUDY.

1165
00:43:22,440 --> 00:43:27,040
HOW MUCH OF THE ACTIVITY OR LACK

1166
00:43:27,040 --> 00:43:29,040
OF ACTIVITY DO YOU THINK WAS DUE

1167
00:43:29,040 --> 00:43:32,760
TO IMMUNOSUPPRESSIVE FACTORS IN

1168
00:43:32,760 --> 00:43:34,560
THE TUMOR MICROENVIRONMENT?

1169
00:43:34,560 --> 00:43:36,040
THAT IS, WERE YOU ABLE TO

1170
00:43:36,040 --> 00:43:37,400
ANALYZE ANYTHING IN THE TUMOR

1171
00:43:37,400 --> 00:43:39,000
MICROENVIRONMENT IN TERMS OF

1172
00:43:39,000 --> 00:43:40,200
STABLE DISEASE VERSUS

1173
00:43:40,200 --> 00:43:45,120
PROGRESSIVE DISEASE?

1174
00:43:45,120 --> 00:43:48,800
>>WELL, WE LOOKED AT

1175
00:43:48,800 --> 00:43:49,640
TRANSCRIPTOME ANALYSIS OF THE

1176
00:43:49,640 --> 00:43:51,200
TUMORS BECAUSE WE HAVE IT IN ALL

1177
00:43:51,200 --> 00:43:53,080
OF THEM AND THE COLORECTAL

1178
00:43:53,080 --> 00:43:53,960
CANCERS, THE MAJORITY OF THEM

1179
00:43:53,960 --> 00:43:55,520
WERE THESE CS4 THAT SEEMS TO BE

1180
00:43:55,520 --> 00:43:57,360
THE MOST IMMUNE SUPPRESSIVE

1181
00:43:57,360 --> 00:43:59,880
WHERE THERE'S NATURAL LESS

1182
00:43:59,880 --> 00:44:00,720
T-CELLS AND THOSE WERE THE ONES

1183
00:44:00,720 --> 00:44:03,800
THAT ARE ACTUALLY MORE COMMON

1184
00:44:03,800 --> 00:44:05,000
THAT DON'T RESPOND TO ALL THE

1185
00:44:05,000 --> 00:44:06,960
THERAPIES.

1186
00:44:06,960 --> 00:44:10,120
I DON'T THINK THE TUMOR

1187
00:44:10,120 --> 00:44:11,200
MICROENVIRONMENT IS WHAT LED TO

1188
00:44:11,200 --> 00:44:13,840
NO RESPONSE, I THINK NOT HAVING

1189
00:44:13,840 --> 00:44:15,720
ENOUGH T-CELLS AND GIVING ENOUGH

1190
00:44:15,720 --> 00:44:16,240
OF THEM.

1191
00:44:16,240 --> 00:44:18,360
THIS WAS LIKE BUILDING A PLANE

1192
00:44:18,360 --> 00:44:20,120
AS WE'RE FLYING IT, AND THE

1193
00:44:20,120 --> 00:44:21,240
MANUFACTURING IMPROVED.

1194
00:44:21,240 --> 00:44:22,440
THE LAST COHORT OF PATIENTS ARE

1195
00:44:22,440 --> 00:44:24,400
THE ONES THAT HAVE ENOUGH

1196
00:44:24,400 --> 00:44:27,040
EXPANSION OF T-CELLS AND ENOUGH

1197
00:44:27,040 --> 00:44:28,120
NUMBERS THAT COULD HAVE A

1198
00:44:28,120 --> 00:44:29,320
POTENTIAL TO WORK, AND THAT'S

1199
00:44:29,320 --> 00:44:31,640
THE ONLY TIME WHERE WE SAW SOME

1200
00:44:31,640 --> 00:44:33,000
ACTIVITY.

1201
00:44:33,000 --> 00:44:34,360
SO WE CANNOT -- I CANNOT ANSWER

1202
00:44:34,360 --> 00:44:35,560
YOUR QUESTION BECAUSE I DON'T

1203
00:44:35,560 --> 00:44:37,360
THINK WE HAVE TREATED ENOUGH

1204
00:44:37,360 --> 00:44:38,960
PATIENTS WITH THE FULL THERAPY

1205
00:44:38,960 --> 00:44:39,720
TO BE ABLE TO ANSWER IT.

1206
00:44:39,720 --> 00:44:43,360
>>THANK YOU.

1207
00:44:43,360 --> 00:44:44,800
>>THANK YOU, THAT WAS
VERY,

1208
00:44:44,800 --> 00:44:45,560
VERY INTERESTING.

1209
00:44:45,560 --> 00:44:46,480
ACTUALLY IT'S NOT THAT MANY

1210
00:44:46,480 --> 00:44:48,640
PEOPLE SO I HAVE TWO QUESTIONS.

1211
00:44:48,640 --> 00:44:52,120
SO THE FIRST QUESTION I HAVE IS,

1212
00:44:52,120 --> 00:44:53,960
THERE'S SO MANY ANTIGENS,

1213
00:44:53,960 --> 00:44:55,720
THERE'S SO MANY EPITOPES, AND

1214
00:44:55,720 --> 00:44:57,120
YOU IDENTIFY THEM ALL, YOU HAVE

1215
00:44:57,120 --> 00:44:59,120
THIS ONE MAP AND THEN -- WHY ARE

1216
00:44:59,120 --> 00:45:01,200
THERE SUCH FEW TCRs FINALLY

1217
00:45:01,200 --> 00:45:04,160
RECOGNIZING THIS?

1218
00:45:04,160 --> 00:45:06,360
>>SO THIS CONCEPT OF

1219
00:45:06,360 --> 00:45:06,960
IMMUNODOMINANCE IS SOMETHING

1220
00:45:06,960 --> 00:45:08,920
THAT HAS EXISTED IN THE VIRAL

1221
00:45:08,920 --> 00:45:12,440
LITERATURE FOR YEARS, WHERE IF

1222
00:45:12,440 --> 00:45:14,840
YOU TAKE AN ANTIGENIC PROTEIN

1223
00:45:14,840 --> 00:45:16,600
AND IMMUNIZE A MOUSE OR A HUMAN,

1224
00:45:16,600 --> 00:45:20,200
IT TENDS TO FOCUS -- AN

1225
00:45:20,200 --> 00:45:21,800
ANTIGENIC VIRUS, IT TENDS TO

1226
00:45:21,800 --> 00:45:24,840
FOCUS ON VERY FEW PROTEINS.

1227
00:45:24,840 --> 00:45:27,960
I REMEMBER STUDIES FROM ELI

1228
00:45:27,960 --> 00:45:29,440
SARCARS ON AUTOIMMUNITY WHERE IF

1229
00:45:29,440 --> 00:45:34,360
YOU TOOK SOME OF THE MORE

1230
00:45:34,360 --> 00:45:36,480
IMMUNOGENIC PROTEIN OUT THEN

1231
00:45:36,480 --> 00:45:40,120
THERE WERE DOM NAPT CLONES THATT

1232
00:45:40,120 --> 00:45:41,280
WOULD BE RECOGNIZED.

1233
00:45:41,280 --> 00:45:44,600
I DON'T KNOW THE BASIS OF

1234
00:45:44,600 --> 00:45:47,160
IMMUNODOMINANCE, THAT'S THE

1235
00:45:47,160 --> 00:45:48,640
DESCRIPTIVE PART OF HIS WORKT.

1236
00:45:48,640 --> 00:45:49,680
WE TRIED TO COVER AS MUCH AS

1237
00:45:49,680 --> 00:45:49,960
POSSIBLE.

1238
00:45:49,960 --> 00:45:52,600
WE KNOW WE HAVE VERY LOW

1239
00:45:52,600 --> 00:45:53,560
BACKGROUND BECAUSE THE WAY WE

1240
00:45:53,560 --> 00:45:55,800
DID THE SORTING OF THE CELLS

1241
00:45:55,800 --> 00:46:01,200
TOOK OUT MOST OF THE --

1242
00:46:01,200 --> 00:46:03,480
FLUORESCENCE, IT WOULD MINIMIZE

1243
00:46:03,480 --> 00:46:03,920
BACKGROUND.

1244
00:46:03,920 --> 00:46:10,360
THE POSITIVE HITS ARE HITS, BUT

1245
00:46:10,360 --> 00:46:13,120
THEY ALL MAKE LET'S -- MUTATION

1246
00:46:13,120 --> 00:46:14,040
AND HLAs, THE MECHANISM, I

1247
00:46:14,040 --> 00:46:14,440
DON'T KNOW.

1248
00:46:14,440 --> 00:46:15,680
>>SO THE OTHER QUESTION
IS, YOU

1249
00:46:15,680 --> 00:46:17,560
KNOW, YOU SHOW IN THE END THE

1250
00:46:17,560 --> 00:46:18,840
DOWN REGULATION OF THE HLA AND

1251
00:46:18,840 --> 00:46:20,560
THAT'S WHY THE TUMOR WAS NOT

1252
00:46:20,560 --> 00:46:21,960
RECOGNIZED IN SOME CASES.

1253
00:46:21,960 --> 00:46:23,280
SO THAT BRINGS UP A QUESTION,

1254
00:46:23,280 --> 00:46:26,120
AND YOU SAY THAT IT TAKES -- IT

1255
00:46:26,120 --> 00:46:28,120
TOOK YOU A YEAR TO DEVELOP THIS.

1256
00:46:28,120 --> 00:46:31,000
SO DOES THIS SUGGEST THAT IT'S

1257
00:46:31,000 --> 00:46:32,240
BETTER TO TREAT A PATIENT THAT

1258
00:46:32,240 --> 00:46:35,040
WOULD ACTUALLY RESPOND TO AN

1259
00:46:35,040 --> 00:46:37,240
IMMUNE CHECKPOINT INHIBITOR, OR

1260
00:46:37,240 --> 00:46:38,400
ONE THAT ACTUALLY POTENTIALLY

1261
00:46:38,400 --> 00:46:39,640
DOES NOT RESPOND BECAUSE IT'S

1262
00:46:39,640 --> 00:46:41,040
LESS LIKELY TO DEVELOP DOWN

1263
00:46:41,040 --> 00:46:42,320
REGULATION OR, YOU KNOW, ANY

1264
00:46:42,320 --> 00:46:46,200
OTHER IMMUNE ESCAPE?

1265
00:46:46,200 --> 00:46:49,920
>>SO THE MORE IMMUNE
EDITING

1266
00:46:49,920 --> 00:46:52,160
WOULD BE -- CANCER IS MORE

1267
00:46:52,160 --> 00:46:52,760
IMMUNOGENIC, ESPECIALLY IF

1268
00:46:52,760 --> 00:46:54,160
YOU'RE DOING IMMUNOTHERAPY AND

1269
00:46:54,160 --> 00:46:55,680
THE TUMOR BECOMES RESISTANT,

1270
00:46:55,680 --> 00:46:57,880
THAT'S WHEN WE SEE GENETIC --

1271
00:46:57,880 --> 00:46:59,600
MORE FREQUENT GENETIC MECHANISMS

1272
00:46:59,600 --> 00:47:01,360
OF RESISTANCE AS OPPOSED TO

1273
00:47:01,360 --> 00:47:03,400
BASELINE, SO IT COULD BE HLA

1274
00:47:03,400 --> 00:47:06,400
LOH, IT COULD BE B2M HOMOZYGOUS

1275
00:47:06,400 --> 00:47:09,720
LOSS OR JAK1 OR JAK2 MUTATIONS

1276
00:47:09,720 --> 00:47:10,640
SO THOSE PATIENTS WOULD NOT BE

1277
00:47:10,640 --> 00:47:12,680
TREATED WITH THESE AND THE

1278
00:47:12,680 --> 00:47:14,480
ALGORITHMS, THE BIOINFORMATIC

1279
00:47:14,480 --> 00:47:16,280
ALGORITHMS ARE NOW ABLE TO

1280
00:47:16,280 --> 00:47:16,680
DETECT THAT.

1281
00:47:16,680 --> 00:47:17,960
IT'S JUST THAT IT NEEDS TO BE ON

1282
00:47:17,960 --> 00:47:19,840
A RECENT BIOPSY, NOT THE

1283
00:47:19,840 --> 00:47:21,080
BASELINE BIOPSY FROM A LONG TIME

1284
00:47:21,080 --> 00:47:27,000
AGO.

1285
00:47:27,000 --> 00:47:28,040
THE LONG TIME, OBVIOUSLY AS

1286
00:47:28,040 --> 00:47:29,120
WE'RE GOING IN, EVERYTHING CAN

1287
00:47:29,120 --> 00:47:29,680
BE IMPROVED.

1288
00:47:29,680 --> 00:47:31,360
IF YOU PUT 10 PEOPLE MORE TO

1289
00:47:31,360 --> 00:47:34,200
WORK ON EVERY STEP, IT WOULD GO

1290
00:47:34,200 --> 00:47:36,400
MUCH FASTER.

1291
00:47:36,400 --> 00:47:38,080
SO IT'S WHAT COULD BE VISIBLY

1292
00:47:38,080 --> 00:47:39,720
DONE WITH A STARTUP COMPANY.

1293
00:47:39,720 --> 00:47:41,040
>>THANK YOU.

1294
00:47:41,040 --> 00:47:43,680
>>SO TONY, JUST WONDERFUL
WORK,

1295
00:47:43,680 --> 00:47:44,680
AND THANKS SO MUCH FOR SHARING

1296
00:47:44,680 --> 00:47:45,680
WITH US.

1297
00:47:45,680 --> 00:47:49,120
I JUST HAD A QUICK QUESTION

1298
00:47:49,120 --> 00:47:52,920
ABOUT THE -- HOW YOU SCREENED

1299
00:47:52,920 --> 00:47:54,680
FOR THE ON TARGET OFF TUMOR

1300
00:47:54,680 --> 00:47:56,440
POTENTIAL FOR THE TCRs BEFORE

1301
00:47:56,440 --> 00:47:59,960
YOU PUT THAT INTO PATIENTS.

1302
00:47:59,960 --> 00:48:02,760
>>THAT WAS NOT -- THAT
WAS NOT

1303
00:48:02,760 --> 00:48:04,560
PART OF THE PROCESS.

1304
00:48:04,560 --> 00:48:06,400
SO THE WHOLE PREMISES THAT THIS

1305
00:48:06,400 --> 00:48:07,760
IS AUTOLOGOUS.

1306
00:48:07,760 --> 00:48:10,040
>>YEAH.

1307
00:48:10,040 --> 00:48:11,400
>>WE WERE ABLE TO GET
THROUGH

1308
00:48:11,400 --> 00:48:13,040
THE FDA REVIEW AND DO THIS IN

1309
00:48:13,040 --> 00:48:15,520
PATIENTS.

1310
00:48:15,520 --> 00:48:19,600
AND THERE'S SOME THINGS WHERE

1311
00:48:19,600 --> 00:48:21,600
THE FDA COULD SAY YOU'RE NOW

1312
00:48:21,600 --> 00:48:23,960
TAKING A TCR, YOU'RE ENGINEERING

1313
00:48:23,960 --> 00:48:25,240
INTO ALL THE T-CELLS EU GIVING

1314
00:48:25,240 --> 00:48:27,440
IT BACK, WHAT IF THAT TCR

1315
00:48:27,440 --> 00:48:29,080
RECOGNIZED THE NON-MU TAITIVE

1316
00:48:29,080 --> 00:48:29,600
PEPTIDE?

1317
00:48:29,600 --> 00:48:33,240
WELL, THAT WAS NOT PART OF THE

1318
00:48:33,240 --> 00:48:33,760
CRITERIA.

1319
00:48:33,760 --> 00:48:35,160
BUT THAT TCR ALREADY CAME FROM

1320
00:48:35,160 --> 00:48:36,560
THE PATIENT, IT WAS ALREADY

1321
00:48:36,560 --> 00:48:36,880
CIRCULATING.

1322
00:48:36,880 --> 00:48:37,160
>>RIGHT.

1323
00:48:37,160 --> 00:48:41,080
>>SO THE CHANCES OF
INDUCED

1324
00:48:41,080 --> 00:48:42,400
AUTOIMMUNITY FROM THAT WOULD BE

1325
00:48:42,400 --> 00:48:44,960
LOWER, THAT'S NOT IMPOSSIBLE.

1326
00:48:44,960 --> 00:48:47,800
MY BIGGEST ARGUMENT FOR ANYBODY

1327
00:48:47,800 --> 00:48:49,160
WHO COULD SAY, OH, YOU SHOULDN'T

1328
00:48:49,160 --> 00:48:50,800
BE DOING THIS, IS THE TIL

1329
00:48:50,800 --> 00:48:51,320
THERAPY.

1330
00:48:51,320 --> 00:48:53,640
SO YOU GUYS HAVE BEEN GIVING TIL

1331
00:48:53,640 --> 00:48:57,280
TO PATIENTS FOR YEARS, HAS THERE

1332
00:48:57,280 --> 00:48:59,840
EVER BEEN A PATIENT WHERE YOU

1333
00:48:59,840 --> 00:49:02,320
INDUCE AUTOIMMUNITY OTHER THAN

1334
00:49:02,320 --> 00:49:03,640
VITILIGO WITH IMMUNE THERAPY?

1335
00:49:03,640 --> 00:49:05,040
I DON'T RECALL IT.

1336
00:49:05,040 --> 00:49:07,520
SO EVEN T-CELLS THAT MAY

1337
00:49:07,520 --> 00:49:08,800
RECOGNIZE SELF ANTIGEN, IF YOU

1338
00:49:08,800 --> 00:49:11,840
GIVE THEM IN LARGE DOSES OR

1339
00:49:11,840 --> 00:49:14,080
ADOPTIVE CELL TRANSFER DO NOT

1340
00:49:14,080 --> 00:49:14,760
BECOME -- AUTO REACT.

1341
00:49:14,760 --> 00:49:15,240
>>PERFECT.

1342
00:49:15,240 --> 00:49:18,400
THANK YOU.

1343
00:49:18,400 --> 00:49:21,440
>>PAUL OR TIM?

1344
00:49:21,440 --> 00:49:25,440
>>YOU SHOW ONE SLIDE
WHICH WAS

1345
00:49:25,440 --> 00:49:26,960
LOOKING, COMPARING THE AVIDITY

1346
00:49:26,960 --> 00:49:29,800
OF THE T-CELLS, I BELIEVE, FROM

1347
00:49:29,800 --> 00:49:30,840
EFFECTIVE TCRs IN PREVIOUS

1348
00:49:30,840 --> 00:49:32,120
TRIALS AND YOUR TCRs.

1349
00:49:32,120 --> 00:49:34,120
I KIND OF PERHAPS APOLOGIZE FOR

1350
00:49:34,120 --> 00:49:35,120
NOT UNDERSTANDING THAT

1351
00:49:35,120 --> 00:49:38,160
COMPLETELY, BUT WERE YOUR TCRs

1352
00:49:38,160 --> 00:49:40,880
OF LOWER AVIDITY SO THAT WAS A

1353
00:49:40,880 --> 00:49:41,600
POTENTIAL PROBLEM, DO YOU HAVE

1354
00:49:41,600 --> 00:49:43,120
AN IDEA OF PERHAPS HOW TO

1355
00:49:43,120 --> 00:49:43,560
OVERCOME THAT ISSUE?

1356
00:49:43,560 --> 00:49:49,200
>>WHEN WE STARTED THE
PROTOCOL,

1357
00:49:49,200 --> 00:49:54,560
SO IF A PATIENT -- WITH ALL OF

1358
00:49:54,560 --> 00:49:57,080
THE APPROACH LED TO 10 TCRs

1359
00:49:57,080 --> 00:49:58,960
AND WE HAD TO CHOOSE THE THREE

1360
00:49:58,960 --> 00:50:01,200
BEST ONES, THEY SET UP A SERIES

1361
00:50:01,200 --> 00:50:04,040
OF CRITERIA, YOU WANT TO HAVE

1362
00:50:04,040 --> 00:50:05,320
THE THREE TCRs STARTED IN

1363
00:50:05,320 --> 00:50:06,280
DIFFERENT HLAs, YOU WANT TO

1364
00:50:06,280 --> 00:50:08,760
HAVE THE THREE TCRs TARGETED

1365
00:50:08,760 --> 00:50:10,120
IN DIFFERENT ANTIGENS IF YOU CAN

1366
00:50:10,120 --> 00:50:14,320
CHOOSE, AND THEN AVIDITY WAS

1367
00:50:14,320 --> 00:50:15,760
SOMETHING THAT AT THE BEGINNING

1368
00:50:15,760 --> 00:50:17,240
WAS NOT PART OF THIS.

1369
00:50:17,240 --> 00:50:19,960
THAT WAS BECAUSE THERE'S THIS

1370
00:50:19,960 --> 00:50:24,080
DATA IN THE LITERATURE SAYING

1371
00:50:24,080 --> 00:50:28,080
THAT LOW AVID IITY T-CELLS MAY E

1372
00:50:28,080 --> 00:50:30,920
ABLE TO STAND MULTIPLE ROUNDS OF

1373
00:50:30,920 --> 00:50:34,840
ANTIGEN EXPOSURE AS OPPOSED TO

1374
00:50:34,840 --> 00:50:36,200
HIGH AVIDITY THAT WOULD BE

1375
00:50:36,200 --> 00:50:37,680
TURNED OFF EARLIER.

1376
00:50:37,680 --> 00:50:39,600
IN RETROSPECT, WE SEE THE ONES

1377
00:50:39,600 --> 00:50:40,920
THAT EXPANDED MORE IN THE TUMOR,

1378
00:50:40,920 --> 00:50:43,240
I DIDN'T SHOW THAT, BUT THE DATA

1379
00:50:43,240 --> 00:50:45,160
IS THERE, WERE THE HIGHER

1380
00:50:45,160 --> 00:50:46,840
AVIDITY T-CELL RECEPTORS AND THE

1381
00:50:46,840 --> 00:50:48,960
ONES THAT EXPANDED LESS IN THE

1382
00:50:48,960 --> 00:50:49,560
TUMORS WERE THE LOWER.

1383
00:50:49,560 --> 00:50:51,320
SO WE HAVE TO DO THIS AGAIN, WE

1384
00:50:51,320 --> 00:50:53,000
WOULD PUT THE AVIDITY AS ONE OF

1385
00:50:53,000 --> 00:50:54,440
THE CRITERIA TO SELECT IF

1386
00:50:54,440 --> 00:50:55,080
POSSIBLE.

1387
00:50:55,080 --> 00:50:57,400
IN SOME PATIENT, THERE WERE ONLY

1388
00:50:57,400 --> 00:51:00,040
ONE OR TWO TCRs THAT WERE

1389
00:51:00,040 --> 00:51:01,120
ISOLATED THAT WERE JUST USED.

1390
00:51:01,120 --> 00:51:01,560
>>THANK YOU.

1391
00:51:01,560 --> 00:51:02,520
>>BEAUTIFUL TALK.

1392
00:51:02,520 --> 00:51:03,400
>>THANKS.

1393
00:51:03,400 --> 00:51:06,600
>>SO WHEN YOU SHOWED THAT
THE

1394
00:51:06,600 --> 00:51:08,680
T-CELL REPERTOIRE, THE TCR

1395
00:51:08,680 --> 00:51:10,440
REPERTOIRE WAS HIGHER IN THE

1396
00:51:10,440 --> 00:51:12,080
RESPONDERS, CAN YOU SPECULATE ON

1397
00:51:12,080 --> 00:51:13,840
WHAT DO YOU THINK THAT MEANS?

1398
00:51:13,840 --> 00:51:16,480
WHY WOULD THAT GIVE YOU A BETTER

1399
00:51:16,480 --> 00:51:17,120
CHANCE OF RESPONDING?

1400
00:51:17,120 --> 00:51:18,600
WHAT DO YOU THINK IS RESPONSIBLE

1401
00:51:18,600 --> 00:51:22,080
FOR THAT?

1402
00:51:22,080 --> 00:51:27,480
>>SO WHATEVER MAKES A
MUTATION

1403
00:51:27,480 --> 00:51:29,200
YOU ME KNOWGENIC IN THOSE

1404
00:51:29,200 --> 00:51:32,240
PATIENTS WHO GO ON TO RESPOND TO

1405
00:51:32,240 --> 00:51:33,760
ANTI-PD-1 HAVE MORE OF THOSE

1406
00:51:33,760 --> 00:51:34,640
MUTATIONS -- DO NOT HAVE MORE OF

1407
00:51:34,640 --> 00:51:38,320
THOSE MUTATIONS BUT HAVE MORE

1408
00:51:38,320 --> 00:51:41,760
T-CELLS THAT RECOGNIZE THE

1409
00:51:41,760 --> 00:51:44,280
MUTATION WITH NONE OR MULTIPLE

1410
00:51:44,280 --> 00:51:44,480
TCRs.

1411
00:51:44,480 --> 00:51:46,040
>>SO IT'S JUST A NUMBERS
GAME,

1412
00:51:46,040 --> 00:51:46,440
YOU THINK?

1413
00:51:46,440 --> 00:51:49,360
>>I THINK IT'S AN
INDIRECT

1414
00:51:49,360 --> 00:51:50,760
MEASURE OF HOW GOOD THAT

1415
00:51:50,760 --> 00:51:53,840
MUTATION AND HLA COMPLEX WAS TO

1416
00:51:53,840 --> 00:51:54,680
TURN ON THE T-CELLS OF THAT

1417
00:51:54,680 --> 00:51:55,960
PATIENT.

1418
00:51:55,960 --> 00:52:02,920
AND IT'S NOT LINEAL LIQUOR LALYD

1419
00:52:02,920 --> 00:52:06,040
WITH THE MUTATIONAL LOAD, THAT'S

1420
00:52:06,040 --> 00:52:10,320
WHY IN -- MUTATIONS, RESPONSE TO

1421
00:52:10,320 --> 00:52:13,480
ANTI -- IS NON-LINEARLY

1422
00:52:13,480 --> 00:52:13,800
CORRELATED.

1423
00:52:13,800 --> 00:52:15,320
>>DO YOU THINK THESE
STUDIES

1424
00:52:15,320 --> 00:52:16,680
WILL CONTINUE THERE OR SOMEPLACE

1425
00:52:16,680 --> 00:52:16,920
ELSE?

1426
00:52:16,920 --> 00:52:21,560
I MEAN --

1427
00:52:21,560 --> 00:52:25,360
>>SO PAUL, IF YOU HAVE --
I

1428
00:52:25,360 --> 00:52:26,560
HAVE CONNECTIONS WITH ONE

1429
00:52:26,560 --> 00:52:29,120
INVESTORS THAT WANT TO PUT MORE

1430
00:52:29,120 --> 00:52:30,000
MONEY --

1431
00:52:30,000 --> 00:52:31,040
[LAUGHTER]

1432
00:52:31,040 --> 00:52:31,160
>>

1433
00:52:31,160 --> 00:52:34,280
>>SORRY TO SAY I DON'T.

1434
00:52:34,280 --> 00:52:38,680
>>THIS WAS -- WE CAN TALK
LONG,

1435
00:52:38,680 --> 00:52:40,760
WE NEED TO TBRAB A BEAR FOR

1436
00:52:40,760 --> 00:52:45,960
TH -- NEED TO GRAB ABEER FOR TH.

1437
00:52:45,960 --> 00:52:47,720
IT TURNS OUT THE BIOTECH

1438
00:52:47,720 --> 00:52:48,920
INVESTMENT FIELD RUN OUT OF

1439
00:52:48,920 --> 00:52:51,040
MONEY, PULLED THE MONEY AWAY,

1440
00:52:51,040 --> 00:52:54,200
AND THINGS LIKE THIS WERE -- WE

1441
00:52:54,200 --> 00:52:56,240
WOULD HAVE TO SPEND DOUBLE THAN

1442
00:52:56,240 --> 00:52:57,920
THIS TO BE ABLE TO MAKE IT THEIR

1443
00:52:57,920 --> 00:52:58,560
TEU PICK.

1444
00:52:58,560 --> 00:52:59,640
I THINK IT'S GOING TO BE THERE

1445
00:52:59,640 --> 00:53:01,360
AND I CONVINCED WE'RE GOING TO

1446
00:53:01,360 --> 00:53:02,960
TREAT CANCER IN THE FUTURE WITH

1447
00:53:02,960 --> 00:53:04,560
AN APPROACH LIKE THIS.

1448
00:53:04,560 --> 00:53:06,600
WE JUST NEED TO MAKE SECONDARY

1449
00:53:06,600 --> 00:53:09,680
GENE EDITS TO MAKE THOSE T-CELLS

1450
00:53:09,680 --> 00:53:10,680
REPEATED ANTIGEN EXPOSURE.

1451
00:53:10,680 --> 00:53:13,120
WE CAN DO SYNTHETIC BIOLOGY, WE

1452
00:53:13,120 --> 00:53:14,440
CAN PUT RECEPTORS LIKE WHAT

1453
00:53:14,440 --> 00:53:15,960
WE'VE DONE WITH CRIS GARCIA

1454
00:53:15,960 --> 00:53:18,760
WHERE WE CAN GIVE AN ORTHOGONAL

1455
00:53:18,760 --> 00:53:20,280
CYTOKINE THAT TURNS ON THOSE

1456
00:53:20,280 --> 00:53:21,160
T-CELLS ONLY SPECIFICALLY.

1457
00:53:21,160 --> 00:53:25,120
THE ABILITY TO DO THIS KNOCK-IN

1458
00:53:25,120 --> 00:53:26,600
ALLOWS US TO PUT TWO OR THREE

1459
00:53:26,600 --> 00:53:28,440
GENES ON THAT PLASMID, AND WE

1460
00:53:28,440 --> 00:53:30,600
DON'T LOSE EFFICIENCY.

1461
00:53:30,600 --> 00:53:36,000
IT'S ALL THERE TO BE DONE.

1462
00:53:36,000 --> 00:53:37,040
SO -- GO BACK TO DOING IT.

1463
00:53:37,040 --> 00:53:38,360
>>OKAY, GREAT.

1464
00:53:38,360 --> 00:53:39,040
>>THANK YOU.

1465
00:53:39,040 --> 00:53:41,200
THERE IS A GOOD BEER PLACE

1466
00:53:41,200 --> 00:53:41,440
NEARBY.

1467
00:53:41,440 --> 00:53:41,920
>>THANK YOU.

1468
00:53:41,920 --> 00:53:43,800
>>SO FROM AN INFORMATION
POINT

1469
00:53:43,800 --> 00:53:45,840
OF VIEW, I'M TRYING TO

1470
00:53:45,840 --> 00:53:47,040
UNDERSTAND THE TWO SYSTEMS OR

1471
00:53:47,040 --> 00:53:48,360
THE PATH OF THE SYSTEM THAT YOU

1472
00:53:48,360 --> 00:53:51,560
COVERED, THE MUTATIONS ON

1473
00:53:51,560 --> 00:53:52,840
NEOANTIGEN AND THE SECOND, THE

1474
00:53:52,840 --> 00:53:53,240
TCR.

1475
00:53:53,240 --> 00:53:54,520
SO I'M TRYING TO UNDERSTAND

1476
00:53:54,520 --> 00:53:56,480
WHICH PART OF THE SYSTEM PLAYS A

1477
00:53:56,480 --> 00:53:57,800
MORE STRONGER ROLE THAN THE

1478
00:53:57,800 --> 00:53:58,240
OTHER.

1479
00:53:58,240 --> 00:54:00,240
SO LET'S SAY YOU HAVE A SINGLE

1480
00:54:00,240 --> 00:54:01,960
MUTATION IN A THOUSAND PATIENTS.

1481
00:54:01,960 --> 00:54:03,320
HOW MANY PATIENTS WOULD YOU SEE

1482
00:54:03,320 --> 00:54:06,560
THAT DO HAVE THE TCR TO TRY TO

1483
00:54:06,560 --> 00:54:12,080
TARGET THAT NEOANTIGEN?

1484
00:54:12,080 --> 00:54:13,240
>>I DON'T HAVE A WAY TO
ANSWER

1485
00:54:13,240 --> 00:54:19,480
THAT QUESTION.

1486
00:54:19,480 --> 00:54:21,360
MORE IMMUNOGENIC CANCER, MO

1487
00:54:21,360 --> 00:54:22,960
TCRs, MORE CLONOTYPES, THAT'S

1488
00:54:22,960 --> 00:54:24,160
GOOD AND THOSE PATIENT RESPOND

1489
00:54:24,160 --> 00:54:25,800
TO APT PD-1, THEY DON'T NEED

1490
00:54:25,800 --> 00:54:26,240
ANYTHING ELSE.

1491
00:54:26,240 --> 00:54:27,640
WE HAVE TO TREAT THE ONES WHERE

1492
00:54:27,640 --> 00:54:28,360
THIS DOESN'T HAPPEN.

1493
00:54:28,360 --> 00:54:31,960
BUT EVEN IN THAT CASE, WHEN WE

1494
00:54:31,960 --> 00:54:34,040
HAVE VERY FEW MUTATIONS, VERY

1495
00:54:34,040 --> 00:54:36,720
FEW TCRs, I SHOW YOU THOSE

1496
00:54:36,720 --> 00:54:38,360
THREE RANDOM PATIENTS WITH

1497
00:54:38,360 --> 00:54:40,360
MELANOMA, WE CLONE FIVE TCRs

1498
00:54:40,360 --> 00:54:42,160
AND ALL OF THEM KILL THE MATCHED

1499
00:54:42,160 --> 00:54:43,200
TUMORS.

1500
00:54:43,200 --> 00:54:45,720
SO THERE'S HOPE THERE THAT EVEN

1501
00:54:45,720 --> 00:54:48,120
IN THE SITUATIONS WHERE THE

1502
00:54:48,120 --> 00:54:49,760
CANCER WASN'T TOO IMMUNOGENIC ON

1503
00:54:49,760 --> 00:54:51,000
THE IMMUNE SYSTEM WASN'T DOING

1504
00:54:51,000 --> 00:54:55,280
MUCH ABOUT IT, AND A SENSITIVE

1505
00:54:55,280 --> 00:54:56,520
APPROACH LIKE THIS THAT CAPTURES

1506
00:54:56,520 --> 00:54:58,720
ENOUGH OF THE LANDSCAPE OF THE

1507
00:54:58,720 --> 00:55:00,480
MUTATION AND HLA PEPTIDE

1508
00:55:00,480 --> 00:55:01,640
DETERMINANTS THAT WE CAN GET

1509
00:55:01,640 --> 00:55:03,880
THOSE TCRs AND USE THEM.

1510
00:55:03,880 --> 00:55:05,560
>>THANK YOU.

1511
00:55:05,560 --> 00:55:06,760
JUST BUILDING ON THAT,

1512
00:55:06,760 --> 00:55:08,480
CONSIDERING SUCH A SMALL SUBSET

1513
00:55:08,480 --> 00:55:10,240
OF THEM WERE ACTUALLY

1514
00:55:10,240 --> 00:55:11,240
IMMUNOGENIC, IT IS A LITTLE

1515
00:55:11,240 --> 00:55:13,560
SURPRISING THAT METHODS LIKE TMB

1516
00:55:13,560 --> 00:55:17,280
DO HAVE SOME POWER POTENTIALLY,

1517
00:55:17,280 --> 00:55:18,200
SO JUST THAT FINAL --

1518
00:55:18,200 --> 00:55:21,280
>>MY FRIEND DON
SCHUMACHER SAYS

1519
00:55:21,280 --> 00:55:22,920
TMB IS LIKE BUYING TICKET TO THE

1520
00:55:22,920 --> 00:55:24,000
LOTTERY, THAT YOU HAVE TO BUY

1521
00:55:24,000 --> 00:55:25,440
SOME TO BE ABLE TO WIN AND IF

1522
00:55:25,440 --> 00:55:27,120
YOU BUY MORE, YOU MAY BE MORE

1523
00:55:27,120 --> 00:55:27,880
LUCKY, BUT THAT DOESN'T MEAN

1524
00:55:27,880 --> 00:55:31,080
THAT YOU HAVE ONE, YOU CANNOT

1525
00:55:31,080 --> 00:55:31,480
WIN IT.

1526
00:55:31,480 --> 00:55:33,320
>>THANK YOU.

1527
00:55:33,320 --> 00:55:36,880
>>THAT WAS AN AMAZING
TOUR

1528
00:55:36,880 --> 00:55:39,480
DEFORCE AND THE SCIENCE IS

1529
00:55:39,480 --> 00:55:40,040
REALLY FASCINATING.

1530
00:55:40,040 --> 00:55:41,120
I HAVE A QUESTION ABOUT YOUR

1531
00:55:41,120 --> 00:55:41,640
MANUFACTURING PROCESS.

1532
00:55:41,640 --> 00:55:42,120
TWO QUESTIONS.

1533
00:55:42,120 --> 00:55:43,720
ONE IS, WHAT MADE IT WORK SO

1534
00:55:43,720 --> 00:55:46,600
MUCH BETTER IN VERSION THREE,

1535
00:55:46,600 --> 00:55:49,720
AND ALSO WHAT IS THE INFUSION

1536
00:55:49,720 --> 00:55:51,560
BACK LOOK LIKE AS FAR AS DATA

1537
00:55:51,560 --> 00:55:53,080
DIFFERENTIATION?

1538
00:55:53,080 --> 00:55:55,200
>>SO THE MANUFACTURING
IMPROVED

1539
00:55:55,200 --> 00:55:57,840
WITH CHANGES IN THE MEDIA,

1540
00:55:57,840 --> 00:55:59,600
CHANGES IN THE -- AT THE END

1541
00:55:59,600 --> 00:56:02,400
THEY HAD THIS BETA TEST OF -- I

1542
00:56:02,400 --> 00:56:05,080
FORGOT -- IT'S IN THE PAPER

1543
00:56:05,080 --> 00:56:07,520
BUT -- AND THEN OPTIMIZATION OF

1544
00:56:07,520 --> 00:56:08,680
EVERY SINGLE STEP.

1545
00:56:08,680 --> 00:56:12,120
SO AT SOME POINT, THEY WERE

1546
00:56:12,120 --> 00:56:14,520
EXPANDING THE CELLS THAT WERE

1547
00:56:14,520 --> 00:56:17,520
TOO CROWDED AND THE DIFFERENT

1548
00:56:17,520 --> 00:56:18,640
MANUFACTURING CHANGES WHICH ARE

1549
00:56:18,640 --> 00:56:22,320
DIFFICULT TO EVOLVE AT CLINICAL

1550
00:56:22,320 --> 00:56:24,160
GRADE AND UNDER THE SAME IND BUT

1551
00:56:24,160 --> 00:56:25,880
IT WAS ABLE TO DO THAT, AND AT

1552
00:56:25,880 --> 00:56:27,960
THE END, THEY ENDED UP WITH GOOD

1553
00:56:27,960 --> 00:56:33,400
CELLS THAT COULD EXPAND IN VIVO.

1554
00:56:33,400 --> 00:56:35,800
THE BACK -- INFUSION -- MOSTLY

1555
00:56:35,800 --> 00:56:39,720
LIKE THE TCR ENGINEERED T-CELLS

1556
00:56:39,720 --> 00:56:41,080
LIKE -- WHERE IT'S NOT LIKE YOUR

1557
00:56:41,080 --> 00:56:43,800
TILES THAT WAS A MILKY THING,

1558
00:56:43,800 --> 00:56:44,160
CRYOPRESERVED --

1559
00:56:44,160 --> 00:56:46,080
>>BUT THERE'S DATA

1560
00:56:46,080 --> 00:56:46,920
DIFFERENTIATION IF YOU LOOKED AT

1561
00:56:46,920 --> 00:56:50,120
THE MAR MARKERS AND SO FORTH, WE

1562
00:56:50,120 --> 00:56:52,840
THEY DIFFERENT THAN A TYPICAL

1563
00:56:52,840 --> 00:56:53,640
RETROVIRAL BAG?

1564
00:56:53,640 --> 00:56:54,880
>>SO WE PUT ALL OF THE
DATA IN

1565
00:56:54,880 --> 00:56:55,800
THE PAPER.

1566
00:56:55,800 --> 00:56:56,560
IT'S ALL THERE.

1567
00:56:56,560 --> 00:56:59,320
IT'S ALL DESCRIPTIVE.

1568
00:56:59,320 --> 00:57:01,400
THERE WAS SOMETHING THAT -- I

1569
00:57:01,400 --> 00:57:07,040
DON'T KNOW, SOME -- THERE WAS A

1570
00:57:07,040 --> 00:57:11,080
DIFFERENT DIFFERENTIATION STAGE.

1571
00:57:11,080 --> 00:57:13,880
THERE WAS AN ATTEMPT TO DO STEM

1572
00:57:13,880 --> 00:57:17,440
CELL -- THERE WERE QUITE A BIT

1573
00:57:17,440 --> 00:57:19,320
OF THEM -- IT DIDN'T

1574
00:57:19,320 --> 00:57:23,400
DIFFERENTIATE ANYTHING IN

1575
00:57:23,400 --> 00:57:25,080
EXPANSION OR TARGETING --

1576
00:57:25,080 --> 00:57:26,040
ACCUMULATION IN TUMOR.

1577
00:57:26,040 --> 00:57:27,440
I'M SORRY I HAVEN'T LOOKED AT

1578
00:57:27,440 --> 00:57:29,120
THAT DATA FOR SIX MONTHS SO I

1579
00:57:29,120 --> 00:57:32,880
CANNOT ANSWER.

1580
00:57:32,880 --> 00:57:35,640
>>SO ON SIMILAR LINES OF
THE

1581
00:57:35,640 --> 00:57:37,000
TUMOR MICRO -- HAVE YOU EVER

1582
00:57:37,000 --> 00:57:38,280
THOUGHT ABOUT TESTING THE

1583
00:57:38,280 --> 00:57:39,640
METABOLISM OF THESE T-CELLS AT

1584
00:57:39,640 --> 00:57:41,120
DIFFERENT STAGES OF YOUR CELL

1585
00:57:41,120 --> 00:57:43,400
GROWTH OR MAKING THIS JUST

1586
00:57:43,400 --> 00:57:44,360
BEFORE -- WHEN YOU'RE INJECTING

1587
00:57:44,360 --> 00:57:45,880
INTO THE PATIENT?

1588
00:57:45,880 --> 00:57:48,400
WHAT IS THE METABOLIC STATE OF

1589
00:57:48,400 --> 00:57:52,440
THE T-CELLS AT DIFFERENT STAGES?

1590
00:57:52,440 --> 00:57:55,760
OF THIS SPECIFIC ONE.

1591
00:57:55,760 --> 00:57:58,360
>>SO THESE T-CELLS, I'M

1592
00:57:58,360 --> 00:57:59,440
THINKING ABOUT JIM'S QUESTION,

1593
00:57:59,440 --> 00:58:02,040
THERE WERE NOT THAT --

1594
00:58:02,040 --> 00:58:03,160
PHENOTYPICALLY THEY WERE NOT

1595
00:58:03,160 --> 00:58:05,640
THAT DIFFERENT FROM RETROVIRALLY

1596
00:58:05,640 --> 00:58:09,000
TRANSDUCED TCR TRANSGENIC

1597
00:58:09,000 --> 00:58:10,320
T-CELLS FROM YOUR PAPERS FROM

1598
00:58:10,320 --> 00:58:11,200
PAUL ROBYNS AND OTHERS.

1599
00:58:11,200 --> 00:58:16,600
ROBBINS AND OTHERS.I DON'T KNOWE

1600
00:58:16,600 --> 00:58:18,000
HAD GOOD MANUFACTURING THAT THE

1601
00:58:18,000 --> 00:58:19,280
METABOLIC STATE OF THOSE CELLS

1602
00:58:19,280 --> 00:58:20,280
WERE ANY ALTERED.

1603
00:58:20,280 --> 00:58:22,800
THEY WERE INFUSED IN LOWER

1604
00:58:22,800 --> 00:58:24,080
NUMBERS THAT WOULD BE THE

1605
00:58:24,080 --> 00:58:25,800
THRESHOLD TO BE ABLE TO HAVE A

1606
00:58:25,800 --> 00:58:27,120
CLINICAL RESPONSE.

1607
00:58:27,120 --> 00:58:28,720
SOME T-CELL RECEPTORS WERE NOT

1608
00:58:28,720 --> 00:58:29,720
TO THE AFFINITY THAT SHOULD BE

1609
00:58:29,720 --> 00:58:30,560
AND THEN THE MAJORITY OF

1610
00:58:30,560 --> 00:58:34,400
PATIENTS DID NOT GET

1611
00:58:34,400 --> 00:58:35,840
SUPPLEMENTAL IL-2.

1612
00:58:35,840 --> 00:58:39,560
SO I THINK TO GET TO THE -- WE

1613
00:58:39,560 --> 00:58:40,600
FIRST LOOK AT THE CELL THERAPY

1614
00:58:40,600 --> 00:58:41,800
RIGHT AND THEN WE CAN GET TO

1615
00:58:41,800 --> 00:58:42,400
YOUR QUESTION.

1616
00:58:42,400 --> 00:58:42,800
>>OKAY.

1617
00:58:42,800 --> 00:58:46,520
THANK YOU.

1618
00:58:46,520 --> 00:58:51,240
>>THANK YOU VERY MUCH.

1619
00:58:51,240 --> 00:59:01,400
[APPLAUSE]