I'M CAROL THIELE, DEPUTY CHIEF
OF PEDIATRIC ONCOLOGY BRANCH,
SENIOR INVESTIGATOR IN THE
BRANCH, I HAVE THE HONOR OF
BEING THE LONGEST SERVING
MEMBER, I THINK, OF THE BRANCH,
PERHAPS THE OLDEST AS WELL.
I THINK TODAY WE'RE GOING TO
CELEBRATE ACHIEVEMENTS IN CAR T
CELL THERAPY, BUILDING ON A LONG
HISTORY OF ACHIEVEMENT IN THE
PEDIATRIC ONCOLOGY BRANCH.
AND FIRST STARTED BY ART LEVINE
IN THE 70s, WHERE WE DEVELOPED
SOME OF THE FIRST THERAPY FOR
TREATING TEDDY, THE BOY IN THE
BUBBLE WITH IMMUNODEFICIENCIES.
LATER THE FELLOW IN CHARGE OF
TREATING TEDDY BECAME OUR BRANCH
CHIEF, PHIL PEAZO'S, DURING HIS
YEARS HERE A RICH ENVIRONMENT
FOR US, SOME FIRST TREATMENTS
FOR KIDS WITH HIV, DEVELOPMENT
OF PSYCHOSOCIAL SUPPORTS FOR
THESE TREATMENTS, AND THEIR
FAMILIES.
DAVID POPLAK AND GROUND-BREAKING
STUDIES ON PREVENTION OF CNS
TOXICITY FOR LEUKEMIA, IN THE
REGIMENS FOR LYMPHOMA.
LEE HELLMUND BECAME THE CHIEF,
BROUGHT TO THE FORE MOLECULAR
ONCOLOGY AND RECRUITMENT OF SOME
OF THE YOUNGER NEWER MEMBERS OF
THE BRANCH, AND DEVELOPING
IMMUNOTHERAPY WITH RECRUITMENT
OF CRYSTAL MAKEL AND IN FACT
CRYSTAL LATER BECAME THE BRANCH
CHIEF AND IT WAS REALLY AT THIS
TIME WHEN IMMUNOTHERAPY CAME TO
THE FORE.
YOU'LL HEAR ABOUT THESE.
ALSO BUILDING ON THIS SUCCESS WE
ALSO HAVE -- I'M HERE TO
INTRODUCE OUR CURRENT BRANCH
CHIEF, DR. WEEDMAN, FOR TREATING
METHYLTREXATE OVERDOSES.
I'D LIKE TO DR. BRIGITTE
WEEDMAN.
>> THANK YOU FOR THIS AMAZING
SYMPOSIUM.
WE HAVE THE NEW FELLOWS HERE AS
WELL TODAY, AND I THINK CAROL'S
BACKGROUND SHOWS A LOT OF
HISTORY AND COLLABORATION.
WE'RE CELEBRATING THE SUCCESSES
IN CAR T CELL THERAPY, NOW TEN
YEARS, AND IT STARTED WITH A
TEAM IN THE POB, FOR CAR T CELL
THERAPY AND POB, AND YOU SEE THE
LEADERS AT THE TIME.
THIS WAS A VERY EXCITING TIME
BUT THEN PEOPLE LEFT TO DO GREAT
WORK IN OTHER PLACES.
AND BY 2018, THIS WAS THE POB
LEUKEMIA TEAM.
NIRALI USED TO SHOW THIS
PICTURE.
AND OF COURSE, THIS DID NOT
DETER NIRALI TO BUILD A FIRST
CLASS TOP NOTCH CLINICAL TEAM.
THIS IS SOME OF THE CLINICAL
MEMBERS.
I'M ONLY FOCUSING ON POB TODAY.
WE HAVE GUESTS HERE, SO MANY
COLLABORATORS, BUT THIS IS THE
CORE CLINICAL TEAM, BONNIE,
HAMIN, AND DR. PERBERMA, AN
EXCELLENT TEAM OF NURSES,
PCCs, FELLOWS, RESEARCH
MANAGERS.
VERY IMPORTANTLY, REALLY
STRATEGIC, WE HAVE A NEW BASIC
EFFORT IN THE BRANCH IN CAR T
CELL THERAPY, IN LEUKEMIAS, THIS
IS LED BY DR. NAOMI TAYLOR.
I'M ALSO HIGHLIGHTING CHRIS
CHEN, NIRALI'S BIOLOGIST, TAKING
THE EFFORTS, BUT MANY MORE IN
POB.
AS I MENTIONED, OUTSIDE OF THE
PEDIATRIC ONCOLOGY BRANCH.
TWO FELLOWS MADE IT THROUGH OUR
ONE-YEAR FELLOWSHIP IN PEDIATRIC
IMMUNOTHERAPY.
I'LL SHOW YOU WHERE THEY HAVE
GONE IN A MOMENT.
AND THEN WONDERFUL ASPECT OF THE
LEUKEMIA TEAM AND IMMUNOTHERAPY
EXPERTISE, WE'VE BEEN ABLE TO
BUILD A SOLID TUMOR
IMMUNOTHERAPY TEAM, I'M SHOWING
SOME OF THE INVESTIGATORS HERE,
ROSY KAPLAN AND OTHERS, AND OF
COURSE CAROL.
THIS IS A GREAT TEAM THAT IS NOW
BUILDING CAR T CELL THERAPIES
FOR OSTEOSARCOMA,
NEUROBLASTOMA.
IT'S BEEN HELPFUL TO HAVE PEOPLE
LIKE THIS HELPING THE SOLID
TUMOR TEAM IN DEVELOPING THE
PROTOCOLS BUT ALSO PROVIDING THE
EXPERTISE AS WE'RE SEEING CAR T
CELL TOXICITY IN THE SOLID TUMOR
PATIENTS.
SO IT IS A REAL TEAM EFFORT.
MY LAST SLIDE IS TO SHOW YOU OUR
PHILOSOPHY.
ANYBODY WHO LEAVES THE POB STAYS
TO BE A POB MEMBER.
IT'S THE POB DIASPORA.
WE HAVE POB COLORADO, WE HAVE
POB CALIFORNIA, POB TEXAS,
MIDWEST, TEXAS, PHILADELPHIA,
FLORIDA, AND INTERNATIONAL POB
WITH FELLOWS AND LEADERS NOW IN
IMMUNOTHERAPY IN ISRAEL,
ENGLAND, GERMANY, IT'S A
SNAPSHOT, NOT COMPLETE.
I WOULD LIKE TO HAND OVER TO
NIRALI SHAH AND REALLY LOOK
FORWARD TO THIS SYMPOSIUM TODAY,
TO CELEBRATING THE SUCCESSES
OVER THE PAST TEN YEARS.
[APPLAUSE]
>> WE'RE GOING TO HAVE TWO
VIDEOS FROM FORMER POB.
FIRST IS ALAN WAYNE.
>>GREETINGS FROM LOS ANGELES.
I HOPE EVERYONE AT THE POB AND
ACROSS THE INTRAMURAL NIH IS
DOING WELL.
PROGRAM BEGIN IN SUMMER OF 2009,
STEVE ROSENBERG AND JIM
COKENBERGER.
THEY WONDERED IF IT WAS TIME TO
EXPAND INTO PEDIATRICS.
WHAT BEGAN AS A PLANNED
AMENDMENT TO END A PEDIATRIC ARM
TO THEIR TRIAL, EVENTUALLY
EVOLVED INTO THE POB'S FIRST CAR
T CELL PROTOCOL.
I DON'T KNOW IF STEVE OR JIM ARE
PRESENT TODAY, BUT TO BE FRANK,
I THINK THEY GREW WEARY OF THE
MULTITUDE OF CHILD-SPECIFIC
ISSUES REQUIRED FOR THE PROTOCOL
AMENDMENT.
THE PEDIATRIC WORLD OF CCs AND
MILLIGRAMS PER KILOGRAM DOSING
FILLED PAGES IN THE PROTOCOL
DOCUMENT.
WE DECIDED TO CREATE 12C 0112.
IN PARALLEL, THIS ALLOWED US TO
MODIFY THE MANUFACTURING.
SOME OF YOU MAY RECALL I HAD
TRAINED AND WORKED IN
TRANSFUSION MEDICINE AND BLOOD
BANKING.
I WAS KEEN TO MOVE AWAY FROM THE
ORIGINAL RESEARCH LAB BASED OPEN
WELL MANUFACTURING PROCESS.
WORKING WITH MARIANA CABITANO,
DAVE AND CRYSTAL AND TREY, WE
SPEND $150,000 OF OUR POB BUDGET
IN 18 MONTHS TO GET THE NEW
PROCESS READY FOR HUMAN TRIALS.
THAT CULMINATED IN THE METHODS
PAPER WITH BARBARA AS FIRST
AUTHOR, IN 2013.
THOSE WERE THE METHODS USED FOR
THE FIRST TRIAL MODIFIED FURTHER
FOR SUBSEQUENT TESTING IN THEIR
TRIALS WHICH LED TO FDA
APPROVALS, FIRST IN OCTOBER OF
2017.
NOW FOR A FEW OTHER HISTORICAL
POINTS THAT MAY BE OF INTEREST.
AS HOLIDAYS APPROACHED IN 2011,
CRYSTAL PRESSURED US TO COMPLETE
APPLICATIONS TO MEET END OF YEAR
SUBMISSION DEADLINES.
PREPARING TO LEAVE THE COUNTRY
ON VACATION, AND I HAD BEEN
PLANNING TO COMPLETE OVER THE
HOLIDAYS, I REMEMBER THINKING,
WHAT'S THE DIFFERENCE IN WAITING
ONE MORE MONTH, WE HAD BEEN
WORKING FOR 2 1/2 YEARS.
I WILL ADMIRE CRYSTAL FOR THAT
PRESSURE AND THAT APPROACH
BECAUSE WE'RE NEVER FAST ENOUGH
OR FAR ENOUGH ALONG FOR ALL OF
OUR PATIENTS.
SO WE INDEED MET THOSE
DEADLINES.
ONE FUNNY NOTE RELATED TO
CRYSTAL'S URGENCY, SHE PUSHED
HARD AT EVERY STEP OF THE WAY,
INCLUDING TO PUBLISH OUR INITIAL
RESULTS OF THAT FIRST CD19 CAR,
PHASE 1 TRIAL.
THAT PAPER APPEARED ONLINE IN
"LANCET," ON MONDAY, OCTOBER 13,
2014.
THREE DAYS LATER, ON THURSDAY,
OCTOBER 16, THE CHOP U PENN
GROUP PUBLISHED THEIR CD19 CAR
PHASE 1 RESULTS IN THE NEW
ENGLAND JOURNAL OF MEDICINE.
WE WERE CLASSMATES AND I WILL
NEVER LET HIM FORGET WE BEAT HIM
TO PRESS BY THREE DAYS.
[LAUGHTER]
OF COURSE, HE WILL NEVER LET ME
FORGET HIS PAPER WAS IN THE NEW
ENGLAND JOURNAL THANK YOU FOR
YOUR GREAT LEADERSHIP AND
URGENCY, CRYSTAL.
AVERY WAS THE FIRST CHILD
TREATED WITH CAR T CELLS IN THE
POB.
HE WAS A BRAVE PIONEER, HAVING
BEEN ONE OF THE FIRST PATIENTS
TREATED ON OUR HA-22, DENDRITIC
CELL VACCINE AND MARKIBO TRIALS.
I PAUSE FOR A MOMENT TO REMEMBER
HIM AND MANY OTHER CHILDREN AND
THEIR FAMILIES WHO HAVE
PARTNERED WITH US OVER THE YEARS
IN OUR WORK AND CONTINUE TO DO
SO.
THE POB RESEARCH TEAM REMAINS
ONE OF THE FINEST I'VE EVER BEEN
ASSOCIATED WITH.
IN ADDITION TO THE INDIVIDUALS
I'VE MENTIONED, I WANT TO
ACKNOWLEDGE OTHER KEY TEAM
MEMBERS OF THE EARLY CAR T
PROGRAM.
RESEARCH NURSES, KELLY RICHARDS,
PAULA LAYTON, CINDY DEL BROOK.
WHO DOESN'T LOVE CINDY?
DATA MANAGEMENT TEAM, KEITH
O'NEIL, LEON, SHALRY AND
EKATERINA.
WITH A PAUSE TO REMEMBER LEON,
WHO SADLY PASSED AWAY FROM
GLIOBLASTOMA WHILE THE EARLY
TEAM WAS ASSEMBLED AT THE POB.
WE RECEIVED GREAT SUPPORT FROM
SHARON, VICKIE RICHMOND AND
OTHERS.
WE HAD FANTASTIC COLLABORATING
COLLEAGUES AND TEAMS ACROSS THE
INTRAMURAL NIH.
CRYSTAL TREY AND I HAD
COLLEAGUES IN TERRY, CHRISTIAN,
JASON, RUMA, AND NIRALI WHO
JOINED IN 2009.
NIRALI CONVINCED ME TO ALLOW HER
TO FORGO LABORATORY TRAINING TO
PURSUE CLINICAL RESEARCH.
THAT MAY HAVE BEEN THE BEST
DECISION I WAS EVER FORCED INTO.
FROM A KNOCK ON THE DOOR, TO A
DECADE OF PARADIGM-CHANGING
CLINICAL DEVELOPMENTS,
CONGRATULATIONS TO EVERYONE
INVOLVED IN THIS REMARKABLE
PROGRESS.
ENJOY THIS WELL-DESERVED
CELEBRATION.
[APPLAUSE]
WE'LL HAVE ONE MORE VIDEO,
>>HI, EVERYONE.
I WISH I COULD BE THERE WITH YOU
AND I MISS YOU ALL TO CELEBRATE
THIS OCCASION OF CELEBRATING ALL
OF THE TREMENDOUS WORK THAT'S
BEEN DONE IN THE PEDIATRIC
ONCOLOGY BRANCH.
WHAT HAS BECOME A TRANSFORMATIVE
FIELD IN THE TREATMENT OF
PATIENTS.
YOU KNOW, WHEN I REFLECT BACK ON
MY TIME IN THE PEDIATRIC
ONCOLOGY BRANCH, I THINK OF IT
AS THE TIME IN MY CAREER WHEN --
THAT I CAN BE MOST PROUD OF.
I REMEMBER, YOU KNOW, THE EARLY
DAYS OF THE CD19 AND CD22 CAR T
CELL PROGRAMS.
YOU KNOW, VERY SPECIFIC MEMORIES
AROUND, YOU KNOW, AN INTERACTION
WITH THE DNA RECOMBINANT
ADVISORY COMMITTEE THAT WAS NOT
ONE OF MY SHINING MOMENTS THAT
PROMPTED ME TO TURN MY MY BACK
ON THE COMMITTEE IN FRUSTRATION
BUT ULTIMATELY FORTUNATELY
DIDN'T RESULT US IN US BEING
ABLE TO OPEN THE TRIAL.
I REMEMBER THE FIRST
MANUFACTURING OF THE CD22 CAR
PRODUCTS WHICH WAS THE FIRST
LENTIVIRAL MANUFACTURING PROCESS
WITHIN THE CELL PROCESSING
SECTION.
AND, YOU KNOW, ON DAY 5 OF
MANUFACTURING, NEEDING TO MAKE
DECISIONS WHETHER WE WERE GOING
TO START CHEMOTHERAPY, AND THE
CELLS LOOKED TERRIBLE ON THAT
DAY.
I REMEMBER A LOT OF OF ANGST
OVER THE WEEKEND AFTER WE MADE
DECISIONS TO START PREPAREATIVE
CHEMOTHERAPY.
I REMEMBER COLLABORATION BETWEEN
MEMBERS OF THE TEAM.
I REMEMBER SPEAKING DIRECTLY
WITH ALL OF THE TECHNICIANS IN
THE CELL PROCESSING SECTION WHO
WOULD CALL ME DURING THE EARLY
MANUFACTURING PROCESSES, I
REMEMBER SITTING DOWN WITH THE
FLOW CYTOMETRY GROUP TO REVIEW
DATA.
I REMEMBER WORKING WITH THE
NURSES ON THE UNIT.
I REMEMBER THE TERRIFIC WORK OF
THE RESEARCH NURSES, YOU KNOW,
TO GET THESE PATIENTS ENROLLED
ON TRIALS.
YOU KNOW, BUT MOSTLY, YOU KNOW,
WHAT I REMEMBER ARE THE PATIENTS
THAT BENEFITED FROM ALL OF THE
TREMENDOUS WORK THAT WENT ON IN
THE PEDIATRIC ONCOLOGY BRANCH.
AND MAYBE EVEN MORE IMPORTANTLY,
I REMEMBER THE PATIENTS THAT
PROMPT US TO WANT TO DO BETTER.
SO, I WISH I COULD THERE BE WITH
ALL OF YOU.
I LOVE YOU ALL.
AND THANK YOU FOR GIVING ME AN
OPPORTUNITY TO SHARE MY
THOUGHTS.
[APPLAUSE]
WELL, THANK YOU, EVERYONE, FOR
BEING HERE.
IT IS REALLY JUST SUCH A
PLEASURE AND HONOR AND TRULY A
PRIVILEGE.
WHAT I WANT TO START OFF BY
SAYING IS ACTUALLY THE
ACKNOWLEDGMENTS.
OFTEN WE DON'T MAKE TIME TO GET
TO THESE TILL THE END BUT TODAY
WE HAVE TO SPEND TIME AND THANK
EVERYBODY.
TO KNOW THIS WORK COULD NOT BE
DONE WITHOUT YOU.
THAT INCLUDES OUR CONSULTING
COLLEAGUES, THOSE FROM CCMD IN
THE ICU, DEPARTMENT OF
TRANSFUSION MEDICINE, NURSING,
BEDSIDE NURSES AND RESEARCH
NURSES, TRAINEES, TWO OF THEM
WHO WENT OUT OF THEIR WAY TODAY
TO MAKE COOKIES AND A CAKE FOR A
PATIENT OF OURS WHO IS
CELEBRATING A BIRTHDAY TODAY.
OUR TEACHERS, TECH TRANSFER
TEAMS, ALL OF CCR AND LEADERSHIP
WHO SUPPORTED THE CAR T CELL
PROGRAMS ALONG THE WAY.
THE CHILDREN'S INN, A PARTNER IN
ALL OF THE WORK WE DO, REFERRING
TEAMS WHERE PATIENTS COME FROM,
FLOW CYTOMETRY TEAMS, TEAMS IN
FREDERICK FOR SUPPORTING CAR T
CELL PROGRAMS AS WELL, THOSE IN
CENTER FOR CELLULAR ENGINEERING,
INTERVENTIONAL RADIOLOGISTS,
WITHOUT WHOM WE COULDN'T DO
APHERESIS, THERAPISTS,
PSYCHOLOGISTS, FOLKSES IN ART
AND REC THERAPY.
IF YOU TRIED TO DO AN APHERESIS
ON A 5-YEAR-OLD YOU NEED MORE
THAN SCIENCE, YOU NEED SOMEONE
WITH THE CHILDREN.
WE'RE GRATEFUL FOR EVERYTHING
YOU DO.
OUR DATA MANAGERS WERE BRIEFLY
MENTIONED BUT WE HAVE PROBABLY
THE MOST WELL ESTABLISHED DATA
MANAGERS IN THE CAR T CELL FIELD
IN OUR GROUP.
WE'VE BEEN ABLE TO KEEP THEM
HERE.
IT'S JUST A TREMENDOUS TESTAMENT
TO WHAT THEY DO FOR US.
SO, THIS WORK COULD NOT BE DONE
WITHOUT YOU.
SO THANK YOU.
I THINK WITH THE CAR T CELL
PROGRAM AND PEDIATRIC ONCOLOGY
BRANCH REPRESENTING TRULY THE
EPITOME OF TEAM SCIENCE.
AT THE CORE, HOWEVER, IS OUR
PATIENTS AND OUR FAMILIES.
SHOWN HERE IN THE TOP LEFT
CORNER, HE ALWAYS RESPONDS AS
AVERY WITH DR. WAYNE, WE'LL HEAR
FROM TRISH DALEY, AVERY'S MOM,
OUR FIRST PATIENT TREATED A YEAR
AGO ON HIS BIRTHDAY.
TODAY WE'LL CELEBRATE ANOTHER
BIRTHDAY AND ANOTHER CAR
INFUSION.
IT TELLS YOU WE'VE REALLY COME
FULL CIRCLE IN WHERE WE ARE,
CAN'T WAIT TO SEE WHAT THE
FUTURE WILL BRING.
OUR PATIENTS TRAVEL THE WORLD TO
COME HERE, SHOWN HERE IS OUR
DEMOGRAPHICS OF -- IT'S ALREADY
OUTDATED BUT YOU CAN SEE WHERE
PATIENTS COME FROM.
THEY REALLY DO SOME HERE FROM
ALL OVER THE WORLD, BUT A THIRD
OF PATIENTS BEING INTERNATIONAL.
TO BE HERE AT WHAT FRANCIS
COLLINS CALLED THE NATIONAL
INSTITUTES OF HOPE.
AND WHO ARE THE PATIENTS WHO
COME TO THE NIH?
THEY ARE PATIENTS WITH RELAPSE
OR REFRACTORY DISEASE,
ESPECIALLY WITH PEDIATRIC B CELL
ALL, MAY HAVE BEEN STANDARD RISK
UP FRONT AT DIAGNOSIS, WITH
CURATIVE INTENT SOMEHOW ALONG
THE WAY THE TREATMENT APPROACHES
FAILED AND THEY HAD TO FIND
ALTERNATIVE OPTIONS.
THE PATIENTS WHO COME HERE ARE
THOSE FOR WHOM STANDARD
THERAPIES HAVE FAILED.
INITIALLY IT WAS JUST
CHEMOTHERAPY OR STEM CELL
TRANSPLANT.
BUT OVER THE YEARS WE'VE HAD
PATIENTS FOR WHOM IMMUNOTHERAPY
FAILS.
HOW WE KNOW OUR PATIENTS AND
FAMILIES IS THEY ARE CHILDREN,
WHO LOVE TO DANCE.
PLAY LEGOS, AND SING.
THEY ARE TEENS WHO WANT TO GO ON
A SHOPPING SPREE, LOVING
BROTHERS AND SISTERS.
THEY ARE STUDENTS WHO BELIEVE IT
OR NOT ARE TAKING THEIR FINAL
EXAMS DURING CYTOKINE RELEASE
SYNDROME.
YOU THINK, YOU HAVE A FEVER TO
104, I THINK I CAN GIVE YOU AN
EXCUSE.
THEY ARE GOING TO FINISH THOSE
FINAL EXAMS, BELIEVE IT OR NOT.
THE OTHER DAY I SAID TO MY TEAM,
HE'S FINE, HE'S JUST CODING.
I REALIZED I SHOULD HAVE
PREFACED HE WAS DOING HIS
COMPUTER PROGRAMMING.
CODING IN A CLINTON CENTER IS
NOT VIEWED FAVORABLY.
[LAUGHTER]
I LEARNED MY LESSON.
THIS IS WHAT OUR PATIENTS ARE
DOING WHILE GETTING INFUSIONS,
WHILE THEY ARE HERE DOING
EVERYTHING TO MAINTAIN A SENSE
OF NORMALCY.
I CANNOT BEGIN TO THANK YOU, ALL
OF YOU, FOR EVERYTHING YOU DO TO
MAKE THIS POSSIBLE FOR THEM.
AS WE TREAT ADOLESCENTS AND
YOUNG ADULTS PATIENTS MAY HAVE
CHILDREN OF THEIR OWN.
THEY ARE PARENTS AND THEY ARE
SPOUSES.
AND OUR PATIENTS ARE LOVED AND
THEY HAVE HOPES AND THEY HAVE
DREAMS.
AND IT IS SUCH A PRIVILEGE AND
HONOR TO BE EVEN A SMALL PART OF
THEIR JOURNEY TO KNOW WE HAVE
CONTRIBUTED THAT IN SOME WAY.
AND I HOPE THAT WHAT I CAN SHOW
YOU IS HOW MEANINGFUL THE
PROGRAM IS BECAUSE OF THE PEOPLE
WE SERVE AND PATIENTS WHO ARE
HERE.
TODAY IS TEN YEARS SINCE THE
FIRST POB CAR T CELL INFUSION.
YOU WILL HEAR, YOU HAVE HEARD A
LITTLE BIT ABOUT OUR HISTORY AND
HOW OUR PROGRAM CAME TO BE.
WE'LL TALK ABOUT OUR
ADVANCEMENTS AND ACHIEVEMENTS
OVER THIS TIME AS WELL AS FUTURE
DIRECTIONS.
MORE IMPORTANTLY, YOU'LL HEAR
EXPERIENCES WITH PATIENTS ANDS
FAMILIES AND LOVED ONES.
I'M GRATEFUL FOR FAMILIES HERE
ON SITE AND LOOK FORWARD TO
INTRODUCING YOU.
WE'LL HAVE A FEW VIDEOS THAT
I'LL SHARE FROM THOSE WHO
COULDN'T MAKE IT BUT REALLY
WANTED TO BE HERE AS WELL AS
NOTES LATER TODAY.
WHILE WE CELEBRATE THOSE
ACHIEVEMENTS, TODAY IS ALSO A
TIME TO REFLECT.
IT IS TIME TO REFLECT ON THOSE
WHO ARE CURED AND HAVE THE HEY
BUILT TO BECOME LONG-TERM
SURVIVORS AND WE'RE SO GRATEFUL
WE SHARE EACH DAY IN YOUR
HAPPINESS.
TIME TO REFLECT ON THOSE STILL
RECEIVING THERAPY WHERE CAR MAY
NOT HAVE OPTIMALLY WORKED, OR
THOSE STARTING THE JOURNEY WITH
US, NOT SURE WHAT THE CRYSTAL
BALANCE WILL -- BALL WITHHOLD.
FOR THOSE NO LONGER WITH US, I
HOPE YOU SEE HOW WE STRIVE TO
KEEP THEIR MEMORIES ALIVE AND
PRESERVE THE LEGACY THAT THEY
HAVE HONORED US WITH.
AND WITH THAT, I'D LIKE TO TAKE
A MOMENT OF SILENCE TO REFLECT
ON ALL THE FAMILIES WHO COME
HERE THROUGH THE NIH.
I'D NOW LIKE TO TAKE THIS
OPPORTUNITY TO TALK ABOUT OUR
CAR T CELL PROGRAM AND PRIDE AND
JOY THAT IT IS.
SHOWN HERE IS HOW OUR SECTION IS
LINED UP.
WE HAVE OUR PATIENTS WHO COME TO
US FROM THE REFERRING CENTERS.
THEY COME TO THE CLINICAL
CENTER.
AGAIN, THE PATIENTS WHO COME
HERE ARE THOSE FOR WHOM STANDARD
THERAPIES FAILED, WE'RE STRIVING
TO FIND WAYS TO IMPROVE UPON
THOSE THERAPIES AND ERADICATE
DISEASE.
EVERY PART OF THE PROCESS FROM
EVALUATION TO T CELL COLLECTION
TO OPTIMIZING APHERESIS AND CAR
T CELL MANUFACTURING TO THE
INFUSIONS PRIMARILY STILL DONE
AS INPATIENT, INCLUDING THE VERY
CLOSE AND EXTENSIVE MONITORING
TOXICITY MANAGEMENT AND RESPONSE
TO TERMINATION IS ALL DONE HERE
AS PART OF THE PROCESS FOR
PATIENT AND THEIR JOURNEY.
WE HAVE EXTENSIVE STUDIES
THROUGH MANY COLLABORATIONS,
LATER TODAY YOU'LL HEAR FROM
MANY COLLEAGUES, THE
EXTRAORDINARY WORK THAT HAS BEEN
DONE OVER THIS PAST DECADE,
YOU'LL HEAR ABOUT WHAT THINGS
ARE FORTHCOMING.
THAT INCLUDES CYTOKINE
PROFILING, LOOKING AT WHERE THE
CAR T CELLS GO, AT THE
TOXICITIES AND RESPONSE, TRYING
TO IMPROVE UPON THEM SO PATIENTS
CAN TOLERATE THERAPY AND COME
OUT EVEN BETTER OFF THAN WHERE
THEY STARTED BEFORE RECEIVING
IT.
PATIENTS ARE EVALUATED FOR
LEUKEMIA BIOLOGY AND WE'RE SO
GRATEFUL TO BE PARTNERED WITH
THE FLOW CYTOMETRY TEAM.
LEUKEMIA CELLS, AS THEY TARGET
PROTEINS THAT MAY GO AWAY OVER
TIME.
WE'RE DOING EVALUATIONS OF CAR T
CELL CHARACTERIZATION, I'M
GRATEFUL TO CENTER FOR CELLULAR
ENGINEERING, UNDER DAVE AND NEW
COLLABORATIONS WITH DR. TAYLOR,
AS THEY INTERROGATE THOSE
PRODUCTS AND LEARN MORE FROM
THEM.
ULTIMATELY WE'RE TRYING TO
OPTIMIZE STRATEGIES IN EVERY
CAPACITY POSSIBLE.
OVER THE YEARS YOU CAN SEE WE
STARTED THE CD19 CAR T CELL
PROGRAM IN 2012, OUR FIRST
INFUSION.
THE CD22 CAR T CELL TRIAL WAS
THE SECOND CAR TRIAL IN A-L-L.
WE STARTED TO EMBARK ON SOLID
TUMORS.
YOU'LL HEAR FROM ROSIE KAPLAN
ABOUT GD2 TARGETING AND WHAT THE
FUTURE HOLDS.
YOU CAN SEE THE RATE OF PROGRESS
STARTS TORE PICK UP.
WE HAVE ONE TRIAL IN 2012, ONE
IN 2014, OUR 19 AND 22 STRATEGY
IN 2018, NOW INTO AML,
ALTERNATIVE RARE DISEASES AND
HAVE A NEW TRIAL FORTH COMING.
OVER THIS TIME WE HAVE
ACCUMULATED A DECADE WORD OF
EXPERIENCE IN CHILDREN AND YOUNG
ADULTS.
WE'RE EXTENDING EFFORTS INTO
AML, SOLID TUMORS, RARE
MALIGNANCIES, AND SUPPORTING THE
DEVELOPMENT OF CAR T CELL
PROGRAMS AND SOLID TUMORS ACROSS
PEDIATRIC BRANCH AND CLINICAL
CENTER AS A WHOLE.
IN ITEMS OF CAR T CELL TOXICITY
I WANT TO HIGHLIGHT A FEW
ACHIEVEMENTS RELATED TO
NEUROTOXICITY, INFECTIOUS
COMPLICATIONS, CYTOKINE RELEASE,
OTHER RARE INFLAMMATORY
RESPONSES.
WE'RE LOOKING AT OPTIMIZING CAR
T CELL RESPONSES PANDEMIC IMPACT
OF OTHER FORMS OF IMMUNOTHERAPY,
HOW THEY MAY IMPACT OUTCOMES.
WE LOOK AT WHAT HAPPENS TO
PATIENTS AFTER GETTING A STEM
CELL TRANSPLANT WHEN THEY GET
CAR T CELLS FIRST AND HOW CAN WE
IMPROVE OUTCOMES.
WE'RE THINKING ABOUT
EXTRAMEDULLARY DISEASE.
YOU KNOW WHAT A HUGE PROBLEM
THAT IS AND HOW IT'S
UNDERRECOGNIZED, UNAPPRECIATED,
HOW OUR EFFORTS ARE HELPING SHED
LINE ON THOSE AREAS THAT ARE
UNKNOWN.
HOW TO THINK ABOUT OPTIMIZING
RESPONSE TO SUBSEQUENT CAR T
CELLS.
NONE OF THESE STUDIES WOULD HAVE
BEEN POSSIBLE WITHOUT HAVING THE
EXPERTISE OVER THE PAST TEN
YEARS TO BE ABLE TO LEARN FROM
OUR PATIENTS AND THEIR
EXPERIENCE.
WE'RE THINKING ABOUT OVERCOMING
ANTIGEN ESCAPE, BY DOING
COMBINATORIAL TREATMENT
STRATEGIES.
THIS STARTED WITH CD22 WHICH WAS
A VERY FIRST CAR T CELL THAT
TARGETED ALTERED ANTIGEN BEYOND
CDAND IT COULD BE JUST AS
EFFECTIVE BUT HAD A DIFFERENT
TOXICITY PROFILE.
WE HAVE SERIAL EVALUATION OF
CD19 EXPRESSION OVER TIME.
ALSO THINKING ABOUT WHAT
PRE-INFUSION FACTORS IMPACT THE
RELAPSE IMMUNOPHENOTYPE FOR
PATIENTS WHO RELAPSE FOLLOWING
CAR T CELLS.
OUR WORK ISN'T DONE.
FOR THOSE PATIENTS WHO DO
ACHIEVE A GOOD RESPONSE, WE'RE
NOW SHIFTING GEARS INTO THINKING
ABOUT THE LONG-TERM OUTCOMES.
WHAT ABOUT OUTCOMES OF FOR --
FER FERTILITY?
FOR PATIENTS WHO DEVELOPED
SECONDARY MALIGNANCIES WHAT IF A
DIAGNOSTIC APPROACH -- HOW DO
YOU EVALUATE IN THE CONTEXT OF
CAR T CELLS?
WHAT ABOUT SUBACUTE TOXICITIES
AND DELAYED EFFECT IN
NEUROCOGNITIVE FUNCTION?
YOU'LL HEAR ABOUT THAT LATER
TODAY, TALKING ABOUT THAT.
AND WHAT ABOUT THE PSYCHOSOCIAL
CARE?
ALL FOUR OF THESE PAPERS
REPRESENT FIRST, THEY HAVE ALL
COME FROM OUR GROUP.
SO WITH THAT, I THANK YOU FOR
THE HONOR AND PRIVILEGE OF BEING
ABLE TO WORK WITH ALL OF YOU.
THANK YOU FOR ALL OF THOSE WHO
HAVE TAKEN ME UNDER THEIR WING.
I'VE BEEN HERE SINCE 2009.
I'VE HAD THE PRIVILEGE OF BEING
HANDED THIS TORCH AND LOOK
FORWARD TO CONTINUING TO WORK
WITH ALL OF YOU AND HOPING WE
CAN CONTINUE THIS PROGRAM AND
MAKE YOU PROUD.
I WANT TO THANK YOU FOR THE
SUPPORT OUR TEAM HAS RECEIVED IN
TAKING CARE OF OUR PATIENTS.
FOR THE TRUST TO OUR FAMILIES,
FOR THE TRUST YOU PUT WITH US
FOR YOUR CHILDREN AND LOVED
ONES.
AND TO SAY WE MUST CONTINUE TO
PUSH FORWARD TO MAKE THESE
THERAPIES BETTER, SAFER, EASIER
TO ACCESS.
WITH THIS I'D LIKE TO INVITE
DAVE TO COME TO THE PODIUM TO
BEGIN HIS PART OF THE
PRESENTATION.
THANK YOU.
[APPLAUSE]
>> THANK YOU, NIRALI.
I'M HERE TO TALK ABOUT THE
TREMENDOUS CHANGE, THE WORK POB
HAD ON CELL PROCESSING.
SO, TO SET THE STAGE, IN 2012
WHEN WE MANUFACTURED THE FIRST
CAR T CELL, REALLY VERY FEW
PLACES WERE MAKING CAR T CELL.
SURGERY BRANCH AND NCI WAS, AND
U PENN.
MANY OF THE THINGS DONE HERE
WERE FIRST-IN-HUMAN, NEARLY
FIRST-IN-HUMAN, MANUFACTURING
EVENTS AND CLINICAL TRIALS.
THEN THE REGULATORY ENVIRONMENT
WAS QUITE DIFFERENT.
WE HEARD IT WASN'T EASY TO GET
THESE THINGS THROUGH AND
APPROVED.
ON THE OTHER HAND, THOUGH, IT'S
MUCH EASIER NOW.
WE HAD INVESTIGATOR INITIATED
INDs AND BENCH TO BEDSIDE
PROCESS REALLY MOVED RELATIVELY
QUICKLY COMPARED TO NOW.
TODAY WE HAVE MANY CAR T CELLS,
MANY CLINICAL TRIALS INVOLVING
CAR T CELLS.
THE WORLD'S CHANGED, THERE ARE
MANY COMMERCIAL CAR T CELL
THERAPIES.
AND FROM REGULATORY POINT OF
VIEW, THE NCI NOW HOLDS IND
CENTRALLY.
SO THE WORK IN POB CHANGED
CLINICAL MEDICINE AND REALLY
CHANGED THE FIELD OF CELL
THERAPIES.
THIS IS A SLIDE THAT I LIKE TO
SHOW.
WE'VE BEEN DOING CELL THERAPIES
FOR 25 YEARS AT THE NIH CLINICAL
CENTER, REALLY 12 YEARS AGO WHEN
IT CAME TO MANUFACTURING CELL
THERAPIES, YES, THINGS WORKED A
LITTLE BIT, BUT NOTHING LIKE CAR
T CELLS.
SO IT WAS KIND OF A SLEEPY FIELD
AND WE DIDN'T GET MUCH
ATTENTION.
WE DID HAVE PEOPLE THOUGH THAT
WERE PERSISTENT AND MOVED
FORWARD.
WE HAD FUNDING BUT IT DIDN'T
CHANGE.
PEOPLE FROM A REGULATORY AND
PERFORMANCE POINT OF VIEW,
PEOPLE LEFT US ALONE.
TEN YEARS AGO, THE SUCCESS OF
CAR T CELLS, PEOPLE BECAME
VERY -- CLINICIANS BECAME
INTERESTED IN MAKING CAR T
CELLS.
WE GOT A LITTLE MORE FUNDING
FROM THE CLINICAL CENTER.
THEIR PERFORMANCE EXPECTATIONS
AND REGULATORY EXPECTATIONS
CHANGED A LITTLE BIT BUT REALLY
WE DIDN'T GET A LOT OF OTHER
ATTENTION FROM PEOPLE.
FIVE OR TEN YEARS AGO WHEN CAR T
CELLS PROVED SO SUCCESSFUL AND
EVERYTHING WORKED, NOW EVERYBODY
CARES, WE HAVE A LOT MORE
FUNDING FOR CELL THERAPY,
INDUSTRIES INVOLVED, AND REALLY
THE FDA, THEIR INVOLVEMENT IN
THE FIELD HAS GROWN
SIGNIFICANTLY AND WE'RE EXPECTED
TO PERFORM LIKE A PHARMA
COMPANY.
SO, FOR THE FIRST 25 YEARS OF
THE CELL THERAPY GROUP, WE WERE
ONE PART OF THE DEPARTMENT OF
TRANSFUSION MEDICINE, THEY HAVE
THE TRANSFUSION SERVICE, BLOOD
COLLECTION GROUP, INFECTIOUS
DISEASE SECTION.
AND WE'RE THE CELL PROCESSING
SECTION.
BUT BASED ON TREMENDOUS GROWTH
OF CAR T CELLS AND OTHER CANCER
IMMUNOTHERAPIES, ABOUT THREE
YEARS AGO THE CENTER OF CELLULAR
ENGINEERING WAS FORMED.
NOW WE HAVE FOUR SECTIONS OF
PRODUCT DEVELOPMENT,
MANUFACTURING SECTION, ASSAY
SECTION, SERVICE COORDINATION,
WE HAVE A LARGE QUALITY GROUP.
I DON'T WANT TO GO IN GREAT
DETAIL BUT WE HAVE MADE A LOT OF
DIFFERENT KIND OF CAR T CELLS,
CD19, CD22, AND BY SPECIFIC
WE'VE ALSO MADE CAR T CELLS FOR
DR. COKENDORF TO TREAT PATIENTS.
AND RECENTLY WE TREATED THE
FIRST PATIENT WITH CD22 CAR T
CELLS WITH HAIRY CELL LEUKEMIA,
WE'VE MADE CAR T CELLS FOR SOME
SOLID TUMORS.
SO, ONE OF THE BIG CHANGES IN
THE FIELD IS THAT WITH THE
SUCCESS OF CAR T CELLS, A NUMBER
OF MANUFACTURERS HAVE GOT
INTERESTED IN THE FIELD.
SO NOW THE EQUIPMENT AVAILABLE
FOR US TO MAKE CAR T CELLS AND
AGENTS AVAILABLE TO MAKE THEM
ARE MUCH IMPROVED.
THERE'S AUTOMATED BIOREACTORS
THAT ARE PURPOSE BUILD OF BUILT
TO MAKE CAR T CELLS.
WE HAVE CELL WASHERS AND CELL
SEPARATORS THAT ARE BUILT TO
WASH AND SEPARATE CELLS FOR
MAKING CAR T CELLS.
THERE'S A NUMBER OF VERY GOOD
GNP REAGENTS TO BUY OFF THE
SHELF.
WHY IS THIS IMPORTANT?
IT'S MADED -- MADE IT EASIER
AND MANY ACADEMIC CENTERS ARE
MAKING CAR T CELLS.
THE OTHER CHANGE WE'VE SEEN IS
INVOLVING ISSUE WHERE WE COLLECT
CELLS, AUTOLOGOUS CELLS FROM
PATIENTS NEEDING CAR T CELL
THERAPY OR OTHER CANCER
IMMUNOTHERAPIES IN THE
DEPARTMENT OF TRANSFUSION
MEDICINE.
WE SEND THEM OFF TO COMPANIES
FOR FURTHER MANUFACTURING.
THOSE CELLS ARE COLLECTED HERE,
THEY COME TO OUR LAB.
WE LABEL THEM AND DOCUMENT
THINGS, PACK THEM UP AND SEND
THEM OFF TO A COMPANY, THE
COMPANIES MAKE A CAR T CELL OR
OTHER CANCER IMMUNOTHERAPY.
WHEN THE MANUFACTURING IS DONE,
THE PRODUCTS ARE FROZEN.
WHEN LOT RELEASE TESTING IS DONE
THEY SEND THEM BACK TO US, WHERE
THEY ARE STORED UNTIL THE
PATIENT NEEDS TO BE TREATED.
THIS IS A VERY IMPORTANT PART OF
TREATING PATIENTS WITH LEUKEMIAS
AND LYMPHOMAS, BUT IT'S ALSO
BECOME A VERY BIG PART OF OUR
BUSINESS AND SOMETHING THAT'S
TOTALLY NEW SINCE 2012.
SO, WHERE ARE WE GOING FROM NOW
TO MEET NEEDS?
IT'S CLEAR TO US THAT IT'S VERY
IMPORTANT EVERY TIME WE TRY AND
MANUFACTURE CAR T CELL, WE WERE
SUCCESSFUL AND WE MANUFACTURE A
VERY HIGH QUALITY PRODUCT.
WE CONSTANTLY WORK ON OPTIMIZING
THE MANUFACTURING PROCESS.
WE'RE ALSO LOOKING AT THE BEST,
HOW TO OPTIMIZE PATIENT CELLS,
TO BEGIN MANUFACTURING.
AGAIN, SO WE GET THE BEST
PRODUCT.
WE'RE ALSO WORKING WITH, AGAIN,
POB AND OTHERS TO MAKE CELLULAR
IMMUNOTHERAPY SUCCESSFUL FOR
PATIENTS WITH CANCER.
IN CLOSING, I WANT TO MENTION
FROM MY POINT OF VIEW THIS HAS
BEEN ONE OF THE BEST
PROFESSIONAL EXPERIENCES OF MY
LIFE, IT'S BEEN INCREDIBLE TO
WATCH THE DEVELOPMENT OF THIS
ENTIRELY NEW CANCER THERAPY.
I WAS ALLOWED BY POB, ME AND ALL
THE OTHERS IN THE CCE, WERE
BROUGHT INTO THIS.
AND WE WERE ALLOWED TO HELP
ADVANCE THIS FIELD, IT'S BEEN
TERRIFIC TO EXPERIENCE THE
FUNDAMENTAL CHANGE IN CLINICAL
MEDICINE AND THE FIELD OF CELL
THERAPY.
THANK YOU, POB.
[APPLAUSE]
>>IT IS MY GREAT PRIVILEGE AND
HONOR TO WELCOME DR. ROSENBERG
TO GIVE A KEYNOTE AND TALK ABOUT
THE HISTORY OF CD19 CAR T CELLS.
I THINK WHAT YOU SAW IN THE
FIRST PART IS HOW FAR WE'VE COME
BUT HE WILL TELL YOU MORE ABOUT
HOW IT ALL STARTED.
SO THANK YOU.
>> I'LL TRY IN THE NEXT TEN
MINUTES TO TALK ABOUT THE LAST
THREE OR FOUR YEARS OF OUR WORK
TRYING TO DEVELOP THESE
TREATMENTS.
IN MY VIEW IT STARTED BACK IN
1988 WHEN WE PUBLISHED A PAPER
IN THE NEW ENGLAND JOURNAL, THE
FIRST PAPER SHOWING TUMOR
INFILTRATING LYMPHOCYTES, THAT
WE COULD ISOLATE AND GROW OUT OF
A GROWING TUMOR, GROWN TO LARGE
AMOUNT ALSO IN VITRO IN
INTERLEUKIN-2 AND REINFUSED TO
MEDIATE OBJECTIVE REGRESSION,
THE FIRST REPORT.
WE CANNOTTED THESE STUDIES AND
HAVE OVER A 50% OBJECTIVE
RESPONSE RATE NOW WITH A
QUARTER OF THOSE PATIENTS
COMPLETE DURABLE RESPONSES, THE
FIRST DEMONSTRATION YOU COULD
USE LYMPHOCYTES AS A LIVING DRUG
TO MEDIATE CANCER AGGRESSION.
WE'VE UTILIZED NATURALLY
OCCURRING CELLS BUT ALMOST
IMMEDIATELY WE BEGAN STUDIES TO
SEE IF WE COULD GENETICALLY
MODIFY THESE CELLS TO IMPROVE
THEIR ANTI-TUMOR ACTIVITY.
AND THAT INVOLVED GENETIC
MODIFICATION OF CELLS,
ADMINISTERED TO PATIENTS WHICH
HADN'T BEEN DONE, A
CONTROVERSIAL ISSUE, BUT I BEGAN
COLLABORATIONS WITH THOSE TO MY
RIGHT TO GENETICALLY MODIFY.
WE SELECTED A BACTERIAL GENE,
THAT WOULD ENABLE US TO TRAFFIC
THESE CELLS FOLLOWING THEIR IN
VIVO ADMINISTRATION AND
DISTINGUISH THEM FROM ENDOGENOUS
LYMPHOCYTES.
WE WENT THROUGH 16 REVIEW
GROUPS, AND I TOOK THIS NOTE
FROM MY NOTEBOOK, WE WENT
THROUGH THE IRB, BIOSAFETY
COMMITTEES, NIH ESTABLISHED
RECOMBINANT COMMITTEE TO LOOK AT
THESE MANIPULATIONS WITH
RECOMBINANT CELLS, AND THE RAC
VOTED TO ALLOW US TO PROCEED
WITH THE 16-5 NOTE, BUT THE
DIRECTOR, JIM WYNGAARDEN, SAID
THAT WAS NOT GOOD ENOUGH.
IF WE WOULD BE PUTTING FOREIGN
GENES INTO PEOPLE FOR THE FIRST
TIME WE NEEDED A UNANIMOUS VOTE,
WE HAD GO BACK BASED ON WHAT WAS
SUGGESTED UNTIL FINALLY IN 1988
THE RAC VOTED 13-0, ONE
ABSTENTION, TO ENABLE US TO
PROCEED.
WE WENT BACK THROUGH THE REVIEW
GROUPS AND ON MAY 22 TREATED OUR
FIRST PATIENT, IN 1989.
DELAYED BECAUSE JEREMY, A
BIOTECHNOLOGY ACTIVIST, FILED A
LAWSUIT AGAINST THE NIH TO
PREVENT US FROM DOING THIS.
THEY DIDN'T FEEL ANYONE SHOULD
BE TAMPERING WITH GOD'S DNA IN
PATIENTS, BUT THAT WAS FINALLY
RESOLVED.
WE WERE ABLE TO PROCEED.
1990 PUBLISHED THIS PAPER IN THE
NEW ENGLAND JOURNAL SHOWING THIS
COULD BE SAFELILY DONE
RETROVIRALLY TRANSDUCING CELLS,
SAFE, MONITORING CELLS TO LOOK
AT SURVIVAL IN PATIENTS.
THAT LED US TO A LOT OF
LABORATORY WORK UNTIL FINALLY
THIS PAPER IN 2006, THE FIRST
TIME WE COULD ACTUALLY INTRODUCE
GENETICALLY MODIFIED CELLS THAT
HAD BEEN RETROVIRALLY
TRANSDEUCED WITH T T-CELL
RECEPTORS THAT RECOGNIZED IN
MELANOMA, SAW TWO RESPONSES IN
THOSE PATIENTS, BUT AT LEAST IT
DID SHOW WE COULD TAKE A NORMAL
LYMPHOCYTE, INSERT T-CELL
RECEPTOR, SHOW TUMOR REGRESSION.
WE THEN PUBLISHED A COUPLE YEARS
LATER, USE OF A VERY HIGHLY AVID
T-CELL RECEPTOR RECOGNIZING IN
SIX OUT OF TWENTY PATIENTS, 30%
OF PATIENTS THEN HAD OBJECTIVE
RESPONSES WITH THEIR OWN NORMAL
LYMPHOCYTES TRANSDUCED WITH THIS
RECEPTOR RECOGNIZING MART-1, AND
A COUPLE YEARS LATER WHEN WE
BEGAN OUR INTERACTIONS WITH THE
PEDIATRIC ONCOLOGY BRANCH IN
2011, WE LOOKED AT T CELLS THAT
WERE TRANSDUCED WITH T-CELL
RECEPTORS THAT RECOGNIZED A CAN
SORRY GERMLINE ANTIGEN NY-ESO-1,
AND IN THESE PATIENTS 4 OUT OF 6
SYNOVIAL SARCOMA.
THE CD19 STORY BEGAN, CD19 AS
YOU'VE HEARD IS A MOLECULE
EXPRESSED ON NORMAL B
LYMPHOCYTES, IN 2007 GOING ON
2008, A FELLOW IN HEMATOLOGY
ONCOLOGY TRAINING PROGRAM JOINED
MY LAB AND BEGAN TO EXPLORE
WHETHER OR NOT WE COULD TARGET
CD19 IN PATIENTS.
AND HE DID ELEGANT STUDIES IN
ANIMAL MODELS SHOWING LYMPHOMAS
COULD BE ELIMINATED IN 2009
TREATED OUR FIRST PATIENT WITH A
HUMAN RECEPTOR, PUBLISHED THAT
IN 2010, THAT BEGAN OUR STUDIES
WITH CD19 ABOUT A YEAR LATER,
CARL JUNE REPORTED EFFECTIVE
TREATMENT OF USE OF CD19 CAR T
CELLS COULD DO THIS AS WELL.
THIS WAS THE FIRST PATIENT
TREATED, A 48-YEAR-OLD
CONSTRUCTION WORKER FROM
FLORIDA, YOU CAN SEE ON THE LEFT
THE LARGE TUMOR MASSES THAT WERE
PRESENT IN THIS PATIENT .
HE UNDERWENT A COMPLETE
REGRESSION OF ALL OF HIS
LYMPHOMA.
UNDERGONE FOUR PRIOR COMBINATION
CHEMOTHERAPY REGIMENS, HAD TUMOR
REPLACING HIS MARROW THAT
DISAPPEARED AS WELL.
AND HE'S BEEN IN ONGOING
COMPLETE RESPONSE NOW SINCE
2009, 13 YEARS LATER.
WHAT WE THEN BEGAN TREATING
PATIENTS, I BRING THIS UP TO THE
TIME WE BEGAN OUR INTERACTIONS,
WE TREATED EIGHT PATIENTS IN THE
SURGERY BRANCH BETWEEN JUNE OF
2009 AND JANUARY OF 2011, FOUR
PATIENTS WITH METASTATIC --
WIDELY SPREAD LYMPHOMAS, WE HAD
FOUR PATIENTS WHO HAD COMPLETE
RESPONSES OUT OF THESE EIGHT,
INTERESTINGLY ALL FOUR OF THOSE
PATIENTS REMAIN COMPLETELY
DISEASE FREE TO THE PRESENT
TIME.
TWO PARTIAL RESPONSES, ONE
NON-RESPONDER, ONE PATIENT HAD A
TREATMENT RELATED MORTALITY.
SEPT 15, I WAS CONTACTED TO SEE
WE COULD ATTAIN ANTI-CD19
SUPERNATANT, TRANSFERRED FIVE
CASSETTES TO THE PEDIATRIC
ONCOLOGY BRANCH, AND THEN IN
MARCH OF 2012, 18 CASSETTES OF
THE GMP MATERIAL WE DEVELOPED
FORECLINICAL TRIAL, JULY 13,
2012, FIRST PEDIATRIC ONCOLOGY
BRANCH PATIENT WAS TREATED.
JUST AS -- I WON'T GO INTO THAT,
YOU HEARD FROM THE GROUP THAT
ACTUALLY DID THE WORK IN
PEDIATRICS ALREADY, BUT JUST AS
A POST SCRIPT TO THIS EFFORT,
INTERESTINGLY IN 2011 I WAS
CONTACTED BY A FORMER FELLOW,
HAD BEEN A SURGERY BRANCH 20
YEARS EARLIER, A UROLOGIST AT
UCLA, WE HAD BEEN IN TOUCH, HE
CAME TO SEE WHAT WE WERE DOING
AND WONDER WHETHER HE COULD
COMMERCIALLY DEVELOP THIS.
OTHERS REVIEWED THE DATA, IF WE
HAD THIS DISEASE WE WOULD BE
DELIGHTED TO COME TO YOU FOR
TREATMENT BUT DON'T SEE HOW WE
CAN COMMERCIALIZE AND MAKE ANY
MONEY WITH THIS.
BUT ARI STARTED KITE PHARMA, IN
2011, WE SIGNED A COOPERATIVE
RESEARCH AND DEVELOPMENT
AGREEMENT TO TRANSFER TECHNOLOGY
TO KITE PHARMA, YOU CAN SEE IN A
MULTI-INSTITUTIONAL STUDY HE
ALMOST EXACTLY REPRODUCED OUR
RESULTS IN THE SURGERY BRANCH UP
TO THAT TIME WITH OBJECTIVE
RESPONSE RATES IN THE 70 TO 80%
RANGE, COMPLETE REGRESSIONS IN
ABOUT THE 50% RANGE.
IN 2017, KITE RECEIVED FDA
APPROVAL AND WAS SOLD TO GILEAD
SCIENCES FOR $11.9 BILLION, SO
KITE PHARMA WENT FROM ZERO TO
$11.9 BILLION IN FIVE YEARS.
I SEE THIS AS A VERY PROUD
EXAMPLE OF HOW BASIC SCIENCE AND
NEW TREATMENTS THAT ARE
DEVELOPED IN ACADEMIC SETTINGS
AND ESPECIALLY THIS ONE HERE AT
THE NIH COULD BE BROUGHT TO MANY
PEOPLE AROUND THE WORLD, AND
PEOPLE NOW IN THE UNITED STATES,
EUROPE, BEGINNING IN ASIA ARE
RECEIVING THIS CD19 FOR THE
TREATMENT OF PATIENTS WITH
LYMPHOMAS, ALL STUDIES DONE BY
KITE PHARMA, IN THE SURGERY
BRANCH HERE WERE THE DIFFUSE
LARGE B CELL LYMPHOMAS, THE MOST
AGGRESSIVE AGGRESSIVE OF THE
LYMPHOMAS IN ADULTS.
MY CONGRATULATIONS TO THE
PHYSICIANS AND SCIENTISTS IN
PEDIATRIC ONCOLOGY BRANCH FOR
PIONEERING WORK TO BRING THE
CELL THERAPY TO PEDIATRIC
PATIENTS, PERFORMING OUTSTANDING
RESEARCH THAT REFINED THE
APPROACH AND IMPROVED THIS
LIVING DRUG TREATMENT FOR
PATIENTS AND FOR THAT THEY HAVE
MY ENDURING THANKS.
THANK YOU FOR YOUR KIND
ATTENTION.
[APPLAUSE]
>> NEXT SESSION, IF I COULD ASK
THE SPEAKERS TO MAKE THEIR WAY
DOWN, WE'LL START OFF WITH A
VIDEO WHICH WILL GO INTO THE
TALKING ABOUT CAR T CELLS AND
ALL OF THE CLINICAL AND RESEARCH
COLLABORATIONS THAT WE HAVE.
WE'LL START OFF WITH TREY LEE
WHO COULDN'T BE HERE IN PERSON,
HE'S ON SERVICE, WE'LL TAKE IT
WITH ANTHONY, SO FOLKS CAN MAKE
THEIR WAY DOWN.
THANK YOU.
>> I'M SORRY I COULDN'T BE WITH
YOU TODAY.
WHEN I WAS THERE MANY YEARS AGO
NOW, AS A NEW FELLOW LOOKING FOR
RESEARCH PROJECT, I WAS STRUCK
BY DR. ROSENBERG'S PRESENTATION
TO THE GROUP ONE DAY ABOUT
RESPONSES IN ADULTS WITH WIDELY
MEDICAL STATIC MELANOMA WITH ONE
OR TWO INFUSIONS OF CELLS,
BEFORE CHECKPOINT INHIBITORS, TO
ME IT WAS AMAZING.
I WANTED TO BRING THIS
GAME-CHANGING THERAPY TO KIDS
WITH RELAPSED REFRACTORY
CANCERS, FORTUNATE TO FIND
PARTNERS AND MENTORS IN CRYSTAL,
ALLEN AND TERRY WHO GUIDED ME
AND WE DID JUST THAT.
EARLY ON IN THE PEDIATRIC CAR
CAR T TRIAL, IT HELD FOR KIDS,
QUITE CLEAR, EVIDENT THE
LIFE-THREATENING TOXICITIES THEY
CAUSE.
WE KNEW ABOUT AND USED STEROIDS
IN PATIENTS BEFORE, WE DID NOT
KNOW IF INTERVENING WOULD ABORT
THE RESPONSE.
THE 14th PATIENT CHANGED THE
PERSPECTIVE.
CYTOKINE RELEASE SYNDROME RAGES
FROM FEVER TO TO PULMONARY
EDEMA, CARDIAC DYSFUNCTION AND
EVEN CARDIAC ARREST, DRIVEN BY
SUPER PHYSIOLOGIC PRODUCTION OF
MULTIPLE INFLAMMATORY CYTOKINES
OVER THE FIRST FEW DAYS AFTER
CELL INFUSION.
AFTER OUR EXPERIENCE WITH
PATIENT NUMBER 14 WHO SURVIVED,
THANKS TO THE AMAZING ICU TEAM
WE DEVELOPED THE FIRST
MANUSCRIPT DESCRIBING CRS,
RELEVANT RATING SYSTEM,
MANAGEMENT ALGORITHM TIED TO
THAT SYSTEM.
LITTLE DID WE KNOW THIS WORK
WOULD BECOME ONE OF THE WORLD'S
MOST WIDELY USED CLINICALLY AND
CITED MANUSCRIPTS FOR CRS, AND
TO SERVE AS PRECURSOR TO PRESENT
DAY ASTCT CRS.
WE HAVE SO MUCH MORE TO DO.
CARs IN THE CLINIC TODAY ARE
JUST THE PROTOTYPES, WE CAN DO
SO MUCH BETTER.
WE NEED TO BROADEN EFFECTIVE AND
SAFE CARs TO DISEASES BEYOND
HEMEOLOGIC MALIGNANCY.
THIS MY LAB'S AIM AT UNIVERSITY
OF VIRGINIA, TARGETING BETA 3
AND DEMONSTRATING EFFICACY IN
GLIOBLASTOMA AND DIPG, ACROSS
NUMEROUS TUMORS, AIMING TO MAKE
ALL CARs SAFER DEVELOPING
INTELLIGENT SELF-CONTAINED
CONTROL MECHANISMS THAT MITIGATE
TOXICITY, PRESERVING EFFICACY,
USING COMPLEMENTARY LABORATORY
AND BIOCOMPLEXITY APPROACHES TO
UNDERSTAND COMPLEX MECHANISMS
AND PATHWAYS FROM A CAR T CELL
THROUGH TO SEVERE CRS, HLH,
ICANs.
WE HAVE ACCOMPLISHED SO MUCH FOR
KIDS WITH LEUKEMIA AND LYMPHOMA,
THIS IS JUST THE BEGINNING, AN
EXCITING TIME BECAUSE I'M
CONVINCED IN YEARS TO COME THE
CAR T FIELD WILL EVOLVE
EXPONENTIALLY, TRANSFORMING
OUTCOMES FOR SO MANY PEDIATRIC
CANCERS ALONG THE WAY.
IT'S BEEN SUCH AN HONOR TO HAVE
WORKED WITH YOU ALL.
THANK YOU VERY MUCH.
>> IF WE COULD GO TO THE SLIDE
DECK.
IT WILL BE A SERIES OF TALKS.
WE'LL HAVE YOU GO AHEAD.
>> THANK YOU VERY MUCH.
I THINK FROM THE ICUs
PERSPECTIVE WE'RE FORTUNATE OR
PRIVILEGED I WOULD SAY TO BE
ABLE TO PARTICIPATE IN REALLY
LIFE-CHANGING CARE THAT IS BEING
DEVELOPED IN THE CLINICAL
CENTER.
SO, HOW DOES THIS RELATE TO
CRITICAL ILLNESS?
YOU HEARD ABOUT THE CYTOKINE
STORM, WHY IS IT RELEVANT TO
CRITICAL CARE?
THE CYTOKINE RELEASE SYNDROME
LEADS TO INFLAMMATORY ORGAN
CAUSING HYPOTENSION, SHOCK,
RESPIRATORY FAILURE,
ENENCEPHALOPARITY, ARE THERE
WAYS TO PREVENT THIS?
PERHAPS, INCLUDING THE
UNDERLYING PULMONARY DISEASE,
HOW FRAGILE THE PATIENT IS,
DISEASE BURDEN, CELL PRODUCT
THEY ARE RECEIVING, SPECIFIC
LIVE INFECTION PROPHYLAXIS
AGAINST FUNGI, AGAINST BACTERIA,
ATTENTION TO BE VERY AGGRESSIVE
ABOUT DIAGNOSING AND TREATING
INFECTION, THE NIGHTMARE TREY
DESCRIBED, ON DAY 7 AS HE
RECEIVED CELLS, AFTER HE
DEVELOPED ACUTE PULMONARY
EDEMA, AND CARDIOGENIC SHOCK.
ECHO SHOWN HERE ON THE LEFT
SIDE, PRE-ARREST, ON THE RIGHT
SIDE YOU CAN SEE HIS LEFT
VENTRICLE IS BARELY MOVING.
HE WALS -- WAS IN PROFOUND
SHOCK, A DISASTER IN THE ICU,
RELATED TO CYTOKINE RELEASE,
CARDIAC ARREST, PROLONGED CPR,
WHEN I SAY PROLONGED, 3 1/2
HOURS OF ON AND OFF HAVING TO DO
CHEST COMPRESSIONS ON THIS YOUNG
PERSON, CARDIOGENIC SHOCK, ARDS,
TREATED WITH FLUIDS,
VASOPRESSORS, INOTROPES, AND A
BALLOON PUMP TO HELP HIS HEART
SURVIVE, GIVEN ANTI-INFLAMMATORY
THERAPY WITH STEROIDS, ANTI-IL-6
THERAPY.
WHAT IS NOTABLE AFTER EIGHT DAYS
HE LEFT THE HOSPITAL, LEFT THE
ICU, AFTER A COMPLEX COURSE,
GREAT COOPERATION AND
COLLABORATION BETWEEN HEM-ONC
TEAMS AND ICU, WENT HOME.
THIS IS THE MOST SEVERE SENSE,
THE WORST CASE SCENARIO.
AS TREY WAS MENTIONING, HOW DO
YOU AVOID IT?
ONE OF THE WAYS IS YOU COME UP
WITH THESE GRADES, THIS IDEA, AS
THE INFLAMMATORY RESPONSE
ESCALATES WHAT CAN YOU DO TO
INTERVENE AND TO NOT HAVE THESE
THINGS DETERIORATE?
THIS IS SOME OF THE THINGS HE
WAS DISCUSSING, THE GRADE 1
THROUGH 4 TOXICITY BASED ON LOW
BLOOD PRESSURE, HOW DO YOU TREAT
IT, BASED UPON HYPOXIA, AND THE
SAME SCALES USED FOR
ENCEPHALOPATHY SYNDROME,
PATIENTS WHO GET CAR CELLS CAN
BE CONFUSED, DELIRIOUS,
UNAROUSABLE.
SEIZURES, MOTOR WEAKNESS,
ELEVATED INTRACRANIAL PRESSURE,
INTERVENING SO YOU DON'T LET
THINGS GET OUT OF HAND LIKE THE
CASE I SHOWED YOU.
FROM THE ICU'S PERSPECTIVE, OUR
MANAGEMENT STRATEGY TO INTERVENE
EARLY, GRADE 2 AND 3 WITH ORGAN
SPECIFIC THERAPY AS LISTED
THERE, SO YOU CAN SEE AROUND THE
WORLD RIGHT NOW IN TERMS OF SOME
THERAPIES DEVELOPED HERE HAVE
EXPLODED ACROSS THE WORLD.
THIS IS STUDY THAT JUST CAME OUT
IN 2021 WAS NOTABLE FOR 922
PATIENTS TREATED AROUND THE
WORLD, ASKING WHAT IS THE
CRITICAL CARE OUTCOME.
NIRALI AND JOHN FROM OUR
DEPARTMENT WROTE A FLIES
EDITORIAL, THERE'S ANOTHER STUDY
THAT RECENTLY CAME OUT AGAIN
ADDRESSING THE COMPLEXITY OF
CRITICAL CARE ILLNESS THAT
DEVELOPS AFTER CAR T CELL
THERAPIES.
WHEN IT HAPPENS, WHAT TO DO, HOW
TO STRATEGIZE TO MINIMIZE THE
CONSEQUENCES AND THE END ORGAN
INJURIES.
I'LL END WITH A QUOTE FROM
NIRALI, DUE TO THE RISKS OF
ICANS, ICU IS PARTNERS IN THE
DELIVERY OF LIFE-SAVING
PARTNERS. PART -- LIFE SAVING
THERAPY.
THANKS VERY MUCH.
[APPLAUSE]
>> I'M HERE TO TALK ABOUT CAR T
CELL ASSOCIATED NEUROTOXICITY,
I'M HANEEN, A PEDIATRIC LEUKEMIA
DOCTOR.
NEUROTOXICITY SYNDROME, ICANS,
IS A NEUROLOGIC DISORDER
FOLLOWING IMMUNE THERAPY THAT
RESULTS IN THE ACTIVATION OF
IMMUNE EFFECTOR CELLS, INCIDENCE
RANGE FROM ZERO TO 64%, SEVERE
ICANS AS GRADED OCCURRED IN FIVE
TO 50% OF PATIENTS TREATED.
PRESENTING SYMPTOMS AND TIMING
OF SYMPTOMS VARIES.
TYPICALLY OCCURS AFTER CYTOKINE
RELEASE SYNDROME, SIGNS AND
SYMPTOMS CAN INCLUDE CONFUSION,
APHAGIA, DYSGRAPHIA, DELIRIUM.
MECHANISMS CONTRIBUTE, RESEARCH
IS UNDERWAY TO PINPOINT WHAT
OCCURS WITH THERAPY.
ENDOTHELIAL DYSREGULATION OCCURS
IN SOME OF THE PATIENTS WE'VE
SEEN.
WHAT WE'VE LEARNED OVER THE LAST
DECADE IS THAT WE'VE HAD
SIGNIFICANT AMOUNT OF PATIENT
EXPERIENCE AND THANKFULLY HAVE
SEEN NO INCREASED RATES OF ICANS
IN TRIALS.
IN CD19 TRIAL WE WERE ABLE TO
DEMONSTRATE THAT WE WERE ABLE TO
GIVE THIS THERAPY SAFELY TO
PEDIATRIC AND YOUNG ADULT
PATIENTS INCLUDING PATIENTS WITH
ACTIVE CNS DISEASE, THIS WAS ONE
OF THE FIRST STUDIES THAT
ALLOWED FOR ENROLLMENT OF
PATIENT WITH CENTRAL NERVOUS
SYSTEM LEUKEMIA.
ICASNS WAS ASSOCIATED WITH
CYTOKINE RELEASE SYNDROME, DID
NOT SEE INCREASED RISK IN
PATIENTS WITH ACTIVE CNS
DISEASE.
VERY IMPORTANTLY, BUT OBVIOUSLY
NOW A DECADE LATER, THIS IS
SHOWN MULTIPLE TIMES, BUT AT THE
TIME WAS VERY NOVEL THAT CAR T
CELLS DID TRAFFIC EFFECTIVELY TO
THE CNS AND WAS ABLE TO
ERADICATE DISEASE.
WITH THE CD22 CAR TRIAL WERE
ABLE TO DEMONSTRATE EFFICACY, AS
A SALVAGE THERAPY ERADICATING
LEUKEMIA WHO RELAPSED.
RATES WERE LOW AND DIDN'T SEE
IRREVERSIBLE NEUROTOXICITY.
WITH THIS WERE ABLE TO
DEMONSTRATE FEASIBILITY OF
SYSTEMATIC ASSESSMENTS IN OUR
PATIENTS WHICH INCLUDED IMAGING,
CYTOKINE SAMPLING,
NEUROCOGNITIVE ASSESSMENTS WHICH
YOU'LL HEAR NEXT AND CAREGIVER
SYMPTOM CHECK LIST BORN IN THE
PEDIATRIC ONCOLOGY BRANCH.
WITH OUR MOST RECENT PROTOCOL,
THE CD19, CD22 CAR T CELL TRIAL
DEMONSTRATED THEY WERE WELL
TOLERATED.
WE HAD A LOW RATE OF ICANS,
DEMONSTRATING INTRATHECAL
HYDROCORTISONE WAS SUCCESSFUL IN
REVERSING A PATIENT WITH SEVERE
ICANS.
IT BUILT THE FOUNDATION TO
PERFORM REMOTE TESTING.
WITH ICANS SIGNIFICANT QUESTIONS
REMAIN IN THE FIELD.
ARE WE ABLE TO PREDICT PATIENTS
WHO WILL HAVE SEVERE ICANS, DO
WE HAVE GOOD TREATMENT OPTIONS,
IF SO WHAT'S THE BEST TREATMENT?
DOES NEUROIMAGING AT BASELINE
PREDICT ICANS AND DOES IT
AEFFECT LONG-TERM OUTCOME?
THROUGH THE WORK WERE ABLE TO
ESTABLISH MULTI-SITE
COLLABORATIONS, HOSTED A BEYOND
THE STORM MEETING, A COUPLE
YEARS AGO.
THROUGH THAT WAS BORN A LARGE
NETWORK OF PROVIDERS IN THE
PEDIATRIC ONCOLOGY CAR T CELL
COMMUNITY.
NOW WE HAVE A STUDY LOOKING AT
OUTCOMES AT THREE SITES HOPING
TO OPEN IN THE FALL,
ASSOCIATIONS.
WE'RE PART OF A STUDY WITH
SEATTLE CHILDREN'S AND ST. JUDE
LOOKING AT QUALITY OF LIFE POST
THERAPY WITH SEATTLE CHILDREN'S
AND CHLA EMBARKED ON A
COLLABORATION TO CREATE A
VIRTUAL ARCHIVE LESION PROTOCOL
TO BANK THE MRIs SO WE CAN
EVALUATE AND CATEGORIZE
NEUROIMAGING FINDINGS POST CAR,
DESCRIBE PATTERNS OF
ABNORMALITIES DURING ICANS,
BUILDING A FOLLOW-UP PROTOCOL
FOR LATE EFFECTS.
WITH THIS, I HOPE YOU HAVE
REALIZED THE HARD WORK OVER THE
LAST DECADE, ALSO NOTE WE HAVE
SO MUCH MORE WORK TO DO.
I THANK YOU FOR YOUR TIME.
[APPLAUSE]
>>BEFORE I GET STARTED, I WANT
TO SAY THERE'S NO WAY IN THREE
MINUTES I COULD BE ABLE TO
ADDRESS THE HONOR AND GIFT IT'S
BEEN TO BE ABLE TO BE PART OF
THIS PROJECT AND TO WORK WITH
THE MOST AMAZING PATIENTS AND
FAMILIES.
WHICH IS THE SLIDE THAT GOES
FORWARD, THIS ONE?
OKAY.
WELL, AS YOU'VE HEARD, CAR T
CELL THERAPY PROVIDES PROMISE
AND HOPE FOR PATIENTS WITH B
CELL MALIGNANCIES RESISTANT TO
TRADITIONAL TREATMENT.
YOU'VE HEARD ABOUT SIGNIFICANT
TOXICITIES, COMING WITH
UNCERTAIN PROGRESS PROGNOSIS
AND OUTCOME.
FAMILIES ARE LEAVING THEIR
PRIMARY SITE, PEOPLE WHO KNOW
THEM, PEOPLE THEY ARE
COMFORTABLE WITH, STARTING
OVERING NOT KNOWING IF THEY ARE
ELIGIBLE FOR THERAPY, LITTLE
THINGS, HOW A LINE CAN BE
ACCESSIONED IN A DIFFERENT WAY
CAN BE TRAUMATIC, COMPLEX FOR
THE PATIENT AND STAFF.
WE REALIZE THERE NEEDS TO BE A
STANDIZED WAY TO TAKE CARE OF
THE NEEDS OF THE PATIENTS BEYOND
MEDICAL OUTCOMES.
WE ASKED TO BE ABLE TO TALK
ABOUT ACCOMPLISHMENTS.
YOU'VE SEEN THESE EARLIER.
HOW DO WE PROVIDE PSYCHOSOCIAL
CARE FOR CHILDREN UNDERGOING CAR
T THERAPY?
TO BE ABLE TO FIND A WAY THAT
COULD BE MORE SYSTEMATIC.
THIS BEGINS RIGHT WHEN THEY
ARRIVED, EVEN BEFORE WHEN THEY
ARE GETTING APHERESIS, BEFORE
TREATMENT STARTS, AS WELL AS
DURING TREATMENT, AND AFTER
TREATMENT.
IT WAS REALLY EXCITING TO
PARTICIPATE IN THE FIRST PAPER
ON FERTILITY POST CAR T THERAPY.
TOM, IF YOU'RE WATCHING, THANK
YOU VERY MUCH.
THE FIRST CAR T ROAD TRIP WE
WANT TO BE ABLE TO HELP PATIENTS
WHEN THEY COME TO BE PREPARED,
TO HAVE A SENSE OF EMPOWERMENT,
OWNERSHIP, UNDERSTANDING.
THAT'S OUR DESI, PLAYING THE
GAME.
WE HAD A FIRST CAR T CELL SOCIAL
STORY.
IT'S AN ACTUAL BOOK THAT THE
CHILDREN WILL GET, WHERE THEY
CAN BE ABLE TO WRITE THEIR NAME
AND SEE EVERYTHING THAT WILL
TAKE PLACE THROUGHOUT THEIR
TREATMENT JOURNEY.
WE CAPTURED THE PATIENT'S
PERSPECTIVE, NOT JUST THE
MEDICAL OBJECTIVE PERSPECTIVES,
AND YOU HEARD FROM HANEEN WHAT
WE'RE COLLECTING, THE PATIENT'S
PERSPECTIVE OF THE SYMPTOMS THEY
ARE EXPERIENCING THROUGH THE
CD33, CHOP, AND FROM SEATTLE.
LOOKING AT QUALITY OF LIFE,
DECISIONS, QUANTITATIVE AND
QUALITATIVE.
QUALITATIVE INTERVIEWS POST CAR
T ARE REALLY INSTRUCTIVE AND
TELL US ABOUT THE EXPERIENCE.
SO WHERE DO WE GO?
WE WANT TO ASSESS SHORT- AND
LONG-TERM SOCIAL EFFECTS
INCLUDING FINANCIAL IMPACT WHICH
CAN BE SIGNIFICANT.
NOT ONLY FOR THE PATIENT, IT'S
SO IMPORTANT TO UNDERSTAND FOR
THE CAREGIVER, SIBLINGS.
WE WANT EVERY CENTER TO HAVE A
COPY OF THIS, TAILORED TO THEIR
OTHER THAN INDIVIDUAL PLACE, WE
WANT TO WORK TOWARDS AGREEMENT
ON RECOMMENDATION ON THOSE
PATIENT-REPORTED OUTCOMES SO WE
HAVE DIFFERENT SITES AND
DIFFERENT TIME POINTS CONSISTENT
BETWEEN ALL THE TRIALS TAKING
PLACE ACROSS THE WORLD.
WE WANT TO CONTINUE TO
COLLABORATE FOR A SMOOTH
TRANSITION, FROM WHEREVER YOU'RE
COMING FROM TO COMING HERE TO GO
BACK TO YOUR TREATMENT CENTERS,
REGARDLESS OF TREATMENT OUTCOME.
THANK YOU.
[APPLAUSE]
>> HI, I'M BONNIE YATES, NURSE
PRACTITIONERS WORKING WITH THE
PROGRAM.
I'M GOING TO GIVE YOU INSIGHT
INTO OUR CLINICAL CORRELATIVES
WE'VE GONE THROUGH.
FIRST OFF, I WANT TO START BY
SAYING ANALYZING CORRELATE DATA
IS A TEAM EFFORT.
WE USE BLOOD DRAWS, FROM A BLOOD
DRAW FROM A SINGLE PATIENT WE
GET CLINICAL SAMPLES.
THEY GO TO THE CLINICAL CENTER
LAB MEDICINE FOR ROUTINE
TESTING.
AND ALSO GO TO OUR FLOW
CYTOMETRY DEPARTMENT, IN NCI,
FOR DISEASE BURDEN AND
CHARACTERISTICS OF LEUKEMIA AND
TO TELLING US CAR T CELL
PERCENTAGE.
RESEARCH SAMPLES ARE COLLECTED.
WE GET INFORMATION ON CYTOKINES
THAT ARE RUN THROUGH NCI
FREDERICK AND WE HAVE
INFORMATION ON CAR T CELL
NUMBERS AND OTHER INFORMATION
FROM OUR LAB IN THE POB.
FINDINGS FROM THE COLLECTION OF
THIS INFORMATION AND DATA THAT'S
RUN HAVE LED TO MULTIPLE
PUBLICATIONS YOU CAN SEE FROM
OUR CD19 CAR, CD22 CAR, LOOKING
AT EXTRAMEDULLARY DISEASE AND
NEUROTOXICITY.
AND YOU CAN SEE WE USE
INFORMATION FROM STUDYING
CYTOKINES, FROM LOOKING AT THE
PERCENTAGE OF CAR, USING
RADIOLOGY STUDIES TO EVALUATE
DISEASE BURDEN, AS WELL AS
FINDINGS FROM LAB MEDICINE,
LOOKING AT BONE MARROW RESULTS.
SO WE'RE LOOKING AT THE IMPACT
OF LYMPHO-DEPLETING CHEMOTHERAPY
AND OUTCOMES, WORKING WITH THE
NIH CLINICAL CENTER INFECTIOUS
DISEASE TEAM TO OPTIMALLY DEFINE
INFECTION RISKS AND TREAT AND
PREVENT INFECTION IN RECIPIENTS
OF CAR T CELLS, COLLABORATING
WITH THE CENTER FOR CELLULAR
ENGINEERING AND TAYLOR LAB TO
FURTHER INTERROGATE PROPERTIES
CRITICAL TO TOXICITIES AND
RESPONSE, TRAINING A NEW
GENERATION OF CAR T CELL
PROVIDERS.
[APPLAUSE]
>> I'M NAOMI TAYLOR, SENIOR
INVESTIGATOR IN THE PEDIATRIC
ONCOLOGY BRANCH, ARRIVED IN
2018, HONOR THE LEADING THE LAB
BASED RESEARCH WORKING WITH
NIRALI AND TEAM.
BEFORE STARTING I WANT TO SPEND
20 SECONDS OF MY THREE MINUTES
IN THANKING AND GIVING A SHOUT
OUT TO THE PEOPLE IN THE LAB
BECAUSE EVERYTHING THAT YOU SEE
HERE TODAY, THE PATIENTS BEING
TREATED BY THERAPIES, THAT
REPRESENTS HOURS AND HOURS AND
HOURS OF WORK AND DAYS AND
MONTHS AND YEARS.
NONE OF THE TREATMENTS THAT ANY
OF THE PATIENTS HAVE GOTTEN HAVE
HAPPENED OVERNIGHT.
I THINK IT'S ALWAYS A MIRACLE
WHEN THESE TREATMENTS WORK.
IT'S ALWAYS WHAT WE LOOK FOR,
NIRALI WILL TELL YOU IT DOESN'T
MATTER WHAT THE MOUTH SAYS, WE
NEED TO SEE WHAT THE PATIENT
SAYS.
WE SPEND HUGE AMOUNTS OF EFFORT
BEFORE GETTING TO THE POINT OF
TREATING A PATIENT.
BEFORE STARTING, I WANT TO -- I
SEE SOME PEOPLE IN THE LAB HERE.
I WANT TO GIVE A SHOUT OUT TO
THE TRAINEES, STUDENTS,
POSTDOCS, STAFFER BIOLOGISTS,
HERE DAY AND NIGHT.
FOR THOSE NOT INVOLVED IN THE
LAB, IT'S OFTEN THAT MORE
EXPERIMENTS FAIL THAN WORK.
AND SO I'M LOOKING AT SOME
PATIENTS AND THEIR FAMILIES TO
SAY THIS REQUIRES A HUGE AMOUNT
OF WORK, HUGE AMOUNT OF EFFORT,
AND SO BEFORE STARTING I WANT TO
GIVE A SHOUT OUT TO THE HEROES
IN THE LAB.
IT'S BECAUSE OF THEM WE MOVE
FORWARD WITH TREATMENTS TO THE
PATIENTS AND THEIR FAMILIES.
I THOUGHT I WOULD GIVE AN
EXAMPLE OF THREE AREAS IN TERMS
OF BIOLOGICAL CORRELATES THAT WE
NEED TO LOOK AT IN ORDER TO MOVE
FORWARD TO DO A BETTER JOB.
DOES THE POINTER WORK?
YEAH.
THREE EXAMPLES.
WE'RE DOING MORE.
THOSE WHO KNOW ME KNOW I DO LOTS
OF DIFFERENT THINGS, PEOPLE IN
THE LAB ARE GOOD AT THIS.
WITH THE CCE, WITH DAVID AND
STEVE, IT'S NOT CLEAR AS TO WHAT
MANUFACTURING PRACTICES ARE THE
BEST FOR MAKING CAR T CELLS.
YOU HEARD FROM DAVID THAT WE'RE
VERY GOOD AT MAKING CAR T CELLS
BUT BEST IS ALWAYS A WORD THAT'S
DIFFICULT TO UNDERSTAND.
WE NEED TO HAVE A MUCH BETTER
IDEA OF THE TOXICITIES COMING
FROM CAR T CELLS, AND ALSO WE
NEED TO FIGURE OUT AGAIN I'M
GOING TO USE THE WORD IN
QUOTATIONS, WHAT IS THE BEST?
IF A PATIENT FAILED A CD19 CAR T
CELL TRIAL WHAT IS THE BEST WAY
TO BRING THEM FORWARD AND WHAT
ARE THE TRIALS WE WANT TO MAKE
SURE THEY CAN GO ON THAT WOULD
GIVE THEM THE BEST CHANCE OF
SUCCEEDING IN A SECOND ONE?
JUST TO GIVE AN EXAMPLE, I'LL
SHOW SOME OF THE WORK ON THIS,
I'M GETTING AHEAD OF MYSELF, IS
THAT IN THE LAB PATIENTS ARE
BEING TREATED, FOR EXAMPLE, IN
THE NIH, IN STANFORD, DIFFERENT
CENTERS BY VERY DIFFERENT
METHODS OF MAKING CAR T CELLS
WITH DIFFERENT CYTOKINE SUPPORT
AND DIFFERENT WAYS OF SELECTING.
YOU HEARD ABOUT CYTOKINE RELEASE
SYNDROME BUT ONE OF THE THINGS
NIRALI AND GROUP HAVE DONE IS TO
SEE THERE'S A SECONDARY PEAK OF
CYTOKINES, INFLAMMATORY
RESPONSE, VERY SIMILAR TO HLH,
WE STILL DON'T UNDERSTAND WHY
THIS OCCURS.
AGAIN, AS I MENTIONED, IF WE
HAVE A PATIENT WHO FAILED A CD19
CAR T CELL TRIAL OR CD22, WHAT
DO WE WANT TO DO NEXT?
HOW DO WE WANT TO TREAT PATIENTS
WHO ARE ACTUALLY HAVING AMLs,
NOT JUST A.L.L.s, AND OTHER
LEUKEMIAS?
TO GIVE A WAY OF WHAT WE'RE
LOOKING AT THIS, INFORMATION
WHICH I DON'T EXPECT YOU TO LOOK
AT IN DETAIL, OR NEITHER TO
UNDERSTAND, BUT JUST TO SAY IF
WE LOOK AT DIFFERENT SUBSETS
MAKING T CELLS IN DIFFERENT
WAYS, THIS IS COMING FROM THE
CCE, CLINICALLY RELEVANT CAR T
CELLS, WE HAVE DIFFERENT T CELL
SUBSETS WITH PERCENTAGES, IF
CELLS ARE MADE IN A BAG OR
PRODIGY.
WHAT DOES THAT MEAN IN TERMS OF
OPTIMAL THINGS GOING FORWARD.
WE'RE NOT SURE.
WE NEED TO DEFINE DIFFERENCES.
WE NEED TO FIGURE OUT WHAT ARE
DIFFERENCES BETWEEN A PATIENT,
SORRY, BETWEEN A PATIENT WHO
GETS THE SECONDARY INFLAMMATORY
RESPONSE AND THOSE WHO DON'T.
YOU CAN SEE WE'RE STARTING --
OKAY, I'LL STOP TRYING TO POINT.
IN THE MIDDLE PANEL, WE'RE
STARTING TO HAVE DIFFERENCES IN
TERMS OF CYTOKINE PROFILES OF
PATIENTS WHO HAVE LATE
TOXICITIES AND THOSE WHO DON'T.
IF YOU CAN SEE AT THE BOTTOM
HERE WE CAN START TO USE
HIGH-THROUGHPUT ROBOTICS TO SEE
HOW THEY ARE GOING TO RESPOND IN
TERMS OF CYTOKINES WHEN GETTING
DIFFERENT CARs.
THE BLUE LINE IS THE CAR WE'VE
MOVE FORWARD WITH IN TERMS OF
CLINICAL TRIALS.
THERE'S STILL A HUGE AMOUNT TO
DO.
WE HAVE NEW CLINICAL TRIALS WITH
THE CD19-22 BY VALENT, CD33 FOR
AML, NEED TO IMPROVE THOSE,
UPCOMING TRIALS WITH THE BLUE
LINE, NEW TARGETS, WORKING ON
TRYING TO MAKE NEW CAR DESIGNS
AND TO USE NEW TECHNOLOGIES TO
TRY TO FIGURE OUT HOW TO
OPTIMIZE EFFICACY AND REDUCE
TOXICITY IN CLINICAL TRIALS AND
TO TRY TO UNDERSTAND HOW IN THE
CONTEXT OF PATIENTS WHO HAVE
DIFFERENT METABOLISMS, HOW WE
CAN MAKE CARs WORK BETTER.
I'LL END THERE AND THANK YOU
AGAIN.
I'LL FINISH BY THANKING ALL THE
PEOPLE IN THE LAB BECAUSE NONE
OF THIS COULD HAVE HAPPENED
WITHOUT THEM.
SO THANK YOU.
[APPLAUSE]
>> I'M CONSTANCE FROM FLOW
CYTOMETRY.
THANK YOU FOR BEING HERE TODAY
TO LISTEN.
IT'S CLEAR IT'S WONDERFUL WHEN
CAR T CELLS WORK BUT WHAT DO YOU
DO WHEN THEY DON'T?
IT'S CLEAR TO US THAT IT'S
IMPORTANT TO UNDERSTAND AND ASK
QUESTIONS ABOUT WHY RESISTANCE
OCCURS.
COULD THIS BE DUE BECAUSE OF A
FUNCTION OF THE CAR T CELLS, DUE
DO A MECHANISM TO AVOID THERAPY?
OR SOME ROLE THE
MICROENVIRONMENT THAT
CONTRIBUTES TO RESISTANCE?
WE'RE HAPPY TO SAY FLOW
CYTOMETRY CAN HELP ANSWER SOME
QUESTIONS, OFTER MULTIPLEX
PHENOTYPING OF MULTIPLE CELL
POPULATIONS FROM SINGLE SAMPLE,
WITH HIGH SENSITIVITY.
WE KNOW FLOW CYTOMETRY
IDENTIFYING CELL POPULATIONS OF
INTEREST, AND THIS CAN BE
EFFECTIVE BRIDGE TO OTHER
MODALITIES TO FURTHER ANSWER
THESE QUESTIONS.
FOR THE LAST TEN YEARS, FLOW
CYTOMETRY HAS MONITORED
EXPANSION, MOST IMPORTANTLY
EXAMINED RELATIONSHIP TO DISEASE
STATUS.
YOU CAN SEE IN THE FIGURE IN THE
LOWER RIGHT CORNER FOR THIS
PARTICULAR PATIENT THAT HAD
LEUKEMIA IN RED, THE DISEASE
DISAPPEARED AT THE SAME TIME
THERE'S AN EXPANSION OF CD19 CAR
T CELLS IN BLUE.
SUBSEQUENTLY THERE'S A RECOVERY
OF NORMAL B CELLS SHOWN IN
GREEN.
THIS WAS FROM THE PAPER
PUBLISHED IN 2015 FROM LEE ET
AL.
WE'VE OBSERVED A VERY NOTABLE
RAPID EARLY RECOVERY OF NORMAL
CIRCULATING TRANSITIONAL B
CELLS, THIS CAN SOMETIMES HAPPEN
AFTER OTHER TIMES OF TRADITIONAL
THERAPY.
BUT WITH CD19 CAR T CELL THERAPY
IT HAPPENS IN TERMS OF WEEKS,
EVEN DAYS AFTER THERAPY IS
RECEIVED.
THE LABORATORY HAS BEEN ABLE TO
IMPLEMENT ALTERNATIVE FLOW
CYTOMETRY STRATEGY TO IDENTIFY
DISEASE, THIS HAD TO BE DONE FOR
DETECTION OF CD19 NEGATIVE
DISEASE, WHEN IT DISAPPEARS FROM
THE SURFACE OF THE CELL.
WITHOUT THIS STRATEGY IN PLACE
YOU CAN ENTIRELY MISS DETECTING
RESIDUAL DISEASE.
WE'RE ABLE TO PROVIDE
INFORMATION ON ANTIGEN
QUANTITATION, WHICH TELLS NUMBER
OF MOLECULES ON THE SURFACE OF
THE CELL THAT YOU'RE INTERESTED
IN LOOKING AT.
THIS HAS BEEN HELPFUL BECAUSE
IT'S ALLOWED US TO UNDERSTAND
BETTER THE RELATIONSHIP TO
RESPONSE TO THERAPY, ALSO
ALLOWED MODULATION OF THE
TARGETED ANTIGEN TO COME APART
IN THE THERAPEUTIC STRATEGY AS
SHOWN IN 2019.
OUR ABILITY TO PROVIDE THIS TYPE
OF TESTING IN PLACES OUTSIDE OF
BLOOD AND BONE MARROW HAS
PROVIDED INSIGHT INTO BIOLOGY OF
EXTRAMEDULLARY DISEASE RELAPSE
SHOWN IN 2021.
SO FOR THE FUTURE WHAT DO WE
SEE?
WE FORESEE DEVELOPMENT OF
DIAGNOSTIC APPROACHES AND
CONTINUING TO TRY TO IMPROVE
RESIDUAL DISEASE DETECTION
ESPECIALLY IN ANTIGEN
REGULATION, LOSS, LINEAGE
SWITCH.
WE SEE CONTINUED DEVELOPMENT OF
ADDITIONAL CAR T CELL DETECTION
ASSAYS, AND EXPLORE
COLLABORATIVE RESEARCH, MEASURE
SUITED TO THE RESEARCH CORE
FACILITY UNDERWAY WITHIN THE
LABORATORY PATHOLOGY.
WE HOPE TO BRING COMPONENTS OF
THIS COLLABORATIVE RESEARCH TO
BE APPLIED TO CLINICAL FLOW
CYTOMETRY TESTING AND HOPEFULLY
IMPROVE THE LIVES OF THE
PATIENTS WE SERVE.
THANK YOU VERY, VERY MUCH.
[APPLAUSE]
>> HI.
THANK YOU.
I'M ROSIE KAPLAN, HAPPY TO BE
HERE TODAY, BOTH BEING IN THE
POB AND PART OF THIS TEN YEARS
THAT HAVE BEEN SO AMAZING.
NOW TO HAVE THE OPPORTUNITY TO
TALK TO YOU TODAY ABOUT
PEDIATRIC ONCOLOGY BRANCH'S
EFFORTS WITH CAR T CELLS AND
SOLID TUMORS.
AND WHAT I'M GOING TO SPEAK
ABOUT IS A BIGGER GROUP.
I REPRESENT STANDING UP HERE BUT
HOPEFULLY YOU SEE ALL THE PEOPLE
INVOLVED IN THIS EFFORT THAT ARE
PART OF IT.
AND CAR T CELL THERAPIES HAVE
BEEN TRADITIONALLY USED IN
LEUKEMIAS AND LYMPHOMAS.
BUT UNLIKE LIQUID SUPERVISORS,
SOLID TUMORS HAVE UNIQUE
CHALLENGES.
AND MOST OF THESE CHALLENGES,
THIS IS ALL SORT OF THE
BEGINNING OF THIS JOURNEY FOR
CAR T CELLS, I BELIEVE.
A LOT HAVE TO DO WITH TUMOR
HETEROGENEITY WHICH ALSO EXISTS
IN LIQUID TUMORS, BUT IS EVEN
MAYBE MORE PRONOUNCED IN SOLID
TUMORS IN TERMS OF EXPRESSION OF
TARGETS AND THE MULTITUDE OF
TUMOR ANTIGENS AND TARGETS THAT
COULD BE EXAMINED.
OF COURSE, AN AREA THAT'S NEAR
AND DEAR TO MY HEART IS
COMPLEXITY OF TUMOR AND
METASTATIC MICROENVIRONMENTS,
PATIENTS CAN HAVE LOCALIZED AND
SYSTEMIC TUMORS AT THE TIME, MAY
BE BOTH DIFFERENT TUMOR BIOLOGY
AND MICROENVIRONMENT.
AND THE CAR T CELLS THEMSELVES
HAVE UNIQUE CHALLENGES AND SOLID
TUMORS RELATED TO LIMITED
PERSISTENCE, EXHAUSTION,
POTENTIALLY IMPAIRED MEMORY, AS
WELL AS PRESENTATION AND DYNAMIC
ISSUES.
YOU CAN SEE THAT IN THE IMAGE
I'M SHOWING, REPRESENTING THE
DENSITY OF TUMOR WHEN YOU HAVE A
SOLID TUMOR AND THE REAL
COMPLEXITIES OF THE UNIQUE AREAS
WITHIN THAT, AND MULTIPLE CELLS
THAT WORK IN CONCERT WITH THE
TUMOR AND ARE INVOLVED IN THIS
PROCESS.
AND ONE OF THE BIGGEST AND FIRST
EFFORTS THAT WERE STARTED IN
CRYSTAL MAKEL'S LAB WHEN SHE WAS
HERE WAS EXPLORING A TARGET
THAT'S A MOIETY KNOWN AS GD2, A
KNOWN TARGET IN NEUROBLASTOMA
AND OSTEOSARCOMA, CRYSTAL'S
GROUP WITH THE HELP OF MICHAEL
AND OTHERS STARTED A PHASE 1
TRIAL OF T CELLS, ANTI-GD2
CHIMERIC ANTIGEN RECEPTORS IN
PATIENTS SOLID TUMORS, NOT ONLY
ABLE TO REALLY DO ROBUST
PHENOTYPING OF SOLID TUMORS TO
DETERMINE THAT OSTEOSARCOMA
INDEED WAS HIGHLY EXPRESSING BUT
ABLE WITH THE HELP OF THE ENTIRE
TEAM IN CCE TO MANUFACTURE THIS
CAR CELL PRODUCT AND EXCITINGLY
WERE ABLE TO SHOW IT WAS QUITE
SAFE AND THAT CONCERNS OF
ON-TARGET OFF-TUMOR NEUROPATHIC
EFFECTS WITH THE ANTIBODY WERE
NOT SEEN WITH THE CAR, EACH
THERAPY IS UNIQUE THAT WAY AND
IT WAS THE FIRST TRIAL TO ENROLL
OSTEOSARCOMA PATIENTS.
THE MOST EXCITING PART FOR THIS,
IT'S BEEN A TREMENDOUS
OPPORTUNITY TO LEARN FROM OUR
CLINICAL TRIAL AND TAKE THIS
CORRELATEIVE STUDY.
WE FOUND WE COULD SEE EXPANSION
IN PATIENTS TO THE LEVEL IN 19
CAR, EXCITING IN LIQUID TUMOR,
GREAT VARIABILITY, WE'RE ABLE TO
SPLIT PATIENTS INTO ONES THAT
EXPAND AND ONES THAT DIDN'T.
IT WAS DISAPPOINTING WE DIDN'T
SEE RESPONSES, WERE WORRIED THAT
WAS MAYBE RELATED TO FINDINGS IN
THE LAB, AND JUST AS NAOMI
TAYLOR WAS SAYING, WE HAD TO GO
BACK TO THE LAB AND UNDERSTAND
WHY.
ONE OF THE THINGS DR. MAKEL'S
GROUP FOUND WAS T CELLS WERE
GETTING EXHAUSTED IN THE MAKING
OF THEM BEFORE THEY GOT INTO THE
PATIENT AND THAT GOES BACK TO
THE DIFFERENCES IN MANUFACTURING
AND HOW MUCH WE SHOULD BE PAYING
ATTENTION TO THAT.
BECAUSE OF THIS KNOWLEDGE WE'VE
IT ITERATED AND HAVE A STUDY
OPEN HERE AND IN OTHER SITES
SOON, GD CAR PERSISTS, THE GROUP
MODIFIED THE CAR ITSELF AND HOW
WE MAKE IT TO ELIMINATE THIS
EXHAUSTION, THIS SHOWS THAT THE
USE OF DEFATINIB, NOT USED FOR
THIS INDICATION COULD QUIET T
CELLS WHILE BEING MADE TO LET
THEM REST AND BE EFFECTIVE WHEN
THEY GO INTO THE PATIENT, WE'RE
EXCITED TO SEE HOW THIS WORKS
GOING FORWARD IN BENCH TO
BEDSIDE APPROACHES.
THERE'S MANY CHALLENGES AHEAD.
I WANT TO REPRESENT THE ENTIRE
BRANCH, I THINK WE ACCEPT THIS
CHALLENGE.
CHALLENGE IS ACCEPTED.
WE'RE EAGER TO MOVE FORWARD.
I'M EXCITED TO TELL YOU ABOUT
DR. NELLEN AND DR. WYNN'S
EFFORTS IN PRE-CLINICAL WORK AND
T CELL ENGINEERING IN THE LABS
AND GOING FORWARD INTO THE
TRIALS AND I THINK WE WANT TO
MOVE FORWARD WITH THE NEW
ENGINEERING, NEW TARGETS, A GPC
2 TRIAL, NEW EVIDENCE IN BRAIN
TUMORS, AS WELL AS B7H 3, WE'RE
EXCITED, AND WE WANT TO
UNDERSTAND HOW WE CAN TAKE
ADVANTAGE OF THESE CHALLENGES OF
THE MICROENVIRONMENT TO OUR
ADVANTAGE TO MAKE CARs WORK
BETTER.
SOME AREAS WE'RE LOOKING AT IS
NOT JUST ENGINEERING T CELLS BUT
ENGINEERING MYELOID CELLS TO
HELP T CELLS WORK BETTER.
SO WE'RE ACTIVELY ENGAGED IN
THAT.
I THINK THE FUTURE FOR OUR WORK
IS VERY BRIGHT AND I REALLY LOOK
FORWARD TO LOTS OF CONTINUED
COLLABORATION ACROSS THE BRANCH
TO MAKE THIS HAPPEN.
[APPLAUSE]
>>DIRECTOR OF HEALTH PSYCHOLOGY
PROGRAM, PEDIATRIC ONCOLOGY
BRANCH.
I'M GOING TO GIVE A BRIEF
SUMMARY OF THE WORK MY COLLEAGUE
DR. MARTIN AND I HAVE BEEN DOING
OVER THE PAST TEN YEARS TO
ADVANCE ASSESSMENT OF CAR T CELL
NEUROTOXICITY, SPECIFICALLY
USING NEURAL COGNITIVE
EVALUATION.
THERE IS A HIGH RISK FOR
DEVELOPING ACUTE SYMPTOMS OF
NEUROTOXICITY ASSOCIATED WITH
CRS, CONFUSION, LANGUAGE
DISTURBANCE, SEIZURES, GENERALLY
TRANSIENT.
SYMPTOMS MAY VARY ACROSS
DIFFERENT THERAPIES, AGES,
SPECIFIC CANCERS, DOMAINS OF
FUNCTION, POSSIBLY LONGER
PERIODS OF TIME.
UNMET NEEDS TO EVALUATE SYMPTOMS
OVER TIME FROM ACUTE TO LONG
TERM, AND COME TO CONSENSUS ON A
CORE SET OF ASSESSMENT METHODS
TO COMPARE RESULTS ACROSS TRIALS
AND GUIDE TREATMENT DECISIONS.
ABOUT TEN YEARS AGO AT THE
BEGINNING OF THE TRIAL, DR.
MAKEEL ASKED US TO DESIGN AN
EVALUATION TO ASSESS SYMPTOMS OF
NEUROTOXICITY.
AT THIS TIME, THERE WERE NO
SYSTEMATIC NEUROCOGNITIVE
EVALUATIONS USED IN ANY PREVIOUS
CAR T CELL TRIALS.
WE DESIGNED A FOCUSED BRIEF
NEUROCOGNITIVE TEST BATTERY TO
EVALUATE DOMAINS IN IN ACUTE
PHASE, AT BASELINE AND ONE MONTH
POST-INFUSION.
IN ADDITION WE DEVELOPED A
CHECKLIST TO ASSESS BEHAVIORAL
SYMPTOMS OF NEUROTOXICITY
EXPERIENCED BY PATIENTS.
DUE TO POTENTIAL OF SEVERE
SYMPTOMS DESIGNED A MEASURE TO
BE COMPLETED BY THE PATIENT'S
PRIMARY CAREGIVER PRESENT IN THE
HOSPITAL, BASED ON SYMPTOMS
OBSERVED IN THE FIRST TRIALS,
ASSESSES SEVERITY AND DURATION
OF SYMPTOMS, ADMINISTERED AS
OFTEN AS NEEDED.
WE ADMINISTERED AT BASELINE, DAY
14, ONE MONTH POST-INFUSION.
ON ALL CURRENT TRIALS.
WE HAVE FOUND BRIEF EVALUATIONS
ARE FEASIBLE IN THIS
POPULATION.
WE HAVE DEMONSTRATED AVERAGE AND
STABLE COGNITIVE FUNCTION OF THE
PEDIATRIC SAMPLES.
IN ADDITION THE CHECKLIST HAS
IDENTIFIED AND MONITORED
SYMPTOMS OVER TIME, BEEN
SENSITIVE TO CHANGES ASSOCIATED
WITH CYTOKINE RELEASE SYNDROME,
AND EXHIBITED INITIAL VALIDITY,
PATIENTS WITH MORE SEVERE
SYMPTOMS HAD HIGHER SERUM
CYTOKINE LEVELS.
WE'RE STARTING TO CONDUCT A
PILOT STUDY TO ASSESS ACUTE AND
LONG-TERM FUNCTIONING.
THIS TEST BATTERY INCLUDES
COMPUTERIZED COGNITIVE TEST,
NEURAL SYMPTOM CHECK LIST,
ELECTRONIC PATIENT REPORTED
MEASURES.
WE INTEND TO USE THE PILOT DATA
FROM THIS STUDY TO PLAN AND
OBTAIN FUNDING FOR LARGER
PERSPECTIVE MULTI-CENTER NEURAL
TOXICITY TRY TO EXPLORE
ASSOCIATIONS BETWEEN OUTCOMES SO
WE CAN BETTER UNDERSTAND OVERALL
EFFECTS OF CAR T CELL THERAPY IN
PEDIATRIC POPULATIONS.
THANK YOU.
[APPLAUSE]
>> NEXT WE'LL HAVE JAMES GULLEY,
PRESENTING, AND GIVING A
PRESENTATION ON THE CENTER FOR
IMMUNO-ONCOLOGY.
>> GOOD AFTERNOON, I'M DELIGHTED
TO TALK TO YOU ABOUT THE CENTER
FOR IMMUNO-ONCOLOGY.
I'M JAMES GULLEY.
THIS CENTER WAS FORMED BY A
MERGER OF THE LABORATORY OF
TUMOR IMMUNOLOGY AND BIOLOGY
WITH COMPONENTS OF THE
EXPERIMENTAL TRANSPLANTATION AND
IMMUNOTHERAPY BRANCH, AND THE
GENITOURINARY MALIGNANCY BRANCH,
CO-DIRECTED BY DR. SLOWMAN AND
MYSELF.
THERE ARE TWO OTHER SENIOR
INVESTIGATORS, ONE TENURE-TRACK
INVESTIGATOR, A SENIOR CLINICIAN
AND A PHYSICIAN-SCIENTIST EARLY
INVESTIGATOR.
WE HAVE MULTIPLE ONGOING
PRE-CLINICAL AND CLINICAL
EFFORTS WITH IMMUNE CHECKPOINT
INHIBITORS, IMMUNOCYTOKINES,
FULL GAMUT OF CELLULAR THERAPY,
AND BY SPECIFIC ANTIBODIES.
WE HOPE TO BE ABLE TO ADD IN
GENETICALLY ENGINEERED MYELOID
CELLS AS YOU JUST HEARD.
THERE ARE MULTIPLE COLLABORATION
OPPORTUNITIES WITH THE CENTER
FOR IMMUNO-ONCOLOGY.
IF YOU COLLABORATE WITH US, YOU
MAY HAVE ACCESS TO NOVEL AGENTS
TO USE IN THE PRE-CLINICAL OR
CLINICAL SPACE.
WE HAVE CRADAs WITH MUST --
MULTIPLE COMPANIES, ALL CRADAs
HAVE THIRD PARTY CLAUSES
ALLOWING US TO COMBINE
INVESTIGATIONAL AGENTS FROM
MULTIPLE COMPANIES IN
PRE-CLINICAL AND CLINICAL
STUDIES.
THERE'S ALSO THE POTENTIAL FOR
ACCESS TO COLLABORATIVE CLINICAL
TRIALS.
WE ACTUALLY COLLABORATE WITH
MOST OF THE CLINICAL LABS AND
BRANCHES IN THE CCR ON CLINICAL
STUDIES.
THERE'S ACCESS TO COLLABORATIVE
IMMUNOASSAYS, PERIPHERAL
IMMUNOPHENOTYPING, LOOKING AT UP
TO 158 SUBSETS, CAN DO MULTIPLEX
AND MULTISPECTRAL IMAGING.
IN THE CENTER FOR
IMMUNO-ONCOLOGY WE BELIEVE THE
BEST PATHWAY TO CURE FOR
PATIENTS IS COMBINATION STUDIES.
SO, WE REALLY FEEL LIKE YOU NEED
TO ADDRESS EACH OF THE PARTS OF
THE TUMOR IMMUNITY CYCLE TO
GENERATE OR GIVE THE RIGHT CELLS
TO GROW THEM UP INSIDE THE
PATIENT, TO ALLOW THEM TO GO TO
THE TUMOR, TO RECOGNIZE THE
TUMOR, AND TO REMAIN FUNCTIONAL
IN THE OFTEN HOSTILE TUMOR
MICROENVIRONMENT.
IN ADDITION, IN YOUR CELL
THERAPY BASED APPROACHES WE'RE
LOOKING AT GIVING MEMBRANE
CYTOKINES, TO LOOK AT IL-12,
IL-15, IL-21, AS WELL AS
OPPORTUNITIES TO SIGNAL BETTER
THROUGH THE T-CELL RECEPTOR.
IN CONCLUSION, I'D LIKE TO THANK
DR. SHAH FOR INVITING ME TO GIVE
A LITTLE BIT OF AN OVERVIEW OF
THE CENTER FOR IMMUNO-ONCOLOGY
AND THANK HER FOR PUTTING ON
THIS AMAZING SYMPOSIUM.
THANK YOU.
[APPLAUSE]
>> FOR A VERY FINAL SESSION
WE'LL END WITH TWO VIDEOS, FIRST
IS GOING TO BE FROM CRYSTAL
MAKEL SHARING THOUGHTS.
SHE'S BEEN A TREMENDOUS
INSPIRATION TO ALL OF THE WORK
THAT'S HAPPENED IN THE BRANCH,
AND, AGAIN, ONE OF OUR POB
LEGENDS.
SO CRYSTAL?
>> I'M CRYSTAL MAKEEL, I WAS AT
THE PEDIATRIC ONCOLOGY BRANCH
FROM 1989 UNTIL 2015.
SO, SPENT A GREAT DEAL OF MY
LIFE THERE.
AND IT IS AN ABSOLUTELY
ESSENTIAL PLACE FOR THE
EVOLUTION AND PROGRESS IN THE
REALM OF PEDIATRIC CANCER.
THE EXPERIENCE WITH CAR T CELLS
IS JUST ONE EXAMPLE OF SPACE
WHERE THE PEDIATRIC ONCOLOGY
BRANCH PLAYED A REMARKABLE ROLE.
BUT IT'S CERTAINLY NOT THE ONLY
EXAMPLE.
I CAN THINK OF MANY.
BUT TODAY WE'RE HERE TO
COMMEMORATE THE TEN-YEAR
ANNIVERSARY OF THE FIRST PATIENT
TREATED WITH CAR T CELLS IN THE
PEDIATRIC ONCOLOGY BRANCH.
I CAN REFLECT BACK A LITTLE BIT
ON WHAT WAS HAPPENING AT THE
TIME.
YOU KNOW, CANCER IMMUNOTHERAPY
REALLY BLEW WIDE OPEN IN 2010,
WHEN THE IMMUNE RESPONSES TO NEW
CHECKPOINT INHIBITORS WERE FIRST
BEING OBSERVED.
BUT TO FOLKS IN THE NCI, THIS
WASN'T A NEW AREA.
THIS WAS SOMETHING THE NCI HAD
BEEN WORKING ON FOR CERTAINLY 30
YEARS, AND IF NOT LONGER.
NOW, THE GOOD NEWS ABOUT IMMUNE
CHECKPOINT INHIBITORS IT PUT
IMMUNOTHERAPY FRONT AND CENTER
IN CANCER MEDICINE.
THE BAD NEWS, THEY HAVEN'T HAD A
TRANSFORMATIVE IMPACT IN
CHILDHOOD CANCERS.
SO, ABOUT THE SAME TIME, WE
STARTED TO SEE THE FIRST SIGNALS
OF ACTIVITY WITH CD19 CAR T
CELLS.
AND I REMEMBER THE FIRST PATIENT
THAT WAS TREATED ON THE THIRD
FLOOR BY STEVE ROSENBERG'S
GROUP, A PATIENT WITH VERY
REFRACTORY LYMPHOMA.
AND THIS PATIENT HAD DRAMATIC
COMPLETE REMISSION.
AND OF COURSE WORD TRAVELS FAST
WHEN SOMETHING EXCITING LIKE
THAT HAPPENS.
AND WE KNEW THAT UNLIKE
RITUXIMAB, WHERE IT WASN'T
WORKING FOR OSTEOSARCOMA, THIS
WAS ONE OF THE FIRST
IMMUNOTHERAPIES THAT REALLY,
REALLY LOOKED LIKE IT WAS
WELL-SUITED FOR CHILDREN'S
CANCERS.
WE IMMEDIATELY GOT TO WORK.
MY LABORATORY PRETTY MUCH
DROPPED EVERYTHING IT WAS DOING.
AND FIGURED OUT HOW WE COULD
DELIVER CD19 CAR T CELLS TO
CHILDREN WITH LEUKEMIA.
AND WE WERE RACING FORWARD.
WE WERE RACING WITH CHOP, I'LL
BE HONEST.
THEY BEAT US BY A FEW MONTHS IN
TERMS OF TREATING THE FIRST
PATIENT WHO TURNED OUT TO BE THE
FAMOUS EMILY WHITEHEAD.
BUT THE WHOLE COMMUNITY WAS
REALLY EXCITED ABOUT WHAT THIS
NEW CLASS OF THERAPEUTICS WAS
GOING TO SHOW.
THEY DID NOT DISAPPOINT.
THERE WERE MANY PATIENTS WHO HAD
EXHAUSTED ALL STANDARD
THERAPIES, AND WERE RENDERED
INTO REMISSION.
SO IT WAS A PERFECT STORM FORT
PEDIATRIC ONCOLOGY BRANCH.
ALL OF THE INFRASTRUCTURE WE
HAVE FOR DOING CLINICAL TRIALS,
ALL OF THE REMARKABLE
IMMUNOLOGY, EXPERTISE WAS JUST
READY TO APPLY TO THIS ARENA.
SO THAT WAS THEN.
TEN YEARS LATER WHERE ARE WE?
YOU KNOW, I THINK THAT CD19 CAR
T CELLS WERE APPROVED FOR
CHILDREN'S CANCER, THAT WAS A
REMARKABLE ACCOMPLISHMENT.
BUT THE TRUTH IS THAT WE STILL
HAVE A LOT OF WORK TO DO.
LESS THAT BE -- LESS THAN HALF
OF CHILDREN ARE EXPERIENCING
LONG-TERM DURABLE CURES.
AND WE REALLY REMAIN HOPEFUL
WE'LL BE ABLE TO EXTEND THE
REACH OF CAR T CELLS BEYOND
ACUTE LYMPHOPLASTIC LEUKEMIA,
AND EVIDENCE SAID WE CAN DO
THAT.
WE HAVE TO MAKE IT HAPPEN BY
DOING GREAT FUNDAMENTAL
RESEARCH, BY DOING RESPONSIBLE
INNOVATIVE AND RAPID
TRANSLATION, AND BY SEEING THAT
THOSE AGENTS THAT HAVE ACTIVITY
ULTIMATELY FIND A PATH TO
COMMERCIALIZATION, BECAUSE THOSE
OF US IN THIS BUSINESS KNOW THAT
JUST BECAUSE A DRUG IS ACTIVE IN
CHILDREN DOESN'T MEAN IT WILL
END UP TO BE A COMMERCIALIZED
DRUG AVAILABLE FOR TREATMENT
AROUND THE WORLD.
WE REALLY WANT OUR DRUGS TO GO
FROM BENCH TO MARKET.
NOT JUST BENCH TO BEDSIDE.
PEDIATRIC ONCOLOGY BRANCH IS
KEEPING THE TORCH ALIVE, DOING
AMAZING WORK IN THIS SPACE.
WE'RE COLLABORATING EXTENSIVELY
WITH THEM AND WITH MANY
INSTITUTIONS ACROSS THE COUNTRY,
HERE AT STANFORD, WE LOOK
FORWARD TO TAKING THESE
IMMUNOTHERAPIES TO THE NEXT
LEVEL AND ALSO TO CONTINUING TO
ADVANCE THERAPIES FOR CHILDREN'S
CANCER WRIT LARGE.
SMALL MOLECULES, DRUGGING THE
UNDRUGGABLE, A WIDE RANGE OF
THERAPEUTICS, NOT JUST
IMMUNOTHERAPY.
SO CONGRATULATIONS ON, YOU KNOW,
THE FELLOWSHIP AND I'M SPEAKING
TO THE NEW FELLOWS HERE.
THE NIH AND JOHNS HOPKINS ARE
AMAZING INSTITUTIONS, THE
PEDIATRIC ONCOLOGY BRANCH IS A
MAGICAL PLACE.
THANK YOU, EVERYONE.
IT'S BEEN GREAT TO TALK TO YOU.
[APPLAUSE]
>> I'LL JUST END IF I COULD HAVE
THE TEN YEAR CONCLUSION SLIDE.
YEP.
AND THE SLIDE DECK IS PERFECT.
THANK YOU.
SO, AGAIN, I GO BACK TO THIS.
THIS WORK COULD NOT BE DONE
WITHOUT YOU.
I LOOK FORWARD TO WHERE WE WILL
BE, YOU KNOW, 20 YEARS FROM THE
FIRST PEDIATRIC CAR T CELL
EXPERIENCE IN THE POB.
THERE'S NOT MUCH MORE I HAVE TO
SAY BUT I'LL END WITH A FINAL
QUOTE FROM ELIZABETH, DESI'S
MOM.
IF IT WASN'T FOR CAR T CELLS, WE
WOULD NEVER HAVE HAD AN EXTRA 29
MONTHS ABOUT OUR SON.
EVERY SINGLE DAY COUNTED.
THANK YOU TO ALL THE RESEARCHERS
WORKING HARD IN THE HOPE ONE DAY
OUR CHILDREN WILL NOT FIGHT
LEUKEMIA WITH ALL THEIR MIGHT.
AS I WENT THROUGH THIS I REACHED
OUT TO MANY FAMILIES, GOING BACK
A DECADE.
I HEARD THE EXTRA TIME THEY HAD,
WE FEEL THEIR LIVES ARE CUT TOO
SHORT SO I HOPE THERAPY WE'RE
DOING AND EVERYBODY WHO IS
INVOLVED AT ANY STAGE OF THIS
PLATFORM IS ABLE TO SORT OF TAKE
THIS AS A CHALLENGE TO SAY LET'S
SEE WHAT WE CAN DO TO REALLY BE
ABLE TO EXTEND THE LIVES OF THE
CHILDREN THAT WE TREAT.
SO WITH THAT, I'LL END WITH A
BEAUTIFUL SONG THAT ELIZABETH
HAS OFFERED TO SHARE WITH US AS
OUR ENDING SLIDE.
THANK YOU SO MUCH.
AND FINAL VIDEO.
PERFECT.
THANK YOU.
[ MUSIC ]
♪ YOU LOOK AT ME, AND BABE I
CATCH ON FIRE ♪
♪ THE STRUGGLE IN MY SOUL ♪
[ MUSIC ]
[APPLAUSE]
>>THANK YOU, EVERYBODY.
[APPLAUSE]