>> WELCOME TO INSPIRED SYMPOSIUM
BIT OF A BRAINSTORMING AND BRAIN
CHILD OF MANY OF US WHO WANT TO
BRING THE COMMUNITY TOGETHER.
THANK YOU. THIS WILL BE
RECORDED AND ARCHIVED FOR THOSE
THAT ARE UNABLE TO SEE IT LATER.
RECENT ADVANCES IN FUTURE
DIRECTIONS, WELCOME. THE GOALS
ARE TO HIGHLIGHT LESSONS LEARNED
FROM EXPERIENCE OF CAR T-CELLS
FOR CHILDREN AND YOUNG ADULTS.
>> ADAM LAMBLE AND KEVIN
MCNERNEY.
THE FIRST SESSION IS
CURRENTS BEST PRACTICES USING
CAR T-CELLS FOLLOWED BY RELAPSE
PREVENTION AND SESSION 3 IS CAR
T-CELL EMERGENT TOXICITY
PREVENTION AND MANAGEMENT AND
WILL HAVE TWO CONCURRENT
SESSIONS DURING SESSION 4 THAT
IS 4A SPECIAL CAR T-CELLS IN
UNIQUE POPULATIONS AND 4A IS IN
MAIN AUDITORIUM AND 4B WILL BE
NEXT 1 AND E2 AND SESSION 5
EXPANDING USE OF CAR T-CELLS AND
B CELLS.
AND WE WILL START THE
INTRODUCTION AND MORNING KEYNOTE
FOLLOWED BY OUR PATIENTS
EXPECTED PRESENTED BY PATRICK
MCSWEENEY AND GO TO SESSIONS 1
AND SMALL BREAK BEFORE GOING
INTO SESSION 2. BETWEEN SESSION
2 AND LUNCH WE WILL HAVE A
PROFESSIONAL PHOTOGRAPHER HERE.
I WOULD LIKE TO ASK EVERYONE TO
COME UP TO THE STAGE AND KEEP A
REMINDER FOR THAT AND CUTTING TO
E1 AND E2 THAT IS ON YOUR AGENDA
FOR THE LUNCH SYMPOSIUM AND
LUNCH KEYNOTE AND SESSIONS 3
WILL BE BACK IN HERE AND AGAIN
SESSION 4 IS THE CONCURRENT
SESSION WITH 4A IN MAIN
AUDITORIUM AND 4B AND E1 AND E2
AND END THE DAY WITH SESSION 5
AND FINAL KEYNOTE FROM KRYSTAL
MAIPLE AND STEPHEN GOD CHECK AND
WE WILL END THE DAY.
THIS IS A COMBINATION OF ALL
SPEAKERS AND YOU CAN TELL IT IS
A REALLY IMPRESSIVE GROUP. A
COUPLE HOUSEKEEPING THINGS, NO
FOOD IS ALLOWED IN THE MAIN
AUDITORIUM AND LUNCH SYMPOSIUM
IN 4B IS NEXT 1 AND E2 AND IT
WILL BE RECORDED AND NIH
VIDEOCAST AND EVERYONE SHOULD
HAVE GOTTEN THE LINK. THIS
MORNING WE HAD A LITTLE OVER 450
PEOPLE REGISTER AND 100 ARE
ONSITE AND EXCEPTION IS 4B IS ON
WEBEX. I WILL GO THROUGH
LOGISTICS WHEN WE GET THERE.
STAYING ON TIME AND TO END TODAY
IS REALLY ONLY THE BEGINNING.
THESE ARE RAPID FIRE SESSIONS
AND NOBODY IS GIVEN MORE THAN 10
MINUTES. IT IS SCRATCH OF THE
SURFACE OF ALL WE LEARNED IN THE
PAST DECADE. CONFERENCE IS
FOLLOWED BY A SERIES OF SIX
MANUSCRIPTS THAT WILL HELP TO
PROPEL THE FIELD AND ONGOING
CONVERSATIONS THAT WILL HAPPEN
AFTER THE CONFERENCE AND
THINKING ABOUT INSPIRED 2 AND
THAT IS IN 2 TO 3 YEARS HOPING
WE CAN BE ACROSS THE ATLANTIC
FOR THAT ONE AND FINAL THANK YOU
TO PATIENT INHERENT SPEAKERS AND
RESEARCH PROGRAM PROVIDING
FUNDING FOR PCTC WHO PROVIDED
FOOD FOR CONFERENCE AND
[INDISCERNIBLE] WHO I HAVE KNOWN
SINCE I WAS A FELLOW AND WITH
EVERYTHING I DO TO MY LEUKEMIA
TEAM ALL OF THE LITTLE MINIONS
THAT HELPED WITH EVERY
ORGANIZATION THING THAT HAPPENED
TODAY AND AV AND IT PEOPLE I
E-MAILED MILLIONS OF YOU OVER
THE LAST COUPLE DAYS.
YOU MADE THIS ALL POSSIBLE.
THANK YOU. WITH THAT, I WOULD
LIKE TO GO AHEAD AND INTRODUCE
STEPHEN GRUPP WHO IS A SECTION
CHIEF FOR CELL THERAPY AND
TRANSPLANT SECTION AND INAUGURAL
DIRECT YOOR OF SUSAN S STEVEN P
KELLY THEATRE AND HE HOLDS A
[INDISCERNIBLE] CHAIR IN
PEDIATRIC ONCOLOGY AND EVERYONE
KNOWS HIM WELL AND HE IS
ATTENDING PHYSICIAN CANCER
CENTER CHIEF OF THERAPY AND
TRANSPLANT SECTION AND.
>> WITH THAT, I WOULD LIKE TO
HAND IT TO STEVE GRUPP.
>> ALL RIGHT. WELL, THANK YOU
VERY MUCH. I AM HIGHLY AWARE OF
THE NEED TO KEEP WITHIN TIME AND
WOULD ENJOY THE PROSPECT BEING
PUSHED OFF THE STAGE WITH NIRALI
THAT I'M PERFECTLY CAPABLE OF
DOING AND EXCITED TO TALK TO THE
GROUP IN THIS IMPORTANT DAY AND
TITLE TODAY REFLECTIONS OF
EMERGENT CHALLENGE IS A PERFECT
TITLE AND ALL CHALLENGES WERE
EMERGENT AND NOTHING WE THOUGHT
WE KNEW GOING INTO THE BUSINESS
WAS THINGS THAT TURNED OUT TO BE
ACTUALLY TRUE. WE WILL TALK
ABOUT WHERE I THINK THINGS ARE
AND ISSUES THAT WE HAVE RUN INTO
ALONG THE WAY AND MY DISCLOSURES
AND RED ONES IN RED ARE SLIGHTLY
TANGENTIAL TO STUFF WE WILL TALK
ABOUT IN THE NEXT 15 MINUTES.
WE ARE TALKING ABOUT A 10 YEAR
JOURNEY AND.
STARTED GLOBAL REGISTRATION
TRIAL IN 2015 AND BROUGHT TO
ODAC IN 2017 AND FIRST FDA
APPROVAL IN CAR T IN LATE AUGUST
AND IT WAS FIRST GENE THERAPY
APPROVED IN US AND IN 2023 WE
HAVE SIX CAR TS AND THEY ARE
CONSIDERABLE AS WE KNOW AND MANY
ARE WORKING ON AND PREINFUSED
GENE THERAPY FOR THOSE THAT ARE
CELL THERAPISTS AND THREE MORE
POTENT
POTENTIALLY COMING THIS YEAR
USING ENGINEERS HEMOPOETIC STEM
CELLS AND ON THE RIGHT YOU SEE
EMILY WHITEHEAD 10 YEARS OUT
POISED 17 YEAR OLD TALKING TO
ALROEKER ON SET OF TODAY SHOW
AND SHE HAS BECOME INTERNATIONAL
FACE OF PEDIATRIC CELL THERAPY
IN MANY WAYS AND IF YOU KNOW HER
AND HER MOM THEY ARE AMAZING
ADVOCATES FOR CAR T AND COMMENT
QUICKLY THAT ONE IMPORTANT
LESSON LEARNED EARLY ON WAS
IMPORTANCE OF APPROPRIATE CELL
MANUFACTURING AND VARIOUS WAYS
TO GET TO THIS PATHWAY AND WAY
YOU ACTIVATE T-CELLS MATTER AZ
LOT AND SOME ACTIVATION MATRIX
BEADS MOST OFTENLY USED ARE
IMPORTANT IN GETTING THIS RIGHT
ALLOWING T-CELL REPERTOIRE
PRESERVATION AND CELLS THAT
MAINTAINED WE LEARNED NOW EARLY
T-CELL PHENOTYPE THAW NEED FOR
REAL APPROPRIATE ACTION
ESPECIALLY IN AAL AND EVERYTHING
MATTERS AND IS NOT PREDICTABLE
AND SERUM MATTERS AND ACTIVATION
MATRIX MATTERS AND TIME AND
CULTURE SHORTER THE BETTER AND
WE ARE TALKING ABOUT SHORT AND
WE WILL TALK ABOUT IT BRIEFLY
AND MEMORY EARLY PHENOTYPES AND
ALL ARE HARD TO PREDICT AND LACK
OF POTENCY ASSAY THAT LET'S YOU
SAY WHAT WILL HAPPEN IN THE
PATI
PATIENT.
WE LOOK AT WHAT HAPPENS A MONTH
LATER AND LEARN ABOUT POTENCY
AND LIKE TO HAVE BETTER TESTS
THAN THAT AND BRIEFLY COMMENTING
ON A QUESTION I GET ASKED FROM
TIME TO TIME THAT IS WHY IS
PEDIATRIC ALL FIRST TARGET OF
FDA APPROVAL AND STARTED OUT
UNIVERSITY OF PENNSYLVANIA THREE
PATIENTS TREATED WITH CLL
IMPORTANT TO REMEMBER THAT AND
WE OPENED ADULT AND PEDIATRIC
ALL TRIALS THAT IS PEDIATRIC
TRIAL THAT IS LITTLE ENGINE THAT
COULD AND KEPT MOVING FORWARD
AND KNOCK ON WOOD TERRIFIED TO
SAY THIS KNOCK ON WOOD CLINICAL
HOLD WENT FROM PHASE 1 STUDY
THAT ENROLLED EVENTUALLY 72
PATIENTS NOT REALLY A PHASE 1
STUDY AND TO NO. VAR TIS TRIALS
THAT LED TO FDA APPROVAL AND WE
ARE DOING MANUFACTURING AND IND
AT CHOC NOW AND EVERYBODY KNOWS
ABOUT ELLI ANA TRIAL AND FIRST
GLOBAL TRIAL AND MANY
PARTICIPANTS IN THE AUDIENCE AND
PURPOSE OF SHOWING THIS SLIDE IS
SHOWING THIS SLIDE UPDATED DATA
FROM ELIANA TRIAL GOING OUT AS
FAR AS 60 MONTHS WITH 5 YEAR
RELAPSE FREE SURVIVAL OF 44% AND
MEDIAN RELAPSE RESURVIVAL OF 47
MONTHS AND IS UPDATED DATA AND
WHAT THINGS LIKE LIKE IN YOU
FOLLOW PATIENTS LONGER AND SHOW
ME 2 OR 3 YEAR DATA WHAT IT
LOOKS LIKE AT YEAR 5 AND IS OUT
NOW AND THANKS FOR A NUMBER OF
PEOPLE WORKING ON THIS INCLUDING
SHANNON AND TED ISSUE B CELL A-
MRASHIA WITH CD19 CARS AND B
CELL AMRASHIA IS IMPORTANT AND 6
MONTHS RETROSPECTIVE STUDIES WE
HAVE DONE AND MIKE WILL TALK TO
YOU ABOUT THIS SO IMPORTANT THAT
SHOWS THAT 6 MONTH MARK HAS
VALIDITY IN ALL AND DOESN'T
APPLY TO LYMPHOMA AND SHORTER
INTENSE CARS AND CD28 CARS PRIOR
TO LYMPHOMA HAVE GREAT EFFICACY
AND PRESERVATION OF A GREAT CR
THAT WE ARE LOOKING FOR AND
ACHIEVING CR AND KEEPING
PATIENTS THERE AND NECESSARY TO
HAVE A 6 MONTH TIMEFRAME TO KEEP
PATIENTS INTO REMISSION AND OWN
EXPERIENCE AT CHOC SUPPORT STAFF
AND IS ABSOLUTELY CELL TYPE
DEPENDENT AND I WANT TO BE CLEAR
ABOUT THAT AND HAPPENS TO BE FDA
APPROVED THERAPY AVAILABLE TO US
AND B MRASHIA FROM A RECENT
TRIAL AND HALF PATIENTS REMAIN
FROM B CELL AMRASHIA IF THERE AT
A YEAR YOU ARE PROBABLY THERE AT
YEAR 5 AND [INDISCERNIBLE] NO.
I DON'T THINK SO. IT IS AN
EITHER OR PROPOSITION FOR US AND
WE ARE DEALING WITH LOTS OF
PATIENTS WITH LONG TERM B CELL
AMRASHIA THAT ARE GOOD NEWS IN
REMISSION AND [INDISCERNIBLE]
AND MIKE WILL TALK TO YOU ABOUT
DATA. I WILL NOT. I WANT TO
ACKNOWLEDGE TYPICAL FLOW MRD IS
USEFUL AND DETERMINES WHETHER
SUCCESS OR FAILURE AND WHETHER
PRODUCT IS PAID FOR OR NEED TO
PAY FOR PRODUCT STRONG OUTCOMES
BASED AGREEMENT IN THE SHORT
TERM AND NGSMRD ADDS INFORMATION
IN TERMS OF PATIENTS IN FLOW AT
MRD AND TELLS US GROUPS ARE
DOING GREAT AND GROUPS THAT
REALLY NEED FURTHER THERAPY AND
ARGUMENT FROM A CURVE LIKE THIS
IS NGS POSITIVE PATIENTS IN BLUE
NEED TO GO TO TRANSPLANT AND AS
I SAY GREEN CURVE HAS TO GO TO
SCHOOL AND WILL BE DISAGREEMENT
ABOUT THAT, THAT I RESPECT
COMPLETELY. GETTING TO ISSUE OF
TRANSPLANT, MOST PATIENTS STILL
ARE NOT GOING TO TRANSPLANT
AFTER CD19 AT CAR SHOP AND
SELECTION BIAS IS THERE WE ARE
BIASED AND HOW WE DO THINGS AND
NO. 2 PEOPLE COME TO US TO AVOID
TRANSPLANT I RUN THE TRANSPLANT
PROGRAM AND THAT IS APPROACH WE
HAVE TAKEN. WE HAD SUCCESS WITH
THAT YOU KNOW HOW THIS WORKS WE
MONITOR B CELL AMRASHIA AND
USEFULNESS IN BONE MARROW.
RELAPSE RATE IS QUITE LOW AND
TOXICITY WE DEAL WITH CYTOKINE
RELEASE SYNDROME AND WE MADE
EARLY OBSERVATIONS ABOUT
ELEVATED CYTOKINES AND THERE
WERE MANY OF THEM. TWO THAT
WERE STRIKINGLY ASSOCIATED WITH
CHALLENGING OUTCOMES GOING TO
INTENSIVE CARE UNIT AND
INTERLEUKIN 6 STORY WAS
INCREDIBLY IMPORTANT AND
INTERFERON GAMA AND MEANS OF
CONTROLLING CRS ON FLY ON
WEDNESDAY AFTERNOON THROUGH
ADVANCED TECH LOGICAL PROCESS
NOTICING IL-6 IS HIGH AND ONLY
CYTOKINE WE HAD A DRUG FOR AND
WHY THAT HAPPENED AND EVERYTHING
ELSE IS RETROSPECTIVELY
UNDERSTOOD AND WE LEARNED WHY
ABOUT MACROPHAGES AND DENDRITIC
CELLS MATTER TO THIS AND
INTERFERON GAMMA IS IMPORTANT
BRINGING US TO ISSUE THAT
PATIENTS WITH CRS HAS ACTIVATION
CIN DROM AND DISCOVER THE IN
LAST YEAR OR 2 AND KNOWN SINCE
FIRST PATIENT AND IS TRUE AND
WAY TO TREAT MS IS TREAT CRMS
AND GREAT WORKING WITH LATER --
ASSOCIATED WITH CDC22 CARS TOESY
REFRACTORY NOT ASSOCIATED WITH
FEVER AND COMPLETE EDITING AND
WE CAN LEARN A LOT FROM THE WORK
AND MAS IS BASICALLY CRS OR CRS
IS MAS AND WE NOW HAVE A TOOL
THAT NEEDS LOTS OF STUDY THAT IS
AVAILABLE TO US WITH PATIENTS
WITH BAD TSOSIE REFRACTORY CMS
AND LOTS TO LEARN ABOUT HOW WELL
THIS WORKS AND TO KNOW THAT
CYTOKINE IS ELEVATED MOST OF US
ARE GETTING CYTOKINE PANELS AND
THIS IS SOMETHING TO LEARN ABOUT
AND SHANNON AND REGINA LOOK BACK
AT TRENDS WE TREAT PATIENT
OUTPATIENT WE ALWAYS HAVE. AND
IF YOU LOOK AT TRENDS OVER TIME
WHAT YOU ARE SEEING IS 80% OF
PATIENTS BEING ADMITTED TO THE
HOSPITAL AND 40% GOING TO ICU IN
EARLY DAYS 2012 OR 2013 IS NOW
DOWN TO HALF OF THE PATIENTS
NEVER IN THE HOSPITAL FOR ONE
MINUTE AND REASSURING PATIENTS
IT IS OKAY TO NOT BE SICK AND
DISEASE PATIENTS AND 12% GOING
INTO ICU GREAT PROGRESS RELATED
TO DISEASE BURDEN GETTING BETTER
AT THIS 12% ARE REALLY SICK
PATIENTS THAT WE WANT TO KNOW
AND BRIEFLY ANDRÉ AND US WERE
TALKING ABOUT EXCEPTIONAL
RESPONDER PROJECT 475 PATIENTS
HAVE BEEN TREATED AT CHOC AND
INSTITUTION WE HAVE 60 PATIENTS
5 OR MORE YEARS OUT WITHOUT
THERAPY AND WE ARE TRYING TO
UNDERSTAND AND REVERSE ENGINEER
THAT AND PRODUCT CHARACTERISTICS
THAT LEAD TO THAT AND LOOKING
FORWARD I PICKED 2028 AND NEW
PATIENT HOSPITAL TOWER IS BEING
BUILT AT CHOC AND SEEMS A LONG
DISTANCE AWAY AND KEEPS GETTING
CLOSER AND CLOSER AND WORRY
ABOUT AT PEDIATRIC ALL WILL IT
BE ONLY OPTION AND WILL WE HAVE
IT AND NOE VAR TIS IS COMPLETE
STATEMENT AND IF YOU IMAGINE
FUTURE MAKING THINGS DIFFERENTLY
FOR OTHER INDICATIONS WILL THAT
KEEP HUGE FACTORIES OPEN AND
MORRIS PLANES AND STEIN TO TREAT
PATIENTS? WHAT ARE OTHER
CHOICES AND THERE ARE FOUR
TRIALS ON HOLD NOW AND WILL SEE
WHETHER THEY WILL PROCEED TO
INDICATION IN PEDIATRICS AND BMS
TRIAL HAS TAKEN A WHILE TO GET
OFF GROUND IN A FULL WAY AND
CAN'T PREDICT WHETHER THIS LICIS
CELL WILL BE AN OPTION FOR US
AND IS VERY EXCITING AND PEDS
LYMPHOMA THAT IS 18 OR ABOVE AS
FAR AS I CAN TELL AND WE DON'T
HAVE THE PRODUCT YET AND WILL
SOON AND THE CELL IS ADULT AND
WILL TAKE PATIENTS MORE THAN 50
KILOGRAMS THAT ARE ADULT SIZED
AND MANUFACTURING I WILL COMMENT
ON BRIEFLY AND NOE VAR TIS HAS
TAKEN A STEP FORWARD IN
MANUFACTURING USING T CHARGE
PROCESS LOTS IS NOT KNOWN AND
VAST MANUFACTURING COUPLE DAYS
MANUFACTURING DOING RELEASE
TAKES TIME NOT LIKE YOU GET
CELLS BACK IN TWO DAYS THAT IS A
STEP FORWARD AND YOU BELIEVE AS
I DO LESS CELLS OUT OF THE BODY
BETTER CELLS YOU GET AT END AND
CHALLENGE IS LACK OF A POTENCY
ASSAY THAT I MENTIONED AND
NOTION IS MANUFACTURER STARTS IN
LAB AND -- TECHNOLOGIES AND
PRODIGY DEVICE IN SHOP AND USED
IN VARIETY OF CLINICAL TRIALS
AND DEVICE THAT I KNOW THAT
HASN'T BEEN USED IN A PATIENT IS
HEADING TOWARDS THAT AND THESE
ALLOW POTENTIAL FOR POINT OF
CARE THAT, AGAIN, MY PERSONAL
OPINION WILL BE LIMITED TO BIG
PLACES THAT HAVE STAFF AND
PAPERWORK TO DO THIS TRIAL AND
DON'T THINK HOSPITALS WILL USE
PRODIGY ANYTIME SOON AND DON'T
SEE THAT AND THAT IS MY PERSONAL
LACK OF VISION AND LOVE THIS
THOUGHT NONCANCER APPLICATIONS
AND WE HAVE ZINTEGLO FROM
BLUEBIRD AND SKY SEWNA FROM ALD
AND FDA APPROVED AND WE WILL SEE
SICKLE CELL PRODUCTS FROM
[INDISCERNIBLE] AND BLUEBERG
THIS YEAR AND IN FRONT OF THE
FDA CAN'T JUDGE WHAT THEY WILL
DO THAT WILL OPEN THAT TO ALL OF
US AND THEY ARE GENE INSERTION
THAT IS BLUEBERG PRODUCT USING
VECTOR AND ACTUAL CRISPR GENE
EDITING AND SURE THAT THE
PRODUCT IS FIRST CRISPR CELL
THERAPY PRODUCT THAT GETS ON TO
THE MARKET AND WILL SEE IF THAT
HAPPENS AND I WILL END WITH THIS
THAT IS A DIAGRAM OF BILLIONS OF
DOLLARS OF INVESTMENT GOING INTO
CAR T DEVELOPMENT AND MESSAGE IS
SIMPLE. WHERE ARE KIDS IN THIS?
WE HAVE TO HOLD THESE
ACCOUNTABLE HAVING PEDIATRIC
PROGRAMS AND IS NOT ENOUGH TO
HAVE A PIP THAT THEY HAVE NO
INTENTION OF ACTUALLY COMPLETING
TO KEEP EMA HAPPY AND PEDIATRIC
QUESTIONS HAVE TO EFFECT WHAT WE
DO FOR PATIENTS IN THE FUTURE
AND INTERACTION IN THE COMPANIES
TO PUSH THEM ON THIS AND WHAT
YOU WILL DO FOR KIDS IN THE
FUTURE AND WE GOT YOU THERE
FIRST AND WHAT WE CAN DO FOR
KIDS IN THE FUTURE AND WITH THAT
I WILL THANK YOU VERY MUCH FOR
YOUR TIME AND --
>> THANK YOU. I'M SHANNON FROM
CHOC AND MY PLEASURE TO
INTRODUCE NEXT SPEAKER PATRICK
MCSWEENEY. I HAVE KNOWN SINCE
HE WAS A TEENAGER. 9 YEARS AGO
IS WHEN WE FIRST MET. PATRICK
WILL TELL YOU HIS STORY THAT IS
REALLY TRULY INSPIRATIONAL.
WHAT I WANT TO TELL YOU IS IN
INTRODUCING HIM IS I WON'T GO
INTO HIS WHOLE STORY. THAT IS
FOR HIM TO TELL. YOU WILL HEAR
THAT HE HAS BEEN IS PARLT OF THE
MEDICAL SYSTEM FOR MANY YEARS.
WHEN HE WENT AWAY TO COLLEGE, HE
DID NOT RUN FROM THAT. HE
DIDN'T TRY TO GET AWAY. HE
ACTUALLY WENT ALL IN TO GIVE
BACK. AND TO BE PART OF THE
IMPROVEMENT OF CARE OF KIDS WITH
CANCER. WHEN HE STARTED COLLEGE
HE BECAME INVOLVED IN A
FUNDRAISING DANCE MARATHON THAT
IS UL RAISE RED. HE WILL TALK
ABOUT THAT A LITTLE BIT. HE
WENT ON TO SERVE ON THE
EXECUTIVE BOARD OF THAT AND
BECAME A PATIENT CARE LIAISON
COORDINATOR AND ACTIVITIES
PUTTING ON FOR CHILDREN WITH
CANCER AND FAMILIES AND HE
GRADUATED FROM UNIVERSITY OF
LOUISVILLE A FEW MONTHS AGO WITH
BSN AND PASSED BOARDS AND WILL
BE STARTING IN HIS NURSING
CAREER VERY SOON GIVING BACK TO
PATIENTS LIKE HIM. IT IS MY
PLEASURE. I THINK THAT INSPIRED
TITLE FOR THE CONFERENCE IS A
GOOD ONE. I KNOW YOU WILL BE AS
INSPIRED AS I HAVE BEEN BY HIM
FOR NINE YEARS AND WELCOME,
PATR
PATRICK.
>> [APPLAUSE].
>> JUST A MOMENT.
>> ONLY THING MIGHT HAVE MISSED
IS I INITIALLY TRIED TO RUN FROM
EVERYTHING AND STARTED OFF
COLLEGE AS A MECHANICAL
ENGINEER. LOOK WHERE WE ARE NOW
BECAUSE NOW I CAN SAY THAT I'M A
REGISTERED NURSE. I HAVE
PROFESSIONAL CREDIBILITY OF
SPEAKING TODAY A LITTLE MORE
THAN 18.5 YEARS BEING A
PEDIATRIC ONCOLOGY PATIENT
DIDN'T GIVE ME ENOUGH
CREDIBILITY. BEFORE OFFICIALLY
STARTING NO THE TO SOUND LIKE AN
OSCAR SPEECH I HAVE TO THANK
PEOPLE. DR. WONG FOR THE
INVITATION AND DR. GRUPP AND
ENTIRE TEAM THAT TOOK CARE OF ME
AT CHOC AND NIH FOR ALLOWING ME
TO SPEAK AND FINALLY MOST
IMPORTANTLY MY MOTHER.
SHE IS A NURSE HERSELF AND SHE
UNDERSTANDS THE IMPORTANCE OF
DOCUMENTATION AND KEEPING A
RECORD OF EVENTS AND KEPT A
2-DECADE LONG RECORD WHAT
HAPPENED TO ME AND TALKING ABOUT
CAR EXPERIENCES READING THAT IS
HOW I GATHERED LOTS OF MY
INFORMATION.
IN FACT FAIR YEARS I RECEIVED
CAR MADE FOR 123 PAGE WORD
DOCUMENT HARD TO FIT INTO 15
MINUTES WILL DO MY BEST AND
APOLOGIZE IF I GO A LITTLE OVER.
THANKS FOR SAVING ME TIME. MY
STORY BEGAN IN APRIL 2004. I
GOT STREP THROAT THREE TIMES AND
MY MOM TOOK ME TO LOCAL
PEDIATRICIANS OFFICE TO GET
BLOOD DRAWN FROM THERE I WAS
SENT TO CHILDREN'S HOSPITAL AND
DIAGNOSED WITH ALL AT AGE OF 5.
AFTER INITIAL DIAGNOSIS I BEGAN
CHEMOTHERAPY RECEIVING 38 MONTHS
OF IT AND COMPLETED
CHEMOREJIMMEN IN 2007 NO THE
BEFORE EXPERIENCING A CEREBRAL
BLOOD CLOT AND PANCREATITIS AND
AFTER BEING IN REMISSION FOR 4.5
YEARS I RELAPSED FIRST TIME IN
APRIL OF 2010 AND AFTER FIRST
RELAPSE WE CONSULTED DOCTORS AT
CINCINNATI CHILDREN'S TO GET
OPINIONS ON IF I SHOULD RECEIVE
A BONE MARROW TRANSPLANT OR
RECEIVE MORE CHEMOTHERAPY. THEY
RECOMMENDED I RECEIVE ADDITIONAL
CHEMOTHERAPY DUE TO FACT IT WAS
A LATE RELAPSE. I ENDURED
ANOTHER 26 MONTHS OF
CHEMOCOMPLETING SEC REJIMMEN IN
2012.
TIME SPENT IN SECOND REMISSION
WAS SHORTER THAN THE FIRST AND
RELAPSED A SECOND TIME AND
KNOWING CHEMOTHERAPY WASN'T MY
LONG-TERM SOLUTION WE WENT TO
CINCINNATI FOR A BMT AND I WAS
PREPPED WITH MORE CHEMOAND BODY
RADIATION AND RECEIVED
TRANSPLANT MAY 14TH, 2013 WITH
MY OLDER BROTHER JOEY BEING A
PERFECTLY MATCHED DONOR AND KEPT
ME IN REMISSION FOR 8 MONTHS OR
SO I RELAPSED FOR THE THIRD TIME
IN MARCH OF 2014 AND FEELING AS
THOUGH WE HAD RUN OUT OF OPTIONS
CINCINNATI POINTED US IN
DIRECTION OF CHOC AND 2019
CLINICAL TRIAL GOING ON AND FEW
WEEKS AFTER THIRD RELAPSE WE
WERE OFFICIALLY ACCEPTED INTO
THE CTL019 STUDY ON APRIL FIRST,
2019 THAT WOULD HAVE SUCKED IF
IT WAS AN APRIL FOOL'S JOKE AND
IT WASN'T AND MOM AND DAD AND I
FLEW TO PHILLY A FEW DAYS LATER
AND HAD T-CELLS EXTRACTED APRIL
EIGHTH AND RETURNED HOME ON 9TH
T-CELL GROWTH WAS SEEN IN LAB BY
MAY FIFTH AND ENTIRE FAMILY AND
INCLUDING TWO BROTHERS FLEW
BLACKING TO PHILLY JULY 27TH
LATER THAT YEAR BETWEEN THESE
DATES I WAS DIAGNOSED WITH TYPE
1 DIABETES THAT WILL MAKE FOR
COMPLICATIONS IN THE FUTURE
COMING TO CYTOKINE STORM
INFLAMMATION AND EFFECT IT'S
CAUSED ON MY BLOOD TRIGGERS AND
EFFECTS THAT [INDISCERNIBLE]
WOULD CAUSE.
I RECEIVED T-CELLS FIRST TIME
AUGUST 25TH, 2014 AND I BECAME
PATIENT NO. 34 AND WHAT I
EXPERIENCED WASN'T TERRIBLE AND
IN-PATIENT TWICE AND BOTH TIMES
FOR TWO DAYS AND I WAS ALLOWED
TO GO BACK TO SCHOOL IN PERSON
AFTER A YEAR AND A HALF OF HOME
SCHOOLING AND BEGAN MY SOPHOMORE
YEAR AT HIGH SCHOOL IN
SEPTEMBER. I HAD AN IPAD TO
WORK ON AND INFORMATION WILL BE
RELEVANT LATER IN THE SPEECH.
NOVEMBER 4TH, 2014 NO T-CELLS
WERE DETECTED AND B CELLS WITH
CD19 WERE PRESENT AND THIS
CHANGE REQUIRED MOM AND I FLY TO
PHILLY NOVEMBER 9TH FOR A
BOOSTER SHOT OF T-CELLS AND FLY
HOME TO LOUISVILLE ON NOVEMBER
21ST THIS BOOSTER HAD NO EFFECT.
AFTER A FEW CONSULTS TOLD TO DO
HUMANIZED CAR TRIAL. JANUARY
26TH, 2015 BACK GETTING T-CELLS
EXTRACTED FOR THE SECOND TIME WE
WR BACK IN PHILLY MAY 17TH AND
BY THAT THURSDAY 21ST, WE FOUND
OUT I RELAPSED FOR THE 4TH TIME.
FORTUNATELY WE WERE UP IN PHILLY
AND I RECEIVED HUMANIZED CAR
CELLS AS PLANNED MAY 26TH AND I
BECAME PATIENT NO. 4 IN HUMANIZE
THE CAR TRIAL AND I WAS
IN-PATIENT FOR 4 DAYS AND BAF IN
LOUISVILLE AFTER 31 DAYS ON JUNE
16TH. I GOT DRIVER'S PERMIT AND
WENT TO CAMP FOR A WEEK AND GOT
5-WEEK T-CELLS DONE AT CAMP AND
BROTHERS AND DAD AND I WENT TO
SEE A SHOW -- A FRIEND OF MINE
BATTLING ALL AND UNDERGOING CAR
HIMSELF AND RECEIVED HIS
TREATMENT IN CINCINNATI AND
NEVER FULLY GOT HIM IN EMISSION.
HE WAS BEN AND HE DIED AND WE
WERE SAME AGE AND DIAGNOSIS AND
HE DIDN'T MAKE IT. I DID.
GETTING BACK TO CAR WE FLEW TO
PHILLY SEPTEMBER 9TH I RECEIVED
NOT ONLY FIRST BOOSTER DOSE OF
HUMANIZED CELLS ON ELEVENTH AND
FIRST BOOSTER DOSE OF HUMANIZED
CELLS EVER GIVEN NO BLASTS WERE
EVER EVIDENT IN MY BODY AS OF
SEPTEMBER 7TH. CHEMOHAD NO
EFFECT ON MY B CELLS AND WAS
DECIDED MOVING FORWARD WHEN I
GOT BOOSTER DOSES CONDITIONING
CHEMONEED TODAY BE GIVEN. THAT
IS WHAT HAPPENED. WHEN WE FLEW
BACK TO PHILLY NOVEMBER 15TH AND
CONDITIONING CHEMOSTARTED 16TH
AND FINISHED 19TH AND SECOND
HUMANIZED BOOSTER DOSE WAS
ADMINISTERED NOVEMBER 9TH, 2015.
WE SPENT THANKSGIVING AS A
FAMILY BECAME A MEMORABLE
EXPERIENCE FOR ALL OF US WE WERE
SPENDING THANKSGIVING IN
PHILADELPHIA AND WENT TO HARD
ROCK CAFE FOR THE BIG MEAL. I
HAD A CHEESEBURGER AND FRIES AND
TWO DAYS LATER I TRIED FIRST
PHILLY CHOOEZ STEAK. ALWAYS
BEEN A PICKY EATER TOOK ME A
WHILE B CELLS WERE ABSENT AS OF
DECEMBER 21ST, GOOD NEWS MOM
CAME TO ROOM MONTH LATER JANUARY
23RD AND BEGAN TO SPEAK TO ME
STARTING WITH THIS NEVER GETS
ANY EASIER I CUT HER OFF AND I
RELAPSED B CELLS ARE GOING SHE
WAS CAUGHT OFF GUARD WHICH
WASN'T THE CASE MY FRIEND MEGAN
DIED THAT DAY I JUMPED TO
CONCLUSION I RELAPSED BASED OFF
FIRST 5 WORDS OUT OF HER MOUTH
WILL TELL YOU SOMETHING NEXT
VISIT TO PHILLY EARLY MARCH
SEEING B CELL INDEED RETURNED
AND DURING VISIT WITH DR. MAUDE
ON 7TH I ASKED HER WHAT IF
TREATMENT DIDN'T WORK? SHE
COULDN'T GIVE DEFINITIVE ANSWER
AND MOM BROUGHT UP PD1 TARGETING
DRUGS AND DR. MAUDE SMILED AND
EVENTUALLY HAD A TRIAL ON
EFFECTIVENESS ON INHIBITORS TO
COMBAT WITH T-CELLS TO COMBAT
LUKEMIA AND CONVERSATION MARCH
16TH 2016 I RECEIVED A BOOSTER
T-CELL INFUSION GOING BACK TO
SPEECH TO BRING UP A POINT THAT
MY SCHOOL USED IPADS I WAS
FACETIMING IN U.S. HISTORY CLASS
AS I RECEIVED 6TH TOTAL T-CELL
INFUSION. DR. GRUPP AS HE
PUSHED CELL IN MADE QUICK REMARK
HE IS LEARNING HISTORY AND
MAKING HISTORY.
FAST FORWARD 6 MONTHS TO
SEPTEMBER 2016 AND I RECEIVED A
BONE MARROW BIOPSY IN LP AND
RESULTS CAME BACK AND FOUND OUT
I RELAPSED FOR FIFTH TIME AND
COMMENT WAS I'M DISAPPOINTED BUT
NOT SURPRISED.
I SHOULDN'T BE EXPECTED TO
RELAPSE WITH CANS ERR WHEN I'M
17 AND SHOULDN'T BE EXPECTING
TREATMENTS TO FAIL AND WHEN
COMES TO CANCER BEING SO
CONDITIONED TO RELAPSING ALL I
CAN SAY IS I'M SDPOIBTED IS
REMARKABLY HORRIBLE.
MY T-CELLS WERE COLLECTED FOR
THIRD TIME I WAS BACK TO SCHOOL
PLAYING BASKETBALL SPENDING TIME
WITH FRIENDS AND SOMETHING A 17
YEAR OLD SHOULD BE DOING AND
BACK IN PHILLY BY 6TH AND
CONDITIONING STARTED ON 7TH AND
-- I WAS ADMITTED TO 3 NORTH
WITH FEVER ON 18TH EXPERIENCING
WORST CYTOKINE STORM IN 7 DOSES
OF T-CELLS I RECEIVED UP TO THIS
POINT AND EXPERIENCED NAUSHIA
DRIVE HEAVING 103° FEVERS
VIGOROUS SHAKING AND CHILLING
AND TYPE 1 DIABETIC EXPERIENCED
SEVERAL BLOOD SUGAR ISSUES TOUGH
TO FIND BALANCE CONSIDER
INFLAMMATION WOULD RAISE SUGARS
WITH LACK OF FOOD INTAKE
DECREASE MY INSULIN. OUT OF THE
HOSPITAL ON 23RD AND MOM AND I
EXPERIENCED SECOND THANKSGIVING
IN A ROW FOR THE THIRD TIME.
THIS TIME DAD AND BROTHERS
WEREN'T ABLE TO JOIN US. I WANT
TO BE HOME FOR CHRISTMAS.
THANKFULLY MY MOM AND I WERE
ABLE TO HAVE SOME FUN THE
FOLLOWING DAY ON 28TH AND I WAS
ABLE TO GO TO PACKERS EAGLES
MONDAY NIGHT FOOTBALL GAME. FOR
EAGLES FANS, I WAS ROOTING FOR
THE PACKERS THEY ARE KIND OF MY
TEAM IRONIC PART WE GOT TICKETS
FROM EAGLES ORGANIZATION.
SO, I COULDN'T BE WEARING
PACKERS GEAR WHEN YOU ARE GOING
ON THE SIDE LINE BEFORE THE GAME
MEETING THE EAGLES PRESIDENT AND
GETTING PHOTOS I WORE A GREEN
PACKERS HOODIE THREW A GREEN
EAGLES SHIRT OVER IT GOT PREGAME
SIDELINE EXPERIENCE AND
PROCEEDED TO TAKE EAGLES SHIRT
OFF GETTING TO SEATS FIRST ROW
50 YARD LINE AND FANS BEHIND US
WERE NOT HAPPY WITH ME AND
PACKERS WON SO I HAD A GOOD
TIME.
VERY NEXT DAY ON 28TH I RECEIVED
KEY TRUTH TO THE FIRST TIME P.
D1 INHIBITOR DR. MAUDE TALKED
ABOUT A LITTLE OVER 8 MONTHS
PRIOR. DR. MAUDE SPECIFIED IT
IS SUCCESSFUL IN TREATING LUNG
CANCER AND MELANOMA BUT WANT
CONCRETE DATA WITH LEUKEMIA
REGARDING EFFECTIVENESS AND
EXPERIENCED NO SIDE-EFFECTS FROM
INFUSION DOWN 12 POUNDS FROM
INITIAL CYTOKINE STORM AS OF
NOVEMBER 30TH ISSUE FOR ME FOR
THAT WAS WEIGHT LOSS RESET
PHYSICAL STRENGTH AND STAMINA
MAKING BASKETBALL THAT WINTER
DIFFICULT DIDN'T SEEM LIKE A
MINOR ISSUE FOR ME BUT IT WAS
BIG AND SPORT AND SOCIAL
INTERACTION WITH FRIENDS MADE ME
FEEL NORMAL AND SUPPORTED WISH
TO BE HOME BEFORE CHRISTMAS CAME
TRUE HOME BY 20TH AND BACK IN
PHILLY STARTING CHEMO-6TH
RECEIVED 4TH BOOSTER AND MY
FIFTH BOOSTER TOTAL AND BY THIS
POINT THERE WAS SMALL AMOUNT OF
T-CELLS EVEN BEFORE BOOSTER DR.
MAUDE EXPLAINING TO US IT WAS
MOST PROBABLE CAUSE OF T-CELL
PERSISTENCE WITH THAT IN MIND I
RECEIVED ANOTHER DOSE TWO WEEKS
LATER AND WAS BACK HOME ON 28TH
I WAS RECEIVING EVERY 4 WEEKS
AFTER THIS TOLD EACH APPOINTMENT
IN JULY THAT EACH DOSE INCREASES
COMPLICATIONS IT WAS DOING WELL
FOR ME I CONTINUE TODAY RECEIVE
IT EVERY 4 WEEKS AND RECEIVED
13TH DOSE OF IT OCTOBER 13TH.
AFTER THAT, I BEGAN TO
EXPERIENCE AUTO IMMUNE
COMPLICATIONS WE HAD BEEN WARNED
ABOUT IN JULY AND OCTOBER 21ST I
EXPERIENCED SEVERE GI ISSUES
VOMITING EVERY DAY NAUSEOUS AND
QUICKLY FILLING UP WAKING UP TO
VOMIT HAVING DIARRHEA AND NO
APPETITE AND KEEP IN MIND PRIOR
TO EFFECTS I WAS 65 KILOS AND I
GOT SCOPED ON NOVEMBER 21ST WITH
A SCOPE DETECTING EARLY STAGES
OF COLITIS IN INTESTINES COLITIS
IS SIDE EFFECT OF
[INDISCERNIBLE] AND DUE TO
VOMITING THAT HAPPENED OVER
COURSE OF PREVIOUS MONTH AND BY
DECEMBER 1ST, 6 WEEKS LATER I
WAS DOWN 9 KILOS, 56.1 AND GOOD
NEWS I DIDN'T HAVE TO GET MORE
KEY TRIDA DR. MAUDE PLANNED TO
STOP IT AT END OF DECEMBER
ANYWAY. IT WAS DISCONTINUED A
FEW WEEKS EARLIER THAN EXPECTED.
NOW, THREE WEEKS AFTER THE SCOPE
ON DECEMBER 13TH, BONE MARROW LP
AND VERY IMPORTANT MILESTONE IN
CAR PROGRAM MOVED INTO LONG-TERM
PROTOCOL IN THREE YEARS I HAD
BEEN RECEIVING CAR. HUGE
MILESTONE REACHED FEW DAYS LATER
HIT WITH NEWS THAT MRD RESULTS
WERE INCONCLUSIVE ASKED TO FLY
TO PHILLY JANUARY 23RD 2018
REPEAT BONE MARROW ON 4TH AND
STARTED ENGINEERING CLASSES NEXT
WEEK STARTING 2 EIGHTH. I KNEW
HOW LONG IT TOOK FOR RESULTS TO
GET BACK AND LIVED BY MYSELF FOR
MY FRESHMAN YEAR THIS IS
IMPORTANT MY MOM SHOULD HAVE
CALLED ME SOMETIME THAT WEEK
TELLING ME I WAS IN REMISSION
SHE WOULD NEVER CALL ME WITH BAD
NEWS KNOWING I WAS BY MYSELF AND
SHE DIDN'T CALL. I HAD MY
ANSWER WITH HER RESULTS BONE
MARROW BEFORE SHE EVEN TOLD ME
AND I WENT HOME FRIDAY AFTER
CLASS FIRST QUESTION OUT OF MY
MOUTH WAS I'M GUESSING I
RELAPSED SHE NODDED AND SHOOK
HEAD YES AND I MADE LEMONADE OUT
OF LEMONS WITH INFORMATION AND
MADE VIDEO ANNOUNCING RELAPSE IN
EARLY FEBRUARY FOR A DANCE
MARATHON RAISE RED THAT RAISES
MONEY FOR PEDIATRIC CANCER AND
USED VIDEO TO FUNDRAISE FOR
ORGANIZATION SETTING IT TO EARN
$5,000 AND ACHIEVED GOAL IN LESS
THAN 24 HOURS AND MADE SECOND
VIDEO LETTING PEOPLE KNOW I WAS
INCREASING IT TO $25,000. WENT
FROM NIGHT OF 23RD TO NOON ON
24TH AND ASPECT OF HOW THIS IS
IMPORTANT IS I WAS SUPPOSED TO
BE BACK UP IN PHILLY ON 18TH
AFTER WHAT I ACCOMPLISHED I WAS
NOT MISSING 18 HOUR DANCE
MARATHON. I ASKED DR. MAUDE IF
I COULD PUSH ARRIVING TO PHILLY
BACK A WEEK. SHE AGREED.
WHEN I LEFT FOR PHILLY ON 2
FIFTH I LEFT ALL SMILES I
EXPERIENCED THE DANCE MARATHON
FOR FIRST TIME AND RAISED OVER
$32,000 FOR PEDIATRIC CANCER AND
BLOOD DISEASES AND COMBINATION
OF HUMANIZED CELLS AND KEY
TREEDA KEEPING ME IN REMISSION I
RECEIVED CELLS ONE MORE TIME AND
USED TREATMENT AS BRIDGE TO
SECOND [INDISCERNIBLE] BACK IN
CINCINNATI RECEIVED 9TH AND
FINAL DOSE OF CAR ON MARCH FIFTH
2019 NEED FOR THIS BECAME MORE
EVIDENT WHEN DAY 28 BONE MARROW
STILL REVEALED B CELLS EVEN
AFTER CHEMOAND FIRST TIME IT
HAPPENED BY DAY 28 WHEN
RECEIVING CONDITIONING
CHEMOPRIOR TO T-CELL INFUSION
AFTER T-CELLS I RECEIVED SECOND
BMT MAY 15TH 2018 AND BEEN IN
REMISSION EVER SINCE AND
APPROACHING 5 YEAR MARK THIS MAY
AND MARK I NEVER HIT SINCE FIRST
DIAGNOSED IN 2004 AND TO SAY I'M
ECSTATIC IS AN UNDERSTATEMENT.
WHILE THAT CONCLUDES MY HISTORY
OF TREATMENT AND OF CAR NOW IS
WHERE I EXPAND UPON WHAT CAN BE
DONE TO IMPROVE CLINICAL TRIALS
IN THE FUTURE. BEST WAY FOR US
AS DOCTORS AND CAREGIVERS TO DO
THIS IS BY HEAVILY FOCUSING ON
PSYCHOSOCIAL ASPECT OF CARE
ESPECIALLY IN CLINICAL TRIALS.
[INDISCERNIBLE] IS STUDYING
LIMITED INFORMATION AVAILABLE
ABOUT PSYCHOSOCIAL ASPECT OF
CARE AND FELT SHE WAS A GOOD
RESOURCE TO UTILIZE WHEN
ADDRESSING THIS THEME TODAY.
SHE PROVIDED ME WITH TWO
ARTICLES TO HELP SPUR FOLLOWING
TRAINS OF THOUGHT. THE WHOLE
REASON I WAS ABLE TO GET THROUGH
CAR TREATMENT FOR FOUR YEARS BY
FOUR RELAPSES DURING THOSE YEARS
IS BECAUSE OF HOW WELL SUPPORTED
I WAS THROUGH TREATMENT AND
POSITIVE EXPERIENCES THAT I
RECEIVED THROUGH TREATMENT.
SURE. I WAS OVER 650 MILES AWAY
FROM HOME IN LOUISVILLE BUT HAD
FAMILY WILLING TO DRIVE TO
PHILLY TO SPEND THANKSGIVING
WITH ME AND MY MOM AND
THROUGHOUT TREATMENT EVEN IF NOT
GOING THROUGH SAME TREATMENT AND
FRIENDS LIKE BEN AND MEGAN AND I
HAD FRIENDS IN SCHOOL THAT WOULD
FACETIME ME DURING CLASS KEEPING
ME UP TO DATE WITH MATERIAL WE
WERE COVERING SO I WOULDN'T FALL
TOO FAR BEHIND AND IN PHILLY I
HAD SEVERAL POSITIVE EXPERIENCES
ALLOWED TO GO TO EAGLES GAMES
AND MOVIES AND THINGS CONSIDERED
NORMAL. I TOURED THE CITY
SEEING RING TERMINAL
INDEPENDENCE HALL AND LIBERTY
BELL AND ROCKY AND MY ONCE
OPINIONS AND INPUT WERE ALL
VALUED THROUGH THIS PROCESS AND
EFFECTED MY CARE. I HAD SOME
CONTROL.
MY AUTONOMY WAS RESPECTED AND
VOICE WAS HEARD. EVEN WHILE I
WAS JUST A TEENAGER. BY GETTING
CAR OUTPATIENT I WAS ABLE TO
ALMOST MAKE A VACATION OUT OF
EACH TIME I CAME UP HERE.
FRIENDS OF MINE RECEIVED CAR IN
CINCINNATI AFTER THEY GOT A
TRIAL OF THEIR OWN AND SPENT ALL
6 WEEKS OF IN CAR PATIENT WHY?
SAFETY HAS BEEN ESTABLISHED AND
FOR A TREATMENT IN AN OUTPATIENT
SETTING CLINICAL TRIAL OR NOT
WHY KEEP ADOLESCENT IN-PATIENT
SO LONG AND ISOLATE THEM SO LONG
AS NECESSARY. I CAN'T IMAGINE
HOW HORRIBLE MY EXPERIENCE WOULD
HAVE BEEN IF I WAS 650 MILES
AWAY FROM HOME IN IN-PATIENT
EACH OF THE NINE TIMES I
RECEIVED CAR. SOME FAMILIES AND
PATIENTS DON'T HAVE LUXURY
ENJOYING TIME IN THE KRILTY THEY
RECEIVED TREATMENT LIKE I DID.
THEY DON'T HAVE SUPPORT OR
ACCESS TO RESOURCES TO HELP
NEEDED TO MAINTAIN GOOD
PSYCHOSOCIAL INTEGRITY AND CAN'T
BE EXPECTED PATIENTS FAMILIES
SOMEHOW HEAR ABOUT RESOURCE
BUSINESS CHANCE AND UPON
ENTERING TRIAL ACING CRESS TO
CERTAIN KNOWLEDGE AND RESOURCES
BE GIVEN TO THEM TO LOWER
EMOTIONAL AND MENTAL BURDEN
COMING WITH NOT ONLY A DIAGNOSIS
BUT BEING IN A CLINICAL TRIAL
CANCER ITSELF IS SCARY ENOUGH
ADD IN A TREATMENT STILL YET TO
BE USE THE WIDELY IN PRACTICE
AND IS STILL BEING STUDIED AND
WHOLE NEW LAYER OF FEAR IS ADDED
TO THE DISEASE AND TO QUOTE
ARTICLE RESEARCHING EXPERIENCES
WITH CHILDREN WITH CANCER
CONSIDERATIONS FOR PRACTICE AND
FEAR OF CANCER PAIRED WITH
ADDITIONAL FEAR OF RECEIVING A
NEW TREATMENT MAKES CHILDREN
ADOLESCENCE DOUBLEBLY VULNERABLE
AND MONSTER UNDER THE BED
DOESN'T SUDDENLY SEEM IMAGINARY
ANYMORE NAUSEOUS UNDER THE BED
FEAR IS TANGIBLE EVERYWHERE IN
THE ROOM TERRIFYING THE CHILD,
PARENT AND ENTIRE FAMILY AS THEY
ENTER TREATMENTS WITH UNKNOWN
RESULTS.
AS DOCTORS AND CARETAKERS WE ARE
THERE TO TELL THEM POTENTIAL
SIDE-EFFECTS TO EXPECT FROM THE
TREATMENT AND WHAT THE TREATMENT
IS SUPPOSED TO ACCOMPLISH. ARE
WE GIVING THEM RESOURCES TO
MENTALLY HANDLE TREATMENTS AND
SIDE-EFFECTS? ARE THEY
SUPPORTED? CAN THEY HANDLE
MENTAL BURDEN? DO THEY
UNDERSTAND WHAT THEY ARE BEING
TOLD SOMETIMES TOO MUCH
INFORMATION TO BE PROCESSED AT
ONCE IF A DECISION DOESN'T HAVE
TO BE RUSHED DON'T RUSH IT
EXPLAIN TO PARENT AND PATIENT
WHAT FUTURE HOLDS AND MAKE SURE
IT IS UNDERSTOOD NOT EXPECTED
PARENT COULD EXPLAIN TO CHILD
WHAT IS GOING ON MY MOM COULD
BUT THAT IS NOT PARENTS JOB
BRING RIGHT PEOPLE INTO
CONVERSATION WHETHER A
PSYCHIATRIST OR SOCIAL WORKER OR
CHILD LIKE SPECIALIST OR
CHAPLAIN BRING THEM IN THE ROOM
TO MAKE CONVERSATION BETTER AND
TREATMENT IS UNDERSTOOD AND
PATIENTS ONCE INPUT IS TAKEN
INTO ACCOUNT AND SEEMS NEEDED
HAVE PARENTS STEP OUT SO PATIENT
COULD GIVE INPUT AND EXPERIENCE
WITHOUT PARENTAL PRESSURE AND
PATIENT CONVERSATION WAS
DIRECTED TO ME AND I WAS
LISTENED TO ENCOURAGED ME TO
MOVE FORWARD ATTEMPTING NEW
TREATMENT AND SAME SHOULD BE
DONE FOREVERY CHILD. IT IS
IMPORTANT TO PRIORITIZE THESE
ALONGSIDE THE TREATMENT ITSELF
AND NOT JUST EVALUATE SUCCESS OF
TREATMENT BASED ON HOW EFFECTIVE
IT IS AGAINST THE DISEASE.
WHILE I'M AWARE OF LIMITATIONS
OF HIPAA BEST SUPPORT COMES FROM
OTHERS EXPERIENCING SAME
TREATMENT AS PATIENT AND THERE
IS A WAY TO CONNECT PATIENTS IN
THE TRIAL WHERE THEY CAN CONSENT
TO SPEAK TO OTHER FAMILIES GOING
THROUGH THE TRIAL OR WHO HAVE
GONE THROUGH IT AND GET
CONNECTED THROUGH THE HOSPITAL
AND KNOW THIS PUTS MANY CHILDREN
AND PARENTS AT EASE AND SPEAKING
TO THEM RELATING TO EXPERIENCES
TO AND WHEN EXPERIENCE IS A NEW
AND FRIGHTENING ONE AT THAT.
THAT IS ONE OF THE BEST THINGS
FOR CHILD AND FAMILY WHO HAS
CANCER TO NOT FEEL ISOLATED AND
TO BE ABLE TO ELATE TO SOMEONE
ELSE IN SIMILAR SHOES BECAUSE
ONLY PEOPLE WHO UNDERSTAND THE
PATH ARE PEOPLE WHO HAVE WALKED
IT.
I MIGHT BE YOUNG AND NAÏVE
COMING TO OTHER SIDE. I HAVE
ONLY BEEN A NURSE TWO MONTHS BUT
THESE ARE MY PERSPECTIVES AND
WHAT TO FOCUS ON TO IMPROVE
CLINICAL TRIALS AND BEGINNING TO
WRAP THIS UP FOLLOWING FAMILY
PERSPECTIVE COMES FROM MY
BROTHER ALEX. I INCLUDED IT
BECAUSE TREATMENT IN THE PATIENT
EFFECTS THE PATIENTS FAMILY AND
THEIR PERSPECTIVE SHOULDN'T BE
LEFT OUT. ALEX GOES ON TO SAY I
THINK ABOUT PATRICK AND HAVING
NO ONE REMOTELY CLOSE TO HIM TO
KEEP HIM COMPANY AND FROM GOING
STIR CRAZY. TRAPPED IN A
HOSPITAL ROOM IN AN UNFAMILIAR
CITY AT ANL WHERE ANGER SURELY
WAS AT FOREFRONT OF HIS EMOTIONS
WHILE HE COULDN'T LIVE A NORMAL
LIFE BUT AT LEAST WHY HE
COULDN'T BE CLOSER TO HOME WHERE
HE COULD WELCOME VISITORS,
FRIENDS, FAMILY, ET CETERA. I
THINK ABOUT MOM, FINDING NEW
PATHS AND AREAS TO WALK AND
WITHOUT ANYONE ABLE TO GO ON
WITH HER AND BE THAT SHOULDER TO
LEAN ON AND WHAT PARENT NEEDS TO
LISTEN TO, TO GET HER THROUGH
TOUGH TIME AND MUCH LESS TAKING
CARE OF YOUNGEST SON IN
UNFAMILIAR TERRITORY AND
UNFAMILIAR MEDICINE. BY SAME
TOKEN THAT IS THE LIFE I HAVE
KNOWN FORGREAT MAJORITY OF MY
CHILDHOOD AND ADOLESCENCE. IT
WAS NOT EASY BUT WAS NORM AND
WHAT MADE IT WORTH IT IS BLIND
FANL AND HOPE THIS NEW CUTTING
TREATMENT WOULD BE KEY TO ALLOW
PATRICK NORMALCY LIVING OUT
INCREDIBLE STORY. LOOK AT HIM
LEAVING THE CITY AGAIN TO
EDUCATE AND INFORM AND INSPIRE
SO MANY OTHERS THAT WHEN IN DARK
AND STORMY SUNSHINE IS CLOSER
THAN ONE MAY THINK.
FOR ALL FUTURE PATIENTS, I HOPE
THAT SUNSHINE IS INCREDIBLY
CLOSE. AS CAREGIVERS, WE ARE
THE ONES WHO CAN BRING THAT
SUNSHINE TO THEM. WE HAVE TO
THINK LIKE A KID IN ORDER TO
TREAT A KID.
INNOVATION AND KNOWING VALUE OF
GREAT CARE AND WHY SWITCH FROM
ENGINEERING TO NURSING STARTING
IN 12 DAYS I WILL WORK AT
CINCINNATI CHILDREN'S ON BONE
MARROW TRANSPLANT AND EVERYONE
TREATED ME HAS BEEN THAT
SUNSHINE FOR ME AND I KNOW
EVERYONE IF IN THE ROOM HAS BEEN
THAT SUNSHINE FOR SOME PATIENT
AT SOME POINT.
IT IS IMPORTANT TO REALIZE THERE
IS ALWAYS ROOM IMPROVEMENT.
NEXT DAY CAN ALWAYS BE BETTER
AND MORE WE CAN IMPROVE THE
FUTURE OF CLINICAL TRIALS THE
BRIGHTER THE FUTURE WILL BE.
THANK YOU FOR ALLOWING ME TO
GIVE MY PERSPECTIVE.
>> WE ARE HERE FOR PATRICK AND
EVERY PATIENT WHO FOLLOWED AFTER
HIM I CAN'T BEGIN TO THANK YOU
FOR STARTING THE CONFERENCE OFF
THIS WAY.
WITH THAT WE WILL TRANSITION TO
SESSION 1 AND YOU ARE OUR FIRST
SPEAKER AND IF PANELISTS AND
CHAIRS COULD COME UP TO THE
STAGE, THAT WOULD BE WONDERFUL.
>> FIRST OF ALL, IF WE ARE
COMING TO BE INSPIRED GOALS HAVE
BEEN ACHIEVED AND WE CAN GO HOME
NOW. THANKS FOR THOSE POWERFUL
WORDS. AS WE TRANSITION, I WANT
TO TAKE A MOMENT TO RECOGNIZE
NIRALI FOR HER HER KUL AN AN
EFFORTS IF IN ENGINEERING THIS
BRILLIANT CONFERENCE AND
EVERYBODY APPRECIATES HOW SHE
APPROACHED EVERY DETAIL WITH
UTMOST THOUGHT AND PRECISION AND
THINK CONFERENCES LIKE THIS ARE
USUALLY ORGANIZED BY ABOUT A
TEAM OF 50.
THIS WAS ORGANIZED BY A TEAM OF
1 AND I LOOK AROUND AND
CONGRATULATE YOU ON BRINGING
THIS COMMUNITY TOGETHER IN
PERSON.
>> [APPLAUSE].
>> I'MLY ORA.
WE KNOW ACROSS CLINICAL TRIALS
AND COMMERCIAL EXPERIENCE EVENT
FREE SURVIVAL HAS REALLY EMERGED
TO BE RELIABLY ABOUT 50%.
WE HAVE SEEN FROM 3 AND 5 YEAR
FOLLOW UP DATA AND THAT STEVE
PRESENTED THAT CURVES REALLY
PLATEAU.
THIS LEAVES STILL A SURVIVAL GAP
THAT NEEDS TO BE CLOSED. MOVING
TOWARDS ENGINEERING TOWARDS NEXT
GENERATION CARS WE WILL HEAR
OVER THE DAY ABOUT PATH
INCLUDING IDENTIFYING NOVEL
TARGETS GENERATING CARS WITH
MULTISPECIFICITY AND ENGINEERING
CARS TO BE OPTIMIZED FOR
PERSISTENCE. THEY ARE CRITICAL
PATHS AND ARE ECONOMICALLY
TAXING AND REQUIRE TIME AND
RESOURCE HEAVY FOR DEVELOPMENT
AND SCALABILITY. WHAT IF WE
COULD COLLECT OR USE EXISTENT
DATA TO OPTIMIZE AVAILABLE CAR
PRODUCTS INCREMENTALLY IMPROVING
CLINICAL OUTCOME AND CHALLENGE
IS SINCE COMMERCIALIZATION AND
SIGNIFICANT PATIENT EXPERIENCE
HAS AMASSED AND DATA HASN'T
SYSTEMATICALLY BEEN COLLECTED OR
EFFECTIVELY MINED AND LED TO
EMERGENCE OF MULTIPLE
COLLABORATIVE EFFORTS WITH GOAL
TO LEVERAGE UNTAPPED CLINICAL
DATA WE WILL HEAR FROM LOTS OF
GROUPS DURING THE DAY AND PART
OF IMPACT HAS BEEN IDENTIFYING
CLINICAL VARIABLES THAT IMPACT
OUTCOMES THAT HAVE BEEN BROUGHT
BACK TO THE PATIENT. I WILL
DISCUSS SOME OVER IN THE NEXT
COUPLE OF MINUTES.
PEDIATRIC REAL WORLD CAR
CONSORTIUM IS A FORUM FOR DATA
AND SAMPLE SHARING ACROSS
INSTITUTIONS.
WE HAVE A MULTIINSTITUTIONAL
RETROSPECTIVE STUDY IDENTIFYING
CO-VARIATES OF OUTCOMES ACROSS
COHORT OF 185 PATIENTS AND
MULTIVARIED ANALYSIS IDENTIFIED
DISEASE BURDEN TO EMERGE AND
ASSOCIATE WITH DECREASED
SURVIVAL THAT YOU CAN SEE FROM
KAPLAN MEYERS HOW DIVERGIENT
OUTCOMES ARE WITH ONE YEAR
EVENTS PRESURVIVAL OF ONLY 34%
OF HIGH DISEASE BURDEN GROUP
OPPOSED TO 70 P RS IN REMAINING
PATIENTS.
IN PARALLEL CAR MA STUDY
IDENTIFIED THAT BURDEN -- ACROSS
COHORT OF 420 PATIENTS AND THIS
DATA WAS CORROBORATED BY
MULTI-SITE REPORTING BY ST.
JUDES AND HOPKINS AND BURDEN IS
CERTIFIGATE OF POOR BIOLOGY AND
PRIOR TO CAR INFUSION MIGHT
IMPROVE OUTCOMES AND FURTHER
STUDY IS WARRANTED AND WANT TO
HIGHLIGHT REAL-WORLD COHORT WAS
SKEWED TOWARDS LOWER DISEASE
BURDEN AND LYMPHOMA BLAST COUNT
WAS 74% -- 55% OF THE REAL WORLD
COHORT HAD A BLAST COUNT OF LESS
THAN 5%.
WITH EMERGING DATA THAT DISEASE
BURDEN MATTERS CONSIDERING
SKEWING TOWARDS LOWER DISEASE
BURDENED COHORT AND EXPECT
MATCHED FOR BURDEN THAT OVERALL
REAL WORLD OUTCOMES WOULD BE
IMPROVED COMPARED TO ELLI ANA
AND NUANCED DIFFERENCES TO
OUTCOMES COMPARED TO PREVIOUS
CLINICAL TRIALS AND WE LOOKED AT
VARIABLES IMPACTING OUTCOMES
THAT I WILL HIGHLIGHT A FEW
EFFORTS AND LOOKED AT CAR DOSE
IMPACT AND LED BY
[INDISCERNIBLE] AND DIVIDING OUR
DOSES INTO QUARTILES WE SAW
THERE WAS NO EFFECT FROM DOSE ON
RESPONSE OR TOXICITY AND WHEN
LOOKING AT SURVIVAL, PATIENTS
WITH HIGHEST DISEASE DOSE COHORT
OR HIGHEST DOSE COHORT HAD
IMPROVED OVERALL AND EVENT FREE
SURVIVAL THAT IS CLINICALLY
MEANINGFUL AND NAVARTIS DOSE
RANGE IS BROAD WITH MULTIPLE
DOSES FALLING IN IMPROVED DOSE
RANGE AND FARMICO KINETICS
EFFORT LED BY VANESSA AND KEVIN
AND IDENTIFIED USING CALCULATED
PK MODEL INFLECTION POINT WITH
AFC13.8 BELOW WHICH RELAPSE
LEVEL WAS HIGHER AND WILL HEAR
MORE ABOUT THIS OVER THE DAY AND
WILL HEAR FROM FRIZZO IN
PARALLEL AND EFFORT DONE USING
MEASURED PK THROUGH ANALYSIS AND
THEY IDENTIFIED FLU DER AVEEN AC
LEVEL OF 14 AND WANT TO
HIGHLIGHT THIS SET
GEOGRAPHICALLY AND MEK
ANNISTICALLY THEY WERE DISTINCT
EFFORTS AND SERVED ACROSS
VALIDATING EACH OTHER AND
CLINICAL RELEVANCE HERE IS
OPTIMIZING THROUGH DER AVEEN
DOSING AND IT IS AN EASILY
MODIFIABLE VARIABLE AND IN
ADDITION TO LOOKING AT CLINICAL
VARIABLES, NOT IMPACTED OR SORRY
YES. IMPACT OUTCOMES IT IS
RECALLY IMPORTANT TO LOOK AT
VARIABLES NOT IMPACTING OUTCOMES
AND MULTIINSTITUTIONAL EFFORTS
PERMIT STUDY OF RARE PATIENT
SUBSETS SINGLE INSTITUTIONS ARE
NOT POWERED TO ACHIEVE
SUFFICIENT SAMPLE SIZES. I WILL
GO OVER SOME EFFORTS.
GENERAL [INDISCERNIBLE] LED A
STUDY LOOKING AT OUTCOMES OF
PATIENTS TREATED WITH OUT OF
SPECIFICATION PRODUCTS AND
IDENTIFIED THAT OUTCOMES AND
SURVIVAL WERE NOT DIFFERENT. IF
IN THE SORT OF MOST PROMINENT
REASON FOR NOT MEETING
SPECIFICATION DECREASED BY DID
VIABILITY SUGGESTING THAT
VIABILITY THRESHOLDS MIGHT HAVE
BEEN TOO STRINGENT AND RACE
OUTCOMES AND HISPANIC POPULATION
AND POPULATION WE KNOW PATIENTS
ARE HISTORICALLY RESISTANT TO
CHEMOTHERAPY AND HAVE INFERIOR
OUTCOMES WITH UP FRONT ALL AND
GIVEN CAR AND OUTCOMES AND
CURVES ESSENTIALLY SUPERIMPOSE
WITH NON-HISPANIC WHITES THAT IS
A SIGNIFICANT COHORT MAKING UP
38% OF COHORT.
WE WILL HEAR FROM ALLIE LEAHY
ABOUT CYTOGENETICS AND IS
IMPORTANT WE ARE LEARNING THAT
RISK STRATIFICATION SYSTEMS WE
USE FORCHEMOTHERAPY DON'T
NECESSARILY APPLY TO CAR. WE
WILL PROBABLY HAVE TO LEARN A
NEW RISK STRATIFICATION PATTERNS
FOR CAR T-CELL PATIENTS AND WILL
HEAR LATER FROM SARAH ABOUT
[INDISCERNIBLE] AND I LIKE THIS.
INTERNATIONAL STUDY LOOKED AT
PATIENTS LESS THAN THREE YEARS
OF AGE THAT WAS A COHORT
EXCLUDED FROM ELLI ANA AND THEY
IDENTIFIED GOOD SURVIVAL THAT
WAS PRETTY EQUIVALENT TO
PATIENTS MEETING FDA INDICATION.
THEY IDENTIFIED COMPARABLE
SURVIVAL AND IN INFANT PATIENTS
AND SERVES TO SHOW AND HIGHLIGHT
BENEFITS OF CROSS-VALIDATION
ACROSS EFFORTS AND VANESSA LED
EFFORT LOOKING AT EXTRA
MEDULLARY DISEASE IDENTIFYING
PATIENTS WITH CNS AND NON-CNS
MENTAL DISEASE HAD SURVIVAL
OUTCOMES OVERLAPPING WITH
PATIENTS WITHOUT EXTRA MEDULLARY
DISEASE AND SIGNAL THAT
PAISHIENTS WITH NON-CNS EXTRA
MEDULLARY DISEASE MIGHT HAVE
DECREASED SURVIVAL AND
INTERNATIONAL GROUPS LOOKS AT
PATIENTS WITH CNS DISEASE AND
IDENTIFIED PATIENTS WITH
ISOLATED CNS RELAPSE HAVE
INCREASED RISK OF POST CNS
RELAPSE AND POPULATIONS
IDENTIFYING DIFFERENT INSIGHTS
LOOKING AT PATIENTS USING
DIFFERENT COHORT AND THROUGH A
DIFFERENT LENS AND WE WILL HEAR
FROM SARAH AT SESSION 4A ABOUT
OUTCOMES WITH PATIENTS WITH DOWN
SYNDROME AND HIGH RISK COHORTS
OF RISK TOXICITIES AND WILL HEAR
ABOUT WORK FROM TED AND HOLLY
AND WANT TO CONCLUDE THAT CAR
T-CELL OUTCOME ANALYSIS YIELD
FINDINGS WITH POSSIBLE CLINICAL
APPLICATIONS LEARNING HIGH
DISEASE BURDEN ASSOCIATES WITH
DECREASED SURVIVAL WITH
OPPORTUNITY TO DEBULK OR IMPROVE
OUTCOMES AND CONSOLIDATE
EMISSIONS IN HIGH RISK GROUP AND
LEARNED INCREASED CAR T-CELL
DOSE ASSOCIATED WITH SURVIVAL
AND OPTIMIZE WITH CAR DOSES WHEN
AVAILABLE AND OPTIMIZED -- AND
FARMICO KINETICS ASSOCIATES WITH
DECREASED RELAPSE AND IDENTIFIED
HIGH RISK POPULATIONS SUCH AS
PATIENTS WITH HIGH DISEASE
BURDEN NON-CNS EXTRA MEDULLARY
WE CAN CONSIDER CONSOLIDATIVE
THERAPY AND TOXICITY MITIGATION
STRATEGIES AND WE IDENTIFIED
CARS VALUED OPTIONS FOR PATIENT
SUBSETS THAT ARE HISTORICALLY
CHEMOTHERAPY RESISTANT AND
INFANTS WITH HISPANIC RACE AND
PATIENTS WITH DOWN SYNDROME AND
TAKEAWAY POINT IS ONGOING
MULTISIGHT COLLABORATIONS ARE
REQUIRED TO ADDRESS FOR
OUTSTANDING QUESTIONS IN THE
FIELD AND WITH THAT I WILL THANK
YOU AND MOVE TO THE NEXT SPEAK
ER.
>> [APPLAUSE].
>> THANK YOU. NEXT SPEAKER IS
REGINA MEYERS WHO WILL DISCUSS
IMPACT OF PRIOR THERAPY AND CAR
TIMING AND WILL DO QUESTIONS FOR
SPEAKERS AT THE END.
>> GOOD MORNING, EVERYONE.
TALKING ABOUT PRIOR THERAPY ON
CAR T-CELL OUTCOMES.
AS WE KNOW CAR T-CELL THERAPY
CAN BE GIVEN TO PATIENTS AT
VARIOUS POINTS AND
[INDISCERNIBLE] MIGHT HAVE
DIFFERENT PRIOR THERAPY
EXPOSURES TO IMPACT CAR OUTCOMES
AND ARE A FEW SPECIFIC THERAPIES
THAT HAVE BEEN OF GREAT INTEREST
AND ANTI-CD19 AND CD3 BITE --
FOR THIS REASON PATIENTS WITH
EXPOSURE WERE SCOMPLUDED FROM
INITIALLE -- MAKING THIS A
CRITICAL QUESTION TO ADDRESS AND
NEXT OF CONSIDER IS -- SEVERAL
CONCERNS HAVE BEEN RAISED HERE
ABOUT POTENTIAL EFFECTS OF INO
T-CELL CORRECTION AND SIMILARLY
-- USED FREAK WENTLY IN RELAPSE
SETTING AND TESTED IN THE
TREATMENT SETTING AND RAISING
AND MAIN QUESTION HERE AROUND
PRODUCT MANUFACTURER FROM DONOR
T-CELLS LEADING TO DIFFERENT
OUTCOMES AND STARTING WITH
[INDISCERNIBLE] AND FIRST STUDY
LOOKING AT ASSOCIATION WITH
RESPONSE TO CAR 19 WAS
RETROSPECTIVE STUDY OUT OF CHUCK
INCLUDING 166 PATIENTS TREATED
BETWEEN 2012 AND 2016 AND
EXPOSED PATIENTS WITH R LIKELY
TO BE CD19 DIM PROFUSION AND IN
VIDEO YOU SEE HERE THEY WERE
MORE LIKELY TO HAVE COMPOSITE
POOR OUTCOME OF NO RESPONSE OR
CD19 RELAPSE COMPARED TO BLOOD
OF NAÏVE PATIENTS BUILDING ON
THIS MULTI-SITE STUDY IN FRANCE
LOOKING AT RISK FACTORS
ASSOCIATED WITH OUTCOMES AND
PATIENTS BETWEEN 2016 AND 2019
AND 51 PATIENTS IN ANALYSIS AND
7 TAENWHOM RECEIVED PRIO BLENA.
BY MULTIVARIABLE MODELING IT
REMAINED INDEPENDENTLY
ASSOCIATED. BUILDING ON THIS
CAR MULTICENTER ANALYSIS WAS
CONDUCTED COLLABORATIVE EFFORT
AMONG 7 CENTERS CAME TOGETHER TO
ADDRESS IMPACT OF EXPOSURE ON
CD19 CAR OUTCOMES ANALYSIS
INCLUDED 420 PATIENTS. CENTERS
REPRESENTED BELOW AND BREAKDOWN
OF PATIENTS BY SITE AND VARIETY
OF CAR CONSTRUCTS AND -- CD19
AND CD28 CONSTRUCT AND
[INDISCERNIBLE].
SO, INITIALLY WE FOUND WHAT WAS
HYPOTHESIZED IN SMALLER STUDIES
AND PATIENTS RECEIVING 420 HAD
WORSE EFS AND BECAME INTERESTING
BREAKING IT DOWN FURTHER AND
BROKE PATIENTS DOWN TO RESPONSE
TO THIS AND WE COMPARE EFS AMONG
THREE GROUPS YOU SEE IN THE
FIGURE HERE THAT BLINA
RESPONDERS AND PATIENTS HAD
IDENTICAL EFS AND PATIENTS WERE
REFRACTORY TO BLINA WITH
[INDISCERNIBLE] NOW, STUDY CAN
ADDRESS MECHANISM OF ASSOCIATION
AND HYPOTHESES HERE IS
NONRESPONSE IS NEARLY SURROGATE
FROM REFRACTORY DISEASE. WE
LOOKED AT THIS NEXT AND
PREINFUSION DISEASE BURDEN IS --
HIGH DISEASE BURDEN PATIENTS
HAVE HIGH MERCURY CFS AND
COMBINE THAT WITH RESPONSE DATA
AND IN THE BLINA THIS IS IN
BLINA EXPOSED PATIENTS FOR EASE
OF SHOWING YOU ON GRAPH HERE AND
STEPWISE DECREASE WITH PATIENTS
WITH LOW DISEASE BURDEN HAVING
BEST EFS AND THOSE COMING INTO
CAR AFTER BEING BLINA REFRACTRY
AND HIGH DISEASE BURDEN THAT IS
DISMAL WITH EFS AND NO LONG-TERM
SURVIVORS THERE AND CONCERN OF
IMPACTS WITH MODULATION WE
WANTED TO LOOK ALSO AT CD19 DIM
EXPRESSION PREPAR AND THIS LOOKS
AT PATIENTS RECEIVING THIS AND
-- BLINA NAÏVE PATIENTS WERE
[INDISCERNIBLE] AND VIRTUALLY
SAME OUTCOMES PATIENTS UNIFORM
LY [INDISCERNIBLE] BECAME CD19
DIM FOLLOWING BLINA WITH DISMAL
OUTCOMES RELAPSING WITH CD19
NEGATIVE DISEASE AND LOOKING AT
PATIENTS WITH NORMAL EXPRESSION
AND RELANCE IMMUNOPHENOTYPE DID
NOT DIFFER BY BLINA EXPOSURE AND
RATES WERE SIMILAR SHOWING CD19
ANTIGEN ESCAPE IS NOT PRIMARY
DRIVER EXPOSING DIFFERENCE IF IN
PATIENTS AND TAKING DATA
TOGETHER WE CAN DRAW A FEW
CONCLUSIONS ASKING MORE
QUESTIONS AND PRIOR BLINA
EXPOSURE DOESN'T PROVE RESPONSE
TO CAR BUT IS ASSOCIATED WITH
WORSE OUTCOMES AND SPECIFICALLY
NONRESPONSE TO PRIOR BLINA AND
EXPLANATIONS HOO ERR IS
REFLECTIVE T-CELL -- ADVERSE
IMPACT OF EXTENSIVE PRIOR
THERAPY THE RESPONSE IS
SURROGATE NONREFRACTORY DISEASE
REFLANCE OF BLINA TIMING IS
STILL NOT KNOWN.
OKAY. SO, THE FIRST DATA
PUBLISHED BY THIS IS RELATIVELY
SMALL RETROSPECTIVE SERIES
SHOWING CONSISTENTLY WORSE
OUTCOMES AND THIS MULTICENTER UK
SERIES EXPOSED -- THREE RECEIVED
THIS AND TWO HAD SUCCESSFUL
MANUFACTURER AND CURVES HERE INO
EXPOSED PATIENTS HAD WORSE THAN
OS AND [INDISCERNIBLE] PATIENTS
AND SAME MULTICENTERED FAMILY
FROM FRANCE AND STUDY LOOKED AT
11INO EXPOSED PATIENTS IN
ANALYSIS AND EFS WAS WORSE THAN
PATIENTS AND OS WAS WORSE THAN
THAT AMONG INO EXPOSED AND
RECENTLY THERE WAS INTERNATIONAL
10 CORRECTOR RETROSPECTIVE
ANALYSIS PUBLISHED THAT INCLUDED
39INO PATIENTS AND 27 IS
BRIDGING THERAPY AND NOTABLY
THIS WAS HEAVILY PRETREATED
SAMPLE AND MAJORITY OF PATIENTS
HAD LOW DISEASE BURDEN PRECAR 19
AND SUCCESSFUL MANUFACTURER AND
FIGURE SHOWS EFS AND ONS AND 12
MONTH ESTIMATES ARE SIMILAR TO
GENERAL PUBLISH THE CAR OUTCOME
DATA AND LOOKING AT PERSISTENCE
34 OUT OF 39 PATIENTS RECEIVED B
CELL AMRASHIA AND 1/3 LOSS
PROPORTION DIDN'T DIFFER BY
PATIENTS RECEIVING -- FOLLOWING
RELAPSE OF THOSE WITH
NONRESPONSE OR RELAPSE WAS HALF
CD19 POSITIVE AND HALF CD19
NEGATIVE AND PUTTING DATA
TOGETHER SIMILARLY DATA BEFORE
CONCLUSIONS AND QUESTIONS AND
T-CELLS COLLECTED AND
SUCCESSFULLY USED TO MANUFACTURE
CAR AND THERE IS CONFLICTING
DATA REPORT AND LARGEST ANALYSIS
SHOWS SIMILAR RATES TO EXPOSE
THE PATIENTS AND UNKNOWN HOW
TIMING IMPACTS INO EXPOSURE ON
OUTCOMES AND CUMULATIVE DOSING
AND WANT TO NOTE THERE IS
PRACTICE VARIATION WHEN TO
INFUSE CAR IN PATIENTS ACHIEVING
-- FOR INSTANCE IN CENTER WE
WAIT FOR PATIENTS TO DEMONSTRATE
RECOVERY AND CAR AND CENTERS GO
DIRECTLY AND FURTHER
UNDERSTANDING IMPACT OF INO
PERSISTENCE AND ENCOURAGING DATA
ABOUT INO AND IMPACT OF HIGH
DISEASE AND INTERESTING QUESTION
COMING UP IS INO A POTENTIALLY
EFFECTIVE BRIDGING STRATEGY FOR
REDUCING BURDEN IN PATIENTS WITH
CHEMOREFRACTORY DISEASE.
SO, FIRST WAS THEY SHOWED NICELY
THAT INCREASED NUMBERS OF LINES
OF PRIOR THERAPY WAS ADVERSELY
IMPACTED WITH SURVIVAL AFTER CAR
PRIOR TRANSPLANT WASN'T
ASSOCIATED WITH OUTCOMES AND
LOOKS LIKE PROTECTIVE EFFECTIVE
PRIOR TRANSPLANT.
I THINK I QUESTION HOW MUCH OF
THIS IS CONFOUNDED BY DISEASE
REFRACTORY ENOUGH AND HAVE WE
NOT QUITE DISENTANGLED THIS
ENOUGH YET? BRINGING TOGETHER
IN CONCLUSION I THINK FOR BLINA
DATA WE HAVE SHOWN AGAIN IT
DOESN'T HAVE A RESPONSE TO CAR
BUT IS ASSOCIATED WITH INFERIOR
CAR OUTCOMES AND PATIENTS WITH
RESPONSE TO IT AND WE NEED MORE
WORK TO UNDERSTAND CONFLICTING
REPORTS AND EXPOSURES ASSOCIATED
WITH OUTCOMES AND MAYBE IT HAD
IS NOT YET BEEN DISENTANGLED
ENOUGH AND IMPACK OF TIMING OF
THERAPIES RELATION TO CAR HAS TO
BE BETTER ILLUS DATED ESPECIALLY
WITH THERAPIES IN OVERALL
SETTING AND BEST INFORMING
OPTIMAL CAR TIMING AND BRIDGING
STRATEGIES.
WITH THAT, I WOULD LIKE TO BE
HAPPY TO TAKE QUESTIONS I KNOW
AT END OF THIS AND HOPING THAT
DATA CAN SPARK DISCUSSION
AMONGST THIS GROUP. THANK YOU.
>> THANK YOU REGINA AND NEXT IS
MAR CELLA TALKING ABOUT CDIR AND
CAR SPECIFIC DATA CAPTURE.
>> THANK YOU VERY MUCH. THANK
YOU FOR INVITATION TO
PARTICIPATE HERE AND FOR
INCLUDING ME. SO, I WILL TALK
ABOUT RESOURCE AND DISCLOSURES
RELATED TO THIS AND PATIENT
OUTCOME REGISTRIES NOW WITH CAR
T-CELL AND WITH TRYING TO USED
THIS FOR MULTIPLE GROUPS AND
UTILIZING THIS FOR DIFFERENT
SOURCES INCLUDING REGULATORY
THAT IS NOT FREQUENTLY USED
BEFORE AND I'M PERSONALLY HAVING
THE SAME VIEW AS THIS IS NOT OR
SHOULD NOT BE ANSWER FOR
EVERYTHING BUT SHOULD BE PART OF
ECOSYSTEM OF DATA BASES THAT ARE
AVAILABLE AND SHOULD INTEGRATE
THIS WITH DIFFERENT DATA BASES
BEING ALREADY COLLECTED AND WE
DON'T MAKE THIS REALLY
REPETITIVE WORK FOR PEOPLE
PARTICIPATING WITH DATA
COLLECTION AND REAL WORLD DATA
IS COOL AND NEW TERM THAT PEOPLE
USE ALL THE TIME AND WE WANT TO
REALLY HAVE SORT OF INTEGRATED
WAY OF USING THIS REAL WORLD
DATA THAT CAN HAVE CERTAIN
CRITERIA THAT WE ESTABLISH BY
FDA AND OTHER GROUPS TO TRY TO
USE THIS AS REGULATORY.
GOING TO NEXT STAGE TO
UNDERSTAND USE OF THIS TO
MAXIMIZE THIS FOR RESEARCH OR
REGULATORY USES.
CAR T-CELL IS NOT SAME REALLY
PROCESS THAT WE ARE TRYING TO
APPLY IT AND TIMELINE OF
DEVELOPMENT ARE ENLTRY AND LOTS
HELPED DEVELOP AND THIS IS A
RESOURCE FOR COMMUNITY BUILT BY
COMMUNITY AND SHOULD BE PART OF
ALL EFFORTS GOING FORWARD THAT
SHOWED AN EXPOSURE IN FIELD
CONTINUING PRESENTATION WE HEARD
FROM DR. GRUPP EARLIER. WE ARE
TRYING TO USE DATA AS SINGLE WAY
OF CAPTURING ALL EXPERIENCE FROM
PATIENTS FOR REGULATORY PURPOSES
AND WE HAVE ALL THESE PROJECTS
CALLED POST AUTHORIZATION
PROTOCOLS CAPTURING DATA NOT
HAVING INDUSTRY CREATING
SEPARATE REGISTRIES TOGETHER AND
USING STANDARDIZED APPROACH TO
CLEK ALL THIS AND SUCCESSFULLY
HAVE BEEN DOING THIS THAT HAVE
ALL COMMERCIAL PRODUCTS BEING
COLLECTED AND OF INTEREST FOR
THIS AUDIENCE WE ARE ONGO GOING
CAPTURING PEDIATRIC DATA AND
CLOSE TO PATIENTS ON ACCRUAL AND
HOW DOES THIS LOOK NOW?
WE ARE REACHING ALMOST 10,000
PATIENT MARKING WITH MORE
INFUSIONS AND LOTS OF DOUBLE
INFUSIONS ARE IN PEDIATRIC A
WILL. L AND DISTRIBUTION 80% IS
COMMERCIAL AND DISTRIBUTION OF
PRODUCTS WE HAVE AND 30% ARE
[INDISCERNIBLE] AND PROPORTION
ARE PEDIATRIC A WILL. L.
LOOKING MOVING FORWARD EXPANSION
OF PRODUCTS AND INDICATIONS WE
SEE MORE OR LESS OF BREAKDOWN OF
240 REPORTED A YEAR FOR ALL AND
MOST ARE PEDIATRIC ALL. IS THIS
QUESTION TOTALITY HOW
REPRESENTATIVE IT IS FOR ACTUAL
NUMBER OF PATIENTS ELJEBL TO
RECEIVE IF IN RECEIVING PRODUCTS
AND NOVARTIS A YEAR AGO WE HAVE
70% REPRESENTATIVE OF CHEMOIA IN
UNITED STATES AND NEED
EVALUATION ONGOING TO SEE HOW
REPRESENTATIVE THESE REPORTS ARE
AND WITH DATA WE SEE CLEAR
INITIALLE PATTERNS YOU HEARD
FROM PREVIOUS SPEAKER REGINA
TALKED ABOUT PRIOR TRANSPLANT.
YOU SEE IT IS REALLY SHIFTING
AND PATIENTS COME TO CAR WITH
LESS PROPORTION OF PATIENTS
HAVING PRIOR [INDISCERNIBLE] AND
SEE IMPACT ON TRANSPLANTS THAT
ARE BEING DONE AND YOU SEE LAST
NUMBERS OF LYMPHOMA AND LOOK AT
SPECIFIC AND PEDIATRIC ALL AND
NUMBERS PEEKED IN 2019 AND
PATIENTS ARE COMING INTO CAR
MORE OFTEN WITH NEXT IMPACT AND
HOW IS USE OF RENLTRY LOOKING AT
FIRST SLIDE I SHOWED YOU AND
POTENTIAL USES WE ARE DOING THIS
AND DOING THIS POST
AUTHORIZATION AND WITH
COLLABORATING WITH MULTIPLE
CENTERS OUTSIDE OF THE US AS
WELL TO USE AS RESOURCE FOR
REGULATORY DATA COLLECTION AND
CREATED A PATTERN BECAUSE
PRODUCTS HAVE OFTEN TIMES
NON-CONFORMING AND WE HAVE A
PROCESS TO CAPTURE THIS WITHIN
DATABASE WITHOUT CREATING A 15
YEAR CLINICAL TRIAL FOR
NONCOMMERCIAL PRODUCTS THAT MEET
SPECIFICATIONS AND BUILD PATIENT
REPORTED OUTCOMES AND INTEGRATE
SAMPLE COLLECTIONS FOR PATIENTS
DEVELOPING SUBSEQUENT NEUROPLASM
IMPORTANT IN ADULT CASES AND IS
FOR ALL CAR T-CELLS AND USE DATA
FOR INTEGRATING AND TRYING TO
UNDERSTAND NEW PRODUCTS USING
THIS AS A CONTROL FOR THESE NEW
PRODUCTS COMING THROUGH USING
DATA AND REGISTRY FOR THAT. I
THINK WHAT WE WANTED TO PROMOTE
IS TRYING TO BUILD DATA AS A
RESOURCE OF GROUPS COMING
TOGETHER THAT IS SUPPORT AND WE
ARE INVESTED IN THIS IDEA
DECENTRALIZING DATA AND
[INDISCERNIBLE] DATA THAT SHARED
WITH US WITH COMMUNITY TO HELP
COLLECT IT AND WORKING COMMITTEE
STUDIES THAT IS CURRENTLY BEING
LED BY AMY MOSKOP IN OUR GROUP
JUST HOW THAT IS COMPARABLE THIS
IS LYMPHOMA AND LOOKING AT DATA
AND PIVOTAL TRIAL AS PD SIMILAR
OUTCOMES THAT IS PAPER WE
PUBLISH WITH YOU PRESENT ON IT
DEMONSTRATING COMPARABLE
EFFICACY ENDPOINTS AS WELL WITH
DATA THAT IS GOOD AND LOOKING AT
PATTERNS WE ARE LOOKING AT
LYMPHOMA AND DECREASE OF
PROPORTIONS OF PISHIENTS WITH
GREAT 3C ARE. S AS WELL AND WE
DON'T SEE WITH PEDIATRIC ALL
STEADY PROPORTION OF GRADE 3CRS
THAT IS RELATED TO THE DISEASE
AND SEEING A SHIFT FROM 2018 TO
2020 MEETING AGE OF PATIENTS HAS
BEEN INCREASING AND IS TO
ILLUSTRATE WITHIN THE DISEASE
AND PRODUCTS THERE IS
DISTRIBUTION OF DIFFERENT
OUTCOMES IN TERMS OF CRS AND
NEUROTOXICITY AND THIS MIGHT
ALSO BE RELEVANT HERE TRYING TO
BUILD COMORBIDITY COURSE TO
ASSESS IMPACT OF THIS IN OUTCOME
THAT IS ADULT LYMPHOMA AND THINK
SIMILAR EFFORTS IN ALL WILL BE
INTERESTING TO SELECT PATIENTS
MATTER THAT IS A EXAMPLE AND
NON-CONFORMING PRODUCTS USING
SAME PLATFORM AND PATIENTS
ENROLL AND EXPAND ACCESS
PROTOCOL TO TRY TO ENROLL THEM
GETTING INITIAL INFORMATION INTO
THEM AND EVENTUALLY ZERO HUNDRED
OR 30 DAYS THERE WILL BE A SHIFT
INTO THE LONG-TERM FOLLOW UP
PROTOCOL USING CMRT DATA
STRUCTURE AND MY SLIDE AND TO
WORK ON IT AND MORE THINGS WE
CAN DO.
I THINK USING PLATFORM FOR
REGULATORY APPROVAL OF NEWER
MODIFICATIONS OF PRODUCT MIGHT
BE GOAL FOR US NO THE TO GO BACK
ONLINE CREATING NEW CLINICAL
TRIALS AND WE WANT TO LEVERAGE
REGISTRY TO LOOK AT BIMARKER
DISCOVERY FINDING WAYS TO
INTEGRATE THIS WITH PATIENT
REPORTED OUTCOME AND FIELD
CONTINUING TO EVOLVE WE NEED TO
BE FLEXIBLE AND HAD TO CHANGE
SINCE TIME WE STARTED REGISTRY
DATA COLLECTION FORMS WERE
REVISED 10 TIMES AND TO
TESTAMENT TO HOW FAST A FIELD IS
MOVING AND HAVE TO BE FLEXIBLE
TO ALLOW THIS TO HAPPEN AND I'M
GLAD TO BE HERE SHARING
INFORMATION AND THIS IS ON
BEHALF OF LOTS OF PEOPLE AND
HAVE TO THANK THEM TO
PARTICIPATE AND THANK YOU FOR
LISTENING AND COLLABORATING WITH
REGISTRY. THANK YOU.
>> THANK YOU, MARCELO.
>> DO I NEED TO CLICK ANYTHING?
JACOBY AND I HAVE AN IMPOSSIBLE
TASK TO TALK ABOUT THE GLOBAL
EXPERIENCE OF CAR T-CELLS
WORLDWIDE.
SO, I'M JUST GOING TO SHARE WITH
YOU GLIMPSE AND THOUGHTS. IT IS
IMPOSSIBLE TO DO IT IN TIMEFRAME
THAT IS HERE.
SO, GLOBALLY LOOKING, THIS IS
LAST MONTH FROM CLINICAL
TRIALS.GOV AND NARROWING CAR
T-CELLS FOR ALL THERE IS
ACTIVITY THAT IS A LOT WORLDWIDE
OUT OF THE US WHETHER IN CHINA
OR EUROPE OR OTHER PLACES AND
WILL DIVIDE TALK INTO TWO PARTS
REAL-WORLD DATA COMING FROM
INTERNATIONAL TRIALS AND SECOND
LOOKING AT NOVEL CARS AND
DISCUSSES THAT A LITTLE BIT AND
T-CELLS WERE ONLY APPROVED CARS
FOR CHILDREN AND APPROVED IN
2018 IN EUROPE AND RECRUITMENT
FROM AUSTRALIA AND JAPAN AND
EUROPEAN COUNTRIES AND MAINLY
BECAUSE OF LOGISTICAL CHALLENGE
TO TRANSFER CELLS ACROSS OCEANS
MANUFACTURING SITES HAVE CHANGED
NOT JUST IN THE US.
MINOR BUT SIGNIFICANT
PARTICIPATION IN TRIAL OUTSIDE
OF THE US AND LOOKING AT SOME
REPORTS OF REAL WORLD DATA
COMING I WANT TO HIGHLIGHT TWO
THINGS I READ IN THESE PAPERS
FIRST COMING FROM US AND BOTTOM
COMING FROM OUTSIDE OF THE US
AND POPULATION IS SLIGHTLY
DIFFERENT AND LYMPHOMA ADULT
COLLEAGUES OBSERVED AS WELL
PATIENTS COMING FROM EUROPE MORE
HEAVILY TREATED AND EFFECTING
OUTCOMES AS WELL COMPARED TO
CONSORTIA OUTSIDE OF THE US AND
MRD MEASURED SIGNIFICANTLY
DIFFERENT FLOW CITOMETRY AND
MOST EUROPEAN COUNTRY PCR-BASED
MOVING TO NGS THAT MIGHT ALSO
IMPACT HOW WE LOOK AT RESULTS
AND WHAT IS TRUE MRD NEGATIVE
ACTIVITY POST CAR T-CELLS AND
PAPERS COMING FROM EUROPEAN
GROUPS THAT IS FIRST THAT
SHOWING YOU EARLIER COMING FROM
PARRIS GROUP AND LOOKING AT
PHENOTYPE OF RELAPSE AFTER CAR
T-CELLS AND YOU KNOW GENERAL
OBSERVATION THAT HIGH DISEASE
BURDEN LEADS TO POOR OUTCOME HAS
BEEN SEEN HERE.
INTERESTING THING IS CD19
POSITIVE RELAPSE WAS PATIENTS
THAT LOST B CELL APLASIA NOT
SURPRISING AND PATIENTS COMING
IN WITH LOWER DISEASE BURDEN
PATIENTS AND THAT IMPACTING CD19
POSITIVE RELAPSE SUGGESTING YOU
NEED SOME SORT OF DISEASE BURDEN
TO PROVIDE PERSISTENCE OF CELLS.
SECOND REPORT CAME OUT ECREPTLY
FROM GERMAN CONSORTIUM LED BY
PETER.
THEY LOOKED AT PROBLEM THAT MOST
PATIENTS THERE CAME AFTER
TRANSPLANT AND 80% OF PATIENTS
RECEIVING CAR T-CELLS IN
GERMANY.
THERE WAS NO SIGNIFICANT
DIFFERENCE WITH PATIENTS WITH
PRIOR TRANSPLANT AND LOOKING AT
TIMING OF RELAPSE POST
TRANSPLANT PATIENTS RELAPSED 6
MONTHS -- DID SIGNIFICANTLY
WORSE THAN PATIENTS HAVING LATER
RELAPSE MIGHT BE DUE TO
SELECTION BIAS OF VERY
AGGRESSIVE DISEASE OR POOR
T-CELL FUNCTIONALITY COLLECTING
T-CELLS IN FIRST 6 MONTHS AFTER
TRANSPLANT IS SOMETHING TO BE
DISCUSSED IN FURTHER RESEARCH.
THERE IS COLLABORATIVE EFFORTS
GOING TO BE DISCUSSED LATER IN
THE MEETING. I WILL HIGHLIGHT
THERE HAVE BEEN PKS LED BY
PRINCESS MAX MA GROUP AND CNS
CAR T-CELLS FOR CNS RELAPSE AND
IN INFANTS AND SOME MORE.
SWITCHING GEARS TO TALK ABOUT
CHERRY PICKING A FEW STUDIES
HIGHLIGHTING DIFFERENT CAR
CUBINGS AND HAVE A QUESTION I
THINK IS IMPORTANT TO DISCUSS
WHAT ARE LESSONS WE CAN LEARN
FROM STUDIES LOOKING AT
DIFFERENT CARS APPLYING IT TO
WHAT WE USE IN DAILY PRACTICE.
THERE IS A LOT OF THINGS GOING
ON AND WILL TALK ABOUT UK
EXPERIENCE FROM GOSH AND UCL AND
THERE IS INTERESTING DATA THAT
IS STILL A LITTLE PREMATURE
COMING FROM MULL 10Y CAR.
YOU SEE THESE REFERENCES FROM
CLAUDIA'S GROUP AND
[INDISCERNIBLE] GROUP AND WILL
TALK ABOUT EXPERIENCE WITH
[INDISCERNIBLE] ASSIMILATED CAR
AND ALL AND ABOUT SPANISH AND
ONE CHINESE EXAMPLE.
SO, UCL GOSH HAVE A SERIES OF
WONDERFUL PHASE 1 TRIALS FIRST
ONE LOOKING AT DIFFERENT BINDER
CAT BINDER LOW AFFINITY AND FAST
ON OFF RATE AND USE IN PHASE 1
TRIAL IN ALL LED BY SARAH AND
WONDERFUL CRA GOOD PERSISTENCE
AND HIGH RATE OF NEGATIVE 19
RELAPSE AND DOMAINS AND AGAIN CR
RATE IS FANTASTIC BUT
PERSISTENCE WAS POOR.
MOVING TO FURTHER CLINICAL
TRIALS IS -- YOU KNOW, THIS IS
AN EXCELLENT CAR BUT IN PHASE 1
TRIAL I WESH WAS IN CONSULTATION
OR COMMERCIALIZATION AND WE USED
CD28-BASED CARS AND LOOKED AT
EXTRA MEDULLARY DISEASE THAT IS
SUGGESTED FROM PEDIATRIC REAL
WORLD CONSORTIUM DOING WORSE
USING T-CELLS AND RESULTS ARE
OPPOSITE AND PATIENTS WITH EXTRA
MEDULLARY DISEASE AND BULKY DO
FANTASTIC WITH CD28
CO-ASSIMILATED CAR AND HAVE TO
BE CONSOLIDATED WITH TRANCE
PLANT PATIENTS AND NOT
CONSOLIDATED WHEN TRANSPLANT
DIDN'T DO WELL WHICH IS NOT
SURPRISING AND SPANISH GROUP HAD
AN EXPERIENCE WITH BASKET TRIAL
WITH NOVEMBEREL BINDER CALLED
REOO1 AND THEY RENTED BASKET
TRIAL OF 53 ADULTS AND CHILDREN
WITH ALL AND OBSERVED B CELL
MRASHIA AND DISEASE ARE
IMPORTANT AND TWO THINGS ARE I
THINK SHOULD BE HIGHLIGHTED FROM
THIS EXPERIENCE THAT IS
UNFORTUNATE THERE IS NO ONE FROM
THE GROUP AND MEETING AND HOPE
THEY WILL CONTINUE OR COME TO
FUTURE MEETINGS.
FIRST OF ALL WE SELL TOXICITY
INITIALLY MOVING TO THOSE
FRACTIONATED REJ P MENTED AND
60% DAY 2 IN CASE OF NO TOXICITY
AND SECOND THING THAT IS
IMPORTANT IS ACTUALLY THE FIRST
CAR T-CELL PRODUCT APPROVED FOR
USE BY REGULATORY AGENCY AND
ALSO IN CHILDREN WITH ALL AND
WAS UNDER THE HOSPITAL EXCEPTION
PATHWAY AND IS LOTS OF
REGULATORY CONSTRAINTS WE TALKED
ABOUT IN PRE-MEETINGS AND THERE
IS A LOT TO LEARN ABOUT HOW TO
TAKE NOVEL CAR TO APPROVAL
PROCESS.
LAST BUT NOT LEAST THERE IS TONS
OF DATA COMING FROM CHINA AND IS
COMPLEX TO LOOK AT IT DETAILS
ARE MISS IN MANY PAPERS RECENT
REVIEW OF HEEM ATOLL AND PHASE 1
AND PHASE 2 AND HIGHLIGHTING
LARGEST 1 COMING FROM GROUP IN
SHANGHAI AND PHASE 2 TRIAL
GIVING COMBINATION OF CD19 AND
CD22 CARS SAME TIME ONE-TO-ONE
RATIO WITH REALLY A MORE THAN
99% CR RATE AND GOOD EVENT
OVERALL SURVIVALS AND 40% OF
PASH YEVENTS WENT TO TRANSPLANT
AND RATE OF CD19 NEGATIVE
RELAPSE IN THE COHORT IS ABOUT
40% OF TOTAL PATIENTS RELAPSING
THAT IS SIMILAR TO WHAT WE SEE
WITH CD19 CAR.
SO, THIS I THIS I IS MY LAST
SLIDE. I THINK THERE ARE THREE
THINGS WE NEED TO TALK ABOUT AND
FIRST OF ALL HOW WE ACCESS AND
HOW WE ACCESS BETWEEN COMMERCIAL
CARS AND NOVEL TRIALS GETTING
ACCESS IN NON-US AND
NON-EUROPEAN COUNTRIES AND THIS
MAP IS HERE TO SHOW NO ACTIVITY
COMING IN AFRICA AND INDIA HAS 1
TRIAL STARTING WITH MEL 10Y
PLATFORM AND A LITTLE IN
SOUTHEAST ASIA AND ONE IN SOUTH
AMERICA AND MOST OF THE WORLD IS
NO THE HAVING ACCESS TO ANY CAR
T-CELLS WHATSOEVER THAT IS
INTERTWINED WITH COST OF THIS
PROCESS AND HAVE TO FIGURE OUT
AS A GROUP HOW TO REDUCE COST TO
GET ACCESS HIGHER AND WITH THIS
THANK YOU FOR LISTENING AND I'M
LOOKING FORWARD TO DISCUSSION
AND THIS WONDERFUL MEETING.
THANK YOU.
>> [APPLAUSE].
>> THANK YOU. WITH IT THAT,
OPENING TO QUESTIONS AND PLEASE
APPROACH THE MICROPHONES AND ASK
YOUR QUESTIONS.
>> A COUPLE QUESTIONS. FIRST,LY
ORA. WITH DOSE ASSOCIATION I
WANT TO ASK SPECIFICALLY YOUR
THOUGHTS WHETHER THAT DOSE IS
TRULY DOSE OR A SIGN WHEN YOU
DID THE ORIGINAL EXPANSION
ASSOCIATED WITH CAR T
MANUFACTURING PROCESS YOU HAD
MORE FIT T-CELL AND HAD A BAG
WITH MORE IN IT AND SAY THIS AS
PRACTICAL CONSIDERATION BECAUSE
WHEN WE GET POOR EXPANSION WITH
THE CELL, YOU WON'T GET EXTRA
BAGS OR YOU WILL HAVE VERY LOW
BAGS.
WAS THE HIGHER DOSE -- IT
PROBABLY WAS ALL A SINGLE BAG;
RIGHT?
>> SORRY YEAH. THESE ARE VERY
EXCELLENT QUESTIONS.
SO, YOU KNOW, WE DEFINITELY HAVE
SOME KNOWLEDGE, EXPERIENTIAL
KNOWLEDGE THAT PATIENTS COMING
WITH HIGHER COUNT COLLECTION
MIGHT HAVE POORER FIT T-CELLS IN
MULTIVARIED ANALYSIS THAT DIDN'T
SHOW UP TO BE A CONFOUNDER AND
DOSE INDEPENDENTLY MATTERED IN
DISEASE BURDEN AND THAT IS
PERTINENT AND VANESSA IN THE
AUDIENCE HERE IS LOOKING AT A
BASELINE BLAST COUNT AND HOW IT
IMPACTS T-CELL FITNESS AND YOUR
QUESTION IS EXTRA ORDINARILY
PERTINENT BECAUSE ONE THING WE
DON'T HAVE SAMPLES TO LOOK AT
T-CELL FITNESS. YOU KNOW, WE
ARE SOMEWHAT, YOU KNOW,
RESTRAINED.
WE CAN'T ACTUALLY DO SOME OF THE
LABS THAT WE NEED TO DO SOME OF
THE TESTS AND STUDIES WE NEED TO
DO ON T-CELLS THEMSELVES THAT
WILL BE VERY HELPFUL IN
CLARIFYING HERE.
>> YEAH. ONE WAY TO KEEP IN
MIND STUDYING PROSPECTIVELY
IMPORTANT STUDY TO DO IS
DISTINGUISHING THOSE WHO HAD
ADEQUATE CELL DOSE WITH ONE BAG
VERSUS THOSE WHO TOOK 2 OR 3
BAGS, AGAIN, AS A SIGN OF POOR
FITNESS. WE HAD A MUCH LOWER
OVERALL EXPANSION AND WOULD LOVE
TO DO T-CELL FITNESS STUDIES AND
DON'T KNOW IF WE WILL BE ABLE TO
DO THOSE. YEAH?
>> DO WE KNOW WHAT IS IN THE
BAG?
>> NO. WE NEED TO KNOW WHAT IS
IN THE BAG FOR SURE.
>> SOMETIMES WE DO
[INDISCERNIBLE].
>> [LAUGHING].
>> [INDISCERNIBLE].
>> YEAH. GO TO THE MIC, ANDRÉ.
YOUR WORDS ARE PEARLS SO.
>> I DON'T WANT TO HIJACK YOUR
QUESTIONS.
>> YOU ARE GOOD.
>> SAYING WHAT WE INFUSE WE
DON'T KNOW WHAT WE INFUSE.
>> YES.
>> THIS IS A BLACK BOX. THERE
IS A TRAVEL. THERE IS THAWING
THAT PROBABLY MODIFIES WHAT THE
SPECIFICATIONS ARE. IN FACT, WE
DON'T KNOW WHAT WE INFUSE AND
FOR SOME PATIENTS WHERE WE HAVE
NO EXPANSION, WE HAVE COMPARED
WHAT WE HAVE FOUNTD RINSING THE
BAG AFTER INFUSION TO WHAT WAS
SUPPOSED TO BE IN THE BAG
ACCORDING TO SPECIFICATION FROM
NEVARTIZ AND SDREPENCY WHAT WE
ARE INTERROGATING.
>> AND WISH WE COULD FIND A WAY
TO KNOW WHAT OUR PRODUCT REALLY
IS.
>> YEAH. TO ANDRÉ'S POINT WE
HAVE TRIED AND WRITTEN MULTIPLE
IRTS TO NEVARTIS AND WE HAVE HAD
MULTIPLE CONVERSATIONS.
>> THE SAME.
>> AND THEY ARE NOT AT THIS TIME
ABLE TO GIVE US SAMPLES AND
SURROGATE IS LOOKING AT AFORESIS
AND COLLABORATION TRYING TO
COLLECT AFOR EESIES THAT ARE
STORED IN INSTITUTIONAL BIOBANKS
TO CHARACTERIZE THESE.
REALLY, THE OTHER OPTION IS TO
COLLECT FROM THE BAG AND RINSE
THE BAG AND IT SOUNDS LIKE A
POOR OPTION. WE DON'T KNOW IF
WHAT WE GET IN THE BAG ARE WHAT
STICKS TO TUBES THAT IS ACTUALLY
REFLECTIVE WHAT GOES INTO THE
PATIENT OR SELECTION THERE.
>> COMMENTING ON THAT, IT IS NOT
ALLOWED.
>> YES.
>> THEY REALLY DON'T WANT TO
FIGURE OUT WHAT IS IN THE BAG.
IN OUR CONTRACT AND I KNOW THAT
THEY SAY A SPECIAL CONTRACT
BECAUSE OF SOME IP ISSUES I
DON'T WANT TO BRING UP.
>> DON'T READ THE CONTRACTS.
>> WE ARE FORBIDDEN TO RINSE THE
BAG AND DEVELOPED OUR -- WE
WANTED TO STUDY BAGS AND WE
DEVELOPED OUR OWN PRODUCT.
I'M ACTUALLY CURIOUS AS CENTERS
ARE YOU ALLOWED NOVARTIS
CONTRACT TO LOOK INTO THE BAG.
>> CENTERS AND ADULT COLLEAGUES
ARE DOG IT.
>> REFLECTION OF FACT WE DON'T
LOOK AT OUR CONTRACTS.
>> OTHER THING IS LIKE YOU KNOW.
>> I'M SERIOUS.
>> HE HAD AN INTERESTING
CHALLENGE COME UP HOW CAN WE
COLLECT BAGS? PHI IS IN BAGS
AND HOW DO WE REMOVE STICKERS TO
AVOID PHI AND OKAY LET'S GET
TUBING AND MAYBE THAT IS OUR OUT
THERE IS TUBING INCLUDED IN YOUR
CONTRACT? I THINK WE HAVE TO
FIGURE THIS OUT. IT IS A
MASSIVE GAP MISSING BIOLOGICAL
SIGNAL RINSING AND COLLECTING
CELLS MIGHT BE ANSWER AND WE
WILL PROBABLY GET INADEQUATE
SAMPLE IT THAT IS REALLY
DISAPPOINTING AT THIS PHASE IN
THE GAME WE CAN'T BE
CHARACTERIZING SAMPLES IN A
SYSTEMATIC WAY.
>> SOMETHING TO THINK ABOUT.
EACH MILL IS AT $30,000 AND
KEEPING THAT IN MIND.
LET'S SEE. MARCELO FOR CIDR,
HOW MANY PATIENTS ARE YOU
MISSING?
THIS IS A VOLUNTEER
ORGANIZATION.
IS THERE ANY WAY OR ANYONE DONE
A CALCULATION APPROXIMATELY HOW
MANY ARE MISSING?
I DON'T KNOW IF WE CAN EVEN DO
THAT BUT THINK YOU ARE MAYBE
GETTING HALF OF T-CELL OR OF
ALL. WHAT DO YOU THINK?
>> YES. THANK YOU, MIKE.
WAY WE DO IS WE KNOW DENOMINATOR
WHICH ARE SHIPPED PRODUCTS THAT
SOMETIMES IS DIFFICULT TO
EXTRACT THAT FROM THE COMPANY
AND THEY SAY PATIENTS HAVEN'T
SHARED CONSENT TO SHARE
INFORMATION AND RESPONSE IS TELL
ME YOU DON'T HAVE TO TELL ME
EXACTLY WHO DID OR WHO DID NOT
BUT TELL ME THE PERCENTAGES AND
WHEN WE DID WITH NOVARTIS WAS
70%. YOU SEE, THERE IS A TIME
LAG BETWEEN TIME THAT THEY GET
PRODUCT AND TIME CENTER WILL
REPORT TO US AND IS STILL A
VOLUNTARY PROCESS WE ARE MISSING
AND LOOKED AT BY CENTERS AND
VARIES FROM 0 TO 90% AND CENTERS
REPORT MOST CASES AND SOME
CENTERS DON'T REPORT ANY OF
THEM.
I THINK THAT FROM US WHAT WE DO
IS WE TRY TO UNDERSTAND. WE
WANT TO SEE FITNESS OF DATA AS
WELL.
SHOULD WE FIT OR INCLUDE
PATIENTS ON STUDIES THAT ONLY
REPORT 20% OF CHIMERA FOR
EXAMPLE WHAT IS THE SELECTION
THERE? YOU KNOW, WHO THEY ARE
REPORTING OR NOT REPORTING AND
IS REALLY EXTREMELY IMPORTANT
FOR US TO DO IT. WE ARE
OPERATING ON VOLUNTARY WORK AND
KNOW PEDIATRIC CENTERS TEND TO
REPORT MUCH BETTER THAN ADULT
CENTERS AND PROBABLY 10 OR 15%
GREATER AND BECAUSE, FOR
EXAMPLE, FOR KITE, IT IS ABOUT
60% FOR LYMPHOMA. SO, I THINK
THAT WE HAVE A FIFTH -- MORE
THAN 50% OF COMMERCIAL
REPRESENTATIVE HERE THAT VARIES
BY PRODUCT.
>> REASON I ASK THE QUESTION IS
TO BE PROVOCATIVE WOULD BE NICE
TO FIGURE OUT HOW TO NOT ONLY
GET BETTER REPORTING BUT WE NEED
MORE DATA TO ACTUALLY GET MOST
OF THE DATA IN. IT IS A BIG
CHALLENGE FOR YOU AND FOR ALL OF
US.
>> YEAH.
>> FINAL QUESTION TO REJENA.
SO, THIS IS A -- YOU KNOW, YOUR
OPINION AND I LOVE PEOPLE'S
COMMENTS IN THE AUDIENCE.
I AM REALLY INTRIGUED ABOUT
COMMENTS OF [INDISCERNIBLE]
WHERE DATA IS MIXED AND DON'T
KNOW WHAT TO DO WITH IT AND
CENTERS ARE WAITING UNTIL WE SEE
CD19 AND BELIEVE YOU NEED
SOMETHING FOR CELLS TO EXPAND
UPON.
HOW CAN WE GET WORD OUT TO
CENTERS OR FIGURE OUT HOW WE CAN
CONSISTENTLY HAVE A PREINFUSION
CD19 COUNT IN A WAY I WANT IT TO
BE PART OF CIDR DATA.
BUT, YOU KNOW, SEATTLE SHOWED
VERY NICE DATA AT CHLA DID THAT
AS WELL AND CONFIRMED DATA AND
IN FIELD WE HAVE TO FIGURE OUT
WHAT CD19 BURDEN IS AT TIME OF
INFUSION AND WHAT THOUGHTS ARE
ABOUT THAT REGINA.
>> IMPORTANT TO KNOW PERIPHERAL
AND BONE MARROW 19 YOU ARE MORE
INTERESTED IN.
>> I WILL TAKE EITHER ONE. I
DON'T CARE.
>> PERIPHERAL AND THIS WORK AND
TRYING TO GET STANDARDIZED
GUIDELINES TOGETHER AND HOW WE
CAN START TO PRACTICE A LITTLE
MORE SIMILARLY AND COMPARATIVE
DATA FOR CONSORTIUMS AND WAY TO
START TO GET PEOPLE TO DO THINGS
ON PULLING DATA AND ANTIGEN
BURDEN AND FOR US WE DO
PREINFUSION AND WE DON'T HAVE
ABILITY TO REPLICATE STUDIES YOU
DID AT SEATTLE. WE DO FOLLOW AT
LEAST FOR-I KNOW TWL ARE MORE
FUSIONS THAT HAVE PRIOR TO CARS
AND WE WILL START ABOUT 1 TO 2
MONTHS AND CHECKING CD19S ABOUT
EVERY 2 WEEKS OR SO TO SEE
RECOVERY AND GETTING PATIENTS TO
BE.
>> TO WHAT PERCENTAGE.
>> WHAT?
>> WHAT PERCENT ATH DO YOU
ACQUIRE?
>> WE HAVE EXACT NUMBER, I
THINK. THERE WAS DISCUSSION
YESTERDAY IT THAT WE HAVE
RECOVERY 3%. WE HAVEN'T SEEN
THAT SOMEWHERE BETWEEN 1% RISING
CLOSER TO THIS AND THERE ARE
TIMES WE GET TO FOUR MONTHS AND
DON'T SEE -- BONE MARROW SHOWING
EVIDENCE OF OVER 1 TO 2% AND
WILL GO AHEAD FROM THERE.
>> OKAY. MAKES SENSE.
IMPORTANT QUESTION?
>> I HAVE A QUESTION ABOUT THAT.
WE SOMETIMES GET SOME OF THE
REGULATOR QUESTIONS THROUGH
COMPANIES THAT THEY -- WE ARE
GETTING MORE OFTEN THESE
SPECIFIC QUESTIONS. HOW OFTEN
CENTERS ARE DOING CD19 AND
WHETHER TO INCORPORATE THAT IN
REGISTRY AND SOMETHING WE NEED
INPUT OF HOW OFTEN THIS IS DONE
AND HOW EASY IT IS COLLECTIBLE.
>> EASY TO INPUT AND DOING AS A
FIELD DECIDING WHAT WE WANT
COLLECTED CONSISTENTLY. IT IS
TRICKY PRE. AS REGINA MENTIONED
THERE IS PERIPHERAL PREAND BONE
MARROW PREAND PREPRIOR TO LD AND
PRE PRIOR TO INFUSION. WE ARE
NOT ALL ON THE SAME PAGE WITH
THAT. IT WOULD BE A NICE THING
FOR US TO THINK ABOUT THAT.
ALSO, WHEN WE DO IT FROM FLOW
FROM BONE MARROW WE DON'T HAVE
TO TELL PEOPLE BLASTS TOTAL CD19
FOR EVERYTHING AND RECALCULATING
HOW THEY DO THAT AND A BIT OF A
BURDEN TO FIGURE OUT AND
IMPORTANT THING FOR US TO
UNDERSTAND I THINK.
>> CLEARING ALL THAT CONFUSION
UP THIS SESSION IS OVER. HAVE A
BREAK NOW TAKE A QUICK BREAK.
11:15 WE WILL BE BACK.
WE WILL GET STARTED.
>> THANK YOU, STEVE, FOR
INTRODUCING AND GIVING THIS
TALK. JUST A JOKE, STEVE. I'M
TEASING.
SO, MY -- THE KEY TO DISCLOSURE
HERE IS SUPPORTING ADAPTIVE
ASSAYS.
I WANT TO FOCUS ON IN THIS
PARTICULAR TALK GOING INTO
DETAIL ABOUT GS THAT IS
IMPORTANT FOR US TO LEARN ABOUT
NGS. I WILL TRY TO DISTINGUISH
FOR EUROPEAN COLLEAGUES MAYBE
WHY GS MIGHT INFORM ABOUT
TECHNIQUES OF PCR. THIS IS NGS
IN THE BONE MARROW AND FLOW IN
IT.
NGS IS GETTING BELOW 10 TO THE
MINUS 4 CONSISTENTLY AND YOU
PICK UP 10 TO THE MINUS 5 WITH
PCR-BASED TECHNIQUES MISSING A
LOT OF PATIENTS AND THESE MATTER
AND NGRSMRD IN BLOOD AND FLOW IN
BONE MARROW YOU ARE MISSING AND
GETTING MORE PATIENTS WITH NGS
IN BLOOD THAN FLOW IN BONE
MARROW.
IMPORTANT OVENGS IN THIS STUDY
STEVE REFERRED TO EARLIER IS
THERE ARE TWO CONCEPTS TO
UNDERSTAND AND LIMITED DETECTION
AND THAT IS REALLY NOT REFERRING
TO WHETHER YOU CAN DETECT OR NOT
BUT REFERRING TO IF YOU REPEAT
SAMPLE 93% OF TIMES YOU WILL BE
ABLE TO DETECT IT. IN OTHER
WORDS IF YOU HAVE A LOW
FREQUENCY EVENT THAT IS THERE IN
THIS ASSAY, IT CAN BE TRUE NEXT
TIME YOU DO BONE MARROW YOU
WON'T NECESSARILY DETECT IT. IT
IS 1 IN 10 MILLION.
IF YOU LOOK AT SAMPLES, LIMITED
DETECTION CAN BE HIGH AND UP
HERE.
THAT IS BECAUSE OF SEQUENCES
USING FOR NGRS ARE NOT AS
SENSITIVE AS OTHERS AND BOTTOM
LINE THERE ARE DETECTIBLE
DISEASES THINGS ARE BELOW
LIMITED DETENTION AND LIMITED
QUANTITY FICTION AND WE FOUND A
PRETTY PROFOUND CUTOFF THAT WAS
BELOW WHAT YOU DO IF YOU LOOKED
AT PCR IF YOU LOOKED AT PCR AND
10 TO THE MINUS 6 THAT IS
SENSITIVE OF LIMITED DETECTION
AND QUANTITY IF IKS WE DIDN'T
SEE A DIFFERENCE BETWEEN THE TWO
AND WHY? PATIENTS TRULY
POSITIVE ARE PUT INTO THE
NEGATIVE CATEGORY AND IF YOU
LOOKED AT DETECTIBLE EVEN ONE
EVENT IN 10 MILLION HAD
PROGNOSTIC SIGNIFICANCE AND DATA
AT 28 DAYS AND AT TWLEE MONTHS
MEANING BY TIME YOU HAVE 3
MONTHS IF IGH CLONE THAT IS
POSITIVE 100% OF PATIENTS HAD
EVENT THAT IS SOMETHING TO KEEP
IN MIND SEEING THINGS AFTER CAR
THEY ARE MEANINGFUL. A COUPLE
THINGS TO UNDERSTAND HOW LONG IS
RELAPSE AND DISEASE DETECTING IT
AND HALF YOUR PATIENTS RELAPSED
PRIOR TO YOU BEING ABLE TO
DETECT THEM AND CUTOFF OF 10 TO
THE MINUS 6 AND QUARTER RELAPSED
BEFORE YOU DETECTED IT AND IF
YOU HAPPENED TO DETECT IT AND
THEY DIDN'T RELAPSE YOU HAD 2
MONTHS ON AVERAGE IF USING
CUTOFF OF 10 TO THE MINUS 6 AND
1 MONTH ON AVERAGE IF YOU USE
FLOW. BOTTOM LINE, YOU HAVE
VERY LITTLE TIME IF YOU USE
THESE TECHNIQUES AND IF YOU
CATCH IT VERY EARLY BELOW 10 TO
THE MINUS 6 CUTOFF WHERE YOU SEE
1 OR 2 EVENTS IN 10 MILLION ON
ADAPTIVE REPORT AND LESS THAN 0
YOU HAVE 6 MONTHS BEFORE
SOMETHING WILL HAPPEN
POTENTIALLY MEDIAN.
SO, IT IS IMPORTANT TO GAUGE
THAT AS YOU THINK ABOUT WHAT YOU
WILL DO IN ORDER TO RESPOND TO
YOUR MRD THESE CURVES ARE
IMPORTANT TO UNDERSTAND AND
QUALIFICATIONS FOR CURVE LOOKING
AT THIS LOSS OF B CELL AMRASHIA
YOU SEE PATIENTS LOST IT BEFORE
3 MONTHS HAD INCREDIBLY LOW
INCOME AND 6 MONTHS WITH 20% OR
ABOVE 20% HAVING DECENT SURVIVAL
AND BETWEEN 9 AND 6 MONTHS IS A
BIG QUESTION MARK I WANT TO HAVE
YOU TOTALLY DON'T BELIEVE THESE
TWO CURVES THAT ARE BASED ON
TOTAL OF 6 PATIENTS. OKAY?
SO, THEY MAY MEAN NOTHING.
TALKING ABOUT THINGS HERE WE
DON'T KNOW 9 TO 6 MONTHS AND
INTUITIVELY KEEPING IF YOU KEEP
THEM FOR 6 MONTHS AND WE DON'T
KNOW IF YOU SHOULD TRANSPLANT
EVERYONE LOSING B CELL APLASIA
AT 9 MONTHS AND SHOULD DO A
STUDY OR MORE AND KEEP IN MIND 6
TO 9 MONTH GROUPS AND NICE TO
SHOW PATIENTS GETTING TO 1 YEAR
AND HAVE B KRCHL APLASIA LONG
TERM SURVIVAL IS ABOUT 80% BASED
ON THIS DATA AND LEADS US TO
THIS TRIAL THAT WILL BE GONE
INTO IN GREAT DETAIL AND BOTTOM
LINE SCREENING INTENSELY TO SEE
IF AND WHEN WE SHOULD ACT ON IT
AND TRANSPLANT IS AN OPTION FOR
THOSE PATIENTS THAT BECOME
POSITIVE OR LOSE BC APLASIA AND
GIVE DETAIL ABOUT THAT
MENTIONING HOW I TREAT PUBLISHED
NOW AND YOU CAN HOPEFULLY REFER
TO THIS.
THIS IS WRONG ONE. I APOLOGIZE
AND I SENT UPDATED SLIDE AND
THINK I HAVE A COUPLE MINUTES
LEFT.
I WILL TALK ABOUT IN THE LAST
MINUTE OR SO ABOUT CAVEATS OF
NGS MONITORING AND LONG AND
SHORT IS THAT SENSITIVITY AND
SPECIFICITY OF NEXT GEN SEQUENCE
MONITORING IS RELATED TO HOW
MANY RECOMBINATIONS OR VDJ
RECOMBINATIONS YOU HAVE OR TCR
RECOMBINATIONS AND IF YOU HAVE
HEAVY CHAIN IGH YOU HAVE IN MOST
CASES IVS AND IDJ AND LOTS OF JS
AND YOU HAVE HIGH SENSITIVITY
AND LOTS OF POSSIBILITY FOR
REARRANGEMENTS AND LIKELY TO
NATURALLY REPLICATE SOMETHING
THAT IS SAME AS YOUR MRAFT. IF
YOU HAVE LIGHT CHAINS YOU WON'T
HAVE D OR WON'T HAVE V AND G AND
USUALLY MUCH LESS KEEP IN MIND
LIGHT CHAINS ARE NOT AS
SENSITIVE AS HEAVY CHAINS CAPPA
OR LAMBDA KEEP IN MIND SAME WITH
TCR GAMMA AND BETA TCR GAMMA IS
WORSE THAN TCR BETA AND BOTTOM
LINE JUST NOT AS MUCH
REARRANGEMENTS IF CAPPA OR GAMMA
OR TCR GAMMA THAT YOUR
REARRANGEMENTS ARE NOT VALID?
NO. DOESN'T MEAN THAT AT ALL.
IT MEANS IF YOU HAVE ONE MARKER
BE SUSPICIOUS OF IT. MIGHT BE
BACKGROUND NOISE IN THAT CASE.
WHAT SHOULD YOU DO?
REPEAT. IF YOU GET A SECOND
MARKER AND ALL OF US GETTING NGS
THINGS AT VERY BEGINNING AND
THREE MARKERS YOU ARE GREAT AND
HOPEFULLY YOU WILL HAVE MORE
THAN THREE MARKERS AND IF YOU
GET A SECOND MARKER THAT
EMERGES, YOU SHOULD ABSOLUTELY
BELIEVE IT AND IF YOU HAVE 2TCR
MARKERS OR TWO CAPPA OR LAMBDA
MARKERS.
BOTTOM LINE YOU CAN IF YOU GET A
SINGLE MARKER ESPECIALLY IF NOT
IG HEAVY CHAIN BESUSPICIOUS OF
IT AND REPEAT IT AND IF RISING
YOU MIGHT WANT TO BELIEVE IT IF
LOW AND STEADY WE FOLLOW A LOT
LIKE THAT AND MIGHT NOT BE REAL
ESPECIALLY IF OTHER MARKERS YOU
HAD PREVIOUSLY ARE NOT SHOWING
UP.
IMPORTANT CAVEATS FOR YOU TO
MAKE SURE TO REPEAT IT AND MAKE
SURE ABOUT IT AND WHEN PROVING
IT IS TRUE YOU CAN TAKE YOUR
ACTION AND THAT IS ALL I HAVE.
THANK YOU.
>> [APPLAUSE].
>> >> WE HAVE SHEENA TALKING
ABOUT THE HUMANIZED CAR NEXT.
THANK YOU VERY MUCH. I WILL
TALK ABOUT THE EXPERIENCE THAT
IS AVAILABLE WITH HUMANIZED CAR.
THESE ARE DISCLOSURES THAT ARE
RELEVANT TO THIS TALK. I WILL
START OFF BY JUST A BRIEF
BACKGROUND OF WHY WE THINK ABOUT
CHANGING CARS THAT WE HAVE
AVAILABLE NOW. AS YOU ALL KNOW,
MOST OF THE CARS INITIALLY
DEVELOPED WERE DEVELOPED WITH
DOMAINS OF [INDISCERNIBLE]
ORIGIN AND THERE WAS A
HYPOTHESIS FROM THE BEGINNING
THAT IS POSSIBLE THAT YOU COULD
SEE ANTIMOUSE IMMUNE REJECTION
OF T-CELLS WE AND OTHERS THOUGHT
THROUGH DEVELOPING HUMANIZED OR
FULLY HUMAN DOMAINS AND REASON
FOR THAT INITIAL EXPERIENCE WITH
CAR T-CELLS YOU SEE DEPENDING ON
PRODUCT DIFFERENT LENGTH
PERSISTENCE WE KNOW AND LEARNED
OVER TIME DEPENDING ON
COSTIMULATORY DOMAIN YOU CAN SEE
DIFFERENT LENGTHS OF PERSISTENCE
WITH CD28 PRODUCTS EXPANDING
MORE RAPIDLY BUT NOT PERSISTING
AS LONG AS 41BB PRODUCTS
PERSISTING LONGER. EVEN WITHIN
ONE PRODUCT, YOU CAN SEE
DIFFERENT PERSISTENCE BASED ON
WHAT YOU SEE IN EACH PATIENT.
WHY IS THAT IMPORTANT?
WELL, WE -- AND OTHERS HAVE
LEARNED OVER TIME THAT
PERSISTENCE PARTICULARLY FOR 1BB
CONTAINING PRODUCTS WHERE YOU
TYPICALLY WILL SEE LONGER
PERSISTENCE IT THAT IS REALLY
IMPORTANT FOR DURABLE EMISSIONS
AND MIKE SHOWED YOU DATA FROM
ELION AND ENSON TRIALS AND FROM
SEATTLE GROUP AND FROM OUR GROUP
I WILL SHOW YOU THAT PATIENTS
THAT HAVE EARLY LOSS OF CD19 CAR
T-CELL PERSISTENCE MARKED AND
MEASURED BY EARLY B CELL
RECOVERY HAD HIGHER RISK OF
RELAPSE AND SEEING CD19 POSITIVE
RELAPSE AND THAT DISEASE WASN'T
CLEARED IN PATIENTS WITH LONG
TERM PERSISTENCE IT COULD COME
BACK.
WHAT WE AND OTHERS HAD DONE WAS
THINK ABOUT HOW WE COULD
POTENTIALLY OVERCOME THAT.
ON RATIONALE THAT IS RELATED TO
IMMUNE MEDIATED REJECTION THAT
SCF DOMAIN WE DID TRIAL WITH
HUMANIZED CAR 19 BASED ON
ORIGINAL MURINE CAR AND SCF
DOMAIN TO LOOK MORE LIKE HUMAN
PROTEIN AND DID THIS WITHOUT
KNOWING IF IT WAS REASON FOR
POOR PERSISTENCE AND MAJORITY OF
PATIENTS AND LOOKED AT PATIENTS
PREVIOUSLY RECEIVING CAR
RETREATMENT COHORT AND OPENED TO
PATIENTS NO THE RECEIVING CAR
LEFT COLUMN CAR NAÏVE AND
DEMOGRAPHICS OF PHASE 1 STUDY WE
DID IN THIS. I WANT TO POINT
OUT THAT MANY PATIENTS WERE
HEAVILY PRETREATED AND WE HAD A
LOWER DISEASE BURDEN THAT WAS
GOING INTO THIS TRIAL.
AND BASED ON REFERRAL PATTERNS
AND ELIANA TRIAL ENROLLING AT
SAME TIME AS THIS AND THAT IS TO
NOTE WHEN LOOKING AT TOXICITY
DATA.
THIS IS TOXICITY WE SAW IN THE
TRI
TRIAL.
WHAT I'M HIGHLIGHTING HERE IS
CRS AND WE SAW SIMILAR RATES
OVERALL OF CRS AND LOWER RATES
OF GRADE 3 AND 4CRS IN BOTH CAR
NIE EF AND CAR RETREATMENT
COHORT BEARING IN MIND PATIENTS
HAD LOWER DISEASE BURDEN GOING
IN.
THIS WAS CERTAINLY AS SAFE AS
WHAT WE SAW WITH THE MURINE
PRODUCT.
WITH NEUROTOXICITY WE SAW ALSO
LOWER RATES OF GRADE 3 AND 4 AND
NEUROTOXICITY IN RETREATMENT
COHORT KNOW GRADE 3 AND 4
NEUROTOXICITY.
WORD ABOUT THE EFFICACY. IT IS
IN THIS GROUP OF PATIENTS AND
I'M SHOWING YOU TWO DIFFERENT
RELAPSED FREE SURVIVAL CURVES
HERE AND ONE FOR RETREATMENT
COHORT IN RED AND COHORT IN
BLUE. IN RETREATMENT COHORT WE
SAW INITIAL CR RATE WAS 79% IN
THIS GROUP OF PATIENTS HOWEVER
MANY OF THESE PATIENTS ACTUALLY
CAME TO US IN REMISSION AND
MIGHT HAVE BEEN REFERRED FOR
POOR PERSISTENCE WITHOUT HAVING
HAD A RELAPSE.
WHAT WE LOOKED AT FOR OVERALL
RESPONSE WE DEFINED AS CR WITH B
CELL EPLASIA SHOWING LOW
BIOACTIVITY IN CAR AND THAT
OVERALL RATE WAS 64% AND WE SAW
IN TERMS OF RELAPSE FREE
SURVIVAL IN THAT GROUP WAS
PRETTY ENCOURAGING. I WILL SHOW
YOU WHAT PERSISTENCE LOOKED
LIKE. IT WAS SHORTER BUT WE
STILL WERE ABLE TO ACHIEVE A
FAIRLY GOOD RELAPSE FREE
SURVIVAL OF 74% OF 12 MONTHS AND
58% AT 24 MONTHS IN THIS GROUP
AND CAR NAÏVE GROUP WAS
ENCOURAGING AS WELL LOOKING AT
INITIAL RESPONSE RATE AND CR
RATE WAS 98% AND RELAPSE FREE
SURVIVAL AT 12 MONTHS WAS 84%
AND 24 MONTHS WAS 74% AND
ENCOURAGING IN HIGHER NUMBERS WE
HAD SEEN ON INITIAL PHASE 1
CHILD MURINE CAR. THESE
POPULATIONS AS I MENTIONED ARE
NOT COMPLETELY COMPARABLE.
I THINK SEEING MORE PATIENTS
WITH LOWER DISEASE BURDEN MAY
PARTIALLY ACCOUNT FOR THIS AND
CURRENTLY ARE CONDUCTING PHASE 2
TRIAL TO TRY TO HOPE TO MATCH UP
PATIENTS TO SEE IF RATES ARE
REALLY BETTER THAB WHAT WE HAVE
SEEN WITH MURINE.
MAIN OBJECTIVE OF THIS IS TO SEE
CAN WE IMPROVE PERSISTENCE?
WHAT I'M SHOWING HERE IS QPCR
DATA FROM THIS ON LEFT AND
RETREATMENT COHORT ON RIEBLTH
AND SEE IN CAR NAÏVE GROUP THERE
ARE SIGNIFICANT FRACTION OF
PATIENTS THAT HAVE PERSISTENCE
OUT TO 1 YEAR OR EVEN OUT TO 2
YEARS WHICH IS WHAT THIS GRAPH
EXTENDS OUT TO. RETREATMENT
GROUP THERE IS A LOWER NUMBER OF
PATIENTS WHO HAVE THAT EXTENDED
PERSISTENCE.
WE DID SEE PATIENTS WHO HAD POOR
PERSISTENCE IN THE PAST WERE
MUCH MORE LIKELY TO HAVE POOR
PERSISTENCE WITH HUMANIZED CAR
AS WELL.
THAT ARGUES AGAINST IMMUNE
MEDIATED REJECTION PHENOMENON
THAT IS PROBABLY NOT TRUE FOR
EVERYBODY. IT IS LIKELY TRUE
FOR SOME PATIENTS.
WE HAD A NUMBER OF PATIENTS IT
THAT RESPOND TO RETREATMENT AND
REINFUSION AND HAVE POOR
PERSISTENCE AGAIN AND WHY WE
STARTED TO GET INTO COMBINING
THAT WITH CHECKPOINT BLOCKADE.
SO WE DID SEE A FEW PATIENTS YOU
CAN SEE THAT DID HAVE EXTENDED
REALLY LONG PERSISTENCE WITH
RETREATMENT WITH HUMANIZED CAR.
IN SOME PATIENCE THIS MIGHT DO
THE TRICK AND IN PATIENTS LOSING
PERSISTENCE EARLY TO GO BACK TO
RELAPSE FREE SURVIVAL WE WERE
ABLE TO OVERCOME THAT WITH
REINFUSION IN MANY CASES TO
IMPROVE THAT RELAPSE FREE
SURVIVAL LONG TERM THAT IS
ENCOURAGING AND SHOWS US WE HAVE
ROOM TO GO WITH THIS.
NEXT QUESTION THAT I THINK IS
PROBABLY A KEY QUESTION THAT IS
GOING FORWARD IS NOT ONLY CAN WE
OVERCOME POOR PERSISTENCE IF IN
RETREATMENT GROUP CAN WE IMPROVE
CAR T PERSISTENCE MOVING NEEDLE
FORWARD AND FIELD FORWARD. WE
DID ANAL SIZE THAT THERE WASN'T
POWER TO LOOK AT THIS WE DID
COMPARISON OF CAR NAÏVE GROUP
WITH INITIAL PHASE 1 TRIAL.
THIS IS NOT STATISTICALLY
SIGNIFICANT IN TERMS OF
DIFFERENCE EFFECT SIZE IS
SUGGESTIVE. WE ONLY SEE 15% 6
MONTH PROBABILITY OF B CELL
RECOVERY IN HUMANIZED CAR NAÏVE
GROUP COMPARED TO 29% OF MURINE
PRODUCT AND WARRANTS STUDY
SEEING IF WE DO THIS FROM OUTSET
CAN WE IMPROVE UPON PERSISTENCE?
THERE IS SEVERAL OTHER GROUPS
THAT HAVE EXPLORED HUMAN OR
HUMANIZED CAR.
SNIPPETS HERE THANK YOU COURTESY
OF CLEAN.
GIVING BRIEF INFORMATION ON
THESE STUDIES THEY STUDIED FULLY
HUMAN FC DOMAIN AND PRIMIARILY
FOR PATIENTS WITH CD19 AFTER CAR
INCLUDED PATIENTS WITH B CELL
RECOVERY WITHIN 12 MONTHS AND
LATER WAS AMENDED TO EXCLUDE
THAT. THERE WAS SOME UNEXPECT
INCREASED TOXICITY SEEN IN THE
TRIAL THAT ENDED UP CLOSING
EARLY.
THE NCI HAS ALSO DEVELOPED A
FUELLY HUMAN CD19 CAR WITH CD20
DOMAIN AND MATCHES MORE CLOSELY
THEIR INITIAL MUIR EVEN PRODUCT
AND THEY DID A PHASE 1 TRIAL IN
ADULTS WITH NIHL AND SHOWING
GOOD CR RATE OF 55% IN 20
PATIENTS AND IN THE GRAPH AT
BOTTOM THAT IS EVENT FREE
SURVIVAL THAT IS REALLY PRETTY
COMPARABLE TO WHAT WAS SEEN WITH
MURINE PRODUCT AND OF NOTE THEY
HAD SEEN A HIGHER RATE OF
NEUROTOXICITY WITH MURINE CD19
CAR AND ON THIS TRIAL SAW
ACTUALLY SEVERE NEUROTOXICITY.
INTERESTINGLY WHAT WE ARE
GETTING AT WITH CAR IT THEY DID
STUDIES OF CAR T-CELL RESPONSES
AND SAW THAT LOWER CAR LEVELS
AND WE DID NOT SEE THAT WITH
HUMAN CARS SUGGESTING THAT. SO,
IN INTEREST OF TIME I CAN'T GO
OVER ALL HUMANIZED CAR SHOWING
REPORTS AND VARIOUS.
CAR HUMANIZED 19 TO GO WE MAY
SEE IMPROVEMENTS. SO THANK YOU
TO EVERYONE INVOLVED AND FOR
EVERYONE ORGANIZING THIS.
>> THANK YOU FOR BRINGING ME
HERE TODAY.
OUT OF OUR INSTITUTION --
HOWEVER WHEN YOU FURTHER
SUBDIVIDE PATIENT POPULATION
THIS PATIENT POPULATION DIDN'T
REALLY SEEM TO --
41BB DOMAIN 21 PATIENTS
PROCEEDED THE TRANSPLANT IN 26
DID NOT FOLLOWING REMISSION AND
YOU CAN SEE FOR EVENT FREE
SURVIVAL AND NOTED RELAPSE FREE
SURVIVAL IMPROVEMENT SHOWN IN
THE RED ON LEFT COMPARED TO
THOSE WHO DIDN'T PROCEED TO
TRANSPLANT IN GREEN AS WELL.
THERE IS A TREND TOWARDS
IMPROVED OVERALL SURVIVAL ON THE
RIGHT. IT DIDN'T REACH.
PR
WITHIN THIS PATIENT POPULATION
THEY DID SEE IMPROVEMENT AND
OVERALL SURVIVAL. THOUGH THEY
ARE LONG-TERM FOLLOW UP IS
SOMEWHAT LIMITED IN REPORT.
I THINK THAT IS LIKELY BECAUSE
THE CD28 CO-STEM IS LIKELY TO
PROVIDE LONG-TERM PERSISTENCE
COMPARED TO 41BB AND NOT ALL
STUDIES SHOW IMPROVEMENT
FOLLOWING CD19 CAR AND REPORT
FROM 2018 AND ADULT COHORT OF 44
PATIENTS AND SURVIVAL ON THE
RIGHT AGAIN OVERLAPPING CURVES
AND 6.
TRANSPLANT COHORT. EVEN STILL
OVERALL SURVIVAL IMPROVED WITH
TRANSPLANT FOLLOWING CD19 CARS
NOT BEING CONSISTENTLY OBSERVED
DATA FROM COHORT OF PATIENTS
TRANSPLANT PATIENTS WERE NOT
[INDISCERNIBLE] AND LINES REALLY
ARE SIGNIFICANTLY OVERLAPPING
AND THEREFORE HOW CAN WE
IDENTIFY HIGH RISK POPULATION
THAT WILL BENEFIT FROM POST CD19
CAR T-CELL TRANSPLANT AND WITHIN
OUR STUDY COHORT LOOKING AT
PATIENTS WITH HISTORY OF
TRANSPLANT REALIZE DIDN'T SEE
BENEFIT FOR PATIENTS TO FOLLOW
TRANCE PLANT FOLLOWING REMISSION
AND RED LINE PROCEEDED THOSE
WITH TRANSPLANT COMPARED TO
BLACK AND SURVIVAL NOT IMPROVED
AND IF PATIENTS HAD EARLY BCA
LOSS DEFINED AT DAY 63 THAT IS
WHERE YOU SEE REALLY NICE
IMPROVEMENT AND LEUKEMIA FREE
SURVIVAL THAT IS INCLUSIVE OF
PATIENTS WITH PRIOR TRANSPLANT
AND CHINA GROUP ALSO FURTHER
SUBDIVIDED PATIENTS AND ANALYZED
PATIENTS THAT ARE PARTICULARLY
HIGH RISK AND IDENTIFIED
PATIENTS THAT WERE HIGH DISEASE
BURDEN DEFINED GREATER THAN 5%
BONE MARROW AT TIME OF CAR
T-CELL INFLUGS AND FREE SURVIVAL
ON THE RIGHT AND OVERALL
SURVIVAL ON THE LEFT AND
SIGNIFICANT IMPROVEMENT AND
EVENT FOR SURVIVAL WITHIN THE
PATIENT COHORT AND THEY NOTED
BENEFIT WITH TRANSPLANT FOR
PATIENTS THAT HAVE POOR
PROGNOSTIC MARKERS WITHIN STUDY
DEFINED AT MLL AND ETAPDX1 AND
HERE, AGAIN, EVENT FREE SURVIVAL
SIGNIFICANTLY IMPROVED AND JUST
A TREND TOWARDS IMPROVEMENT OF
OVER ALL SURVIVAL AND REPORT OUT
OF THE HUTCH REPORTING ON ADULT
PATIENT POPULATION THAT RECEIVES
CD19 CAR AND PROCEEDED TO
TRANSPLANT REALLY HIGHLIGHTED
ALL WE WOULD EXPECT THERE IS
REALLY INCREASED MORTALITY RISK
ASSOCIATED WITH PATIENTS COMING
TO TRANSPLANT WITH HIGH
COMORBIDITY INDEX THAT
HIGHLIGHTS WE NEED TO DO A GOOD
JOB PICKING AND SELECTING
TRANSPLANT ELIGIBLE PATIENTS AND
THEN REPORTS OUT OF THE NIH
EXPERIENCE THIS IS A MULTITUDE
OF CARS WITH CD19 CARS AND
CD1922 AND CAR AND LOOKED AT
TRANSPLANT NAÏVE PATIENTS THOSE
PROCEEDING TRANSPLANT REMISSION
ATTAINMENT OVERALL DID WELL AND
THEY NOTED THAT PATIENTS WITH
OVER 5 LINES THERAPY PRIOR TO
IMMUNOTHERAPY DISEASE BURDEN HAD
TROUBLE AFTER RELAPSE AND
APOLOGIZE.
THAT IS A TYPO. ONE OF THE
EFFORTS WE ARE PROCEEDING
BECAUSE OF THE CAR CARE TRIAL
THAT MIKE MENTIONED IN
DISCUSSION OF THE CLONO SEEK AND
OBJECTIVE OF THIS TRIAL IS TO
ASSESS EFFICACY OF BIMARKER
GUIDED RISK BASED STRATEGY TO
MONTH N TORE REMISSION AND
SEQUENCING COLONO SEEK
MONITORING TO INFORM DECISION
MAKING FOR TRANSPLANTS AND WITH
THESE TRIAL AND WHAT THEY AIM TO
DO ENROLLING PATIENTS AROUND DAY
42 FOLLOWING CD19 CAR WITH
STIMULATORY DOMAIN WILL MONITOR
PATIENTS PERIPHERAL BLOOD EVERY
TWO WEEKS FOR B CELL APLASIA AND
CLONO SEEK MONITORING AND THEN
FREQUENT BONE MARROWS AT MONTH
2, 3, 6, 9 AND 12. WE ARE
HOPING TO IDENTIFY PATIENTS
PRIOR TO RELAPSE OR PATIENTS
REALLY HIGH RISK OF RELAPSING
RECOMMENDING TRANSPLANT DEFINED
IN B CELL RECOVERY IN 6 MONTHS
OR COLONO SEEK POSITIVITY AS
MIKE WAS DISCUSSING TOWARDS END
OF HIS PRESENTATION.
IT IS WITHIN 1 YEAR OF CAR
T-CELLS AND SECONDARY OBJECTIVES
TO DESCRIBE LEUKEMIA FREE
SURVIVAL AND RELAPSE WITHIN
PATIENT POPULATION AND
EXPLORATORY OBJECTIVES TO
EVALUATE RELATIONSHIP OF COLONO
SEEK TESTING IN BLOOD COMPARED
TO MARROW BLOOD COMPARED TO BONE
MARROW FLOW CITE OWE MTRY AND IN
BLOOD ELATING TO ABOUT. CELL
APLASIA AND WE ARE HOPING TO
EXPLORE T-CELL REPERTOIRE AND
DYNAMICS FOLLOWING CD19 T-CELL
AND PATIENTS AGES 1 THROUGH 25
YEARS AT TIME OF T-CELL CAR
TEEGS AND FLOW CITOMETRY AND
COLONO SEEK BY DAY 42 AND
EXPECTED TO HAVE ACCOUNT
RECOVERY ANC GREATER THAN 500
AND ABOUT. CELL APLASIA AND
NEED TO BE TRANSPLANT NAÏVE WITH
SUITABLE IDENTIFIED DONOR.
AND IN INCLUSION FROM MY VERY
SHORT TALK AND TRANSPLANT FOLLOW
ING CD19 CAR WITH 41B DOMAIN --
THERE IS LIKELY A LOW RISK
POPULATION TO AVOID TRANSPLANT
WITHOUT COMPROMISING LEUKEMIA
SURVIVAL AND SAFELY AVOIDING
TRANSPLANT THAT MAY -- PRIOR
LINES OF THERAPY AND PATIENTS
HEAVILY PRE-TREATED IN THOSE WE
TRANLS PLANT AND AVOIDING
FEASIBILITY OF NEXT GEN
SEQUENCING HOPEFULLY WILL OFFER
IMPORTANT INSIGHTS.
I WOULD LIKE TO THANK SEATTLE
IMMUNOTHERAPY CREW AND PROTOCOL
DEVELOPMENT IS PATIENTS AND
FAMILIES AND THANKS FOR ALLOWING
ME TO SPEAK TO YOU TODAY.
NEXT IS -- CD19 RELAPSE
PREVEN
PREVENTION.
>> ALL RIGHT. I'M FROM SEATTLE
CHILDREN'S HOSPITAL AND I WILL
TALK ABOUT CD19 EXPRESSING TAPCS
BOOSTER STRATEGY FOLLOWING CD19
CAR T AND SORRY FOR FORMATTING
ISSUES CONVERSATION EARLIER
BETWEEN MIKE AND REGINA AND THIS
PROMPTED THAT AND ON STUDY PLAT
2 INVESTIGATION OF STRI CAR
1941BB CAR WE DID SHOW THAT WE
IDENTIFIED TWO RISK FACTORS FOR
PATIENTS EXPERIENCING EARLY LOSS
OF CAR T-CELL PERSISTENCE AND
FIRST IS ANTIGEN BONE MARROW
PRIOR TO DEPLETION.
BURDEN IN MARROW INCLUSIVE OF
MALIGNANT AND NONMALIGNANT B
CELLS AND INFERIOR DURATION IN
RED COMPARED TO B CELL DURATION
COMPARED TO THOSE WITH HIGHER
DISEASE OR ANTIGEN BURDEN AND
SECOND RISK FACTOR WE IDENTIFIED
IS EXPERIENCING RAPID EARLIER
CONTRACTION OF CARS FOLLOWING
INFLUGS APPEARED TO LOSE ABOUT.
CELL AMRASHIA EARLIER LOSS OF
PERSISTENCE DAY 10 AND 14 AFTER
CAR INFUSION CALCULATING A RATIO
AND PATIENTS WITH HIGH ERR
RATIOS EARLIER AND FASTER
CONTRACTIONS OF CAR T-CELL
NUMBERS AND IN BLUE YOU SEE
PATIENTS WITH HIGHER RATIOS AND
ARE PATIENTS THAT DIDN'T HAVE
PERSISTENCE OF CARS AT DAY 63 OR
ROUGHLY 2 MONTHS FOLLOWINGIN
FLUGS AND SETTING THRESHOLD OF
RATIO OF 1.5 AND HIGHER RATIO
PATIENTS RAPID EARLY CONTRACTORS
IN BLACK THEY HAVE FAR INFERIOR
PERSISTENCE COMPARED TO THOSE
THAT DIDN'T CONTRACT QUICKLY AND
WE SAID COMING TO HYPOTHESIZE IF
WE CAN FEED CARS IN VIVO POST
INFLUGS GIVING ANTIGEN
STIMULATION EXPANSION OF CARS IN
VIVO LEADING TO ENHANCED
PERSISTENCE AND DURABLE
REMISSIONS AND DOG THIS CREATED
NOVEL CELLULAR PRODUCT CD19
EXPRESSING ANTIGEN EXPRESSING
CELLS AND WE CLONED TRUNCATED
CD19 DESIGNATED BY T AND THIS
INCLUDED TRANS MEMBRANE AND WE
BASICALLY USED PATIENTS OT OL
GAUS T-CELLS TO TRANSDEUCE THIS
SHOWING UP TOP VECTOR DESIGNED
FOR CAR 19 AND WE HAVE IN
SEATTLE TAG FOR FLOW DETECTION
WITH -- TO TRANSLATE THIS WE
DEVELOP PLATTO 3 PILOT STUDY
FOLLOWING CAR 19 AND DIVIDED
INTO 2 PATIENT KOER HORTS AND
MANUFACTURING PLATFORMS ON THE
LEFT AND STARTING MATERIAL WE
USED WAS LEFTOVER AFORESIS
MATERIAL T-CELLS FROZEN DOWN
CRYOPRESERVE THE FORESIS FOR CAR
19 PRODUCTION AND THESE LOW
ANTIGEN PATIENTS IN DEPLETION
AND FOR PATIENTS THEY ARE
IDENTIFIED AT EARLY TIME POINT
AT WHICH POINT WE MANUFACTURER
TAPCS AND PATIENTS COULD BEGIN
DOSING OF TAPCS DAY 21 PROVIDED
CARS TOXICITY RESULTED AT THAT
TIME AND DOSING IS BELOW AND
PATIENT HAS 1 MILLION CAR CELLS
PER KILO AND THEY ARE DOSED
10 x 10 -- FLAT DOSE OF 5 x 10
CELLS FOR BIGGER PATIENTS THAT
CAN RECEIVE UP TO 6 DOSES OF
TAPCS EVERY FOUR WEEKS AND
PATIENTS DEMONSTRATE ONGOING
FUNCTIONAL PERSISTENCE OF
T-CELLS AND COHORT B INCLUDED
PATIENTS RAPID EARLIER
CONTRACTORS I PREVIOUSLY MENTION
THE AND OVERLAP BETWEEN TWO
PATIENT COHORTS THERE ARE
PATIENTS IN COHORT B WITH HIGH
ANTIGEN BURDEN AND CONTRACTION
OF T-CELLS AND FOR TIME I WON'T
GO INTO TOO MUCH WE ARE ABLE TO
CHARACTERIZE SOME EARLY SUBJECTS
CLINICAL TAPC PRODUCTS AND
SHOWING IN THE FIRST 7 SUBJECTS
OR SO OF THE FINAL TAPC PRODUCT
HOW MUCH WAS CD19 EXPRESSING AND
BLUE AND GREEN ARE BREAKDOWN OF
CD48 AND PRODUCTS WE DIDN'T
CONTROL FOR AND IDEA BEHIND THIS
IS MIMICKING WHAT MARROW OR B
CELLS IN PERIPHERAL BLOOD COULD
STIMULATE CARS AND LOOKING TO
SEE FOR EXAMPLE HOW TAPCS
COMPARE AND ANTIGEN BINDING
CAPACITY AND PRODUCTS IN PURPLE
THAT ARE COMPARED TO O AND
PERIPHERAL BLOOD SAMPLES AND
T-CELL INFLUGS AND TAPCS LOOKED
SIMILAR TO BONE MARROW FOR
EXAMPLE AND CD19 EXPRESSION IN
BINDING CAPACITY COMPARED TO THE
BLOOD AND LOOKED TO SEE HOW
THESE COMPARE TO BLOOD AND
MARROW IN TERMS OF COSTIMULATORY
MARKER IN EXPRESSION AND OVERALL
IN PURPLE OR TAPCS MARROW IS
GREEN AND BLOOD IS BLUE AND YOU
SEE FOR EXAMPLE CD54ICAM1 AND
LESS PROPORTION OF IT TAPCS
EXPRESS THIS WITH OVERALL HIGH
FMI AND CD80 AND CD6 EXPRESSION
THAT IS ENDOGENOUS ANTIGEN
PRESENTING CELL MARKER ON B
CELLS AND DENDRITIC CELLS NOT
EXPECT TODAY BE ON T-CELLS AND
OVERALL NOT LOOKING ACROSS
MARKERS I WILL SAY THAT TAPC
PRODUCTS IN BOTTOM ROW HAVE FAIR
NUMBER OF COSTIMULATORY MARKERS
COMPARED TO BLOOD AND MARROW AND
INCUBATED PATIENTS TACP PRODUCTS
BONE MARROW IS ONE-TO-ONE TARGET
2 EFFECTOR RATIO FOR BONE MARROW
CD19 EXPRESSING CELLS AND TAPCS
YOU SEE OVERALL THESE PRODUCTS
PRODUCED FAIR AMOUNT OF
PRODUCTION WITH CAR PRODUCTS AND
OVERALL FOR THE TRIAL, WE HAD
SUCCESSFUL CLINICAL EXPERIENCE
TO DATE AND CELLS WERE
MANUFACTURED IN ONE DOSE FOR
MAJORITY OF PATIENTS WITH
AVERAGE OF 5 DOSES PRODUCED PER
PATIENT AND ONE PATIENT LOST
PERSISTENCE OF CAR T-CELLS PRIOR
TO DOSING NOT ELIGIBLE TO GET
TAPCS AND PRODUCT FOR
CONTAMINATION AND SO ALL
TOGETHER WE TREATED 7
TAENSUBJECTS WITH 1 DOSE OF
TAPCS AND HAVE BEEN TOLERATED
EXTREMELY WELL AND ONE TOXICITY
GRANT GRADE 3 REACTION AFTER
SUBJECT SECOND TAPC DOSE THAT
PRECLUDED FURTHER TAPC DOSING AT
THAT POINT IN TIME NEUROTOXICITY
AND SO FAR RIGHT NOW WE HAVE
SUBJECTS THAT COMPLETED APC
INFUSIONS.
SO, JUST TO WALK THROUGH A
COUPLE PATIENT EXPERIENCES THIS
IS ONE PATIENT'S TIME COURSE AND
TO ORIENT YOU OPEN TRIANGLE IS
CAR INFUSION IN EACH OF THE
CLOSED TRIANGLES ARE TAPC
INFUSION OVER TIME AND IN BLUE
IS POSITIVE CAR T-CELLS
DETECTING THROUGH TAG AND CD3
COEXPRESSION AND IN GREEN ARE
TAPCS IDENTIFYING BY FLOWS
EXPRESSING -- AFTER PATIENTS
INITIAL CAR T-CELL EXPANSION
COMMENCING WITH TAPCS AND SEEING
NOT AFTER EVERY DOSE BUT SEVERAL
DOSES OF TAPCS REEXPANSION OF
CAR POSITIVE CELLS AND THEY ARE
TRANSIENTLY DETECTED AND ARE
ELIMINATE THE QUICKLY AS YOU
EXPECT WITH ONGOING FUNCTIONAL
CAR T PERSISTENCE AND APLASIA IS
IN ORANGE AND NOTABLE DETECTIBLE
CELLS THROUGHOUT THE COURSE IS
ANOTHER SUBJECT THAT IS SHOWING
THAT AFTER THEY COMPLETED THEIR
COURSE THIS PATIENT WENT ON TO
HAVE RECOVERY OF ABOUT. CELLS
THAT IS INTERESTING AND NOT TOO
LONG AFTER ABOUT A MONTH AFTER
LAST TAPC DOSE THAT WOULD HAVE
BEEN DUE FOR ANOTHER DOSE TO
HAVE THEM AND INTERESTING TO SEE
THAT RECOVERY AND WITH IT THAT
DID NOT HAVE SUBSEQUENT
REEXPANSION OF CELLS NOT
TRIGGERED BY B CELLS AND YOU CAN
SEE NUMBER UP THERE.
ESSENTIALLY ONE INTERESTING
THING WE SAW IS 3 OF 17 TREATED
SUBJECTS HAD HIGHEST DETECTIBLE
EFGR CAR NOTE NUMBER FOLLOWING
TAPC DOSE RATHER THAN INITIAL
EXPANSION AFTER CARS.
THIS IS A COHORT A SUBJECT AND
HAD LOW ANTIGEN BURDEN THAT SORT
OF REFLECTS THAT DIMINISH RED
EXPANSION WE SOMETIMES SEE
FOLLOWING CARS WITH LOW ANTIGEN
BURDEN.
ANOTHER INTERESTING PHENOMENON
AFTER A COUPLE PATIENTS AFTER
TAPC DOSE LOST CAR T-CELL
PERSISTENCE RECOVERY B CELLS IN
ORANGE IN BOTH PATIENTS IN
SETTING WE SAW PROLIFERATION OF
TAPCS AS WELL NO LONGER
FUNCTIONAL CAR T-CELL
PERSISTENCE TO ELIMINATE CELLS
AND SHORT OF GRAPHS HERE
PATIENTS WENT ON TO RECEIVE
ADDITIONAL DIRECTED THERAPY FOR
TRANSPLANT 1 OR ADDITIONAL
THERAPY AFTER RELAPSE 1 FOR A
SEBLGD AND FOLLOWED IN TPCS WE
WERE ELIMINATED BUT INTERESTING
PHENOMENON TO SEE THEM
PROLIFERATING IN VIVO TOO THIS
IS PRELIMINARY.
LOOKING ACROSS PATIENTS FOR
ESSENTIALLY B CELL RECOVERY ON
THE RIGHT LOOKING AT HIGH LEVEL
VIEW NOT ALL THAT DIFFERENCE AND
GOES OUT TO 2 YEARS FOR PATIENTS
BETTER FOR WHAT WE REPORTED FOR
CAR 19 ALONE AND I WILL SEE
PATTERN RELAPSE THAT IS
INTERESTING SEVERAL PATIENTS
ONGOING B CELL APLASIA AND CD19
POSITIVE RELAPSE AND INTERESTING
TO HEAR IT AND WHAT OTHERS
EXPERIENCED WITH US AS WELL AND
PATIENTS BEYOND THIS DATA MORE
RECENTLY THAT RELAPSED LATER
THAN WHAT PATIENTS HAD WITH CD19
POSITIVE DISEASE AND PUSHING
BACK TIMING OF CD19 POSITIVE
RELAPSE AND NOTHING TO PROHIBIT
ANTIGEN ESCAPE AND SEVERAL
PATIENTS SEEING CD19 -- LINEAGE
SWITCH WITH ARRANGEMENT.
SO, NEXT STEPS FOR TAPCS I THINK
STILL A LITTLE UNCLEAR COLLATING
DATA AND COMPLETING IT WE HAVE
SHOWN HAVE BEEN SUCCESSFULLY
MANUFACTURED STORING -- WITHOUT
SIGNIFICANT TOXICITY.
IT IS INTERESTING TO SEE EP
SOTIC REEXPANSIONS THEY PRODUCE
IN VIVO IN CD19 CARS AND THINK
IN TERMS WHETHER THIS WILL
TRANSLATE INTO DURABLE REMISSION
AND PREVENTION OF CD19 POSITIVE
RELAPSE IS UNKNOWN AND
RANDOMIZING PATIENTS TO TAPCS OR
NOT TO ANSWER THIS QUESTION.
I WILL STOP THERE THANKING
SEATTLE TEAM AS WELL AND THANKS
TO ORGANIZERS AND PLANNING
COMMITTEE FOR HAVING ME TALK
ABOUT THIS TODAY.
>> TO THE NEXT SPEAKERS.
>> THANK YOU. THANK YOU TO
NIRALI AND ORGANIZERS FOR
INVITING ME FOR DIFFICULT
SUBJECTS.
THIS MAYBE WORKS.
>> I MUST EMPHASIZE HERE FREAK
WEDNESDAY OF MONITORING AND
DEFINITION OF APLASIA AND
PERIPHERAL BLOOD IS NOT
CONSENSUAL AT THE MOMENT AND
COULD BE COLLABORATION ITEM FOR
THIS GROUP AND SECOND POINT IS
MAYBE IT IS MORE INTERESTING TO
DETECT EARLIER BONE MARROW
RECOVERY AND SHOWN IN
[INDISCERNIBLE] 2021 AND SECOND
POSSIBILITIES REINFUSION FOR
NONRESPONSE OR RELAPSE WHATEVER
YOU DEFINE RELAPSE BY POSITIVITY
AND MORPHOLOGY AND QUESTION IS
IS CD19 POSITIVE OR NEGATIVE AND
PRODUCT ACCORDING TO
CHARACTERISTIC IS OF UTMOST
IMPORTANCE AND CD19 POSITIVE
SECOND INFUSION COULD BE OF SAME
PRODUCT IF YOU HAVE REMAINING
CELLS AND QUESTIONING OF DOSE
THAT WE HAVE SPOKEN THIS MORNING
AND COULD ALSO THINK BRILLIANTLY
SHOWN BY SHANNON DIFFERENT CAR
FOR EXAMPLE HUMANIZED 1 AND CD19
NEGATIVE YOU HAVE TO THINK NOT
ABOUT REINFUSION BUT INFUSION OF
TOTALLY DIFFERENT CAR TARGETING
ANOTHER ANCONTINUALEN AND OF
NOTE IN REAL WORLD DATA SHOWN BY
US IN URA CD19 RELAPSE
PROPORTION IS 50 TO 60% THAT IS
ONLY 15% IN THE ILIANA TRIAL AND
IN THIS CONTEXT CHOICE PROBLEM
IS DO YOU HAVE AVAILABLE OF
ALTERNATIVE CAR T SHOWN BY ELAD
DIFFERENT TRIALS IN THE WORLD
ARE EXTREMELY SPARSED AND
PREVIOUS EXPANSION IS PARAMETER.
REMAINING PRODUCT AND I QUOTED
THIS SENTENCE FROM BLOOD THAT
DOSE INCREASE PRAR EFFECTS OF
ANTI-CAR IMMUNE RESPONSE AND
TREND THAT IS INCREASING IN THE
WORLD IS IF CAR T1 HAVE BEEN
DONE FOR RELAPSE POST TRANSPLANT
CAN WE THINK ABOUT THE
AVAILABILITY OF DONOR DERIVED
T-CELLS IT THAT COULD BE FITTER,
OBVIOUSLY. ANOTHER ITEM IS
DEPLETION AND NO LYMPHO
DEPLETION PRIOR TO REINFUSIONS
TO BE AVOIDED AND SAME WITH
DEPLETION THAT IS GENERALLY
CHOOSING OR INTENSIFIED FOR
DEPLETION BECAUSE PREVIOUS
EXPANSION IF VERY LOW FOR
EXAMPLE OUR RESPONSE COULD BE
PARAMETERS OF CHOICE TO DECIDE
TO INCREASE LYMPHO DEPLETION AND
SHOWN BY NIRALI IN
[INDISCERNIBLE] AND SHOWN ALSO
THIS MORNING MODELING OF
PREVIOUS FLU EXPOSURE COULD BE
WAY TO SAY LET'S INCREASE DOSE
OF FLU TO MAYBE HAVE ADEQUATE
EXPOSURE TO FLU FOR BETTER
EXPANSION.
DATA AND EARLIER EXPERIENCES
WITH REINFUSION SHOWN BY SHANNON
IN DUBLIN IN 2016 AND SHANNON
PROBABLY REMIND THIS THIS IS OLD
THING NOW AND HAS BEEN UPDATED
ASH 2021 BY [INDISCERNIBLE] AND
I WILL TALK ABOUT DATA A LITTLE
AFTER.
REBECCA PUBLISHED IN BLOOD
SEATTLE EXPERIENCE IN 10
PATIENTS LOSS OF MRASHIA 8
INFUSED AND 2 OUT OF THEM HAVE
REENGRAPHMENT AND INTERESTINGLY
6 OF 8 HAD NO FLU BEFORE CAR T1
AND RELAPSE OUT OF TWO PATIENTS
ONE HAD [INDISCERNIBLE] AND VERY
SMALL NUMBERS THAT ARE DIFFICULT
TO EXTRACT SOMETHING.
REGINA, THANK YOU TO ALLOW ME TO
SHOW 2 OF THREE SLIDES FOR
PRESENTATION AT ASH. WE CAN
CONCLUDE C AND FIRST IN TERMS OF
RELAPSE PREVENTION AND
REINSTALLATION OF B CELL
APLASIA. IF YOU DO LYMPHO
DEPLETING CHEMOTHERAPY
APPROXIMATELY HALF OF PATIENT OR
48% AND DOING IT AT
[INDISCERNIBLE] LEVEL AND BONE
MARROW RECOVERY IS 76%.
SO, MAYBE ACTING EARLIER IS
BETTER DOING RELAPSE RATE OF
THIS IS 50% APPROXIMATELY AND IF
DOING FOR NONINITIAL RESPONSE
RATE OF RESPONSE IS 0 IF YOU DO
REINFUSION FOR CAR T-CELL
PREVENTION YOU HAVE OBSERVE THE
NOTHING AND FOR RELAPSE YOU HAVE
CMS AND THIS PAPER IS FIRST
REINFUSION ARE SAFE AND SECOND
THERE MIGHT BE B CELL APLASIA
AND SHORT CAR T PERSISTENCE AND
PASHGIENTS WITH CD19 POSITIVE
NOT EFFECTIVE FOR NONRESPONSE
AND PROPOSAL OF GROUP IS
OFFERING REINFUSION FOR BCR
RECOVERY IN [INDISCERNIBLE]
WITHIN 6 MONTHS OF INITIAL
INFUSION AND PRWCC HAVE SHOWN
THIS AND 57 PATIENTS RELAPSE
AFTER T-CELL AND UNFORTUNATELY
ONLY 10 PATIENTS RECEIVED CAR T
THERAPY AND OUT OF THIS I FOUND
ONLY 5 THAT RECEIVED REINFUSION
OF T-CELL GLUCOCELL AND IN TERMS
OF RESPONSE OF RELAPSE THREE OF
THE FIVE ARE REINFUSION AND 3
OUT OF 3 FOR HUMANIZED CD19 CAR
AND ONE FOR COMBINATION OF
INFUSION PLUS VOLUME AND PLUS
[INDISCERNIBLE].
GROUP OF NIRALI PUBLISHED ALSO
IS EXPERIENCE AND UNFORTUNATELY
HERE AGAIN NUMBER ARE SMALL AND
7 PATIENTS HAVE CR AND P. ARE.
AT CAR 2 AND RESPONSE IS ONLY
38% COMPARED TO 72% AFTER CAR
T1. AFTER YOU LOOK AT DOWNSIDE
OF THE PANEL AND DATA IN TERMS
OF LONG-TERM THAT HAVE COME FOR
PATIENT BROUGHT TO CR BY SECOND
INFUSION OF CAR T IS RED THAT I
PUT AND ALL PATIENT DIE
ESSENTIALLY AND EXPERIENCE HAS
BEEN MORE THAN DISAPPOINTING FOR
EARLY LOSS OF BC APLASIA AND
EXPANSE PATIENTS 2 VOLUME UP AND
3 WITH NOT VOLUME UP AND NONE OF
PATIENTS HAS REEXPANSION OR
REAPPEARANCE OF B CELL APLASIA
AFTER CAR 2 DOING FOR RELAPSE 8
PATIENTS IN HOSPITAL WITH THIS
DEPARTMENT AND ONE RESPOND TO
REESTABLISHMENT OF CR POST CAR 2
AND UNFORTUNATELY YOU CAN SEE
MOST OF THE PATIENTS HAVE DIED.
ONLY TWO PATIENTS ARE ALIVE AND
INTERESTINGLY, ONE HAS RECEIVED
DONOR DER I'VED CAR T-CELL AFTER
TWO FAILING OF CAR T-CELL AND 1
IS ALIVE AT THESE AND
ADMINISTERED THIS WHICH HAS
BROUGHT THEM TO CR.
SO, I HAVE ASKED MY DEER
COLLEAGUE FROM LONDON AND BARS
LONA AND MUNSTER AND TEL AVIV
AND ZURICH WHAT THEIR EXPERIENCE
IS AND IF WE PUT WITH OUR
EXPERIENCE IF YOU USE
REINFUSIONS TO TRY TO HAVE A
RETURN TO BCA AFTER LOSS OF B
CELL APLASIA, OVERALL OUT OF 39
PATIENTS 29% HAVE RETURN TO B
CELL APLASIA AND 4 OUT OF 5 WERE
TRANSIENT AND BASICALLY NOT VERY
HIGH SUCCESS RATE AND IN TERMS
OF KALGS IN RELAPSE DATA IS ALSO
DISAPPOINTING 4 OUT OF 21 SO 19%
CR RATE AFTER REINFUSION.
WE HAVE EMBARKED AND
UNFORTUNATELY I HAVE NO DATA TO
SHOW YOU ON DUE TO PRECLINICAL
DATA AND ALSO EXPERIENCE OF
SHANNON AND SHOP GROUP WITH
[INDISCERNIBLE]. WE HAVE
EMBARKED ON CAR T-CELL
REINFUSION TRIAL AND PATIENTS
WITH LAST B CELL APLASIA WITHIN
FIRST 6 MONTHS AND DESIGN AND
ADAPTIVE TRIAL WHERE VOLUME UP
WILL BE DEPENDING ON THE
REASSESSMENT METHOD AND MORE AND
MORE CLOSE TO THE REINFUSION OF
THE CAR.
DAY 14 AND 11 AND AT MOMENT NO
DATA ARE AVAILABLE FOR THESE
COHORTS AND IN TERMS OF
CONCLUSION OF REINFUSION DATA
WITHIN LIMITS OF RETROSPECTIVE
SMALL NUMBERS AND LOTS OF
CONFOUNDING FACTORS, IF WE SPEAK
ABOUT RELAPSE PREVENTION FOR
EARLY LOSS OF B CELL APLASIA
THERE ARE DISCREPANCIES
OBVIOUSLY AND NO CLEAR TREND FOR
MAJOR EFFICACY.
IF WE WANT TO PURSUE STRATEGY,
WE HAVE TO FIRST THINK ABOUT
ACTING EARLIER AND FOR EXAMPLE
BONE MARROW B CELL RECOVERY AND
INCLUDE PATIENTS IN CLINICAL
TRIALS AND HUMANIZE IF AVAILABLE
AND REINFUSION PLUS SOMETHING
AND DIDN'T PUT ON SLIDES
INTERESTING PRELIMINARY DATA OF
SARAN GROUP USING MAINTENANCE
THERAPY AVAILABLE.
BUT, ANYWAY, IF EVEN IF YOU
THINK ABOUT ESTABLISHING SECOND
B CELL APLASIA WITH FIRST TWO
BULLET POINTS YOU COULD QUESTION
DURABILITY OF THE SEBLGD B CELL
APLASIA. OF NOTE, FACT THAT
PROPORTION OF PATIENTS COMING TO
CAR T1 WITH HISTORY OF
TRANSPLANT DECREASED 60% TO LESS
THAN 20% MARCELO SHOWED DATA
THIS MORNING COULD RENDER
TRANSPLANT AS POTENTIAL OPTION
IN MANY CASES AND IN CASE OF
NONRESPONSE TO CAR T1 NO
INDICATION OF REINFUSION AND IN
CASE OF RELAPSE TREATMENT YOU
HAVE SEEN ON MY SLIDES CR RATE
IS BETWEEN 0 AND 50% MAYBE 25
AND ANY CASE DURABILITY AND
[INDISCERNIBLE] ARE NO TREATMENT
AND MAYBE THESE ARE
DISAPPOINTING AND WOULD LIKE TO
THAK CLAUDIO AND NICO FOR
SHARING INFUSION DATA AND THANKS
VERY MUCH.
>> GREAT TO SEE EVERYONE IN
PERSON. TITLE OF TALK IS POST
CAR RELAPSE PHENOTYPE AND
REIMPLICATIONS AND WE HAVE
ADDRESSED THAT CAR IS GREAT AT
INDUCING REMISSION AND RELAPSE
REMAINS A CHALLENGE AND PART OF
THIS TALK IS NOT ONLY IS RELAPSE
A CHALLENGE AND SURVIVAL OF
FOLLOWING RELAPSE OF CAR
INFUSION AND TWO PAPERS I WILL
REALLY HIGHLIGHT THROUGHOUT THE
TALK AND FIRST IS FROM
[INDISCERNIBLE] CONSORTIUM AS WE
TALKED ABOUT A FEW TIMES LIKE
THREE DIFFERENT CD19 CARS AND
419 PATIENTS AND SECOND FROM
PEDIATRIC REAL WORLD CONSORTIUM
THEY LOOKED AT OUTCOMES
FOLLOWING CHIMERA AND YOU SEE
FROM THESE KAPLAN MEYER
[INDISCERNIBLE] FOR OVERALL
SURVIVAL THAT FOLLOWING EVENT
AFTER INFUSION OUTCOMES ARE VERY
POOR WITH OVERALL SURVIVAL
APPROACHING ABOUT 20%.
THERE IS A LOT OF WAYS TO THINK
ABOUT RELAPSE FOLLOWING CAR. I
THINK THERE IS KIND OF PROS AND
CONS TO EACH OF THESE AND THINK
ABOUT THE MECHANISM OF RELAPSE
AND CLOSELY RELATED TO THAT IS
IMMUNOPHENOTYPE AND PRESENCE OR
ABSENCE OF CD19 THAT WILL BE
PRIMARY FOCUS OF MY TALK. THEN
WE HAVE TALKED A LOT ABOUT
TIMING OF RELAPSE AND LATE
VERSUS EARLY NOT NECESSARILY
ARBITRARY AND 6 MONTHS BEING A
CUTOFF WE TYPICALLY THINK ABOUT
AND ALL THESE REALLY INFORM
TREATMENT OPTIONS AVAILABLE TO A
PATIENT. THIS IS A CHART
SUMMARIZING LANDMARK THAT WE
DISCUSSED TODAY AND IS
REMARKABLE REMISSION AND RELAPSE
RATES THAT ARE RELATIVELY
SIMILAR BETWEEN TRIALS AND
REALLY ON THESE EARLY TRIALS WE
TALKED ABOUT RELAPSES PRESENCE
OR ABSENCE OF CD19 AND WASN'T
TALK ABOUT LINEAGE SWITCH AND
PROBABLY THOSE THAT ARE CAPTURE
THE IN CD19 NEGATIVE GROUP OR
RARE PHENOMENON CAPTURED IN SOME
SMALLER TRIALS SEEMS TO BE LIGHT
PREVENS TOWARDS CD19 TOWARDS
POSITIVE RELAPSES AND
EXPERIENCES EVOLVING STARTING
PATIENT POPULATIONS THAT ARE
ALSO EVOLVING.
WITHIN WHAT WE WANT TO DO WHAT
IS REALLY WE WANT TO DEFINE
CUMULATIVE INCIDENCE OF RELAPSE
BASED OFF PATTERN OF
IMMUNOPHENOTYPE AND THIS KAPLAN
MEYER CURVE ON LEFT AND GREEN IS
LINEAGE SWITCH AND CHART AT
BOTTOM IS LOOKING AT 24 MONTH
CUMULATIVE INCIDENCE RELAPSE OF
ALL THOSE AND COHORT WE SAW 42%
CIR AND CD19 POSITIVE IS 22 PS
CD19 NEGATIVE AND IS 16% AND 12
PATIENTS OR 3% THAT EXPERIENCE
LINEAGE SWITCH AND CD19 POSITIVE
AND NEGATIVE VAST MAJORITY OF
THOSE HAPPEN IN FIRST 1 TO 2
YEARS FOLLOWING INFUSION
FOLLOWING PATIENTS OUT FOR
SEVERAL YEARS WE ARE SEEING
SEVERAL LATE RELAPSES IN BOTH
COHORTS IN CONTRAST TO SWITCH
AND FOR THE MOST PART IF A
PATIENT HAS LINEAGE SWITCH THEY
HAVE IT IN 6 TO 12 MONTHS
FOLLOWING INFUSION AND AGAIN
JUST REMARKABLY SIMILAR RESULTS
FROM PEDIATRIC REAL WORLD
CONSORTIUM WITH CD19 POSITIVE
RELAPSES IN RED AND CD19
NEGATIVE RELAPSES IN GREEN AND
SLIGHT PREFERENCE TOWARDS
CONSIDER. D19 POSITIVE RELAPSES
I SUSPECT THEY FOLLOW PATIENTS
OUT FURTHER AND IT WILL CONTINUE
TO TAKE UP AND PREINFUSION
VARIABLES PREDICTIVE OF RELAPSE
THAT PATIENT MIGHT HAVE AND
REJENA SHARED ABOUT PREINFUSION
CHARACTERISTICS PREDICTING
RELAPSE AND LOOKING AT IF
PATIENT HAS RELAPSE IS THERE WAY
TO PREDICT WHAT RELAPSE THEY
HAVE? AGE AND GENDER AND
GENETICS AND TYPE OF CAR AND
PREVIOUS TREATMENT INCLUDING
STEM CELL TRANSPLANT AND DISEASE
BURDEN, ET CETERA. WE SAW FOR
CD19 POSITIVE RELAPSE THERE IS
NOT A LOT COMING OUT IN
MULTIVARIATE ANALYSIS AND
CUMULATIVE NUMBER OF REMISSIONS
AND CONTRAST CD19 NEGATIVE
RELAPSE SEVERAL VARIABLES CAME
OUT AND YOUNGER ANL AND ABSENCE
OF 41BB CAR AND HIGH DISEASE
BURDEN AND NONRESPONSE AND A FEW
OTHER GROUPS REPORTED SIMILAR
FINDINGS SPECIFICALLY RELATING
TO 41BB CAR AND HIGH DISEASE
BURDEN AND THOSE TRANSLATE TO
LONGER PERSISTENCE AND WE KNOW
SUSTAINED IMMUNOTHERAPEUTIC
PRESSURE IS IMPORTANT FOR CD19
NEGATIVE RELAPSES AND SWITCH WE
SAW THAT CAME OUT PRESENCE OF
KM22A ARRANGEMENT OBSERVATIONS
THAT GROUPS MADE AND WE FOUND
THAT IS STRIKING IS PATIENTS
THAT CAME TO 22A ARRANGEMENT
RELAPSE 6 60% ARE -- AND WHAT
ABOUT PROGNOSIS BASED OFF
PATTERN OF RELAPSE?
AGAIN ON LEFT-HAND SIDE GREEN
REPRESENTS LINEAGE SWITCH AND 12
PATIENTS EXPERIENCING LINEAGE
SWITCH THERE WERE NO LONG TERM
SURVIVAL AND DISMAL OUTCOME FOR
PATIENTS AND EARLY ON AT 2 YEARS
SEEM THE LIKE CD19 POSITIVE
PATIENTS ARE OVERALL --
TARGETING STRATEGIES FOLLOWING
PATIENTS OUT A LITTLE FURTHER
CURVES HAVE OVERLAPPED CD19
NEGATIVE PATIENTS AND PEDIATRIC
REAL WORLD CONSORTIUM VERY
SIMILAR DATA AT 2 YEARS THAT
FOLLOW PATIENTS AND CURVES MIGHT
COME A LITTLE CLOSER TOGETHER DO
PATIENTS HAVE THIS IN RELAPSE
AND EARLY ON PATIENTS COME TO
CARS MULTIPLY RELAPSE AND
CHEMORESDIFLTANT DISEASE AND
LARGE CUMULATIVE TREATMENT
BURDEN STEM CELL PLANT LEADING
TO COMORBIDITIES AND LEADING TO
STEM CELL TRANSPLANT AND
IMPORTANT IS REDUCED
IMMUNOTHERAPEUTIC OPTIONS
DEPENDING ON PATTERN OF RELAPSE
THAT IS AN EXERCISE THAT WE DO
WHEN WE HAVE A PATIENT TREATED
WITH CAR T-CELLS WHEN THEY
RELAPSE IS AN ALGORITHM THAT I
PUT IN NUMBERS THAT I GENERATED
FROM CONSORTIUM AND PATIENT ARE
CD19 POSITIVE -- THEY HAVE 60%
CHANCE SUSTAINED REMISSION
WHETHER DURABLE REMISSION OR
CONSOLIDATED WITH TRANSPLANT AND
CONTRAST 22% EXPERIENCE POSITIVE
RELAPSE AND 15% EXPERIENCE
NEGATIVE RELAPSE AND EXPERIENCE
NEGATIVE SWITCH AND CD19
POSITIVE PATIENTS THEY CAN YOU
CAN TARGET CD19 ANTIGENS FOR
REINFUSION AND ALTERNATIVE CAR
PRODUCT AND YOU HAVE ALL CD22
OPTIONS AND OF COURSE CAN PIVOT
BACK TO CHEMOTHERAPY AND THAT
PRIMARILY IF YOU TARGET CD19 OWE
MGSS AND WE ARE TALKING MORE AND
MORE ABOUT CHEMOTHERAPY OR L-
LONG TERM BLINA AND PERHAPS
PATIENTS COULD GET A LONG
RESPONSE AND BE ALLOCATED TO
STEM CELL TRANSPLANT AND
CONTRAST CD19 RELAPSES POSITIVE
OPTIONS AND CD2 TARGETING
OPTIONS AND FOR MOST PART SHOULD
BE ALLOCATED TO TRANCE PLANT
THAT IS SIMILAR FOR LINEAGE
SWITCH. WE DON'T KNOW WHAT BEST
TREATMENT APPROACH SHOULD BE FOR
LINEAGE SWITCH. IF YOU ARE ABLE
TO GET A PATIENT INTO REMISSION
PROBABLY SHOULD BE ALLOCATED TO
TRANSPLANT THAT IS A VERY
SIMPLIFIED ALGORITHM WE ARE
LOOKING AT BINARY RELATIONSHIP
BETWEEN CD19 AND AS EVERYBODY
KNOWS IT IS MUCH MORE
COMPLICATED THAN THAT AND
PRIMARILY INCORPORATING CD22 AND
SOME PATIENTS COMING INTO CARS
AND RECEIVING [INDISCERNIBLE]
AND PERHAPS SALVAGED WITH CD22
CARS AND GETS COMPLICATED FROM
THERE AND INFORMING DIFFERENT
TREATMENT OPTIONS AND FOCUS OF
OUR GROUP IS LOOKING AT ANTIGEN
NEGATIVE OR LINEAGE SWITCH
PATIENTS WHERE WE DON'T KNOW
WHAT TO DO WITH THEM OR WHAT
BEST TREATMENT IS AND THIS IS AN
INSTITUTIONAL EXPERIENCE AND
ANECDOTES WHAT WE TRIED FOR
PATIENTS WITHOUT GREAT
IMMUNOTARGETS AND GENERALLY WE
ARE GIVING INTENSIVE MILOID
DIRECTIVE THERAPY AND INHIBITOR
TRIALS AND WE HAVE SEEN YOU KNOW
ARE REALLY ENCOURAGING SIGNAL IN
PATIENTS WITH AML AND THEY SEEM
LIKE REASONABLE AGENT FOR AML
THAT IS REASONABLE FOR PATIENTS
AND IMMUNOTHERAPY TRIALS AND
TARGETS AND TRYING TO GET
PATIENTS TO TRANSPLANT AND
FINALLY, LAST THING TO CALL OUT
IS A UNIQUE PHENOMENON WE HAVE
SEEN IN A FEW PATIENTS DISEASE
PLASTICITY FOLLOWING LINEAGE
SWITCH AND BLUE LINE IS FLOW
DETECTIBLE ALL AND RED IS FLOW
DETECTIBLE AML AND GREEN IS
[INDISCERNIBLE] AND THIS IS
PATIENT WITH PERSISTENT DISEASE
AND GOT CD19 BY CD22 T-CELL AND
FLOW RAISED REMISSION AND HAD
LINEAGE SWITCH TREATING WITH
INTENSIVE MYELOID DIRECTIVE
THERAPY AND GOT TO REMISSION AND
WEPT TO TRANSPLANT AND AFTER
TRANSPLANT THEY REOCCURRED WITH
CD19 POSITIVE A WILL. L.
WE DID RECHALLENGE PATIENT AND
THERE WAS CONCERN THAT IF THEY
HAD LINEAGE SWITCH IN THE
BEGINNING THEY MIGHT BE
PREDETERMINE THE TO HAVE LINEAGE
SWITCH AND THEY HAVE BEEN IN
CLONO SEEK REMISSION AND
PERCEIVED MAINTENANCE AND
REPORTED WITH A SIMILAR PATIENT
WITH IDENTICAL PHENOMENON OCCUR
AND SWITCH IS RARE AND WE DON'T
HAVE LOTS OF DATA ON HOW IT IS
DIAGNOSED OR TREATED AND PLUG
FOR RETROSPECTIVE ANALYSIS AND
IF YOU HAVE A PATIENT
EXPERIENCING THIS NOT JUST FROM
CAR T-CELLS OR THIS WE WOULD
LOVE TO HEAR ABOUT IT AND IF
INTERESTED IN PARTICIPATING
E-MAIL ME AT NIRALI SHAH AT
NIH.GOV. FOR SAKE OF TIME I
WILL SKIP THROUGH THE SUMMARY
AND SAY THANK YOU.
>> [APPLAUSE].
>> THANK YOU FINAL SPEAKER IS
NIRALI TALKING ABOUT
[INDISCERN
[INDISCERNIBLE].
>> THANK YOU, EVERYBODY.
TALKING ABOUT COMBIN TORIAL
STRATEGIES. COMBIN ATORIAL
STRATEGIES ARE BASED IN ALL.
[INDISCERNIBLE] CLEARLY ALL OF
THE COMBIN ATORIAL STRATEGIES
SEQUENCING THEM IN AND
SEPARATING THEM OUT LED TO
IMPROVED OUTCOMES OVER TIME AND
ANTIGEN LOSS IS PRIMARY CAUSE OF
[INDISCERNIBLE]. THE OTHER
THING I THINK IS A LITTLE
INTERESTING AND DON'T KNOW IT IS
FULLY EVALUATIVE EVEN LOSS OF
CD19 IN EXPRESSED
[INDISCERNIBLE] WHEN YOU LOSE
CD19CD22 ALSO TENDS TO
DOWNREGULATE AND THIS IS LOOKING
AT PATIENTS.
RETENTION OF CD19 AND FOLLOWING
IT IS LOOKING AT CD22 EXPRESSION
IN SAMPLES THAT ARE IN PATIENTS
THAT ARE SUBSEQUENTLY CD19
NEGATIVE AND YOU SEE HERE THERE
IS I MEAN THERE IS NO
EXPLANATION WHY YOU WOULD LOSE
CD22 ALONG WITH IT AND IS
SOMETHING WE ARE STARTING TO
SEE. ANOTHER EXAMPLE LOOKING AT
FLOW DOT PLOTS CD22 ON LEFT AND
CD19 ON X AXIS YOU HAVE CD19
NEGATIVE POPULATION AND PARTIAL
EXPRESSION OF CD22.
SO, JUST SPEAKING QUICKLY ABOUT
CD22 CAR T-CELLS AND INITIAL
THAT HAS MOST LONGEVITY IN TERMS
OF EFFICACY IS SHOWING OVERALL
CAR T-CELL CONSTRUCT AND BASED
ON RESULTS IT IS FIRST IN HUMAN
AND FIRST IN CHILD EXPERIENCE.
ON SAME DISEASE WE APPLIED
RECEIVING BREAK THROUGH THERAPY
SEVERAL YEARS AGO AND SHOWING
OVERALL -- BOTTOM LINE HIGHLY
EFFECTIVE 70% COMPLETE REMISSION
RATES AND CD19 NEGATIVE DISEASE
RATES.
WE LEARNED THAT CRS SEVERITY IS
WLOEER THAN NEUROTOXICITY IS
SUBSTANTIALLY MILDER AND THAT
CD22 EXPRESSION OVERALL WAS EVEN
THOUGH IT IS ON A B CELL IT
DIFFERS FROM CD19 AND MANUSCRIPT
WE HAVE CURRENTLY IN REVIEW
LOOKING AT DIFFERENCES IN
NEUROTOXICITY AND WHY THEY MIGHT
BE DIFFERENT THERE AND KNOWING
YOU HAVE A DIFFERENT EFFECTIVE
CD22 CAR T-CELL AND EFFECTIVE
CD19 TARGETING THOUGHT IS HOW TO
TAKE THIS FORWARD THINKING OF
COMBIN ATORIAL CAR T-CELL
STRATEGIES AND GIVING CD19 CAR
AND THEY CAN BE DONE
SIMULTANEOUSLY AND THEY CAN BE
DONE IN CLOSE SEQUENCE OR SUB
WRITE IT OUT IS.
THERE ARE EFFECTIVES AND T-CELL
PRODUCT AND SEATTLE GROUP IS
TESTING THIS AND MODEL IS ONE
THAT WE HAVE A TRIAL THAT WE
OPENED THAT IS A SINGLE VECTOR
GOING INTO T-CELLS INTERNAL
CLEAVAGE AND SHOW THESE IN EQUAL
PROPORTION ON CELL SURFACE AND
HAVING A LITTLE MIX YOU HAVE ALL
YOUR T-CELLS EXPRESSING CD19 AND
CD22 AND YOU HAVE TANDEM MODELS
WITH ONE VECTOR GOING INTO THE
T-CELL AND BEING ABLE TO
RESPECTIVELY POTENTIALLY
EFFECTIVELY TARGET THAT AS WELL.
WALKING THROUGH STRATEGIES PROS
ARE YOU ARE ABLE TO TAKE TWO
EFFECTIVE CAR T-CELLS ENSURING
EFFICACY AND YOU HAVE TO MAKE
TWO DIFFERENT VECTORS AND CAR
T-CELL PRODUCTS AND THAT COULD
REALLY REPRESENT A HUGE
LOGISTICAL HURDLE TRYING TO DO
SOMETHING LIKE THIS IN
PEDIATRICS AND CONCERN FOR
SYNERGISTIC TOXICITY AND AGAIN
DEPENDING WHAT MODEL YOU USE
GIVEN TOGETHER LOWER DOSES OF
TWO GIVEN SIMULTANEOUSLY AND
INDUCTION AND SUBSEQUENTLY
CONSOLIDATION AND YOU MIGHT BE
ABLE TO ADDRESS IT AND GOT
BETTER AT ADDRESSING TOXICITY
AND COINFUSION STRATEGIES
SIMULTANEOUS OR PAPER PRESENTED
EARLIER. IT THIS IS WORK DONE
BY GROUP IN CHINA AND LARGEST
STUDY DONE PROSPECTIVELY IN
PEDIATRIC ALL. THEY HAD REALLY
EXCEPTIONAL OUTCOMES AND LARGE
PART OF PATIENT POPULATION IS
FIRST RELAPSE THAT IS CLEARLY
UNMET NEED FOR CHILDREN AT LEAST
IN THE UNITED STATES AND IN
EUROPE.
SEQUENTIAL SEATING HAD
OPPORTUNITY TO DO COMMENT AND
THEY ARE GETTING CD19 SORT OF
LIKE INDUCTION CD22 IN
CONSOLIDATION TO TRY TO IMPROVE
OVERALL DURABLE REMISSIONS AND
COTRANSDUCTION YOU HAVE A SINGLE
AND YOU HAVE [INDISCERNIBLE] AND
YOU ARE LEVERAGING DUAL EFFICACY
KNOWING THAT SINGLE ANTIGENS
WILL POTENTIALLY HAVE EFFICACY
NOT DUALLY TRANCE DEUCED PAYING
FOR TWO EFFECTORS AND
HETEROGENEITY IN TERMS OF FINAL
PRODUCT AND DATA SHARED WITH
REBECCA GARDENER BASED ON
STUDIES TWO DIFFERENT VERSIONS
USING CD22 AND ORIGINAL VERSION
INCORPORATING CD19 AND CD22 THAT
WAS NOT VERY EFFECTIVE AND
BREAKDOWN OF ACTUAL CAR T-CELLS
THEY HAD PRIMARILY THIS PRODUCT
AND CD22 IN TERMS OF OVERALL
EXPANSION AND LOOKING AT DUAL
TRANSDUCTION AND REVISE THE IT
LATER CD22 OPTIMIZED IT IMPROVED
EFFICACY AND YOU SEE EXPANSION
PARAMETERS ARE DIFFERENT AND YOU
END UP WITH LOTS MORE CD22 AND
LOTS OF BIOLOGY NEEDING TO BE
EXPLORED HERE IN TERMS OF
DIFFERENCES BETWEEN TWO AND THEY
ARE CURRENTLY WORKING ON
REVISING THEIR PROTOCOL A LITTLE
TO THINK ABOUT DOSING STRATEGIES
AND IN TERMS OF BIVAILANT WE
PUBLISHED DATA AGAIN THAT IS
SINGLE ACTIVATION SINGLE ONE
VECTOR THAT LOWERS COST AND
CAUSES I HAVE YET TO SEE DATA
DUAL TARGETING TO EFFECTIVELY
TARGET THIS SINGLE CAR T-CELL
STRATEGIES TARGETING WAS LESS
EFFECTIVE AND CLINICAL -- SHOWED
LIMITED PERSISTENCE THAT IS
PARTICULARLY PROBLEMATIC IN B
CELL ALL. SAME VECTOR IN
CONSTRUCT WAS USED IN LYMPHOMA
COHORT WONDERFUL AND LONG-TERM
RESULTS AND WE HAVE TO BE
COGNIZANT OF THE LIMITATION AND
WITH [INDISCERNIBLE] AND OUR
TRIAL IS CURRENTLY UP AND
RUNNING AND TREATED 1 PATIENT
AND SIMILAR TO BIVAILABILITY
SINGLE ACTIVATION SINGLE AND
UNIFORM PRODUCT AND THIS IS DATA
FROM PERSISTENT SARA'S GROUP IN
THE UK SHOW LIMITATIONS ON DUAL
TARGETING THAT IS LESS EFFECTIVE
AND PROBLEM WITH PERSISTENCE
USING SLIGHTLY DIFFERENT
CONSTRUCT AND GOING BACK TO WHAT
MAKES GOOD CAR T-CELL AND
POINTING OUT B CELL LYMPHOMA
VERSUS BCALL THERE ARE HUGE
DIFFERENCES BEING MINDFUL WHAT
PEDIATRIC DATA SHOWS IN PATIENTS
AND PATIENTS REQUIRE YEARS OF
THERAPY AND LYMPHOMA PATIENTS
HAVE NEVER REALLY REQUIRED THAT
THAT IS IMPORTANT AND -- AND I
THINK THAT THE OTHER THING IN
TERMS OF TRIAL IS WE ARE TAKING
PATIENTS RECEIVING PRIOR CAR
T-CELLS THAT WILL HAVE IMPACT
WHEN YOU ARE TRYING TO TEST A
NEW COMBIN ATORIAL STRATEGY AND
IMPACTING TRIALS FOR EFFICACY
AND PERSISTENCE AND IN
CONCLUSION DUAL ANCONTINUALEN
TARGETED APPROACHES MAY IMPROVE
OUTCOMES AND -- MAY BE COST
PROHIBITED AND NEED SECOND
PROJECT AVAILABLE AND CAR
T-CELLS WILL BE A NEED TO
OPTIMIZE UPON SINGLE ANTIGEN
TARGETING AND WORRY ABOUT
ANCONTINUALEN MODULATION EVEN IF
NOT DIRECTLY TARGETED WITH
SPECIFIC ANTIGEN AND SOMETHING
TO THINK ABOUT AND WE ARE OPEN
FOR QUESTIONS FOR THIS SESSION.
>> [APPLAUSE].
>> THANK YOU, NIRALI AND ALL
SPEAKERS FOR A FANTASTIC
SESSION. QUESTIONS?
I THINK THE GRAPH YOU SHOWED WAS
COMPARING CD22 -- DO YOU ALSO
HAVE THAT SAME ANALYSIS
COMPARING THEIR PRE-TREATMENT
AND WHAT IS THE DIFFERENCE IN 22
EXPRESSION PRIOR TO TREATMENT
AND POST TREATMENT?
>> [INDISCERNIBLE].
>> POST 19 TARGETED THERAPY
[INDISCERNIBLE] I WILL SAY THAT
COHORT [INDISCERNIBLE] WE WANTED
TO MAKE SURE IT WAS
[INDISCERNIBLE] POPULATION AND
IN PRECLINICAL [INDISCERNIBLE].
>> I GUESS IT WAS A LEADING
QUESTION TO KNOW IS LOW DENSITY
2022 EXPRESSION A MARKER WHAT
WILL COME WITH CD19 RELAPSE? AS
THEY LOSE 19 DOES THAT TYPE OF
LEUKEMIA HAVE LOW 2022
EXPRESSION?
>> YEAH. [INDISCERNIBLE].
>> COOL. THANKS.
>> I'M ASKING A QUESTION. ABOUT
NGS, YOU KNOW, RIGHT NOW THERE
IS ONLY ONE BIOTECH COMPANY THAT
CAN DO THAT FOR US.
BECAUSE IT IS VERY HARD. YOU
KNOW, IF YOU LOOK TO GET BELOW
10 TO THE FIFTH TACKING TO
MOLECULAR LABS WONDERING IF YOU
ARE WORRIED AND HAVING ACCESS TO
ROBUST NGS TESTING TO LESS TAN
10 TO THE 6 CAN YOU COMMENT ON
THAT?
>> SO, THIS IS A PROBLEM
CERTAINLY. NO ONE EXCEPT FOR
CUSTOMERS IN THE UNITED STATES
HAVE ACCESS TO IT AND IT IS
MOVING TO AUSTRALIA. DON'T KNOW
ABOUT EUROPE WHETHER ADAPTIVE IS
PLANNING TO DO ANYTHING IN
EUROPE. INTERESTINGLY ADAPTIVE
IS HAPPY TO CELL TECHNOLOGY AND
HAVE DONE THAT AND ARRANGED IT
IN AUSTRALIA AND VERY SOON WE
CAN DO IT IN AUSTRALIA.
ADAPTIVE IS DOING JUST FINE IT
IS ONE COMPANY AND VIGOROUS AND
VERY GOOD TESTING AND AS I
SHOWED IT REALLY MAKES A
DIFFERENCE TO GO AS DEEP AS YOU
CAN.
SO, I THINK THAT TECHNOLOGY WILL
BE HERE. WHAT I HOPE IS
ADAPTIVE FIGURES OUT A WAY TO
PARTNER WITH THOSE IN EUROPE
EUROPE IS CLOSE AND WILL GIVE A
GOOD SIGNAL IF POSITIVE WITH PCR
BAD THINGS WILL HAPPEN. IT IS
JUST BETTER IF YOU HAVE THE
DEEPER SIGNAL. I THINK IT WILL
BE AROUND FOR A WHILE.
>> GOOD.
>> [INDISCERNIBLE].
>> >> SO, JUST TO REPEAT FOR THE
AUDIENCE AT HOME THE QUESTION IS
IS IT REALLY A PREDICTOR OF
RELAPSE OR LOW-LEVEL PERSISTENT
DISEASE? IT IS LOW-LEVEL
PERSISTENT DISEASE AND IMPORTANT
THING TO UNDERSTAND WE CAN DO
DIFFERENT THINGS BASED ON WHERE
THE DISEASE STARTS AND
TRANSPLANT IF YOU TRY TO
TRANSPLANT ALL PATIENT LESS --
WITH MORE THAN 10 TO THE MINUS 3
AT TRANSPLANT, OUTCOME IS DISS
MAL AND RELAPSE RATE IS
EXCEPTIONALLY HIGH AND GETTING
THEM FLOW NEGATIVE WE ARE OKAY
HAVING DEEP IN NGS WE KNOW WE
CAN DO THINGS AND ALTHOUGH YES
IT IS JUST A MARKER OF
PERSISTENT DISEASE I THINK THAT
YOU WANT TO CALL IT A BIOMARKER.
PERSISTENT DISEASE YOU CAN DO
SOMETHING WITH AND THERAPIES
WILL BE GAUGED UPON WHETHER
THERE WILL BE A GOOD OUTCOME AND
IMPORTANT TO UNDERSTAND PATIENTS
FLOW NEGATIVE AND NGS POSITIVE
IT IS NOT BAD AND YOU CAN
SALVAGE MORE THAN 50% OF THEM
AND WE SHOWED AT LAST TANDEM
MEETING AND IS PERSISTENT TO
SEE.
>> THANK YOU.
>> QUESTION IS TO
[INDISCERNIBLE] AND SECOND
INFUSION OF FM63 AND SINGLE
CHAIN BINDING PRODUCT AND YOU
LOSE VERY SOON OR HAS TEMPORARY
EFFICACY IT IS OBVIOUS
IMMUNOLOGICAL REJECTION COULD BE
INVOLVED IN THIS PHENOMENON THAT
IS OBVIOUS AND I'M NOT AWARE OF
ANYONE HAVING SHOWN IT. ARE
YOU?
>> THANK YOU. HAS BEEN WORK
FROM SEATTLE GROUP AND DON'T
KNOW. MOSTLY FROM ADULT STUDIES
YOU MIGHT BE ABLE TO COMMENT TO
THAT. YOU KNOW, THEY HAD
DETECTED T-CELL RESPONSES
LEADING TO IMMUNE LOGIC
REJECTION. WE DO NOT HAVE
DEFINITIVE DATA SHOWING THAT.
NEVARTIS LOOKED AT PHASE 2
TRIALS AND HAVE NOT DETECTED
THAT.
I WOULD SAY THAT I THINK AS I
HAVE SAID TO THEM ABOUT DATA 2,
I THINK LACK OF DETECTION
DOESN'T MEAN IT IS NOT THERE BUT
IS A HARD THING TO LOOK FOR AND
FIND AND WE NEED TO LOOK FOR IT
IN OTHER WAYS. BUT, SOMETHING
THAT WE STILL NEED TO WORK ON.
>> ANYONE WORKED IT OUT IN VITRO
TRYING TO GROW? I MEAN IT WOULD
ONLY BE AN INDICATOR.
>> AS A WAY TO PREDICT?
>> PORTION OF FM63.
>> OH.
>> TO RAISE CTL RESPONSES TO
REJECT ADDITIONAL FURTHER CTLS.
>> YEAH. IT HASN'T BEEN
WELL-CHARACTERIZED. WOULD
T-CELL RESPONSE ASSAYS DO IT BY
PULLING DIFFERENT SECTIONS OF IT
IT HASN'T BEEN CHARACTERIZED.
>> THANK YOU.
>> [INDISCERNIBLE].
>> CAN YOU REPEAT QUESTION?
>> YEAH. CAN YOU HEAR ME?
QUESTION WAS HAVE WE CONSIDERED
GIVING CD19APCS BOOSTER STRATEGY
PRECAR AND NO. WE HAVE NOT IS
THE SHORT ANSWER AND WAY WE
DESIGNED TRIAL IS TO DO IT AFTER
AND INTRIGUING IDEA TO HAVE THAT
SETUP TO HAVE ENERGY BURDEN FROM
THE GET-GO AND BRAND NEW PRODUCT
WITHOUT KNOWING WHAT TO EXPECT
OR DO WE HADN'T CONSIDERED THAT
AND THINK THAT SOME THINGS ABOUT
THIS ARBITRARILY ARE CHOSEN TOO.
DOSING AND TIMEFRAME WE DECIDED
FIRST IN HUMAN TRIAL AND
TWEAKING WE CAN DO TIMING OF
TAPCS WHEN WE START THEM AND
DOING THIS MOVING IT FORWARD HOW
LONG TO GIVE THEM AND HOW LONG
THEY NEED DOSING AND IF DOSE
ITSELF COULD BE OPTIMIZED AND WE
HAVE THAT TYPE OF WORK TO DO.
>>
>> GREAT TALKS ALL AROUND AND
STUFF WE ARE STRUGGLING WITH AND
INFORMATION WE SOMETIMES DON'T
KNOW WHAT TO DO WITH. YOUR
POINT MIKE ABOUT POTENTIAL
EFFICACY GOING TO THAT MODALITY
IS SOMETHING TO AFFIRMATIVELY
EITHER EMBRACE OR NOT.
I THINK THAT MORE DATA WE HAVE
IN THAT AREA THE BETTER AND
PRESENTATION WAS A REALLY
IMPORTANT IN THAT REGARD. IN MY
FAVORITE TOPIC OF TRANSPLANT I
WOULD LIKE TO PUT A COUPLE
THINGS TOGETHER HEARING FROM ALL
OF THE PRESENTATIONS AND ONE IS
THE OBSERVATION THAT FEWER AND
FEWER AND ANDRÉ YOU MADE THIS
POINT OF THE RELAPSES WE ARE
SEEING THAT ARE NEGATIVE AFTER
COMMERCIAL CAR.
AND THAT MAY HAVE AN IMPACT ON A
NUMBER OF THINGS. THE UP-FRONT
COG STUDY AND GENERAL ISSUE OF
IF THERE IS SAME PERSISTENCE WE
DON'T KNOW ANSWER TO THAT
QUESTION AND IS IMPORTANT TO
ACKNOWLEDGE THAT PERSISTENCE HAS
TAKEN A DIP IN THE COMMERCIAL
ERA THAT IS HOPEFULLY COMING UP
AND WHAT WE KNOW FROM PUBLIC
DATA IS NOVARIS CHANGED APPROACH
AND SOMEWHAT LESS PERSISTENT AND
CHARACTERISTICS GETTING PATIENTS
INTO REMISSION AND SHORT TERM NO
PROBLEM AND LONGER TERM AND
MEETING EXPECTATIONS HIGHER
LEVEL OF CD19 POSITIVE RELAPSE
AND LOWER LEVEL CD19 RELAPSE
GOES ALONG WITH THAT AND IS
INDIRECT AND PROBABLY TRUE AND
WE DON'T KNOW AND I'M
HYPOTHESIZING THAT IS THE CASE
AND I HOPE THIS IS REALLY THE
COMMENT I WOULD LIKE TO HEAR
ANYBODY'S COMMENTS ON THIS IS
THAT WITH RESTORATION OF
NOVARTIS MANUFACTURING APPROACH
WHAT THEY PROCESS AS F THAT IS
INFORMATION THAT IS BACK TO THE
SORT OF MEDIAN CHARACTERISTICS
THAT THEY STARTED WITH THAT WILL
BE BACK IN A SITUATION WHERE WE
SEE THAT, YOU KNOW, 50%
LONG-TERM B CELL APLASIA WE SAW
NEXT LIANA AND OTHER STUDIES AND
IF FOLKS FEEL THAT IS THE CASE
THEY DON'T HAVE DATA TO ADDRESS
IT BUT CHANGING CHARACTERISTICS
OF CD19 POSITIVE VERSUS CD19
NEGATIVE MIGHT BE A CLUE.
>> IT IS LEVEL OF DISEASE AT
TREATMENT ALSO. MUST HAVE
SOMETHING TO DO WITH IT.
>> MUST HAVE SOMETHING?
SORRY.
>> I THINK IF YOU LOOK AT REAL
WORLD DATA SO MANY PATIENTS ARE
TREATED AT A LOWER LEVEL OF
DISEASE. SO TROUBLE IS I WOULD
LOVE FOR FORM LALGS F?
>> THAT IS RIGHT. TWO THINGS
ARE HAPPENING AND MAYBE THERE IS
FOR SURE DISRUPTION IN THE
PRODUCT AND MAYBE EFFECTED
QUALITY AND SAME TIME WE
TRANSPLANT PATIENTS AT LOWER
LEVELS.
>> GREAT POINT.
>> OF DISEASE AND DON'T KNOW HOW
TO TEASE IT APART BUT HAVE TO
THINK CAREFULLY ABOUT IT.
>> COMMENTING ON THAT IS A GREAT
POINT AND THERE ARE OR HAVE BEEN
DATA THAT IS SHOWING THAT
PATIENTS WITH HIGH DISEASE
BURDEN ARE LIKELY TO RELAPSE IN
19 NEGATIVE DISEASE AND HOWEVER
I THINK THAT NUMBER OF THE
PROPORTION OF PATIENTS RELAPSING
WITH COMMERCIAL PRODUCT IS
HOLDING KIND OF STEADY WITH WHAT
WE WERE SEEING ON INITIAL PHASE
1 TRIAL AND ELIANA TRIAL AND YOU
EXPECT WITH PATIENTS WITH LOWER
DISEASE BURDEN THERE WOULD BE
FEWER PATIENTS RELAPSING AND
HIGHER PROPORTION OF 19 POSITIVE
RELAPSES AND SEEING THEM IS
SUGGESTING WE ARE SEEING POORER
PERSISTENCE AND QUESTION IS
WHETHER IT GOT BETTER WITH A
CHANGE AND DO WE HAVE LONG
ENOUGH DATA TO KNOW THAT?
>> THANK YOU EVERYBODY. IN
INTEREST OF TIME WE HAVE TO MOVE
TO THE NEXT EVENT THAT IS A
GROUP PHOTO IN THE BACK.
AND LUNCH.
>> WE WILL GET STARTED THIS IS
THIRD SESSION PREVENTION AND
MANAGEMENT AND WILL START WITH
REBEKAH GARDNER FROM SEATTLE
CHILDREN'S TALKING ABOUT
PRE-EMPTIVE PROPHYLACTIVE
OPTIONS FOR CF.
>> I WILL TRY NOT TO BE OFFENDED
THAT NOBODY CAME BACK FOR MY
TALK.
JUST KIDDING.
APPARENTLY I DON'T KNOW HOW TO
WORK A COMPUTER EITHER.
THERE WE GO.
NOW IT IS GOING.
OKAY. SO, I AM HAPPY TO TALK TO
YOU ABOUT PRE-EMPTIVE AND
PROPHYLACTIVE STRATEGIES
FOR-CRS. CHALLENGE TO DO IN 8
MINUTES AND WILL DO MY BEST AND
A LOT OF INFORMATION WON'T BE
INCLUDED BUT WE CAN TALK ABOUT
IT WITH OUR DISCUSSION.
THIS EARLY INTERVENTION AFTER WE
TREATED 20 MASHIENTS AND MANY
GOING TO ICU AND STARTED TO
NOTICE WHEN ADMINISTERING
STEROIDS PATIENTS WERE HAVING
ROBUST EXPANSION GETTING INTO
COMPLETE REMISSIONS AND STARTED
TO CHANGE R OUR STRATEGY AND DO
INTERVENTION EARLY ON WITH
PERSISTENT SYMPTOMS OF MILD CRS
TO PREVENT MILD CRS. THIS IS A
GRAPH OF OUR STRATEGY THAT IS
ESSENTIALLY HAVING PERSISTENT
FEVERS AND RECURRENT
HYPERTENSION NOT RESPONDING TO
FLUID BOLISES OR REFUSING OXYGEN
SUPPLEMENTATION AND ADMINISTERED
T OWE, SIE. IF SYMPTOMS
PROGRESSED -- HOWEVER AFTER 48
HOURS YOU COULD GET A SECOND
DOSE OF TOESEE. IN THE GRAPHS
YOU CAN SEE IN THE COHORT BEFORE
EARLIER INTERVENTION YOU SEE A
DIFFERENCE IN MAX TEMPERATURE
BETWEEN NOT SEVERE CRS AND
SEVERE CRS AND NO LONGER SAW
DIFFERENCE IN TEMPERATURE AND
PATIENTS THAT WENT ON TO HAVE
SEVERE CRS AND THOSE THAT DIDN'T
AND BOTTOM DLT COHORT WE WERE
INTERVENING WITH PATIENTS WITH
-- INTERVENING FOR MILD CRS THAT
IS DESCRIPTIVE AND NOT POWERED
AND WE SAW A DROP IN RATE OF
SEVERE CRS FROM 30 TO 15% AND
IMPORTANTLY SAW NO DIFFERENCE
AND IMPORTANTLY FOR MANY REASONS
WE SAW NO DITCHES IN SEVERE
NEUROTOXICITY WE WERE NOT MAKING
IT WORSE AT SAME TIME
INTERVENING TOES SEE AND
STEROIDS IS NOT IMPACTING IN A
GOOD WAY THE NEUROTOXICITY AND
SAW NO IMPACT ON --
>> ANTIGEN RECEPTOR.
>> THANK YOU, KRYSTAL.
>> [LAUGHING].
>> AS WE WERE DOING THIS OTHER
GROUPS STARTED TO DO THIS AS
WELL AND HAVING LESS CONCERN
ABOUT EARLIER INTERVENTION AND I
DIDN'T SAY THAT IN THE BEGINNING
NOBODY WANT THE TO TAKE AWAY
EFFICACY OF CARS AND WE LET
PATIENTS GET VERY SICK AND CHOC
WENT ON TO DO AN EARLY STUDY OF
IT IN EARLY COHORT AND
PERSISTENT FEVER AND TWO
TEMPERATURES MEASURED 4 HOURS
APART AND THEY COMPARED THIS TO
AN INITIAL COHORT.
AND THEY WERE SAYING IT WOULD BE
SUCCESS IF LESS THAN OR EQUAL TO
5 OF 15 HIGH REGARDING PAIENTS
PATIENTS WENT ON TO DEVELOP
GRADE FOR CRS. THAT WAS
MEASURED AS A SUCCESS AND
HISTORIC PHASE 1 CONTROL HAD 51%
RATE OF GRADE 4 AND SUGING THAT
IT WAS PREVENTING SEVERE CRSS.
RECENTLY THIS IS FROM SDVMENT
UMA1 AND THIS CELL POPULATION
AND THERE IS A LOT OF COHORTS ON
SDOOUMA. I DIDN'T PARTICIPATE
IN IT AND GET CONFUSE THE AND
COHORT 6 IS ONE THEY LOOKED AT
PROPHYLACTIC STEROIDS AND IDEA
IS PATIENTS GET 10 MILLIGRAMS ON
DAY 0 AND DAY 1 AND DAY 2 AND
THREE DAYS ARROW AND AT TOP
ORIGINAL STRATEGY AND PATIENTS
WERE NOT GETTING TOSIE OR
STEROIDS WELL UNTIL THEY WERE IN
GRADE 2 AND 4 AND COHORT 6
INTERVENING EARLIER AT CRS FOR
GRADE 1 AND INITIAL TWO COHORTS
SEVERE CRS RATE WAS THEIR TA EN%
THAT IS BASED ON LEAD CRITERIA
OF GRADING AND SEVERE CRS COHORT
INTERVENTION WITH THIS
PROPHYLACTICALLY. HOST WOULD
LIKE TO UNMUTE ME. STAY MUTED.
SEVERE CRS DROPPED FROM 13 TO 0%
THAT IS DESCRIPTIVE NOT
STATISTICALLY POWERED AND THEY
NOTICED CRS OCCURRED IN 80% OF
PATIENTS ALL GRADE 1 AND 2 AND
ALL RESOLVED AND MEDIAN TIME TO
ONSET CRS WAS 5 DAYS WITH
DURATION OF 4 DAYS AND COMPARE
TODAY COHORT 1 AND 2 DELAYED ON
SET OF CRS AND DURATION AND
IMPORTANT FACT INTERVENING EARLY
WITH STEROIDS 7 TAEN% OF
PATIENTS RECEIVED STEROIDS FOR
TREATMENT RATHER THAN
PROPHYLAXIS AND DOSE THAT WAS
GIVEN IN COHORT 1 AND 2 WAS
HIGHER AND COHORT 1 AND 2
CUMULATIVE DOSE OF STEROIDS WAS
THIS VERSUS 1800 IN COHORT 6 AND
INTERVENING EARLY YOU CAN
PREVENT CRS AND OVERALL GIVE
LESS STEROIDS AND INTERESTING
THING HERE DESCRIPTIVELY IS
PATIENTS HAD IMPROVED EFFICACY
FROM AXIES CELL.
SO TOSIE AND STEROIDS WERE GREAT
TO GET US STARTED AND WE SHOULD
HEAD NOW AND BE MORE PRECISE AND
LIKE THIS DIAGRAM THAT IS
CONTEMPORARY OVERVIEW OF
PATHOLOGY OF CRS THAT OBVIOUSLY
IS MULTIFACTORIAL AND YOU ARE
ENGAGING CAR T-CELL WITH TUMOR
AND RECRUITING PARTS OF THE
IMMUNE SYSTEM AND MONOCITES PLAY
A BIG ROLE IN CRS AND THERE IS
AISLE 1 TO AISLE 6 CREATING
CYTOKINE CASCADE AND SYNDROME IN
ORGAN TOXICITY YOU SEE AND
CORRELATED WITH ENGRAPHMENT AND
HAVE DIFFERENTIATING PEEKS WITH
ICANS RELATED TO DIFFERENTIAL
EXPRESSION OF CYTOKINES AS WELL
AND THIS IS A STUDY PUBLISHED 6
OR 5 YEARS AGO NOW LOOKING AT
MOUSE MODEL AT ROLE OF MONOCITES
DRIVING IN CRS AND THOSE THAT
HAVE NOT READ THIS PAPER I
RECOMMEND GOING THROUGH LOOKING
AT PAPER IN ENTIRETY AND IF YOU
DEPLETED MONOCITES YOU ARE ABLE
TO HAVE LONG-TERM SURVIVAL AND
HAVING MONOCITES IN THERE YOU
HAVE MORTALITY FROM CRS. THIS
REALLY LED TO SOME INCLINATION
THAT ANAKINRA WOULD BE HELPFUL
IN MANAGEMENT OF CRS THAT THERE
HAVE BEEN SEVERAL SMALL
INVESTIGATED INITIATIVE TRIALS
IT THAT HAVE BEEN TALKED ABOUT
AT VARIOUS MEETINGS OVER THE
LAST COUPLE OF YEARS AND THIS IS
TWO OF THEM AND ONE IS FROM
KETERRING AND B CELL PATIENTS
AND THEY LOOKED AND SAID YOU CAN
GET 100 MILLIGRAM SUBCUTANEOUS
HOURS ON DAY 2 AND PROPHYLACTIC
SETTING IN TWO FEVERS AND 74%
RATE CRS AND LOW RATES OF GRADE
3 AND 4 AND 20% OF ICANS MOSTLY
LOW GRADE OR NO GRADE 3 OR 5 AND
WHAT IS FASCINATING ABOUT KINN
RA IS EFFECTIVE FOR CRS AND
ICANS WE FEEL LIKE TOESO LUS
MAED IS NOT EFFECTIVE WITH ICANS
AND PATIENTS WERE GETTING TOE
SEE AND COURTI CO STEROIDS AND
THAT SAME 100 TO 2 MILLIGRAMS
SUBIS CUTANEOUS OR
[INDISCERNIBLE] WAS MORE FOR
TREATMENT REFRACTORY CRS ANY
CANS AND NOTED 73% OF PATIENTS
HAD IMPROVEMENT IN SYMPTOMS AND
WITH HIGH DOSE REJIMMEN AND
SIDENOTE THEY ARE LOGISTICALLY
CHALLENGING AND IS EXPENSIVE AND
SOBI IS ENGAGED INITIALLY
GETTING CRS AND ICANS AND THEY
BACKED AWAY FROM IT THINKING IT
LOGISTICALLY WOULD BE
CHALLENGING MOVING FORWARD WITH
ANAKIN IN A BIG WAY WITH
PROPHYLAXIS AND OTHER
ALTERNATIVES OUT THERE BEING
INVESTIGATED CLINICALLY IS
RAERLLY RESULTS FROM
[INDISCERNIBLE] AN ANTI-GMSCSF
ANTIBODY AND ON SDOOUMA THEY
LOOKED AT 6 PATIENTS AND 3 + 3
DESIGN DOSING PRIOR TO CAR AND
ADMINISTRATION OF IT REDUCED --
THEY DID NOT SEE IMPACT ON
RESPONSES AND ALL 6 PATIENTS HAD
OBJECTIVE RESPONSES AND DIDN'T
SEE SEVERE CRS OR SEVERE I KANS
AND ARE WORKING ON PHASE 2
POTENTIAL REGISTRATION TRIAL AND
LYMPHOMA TO USE IN PROPHYLACTIC
SETTING AND YOU SEE REFERENCE OF
BLOOD AND EARLY PRECLINICAL DATA
LEADING TO INITIAL EXPLORATION
OF THIS AS PART OF ZUMA.
THEN LASTLY I THINK THIS IS ONE
THAT I AM MOST EXCITED ABOUT AND
STEVE ELUDED TO THIS EARLIER
TODAY INTERFERING GAMA IS A
CYTOKINE THAT IS QUITE ELEVATED
AND MIGHT BE A TRUE DRIVER. IF
WE CAN BLOCK INTERFERING GAMMA
AND POTENTIALLY WE COULD ABROW
GATE CRS AND DOWNSTREAM EFFECTS
OF THAT INCLUDING I- KANS AND
CARS HRH AND THIS IS A GROUP IN
BOSTON AND SHOWING ACTIVATION OF
CAR T-CELLS LEADS TO PRODUCTION
THAT LEADS TO MACROPHAGES AND
BLOCKING INTERFERING GAMMA YOU
CAN GO TO IMPROVED EFFICACY AND
DATA FROM TRIALS WITH PATIENTS
WITH SEVERE TOXICITY MATCH IN
MACHINE LEARNING WAY
DYSFUNCTIONAL RESPONDERS AND
THERE IS THOUGHT BLOCKING
INTERFERON GAMMA YOU WILL NOT
ONLY REDUCE TOXICITY BUT YOU CAN
IMPROVE EFFICACY AND ON BOTTOM
HERE YOU CAN SEE COMPARING GAMMA
WITH ANAKIN RA AND TOE SEW LUSA
MAB CYTOKINES IN COMPARISON TO
BLOCKING AISLE 1 AND RECEPTOR
BLOCKADE AND THIS IS EXCITING
AND SOBI SEEMS TO BE MORE
ENGAGED NOW USING GAMMA IN
PROPHYLACTIC SETTING IN CAR
T-CELLS AND INVESTIGATOR
INITIATED TRIALS COME OUT IN THE
NEXT YEAR TO INVESTIGATE THIS
CLINICALLY AND ONE THING THAT IS
IMPORTANT MOVING LATER IN THE
DAY TALKING ABOUT SOLID TUMORS
BLOCKING INTERFERON GAMMA IN
TUMORS IN PROPHYLACTIC SETTING
IT IS CRITICAL FOR TUMOR KILLING
IN SOLID TUMORS AND WOULD BE
SPECIFIC TO LIQUID TUMORS.
MOVING FORWARD QUESTIONS TO ASK
OURSELVES IS HOW TO PRIORITIZE
AGENTS TO INVESTIGATE AND
DECIDING WHEN TO INTERVENE AND
DECIDE WHAT OPTIMAL THERAPY IS
FOR PREVENTION AND TREATMENT AND
WITH THAT I WILL SIT DOWN.
>> WE WILL GET INTO THE NEXT
TALK. I HAVE BEEN TASKED WITH
DISCUSSING PRE-EMPTIVE
STRATEGIES AND MANAGEMENT
STRATEGIES ANY CANS THERAPY AND
I HAVE NO DISCLOSURES. AS YOU
KNOW IN PIVOTAL STUDIES NO
UNIFORM GRADING EXISTED TALKING
ABOUT TOXICITY IN T-CELL THERAPY
AND ACROSS TRIALS EVALUATING
SUBJECTS EFFECTIVELY TO HAVE
REPRODUCIBILITY AND
COMPARABILITY AND WHAT WE NEEDED
WAS TO HAVE TESTS OR TESTING TO
EASILY ADMINISTER ALLOWING FOR
RAPID AND DYNAMIC ASSESSMENTS
AND AS SUCH ASTCT LIKE CRS
CREATED CONSENSUS UNIFORM
GRADING SYSTEM TERMS ICANS AND
IT INCLUDES COMPOSITE SCORE OF
ENCEPHALOPATHY SCALES THAT IS
BASED ON AGE AND SCIENCE AND
SYMPTOMS OF FOUR GLOBAL DOMAINS
INCLUDING LEVEL OF CONSCIOUSNESS
AND SEIZURES AND MOTOR WEAKNESS
AND NOTABLY SYMPTOMS EXCLUDED
FROM ICANS INCLUDE HEADACHE
TREMORS WEAKNESS HALLUCINATIONS
AND INTERCRANIAL HEMORRHAGE. IN
PIVOTAL PEDIATRIC TRIALS THERE
ARE VARYING RATES OF SEVERE
NEUROTOXICITY AND WE DISCUSSED
NO UNIFORM GRADING ACROSS TRIALS
AND ADVERSE EVENTS DIFFERED IN
DESCRIPTIONS AND DEFINITIONS
THAT IS NOT COMPARABLE. THERE
ARE SEVERAL SPECIFIC AND
PEDIATRIC CONSIDERATIONS NEEDING
TO BE TAKEN WHEN DISCUSSING
ICANN AND CURRENT TREATMENT
PARADIGM ASSESSING NEUROTOXICITY
RELIES ON LANGUAGE AND MOTOR
SKILLS CHILDREN MIGHT NOT HAVE
DEPENDING ON AGE AND
ADDITIONALLY IS IMPORTANT TO
NOTE THAT THEY ARE CAPTIVE
RECOGNIZING DELL EARIUM IN ICU
SETTINGS AND IS NOT VALIDATED IN
INPATIENT AND OUTPATIENT
SETTINGS AND WHAT WE USE IT
FORMILD TOXICITY MAY MANIFEST
SUBTLE BEHAVIORAL CHANGES NOTING
CAREGIVERS WITH PATIENTS AND
NEUR LOGIC EXAM COULD BE
DIFFICULT IN CHILDREN THAT ARE
HEALTHY AND COMPOUND WITH
PATIENTS RECEIVING CAR T-CELL
THERAPY AND ARE ASKING PATIENTS
WITH REGARDS TO COOPERATION AND
PARTICIPATION TO OBTAIN MOST
EXCELLENT NEUROEXAM WE CAN.
PATIENT DEPENDENT FACTORS
INCLUDE ABILITY TO TOLERATE MRIS
AND EEGS WITHOUT PUNCTURES OR
ANTHEESHA AND IF THEY CAN'T DO
IT IT COULD DELAY DIAGNOSIS AND
COURSE OF THE DAY AND COMMON
SYMPTOMS OF ICANS INCLUDES
DLEERIUM AND LANGUAGE
DISTURBANCES AND CONFUSION AND
ALTERED MENTAL STATUS WITH
CONCEPTS BEING FOCAL DEFICITS
AND EDEMA IN PEDIATRIC
POPULATION AND DEMONSTRATING IN
SCHEMATIC IT PROCEEDS ICANS AND
THEY HAVE TEMPORAL OVERLAP AND
TALK WILL HAVE LOTS OF OVERLAP
AS WELL. THANKFULLY IN
PEDIATRICS ICANS IS REVERSIBLE
AND SELF-LIMITED TREATMENT
APPROACH IS BASED ON SEVERITY
AND SYMPTOMS PRESENT AND TO DATE
COURTI CO STEROIDS EXIST -- AREA
OF ACTIVE INVESTIGATION INCLUDES
SUPPORTIVE CARE AND PREVENTION
STRATEGIES METHODS AND CURRENT
PRACTICES FOR PREVENTION
STRATEGIES ARE ANTISEIZURE
PROPHYLAXIS AND SCHEMATIC PUT
FORTH IN REVIEW PAPER SIMILAR TO
CRS ICANS PREVENTION STRATEGIES
ARE TARGETING INFLAMMATORY
CYTOKINES AND BY ACTIVATION OF
CAR T-CELLS BINDING TUMOR
ANTIGENS RESULTS IN
PROINFLAMMATORY CYTOKINE CASCADE
LEADING TO ACTIVATION THAT IN
TURN CONTINUES CASCADE WITH
AISLE 1 AND NITRIC OXIDE AND
THERE IS SIGNIFICANT PRECLINICAL
DATA SHOWING PROMISING RESULTS
USING SEVERAL BYLOGIC AGENTS TO
TREAT AND PREVENT CRS ICANS. WE
HEARD THERE IS SEVERAL PHASE 1
AND 2 STUDIES PUT FORTH IN ADULT
LITERATURE DEMONSTRATING
FEASIBILITY SAFETY AND EFFICACY
USING BUY LOGIC AGENTS TO REDUCE
CRS IN ICANS.
INTEGRAL PART SEEN AS
PROPHYLAXIS IN PEDIATRIC ALL
THERAPY PARADIGM UTILIZATION OF
ANL-BASED CHILDREN'S ONCOLOGY
GROUP HAS DEMONSTRATED
FEASIBILITY AND EFFECTIVENESS IN
TREATMENT FOR ICANS IN NIH AND
PEDIATRIC ONCOLOGY BADGE AND
CHALLENGES REMAIN IN POPULATION
AND WITH PEDIATRICS YOUNG
PATIENTS REQUIRING ANESTHESIA
AND DEPENDENT ON CAR CONSTRUCT
THEY ARE RECEIVING AND WITH
CEREBRAL ED EMA AND SAFE
PUVENGURE AND WE HAVE BEEN ABLE
TO UTILIZE CORTISONE AND FIVE
SUBJECTS WITH CD19 DIRECTED OR
CD19-22 DIRECTED CAR T-CELLS OR
WORSENING SYMPTOMOLOGY DESPITE
USE OF SYSTEMIC HYDRO STEROIDS
THERE IS RAPID SYMPTOMS WITHIN
24 HOURS OF ADMINISTRATION OF
CORTISONE WE ARE ABLE TO
FACILITATE RAPID SYSTEMIC
[INDISCERNIBLE] AND NOTABLY ABLE
TO DEMONSTRATE CAR T-CELL
PERSISTENCE IN CSF IS UNCHANGED
IN COMPARING PATIENTS RECEIVING
HYDROCORTISONE VERSUS THOSE THAT
RECEIVED STANDARD OF CARE THAT
INCLUDED PATIENTS RECEIVING HIGH
DOSE SYSTEMIC STEROIDS AND SO IN
THIS GRAPH THAT YOU SEE TO THE
RIGHT OF THE SCREEN, PERCENTAGE
OF T-CELLS POSITIVE FOR CAR IN
CSF, IT IS AS COMPARED TO THE
GROUP VERSUS STANDARD OF CARE
GROUP DEMONSTRATES GROUPS HAVE
CAR T-CELL PERSISTENCE AT DAY 28
AND THUS INTRATHECAL
HYDROCORTISONE -- ICANS AS
PRE-EMPTIVE STRATEGY TO PREVENT
GRADE 4 ICANS AND MOST PATIENTS
WILL HAVE EVOLVED TO SEVERE
ICANS WHILE ON SYSTEMIC STEROIDS
AND SEVERAL ADULT CASE RESUPORT
HAVE BEEN PUBLISHED PLUS OR
MINUS CHEMOTHERAPY AND TREATING
STEROID REFRACTORY ICANS AND
PAPER PUBLISHED IS DEMONSTRATED
INTRATHECAL THERAPY WITH
HYDROCORTISONE -- IMPROVED
PROGRESSION FREE SURVIVAL AND
OVERALL SURVIVAL IN THOSE THAT
RECEIVE THERAPY AND ADDITIONALLY
LOWER MEDIAN CUMULATIVE DOSE OF
SYSTEMIC STEROIDS USED.
USE IN PEDIATRIC PATIENTS WITH
T-CELL TOXICITIES IS PUBLISHED
BY SEVERAL CENTERS PRESENT HERE
TODAY MULTICENTER RETROSPECTIVE
STUDY EVALUATING INDICATIONS
TIMING OF ADMINISTRATION AND
DOSING FOR ANAKIN RA AND MOST
FROO EBBING WENT INDICATIONS --
AS DEMONSTRATED EARLIER ANAKIN
RIN TREATMENT FOR ICANS ADULTS
BENEFIT IN MOST REPORTS AND I
WILL SKIP THROUGH SLIDE FOR SAKE
OF TIME. DATA WAS PRESENTED
ALTERNATIVE TREATMENT OPTIONS
INCLUDE MONO CLONAL ANTIBODY AND
WILL SAY THERE IS NO DATA IN
TREATMENT FOR ICANS IN PEDIATRIC
POPULATION AND THERE IS EMERGING
DATA AND POOR TOXIN OF USE IN
FIRST LINE THERAPY THAT WAS
RECENTLY PRESENTED AT TCT THIS
PAST YEAR.
AS WE MOVE FORWARD INTO THE
WORLD IT IS IMPORTANT TO NOTE
NOT ALL NEUROTOXICITIES ARE
EQUAL WHAT WE KNOW SO FAR IS
ENDOTHELIAL ACTIVATIONS ARE
IMPLEMENTED AND CD22 CAR T-CELL
TRIAL ENDOTHELIAL ACTIVATION AND
DISRUPTION CITY DIDN'T SEE
CORRELATIONS WITH HIGH LEVELS OF
NEUROTOXICITY AND WHEN LOOKING
AT SINGLE CELL RNA EXPRESSION
OVER THREE DATABASES WE DIDN'T
SEE CD22 EXPRESSION DEMONSTRATED
IN NEUROVASCULAR CELLS AND
HYPOTHESIS COULD BE DIFFERENTIAL
ANTIGEN EXPRESSION IN CNS MAY
IMPACT CLINICAL SYMPTOMS AND
ADDITIONALLY MOST RECENT
PUBLICATION OUT OF STANFORD
USING GT2 CAR CELLS WITH
PATIENTS WITH CAR CELLS WITH
GLEOMAS DEMONSTRATED DIFFERENT
TYPE OF NEUROTOXICITY -- WHERE
PATIENTS DEVELOP TRANSIENT
WORSENING OF EXISTING DEFICITS
WITH EPISODES OF EDEMA AND THIS
IS DIFFERENT THAN ICANS
TRADITIONALLY AND HAVE TO KEEP
IT IN MIND AS WE MOVE FORWARD IN
THE CAR T-CELL WORLD AND CURRENT
APPROACH TO DIAGNOSIS AND
MANAGEMENT OF ICANS IS DOG
COMPREHENSIVE PREINFUSION
EVALUATION WITH BASELINE NEUR
LOGIC EVALUATIONS WITH
NEUROTESTING AND NEUROCONSULTS
FOR HIGH RISK PATIENTS ENGAGING
PROPHYLACTIC KEPPRA FOR PATIENTS
POST MONITORING LOOKS TO
ADDITIONAL INCREASED TESTING FOR
PATIENTS DEVELOPING CYTOKINE
SYNDROME OR PATIENTS GETTING CAR
WE KNOW TO HAVE HIGHER TOXICITY
PROFILE AND FOR SAKE OF TIME I
WILL SAY THIS IS THE CURRENT
ICANS MANAGEMENT STRATEGY AND
HIGHLIGHTING GRADE 3 WE
TYPICALLY DO LUMBAR PUNCTURE AND
DURING THAT TIME POINT IF NOT
CONCERNED FOR INFECTION WE
ADMINISTER -- GOAL PREVENTING
SEVERE LIFE THREATENING TOXICITY
IN PATIENTS RECEIVING CAR T-CELL
THERAPY THERE IS LARGE NEED TO
PATIENT POPULATION TO UTILIZE
BIOMARKERS AND PREDICTIVE
MODELING TO ASSESS PATIENTS WITH
SIGNIFICANT ICANS AS WE
DEVELOPED A RETROSPECTIVE STUDY
ALONGSIDE INSTITUTIONS PRESENT
HERE THAT ARE RETROSPECTIVE
NEUROIMAGING STUDY DATA BASE AND
BRAIN IMAGING FINDINGS AT
VARIOUS TIME POINTS CORRELATING
WITH ICANS AND I WOULD LIKE TO
INCORPORATE PRE-EMPTIVE
TREATMENT STRATEGIES TO PREVENT
WORSENING ICANS. WE ARE HERE TO
CONTINUE TO CONDUCT PRESCRIPTIVE
CLINICAL TRIALS COLLABORATIVELY
AND WE OPENED A THREE SITE
MULTICENTER TRIAL LOOKING AT
LONG TERM OUTCOMES AND -- POST
CAR T-CELL THERAPY AND WOULD
LOVE TO PROPOSE AND TALK TO
THOSE INTERESTED IN
NEUROTOXICITY WORKING MANAGEMENT
GROUP TO CONSIDER DEVELOPING A
MULTI-SITE INTERVENTIONAL STUDY
FOR THESE PATIENTS AND WITH THAT
I THANK YOU FOR YOUR ATTENTION.
>> NEXT IS KEVIN MCNERNEY FROM
JOHNS HOPKINS HOSPITAL.
>> THANKS SO MUCH. MY NAME IS
KEVIN MCNERNEY.
NO DISCLOSURES TO REPORT AND
JUST A BRIEF OUTLINE I WILL TALK
ABOUT CRS AND OVERLAP WITH HLH
AND GO INTO HLHLIKE TOXICITIES
INCLUDING DEFINITIONS THAT HAVE
BEEN USED SO FAR AND INCIDENCE
IN TIMING AND CLINICAL FINDINGS
AND CORE BIOLOGY AND OUTCOMES
AND POTENTIAL CONCLUSIONS AND
STARTING WITH OVERLAP OF
CYTOKINE SYNDROME AND HLH IS A
TERM INITIALLY USED TO DESCRIBE
A SYNDROME THAT OCCURRED WITH
CD3 MONOCLONAL ANTIBODY THAT
RESEMBLED WHAT WAS HAPPENING
WHEN MICE WERE DIRECTLY INJECTED
WITH CYTOKINES AND SYMPTOMS
RANGING WITH MILD FEVER MAIALGIA
AND NAUSHIA AND THIS HAS BEEN
OBSERVED BY SPECIFIC T-CELL
ENGAGERS AND STEM CELL
TRANSPLANT AND CAR T-CELL
THERAPY AND DISEASE BURDEN AND
ANCONTINUAL ENLOAD AND -- ARE
SIMILAR TO WHAT IS DESCRIBED IN
HLH AND BOTTOM RIGHT SEE WORKED
BY SHOWING PATIENTS WITH GRADE 4
TO 5CRS IN RED AND GRADE 0 TO
3CRS WITH OPEN CIRCLES THAT
THERE IS GREATER ELEVATION OF
INTERFERON GAMMA AND TO NAME A
FEW THAT ARE CONSISTENT WITH
WHAT IS SEEN IN HLH AND
SIMILARLY CRITERIA FOR HLH ARE
ALSO OFTEN MET BY HIGH GRADE C
ARE. S PATIENTS AND LEFT IS
HLH2004 CRITERIA DEVELOPED TO
DIAGNOSE HLH IN PRIMARY HLH
SETTING IN A CLINICAL TRIAL AND
ON RIGHT IS TABLE BY CAROLINE
WITH EACH ROW REPRESENTING A
PATIENT WITH GRADE 3 AND 4CRS
AND COLUMN WITH CRITERIA AND
MEETING SOME GRADE 3 PATIENTS AS
WELL RECOGNIZING THAT POST CAR T
BAR FOR HLH MIGHT BE HIGHER AND
SEEMS TO BE POPULATION THAT
EXPERIENCES EXTREME
HYPERINFLAMMATION AND TWO
DIFFERENT CRITERIA INITIALLY PUT
FORTH AND SUGGESTING THRESHOLD
OF OVER 10,000 CRS WITH ORGAN
TOXICITIES AND PHAGOCYTOSIS AND
-- 100,000 THAT WAS RECOMMENDED
IN A PATIENT WHO HAD CRS AND IN
ADDITION TO AT LEAST TWO ORGAN
TOXICITIES AND PHAGOCYTOSIS AND
CO AGROLOP OJY AND MOST DATA I
WILL PRESENT GOING FORWARD IS
USING THESE DEFINITIONS AND
WORKING GROUP DEVELOPED
CONSENSUS CRITERIA. I WILL SHOW
THEM AT THE END AND INCIDENCE
USING TWO DEFINITIONS RANGES AND
SEEMS IT DEPENDS ON CAR T-CELL
PRODUCT IT THAT IS BEING USED
AND INCIDENCE WAS REPORT TODAY
BE 35.6% THAT IS HIGHEST
REPORTED YET.
WITH CD19 CARS SEEMS LOWER
RANGING FROM 0 TO 14.8%.
MEDIAN ONSETS REPORTED A RANGE
FROM 9 TO 14 DAYS AND NOTABLY
YOU CAN SEE SOME PATIENTS
DEVELOP TOXICITY QUITE LATE WITH
LATEST HERE BEING 25 DAYS AFTER
CAR T-CELL INFUSION.
THEN THIS IS LOOKING AT CD22
DIRECTED EXPERIENCE THAT WE HAVE
MOST OF THE CORRELATIVE BIOLOGY
DATA IS FROM AND LAB FINDINGS
AND PATIENTS WITH CAR HLH ARE
SHOWN IN RED AND CRS IS SHOWN IN
BLUE AND THOSE TAKEAWAY ARE
HIGHER BILLY RUBIN LEVELS AND
COMPARED TO PATIENTS WHO JUST
HAD CRS AND MORE PROFOUND AND
PROLONGED NEUTROPENIA AND --
WHEN CYTOKINES WERE EVALUATED
SIMILAR CYTOKINES TO WHAT HAS
BEEN DESCRIBED IN HLH IN THESE
PATIENTS THESE ARE PUT AT THE
TOP. THEY ARE MOST COMMONLY
TARGETED ONES AND THERE IS A
HOST OF OTHER MONOCITE AND
MACROFANL DERIVED CYTOKINES THAT
ARE HIGHER IN THIS GROUP AND
FROM ALPHA T-CELLS AND CELLULAR
KINETICS LOOKING AT T-CELL
PROLIFERATION IS HIGHER AND
PERSISTED AT DAY 28 AND ARE
FEWER PERIPHERAL BLOOD AND K
CELLS IN GROUP THAT HAD CAR HLH
THAT IS SHOWN BELOW WITH FEWER K
CELLS IN BASELINE AND GROUP OF
CAR HLH ON LEFT AND CAR T-CELL
EXPANSION THIS IS ACKREN TUATED
AND THEN AT D28 THESE CHANGES
WERE PERSISTENT AND ON FAR RIGHT
YOU SEE PATIENTS RECEIVING
T-CELL EXPANDED CAR T-CELLS AND
GREATER PROPORTION OF PATIENTS
THAT HAD T-CELL SELECTED
PRODUCTS DEVELOPED CAR
ASSOCIATED HLH.
SO, SHIFTING NOW TO CD19
DIRECTED CAR T-CELL PRODUCTS
THIS IS DATA FROM PEDIATRIC REAL
WORLD CONSORTIUM AND IDENTIFIED
A POPULATION DEVELOPING CARS HLH
AND LOOKED AT PREINFUSION LAB
VALUES FINDING BONE MARROW BLAST
REACTIVE PROTEIN FAIR ACONTINUE
AND PLATELETS WERE ASSOCIATED
WITH DEVELOPMENT OF CAR HRH AND
WE DEVELOPED THRESHOLDS USING
ROC ANALYSIS TO DETERMINE A
POINT TO HELP DISTINGUISH THOSE
THAT GO ON TO DEVELOP IT AND
THOSE THAT DON'T. WHEN ALL ARE
PUT INTO MULTIVARIABLE LOGISTIC
REGRESSION MODEL DISEASE BURDEN
AND LESS THAN 2% ARE PREDICTIVE
WHO GOES ON TO DEVELOP CAR HRH
AND MODEL BIOLOGY DESCRIBED
BEFORE B CELL BLASTS ACTIVATING
CAR T-CELL ACTIVATE AZ MACROFANL
AND CRS YOU HAVE NATURAL
REACTION TO CAR T-CELL AND
PROCESS WILL RESOLVE AND CAR
ASSOCIATED HLH WE PROPOSE
ACTIVATION OF T-CELLS AND
EXTREME ACTIVATION OF ENDOGENOUS
T-CELLS AND TISSUE INJURY OCCURS
AND EXCESSIVE ACTIVATION OF
CYTOKINE RELEASE AND POSITIVE
FEEDBACK LOOP AND DOWNREGULATION
OF T-CELLS WITH OTHER CELLS THAT
DOWNREGULATE T-CELLS THAT LEADS
TO HYPERFAIRO 10EMIA AND
SHIFTING TO OUTCOMES OF PATIENTS
DEVELOPING HLHLIKE TOXICITIES IS
DATA FROM PEDIATRIC WORLD AND WE
IDENTIFIED 26 PATIENTS
DEVELOPING HLH TOXICITIES OR
THESE AND FOUND THEY HAD
INFERIOR OVERALL SURVIVAL
COMPARED TO GROUP WITH GRADE
TWLEE OR 4CRS AND 12 MONTH
RELAPSE SURVIVAL ARE 25 AND 5%
AND SIMILAR OUTCOMES WERE SHOWN
IN PATIENTS DEVELOPING CAR HLH
AND ADULT LYMPHOMA PATIENTS
TREATED WITH AXI CELL AND
LOOKING AT CAUSES OF DAENL AND
PATIENTS DYING IN PEDIATRIC REAL
WORLD WHO DEVELOPED LEUKEMIA WAS
MAIN CAUSE AND OF THESE
INFECTIONS, DYING DRINKS CRS OR
ICANS AND CARDIAC FAILURE WHERE
CAUSE IS LISTED.
BECAUSE DATA HAS BEEN PRESENTED
UP TO NOW HAS BEEN USED
DIFFERING IN CRITERIA AND LARGE
EFFORT WAS MADE BY NIRALI TO
ORGANIZE THROUGH ASCT A GROUP OF
ONCOLOGIST, RUM TOLLS AND HLH
EXPERTS TO COME UP WITH
CONSENSUS CRITERIA AFTER IECS
AND THAT IS IECHS.
GOAL OF THIS IS TO UNIFY FIELD
GOING FORWARD TO BE ABLE TO
CHARACTERIZE IT BETTER IN TERMS
OF INCIDENCE AND OUTCOMES IN
CORRELATIVE BIOLOGY AND FOCUS TO
DISTINGUISH IS THAT MUCH OF THE
HLH LIKE TOXICITIES WE OBSERVE
MAY HAVE BEEN OVERLAPPING WITH
CRS AND GOAL TO DISTINGUISH
PATIENTS DEVELOPING LATER AFTER
RESOLUTION OF CRS AND GOING
FORWARD THAT IS ONE GOAL WE HAVE
TO CHARACTERIZE THAT BETTER AND
THROUGH THIS GROUP SUGGESTED
ICHS TREATMENT IS PUT FORTH
FOCUSED ON GROUP DEVELOPING
TOXICITIES AFTER RESOLUTION OF
CRS AND ONCE THESE HAVE BEEN
USED AND GIVEN INCREASE IN IO1
BETA AND IT WAS SUGGESTED AS
FIRST LINE THERAPY AND THOSE
WITH MORE SEVERE DISEASE OR
THOSE THAT DIDN'T RESPOND AND
STEROIDS HAVE NOW BEEN ADDED
CONSIDERING STARTING THOSE AND
CONSIDERING ADDING
[INDISCERNIBLE] AS WELL AND
THIRD LINER LIFE THREATENING
TOXICITIES GIVEN -- AND THESE
ARE BALANCED WITH CONCERN FOR
POTENTIAL IMPACT AND EFFICACY
FOR CAR T-CELLS AND TO CONCLUDE
HLHLIKE TOXICITIES THERE IS
TIMING IN PATIENTS DEVELOPING
TOXICITIES AND INCREASE
EXPANSION SUCH AS T-CELL
SELECTION AND DISEASE BURDEN AND
INCREASE T-CELL DOWN REGULATION
AND DESCRIBED SURVIVALS ARE POOR
AND CONSENSUS CRITERIA RECENTLY
DEVELOPED FOR BETTER
CHARACTERIZATIONS OF RISK
FACTORS AND TREATMENT OUTCOMES
AND NEXT STEPS ARE TO DO
RETROSPECTIVE DATA COLLECTION
STUDYING TOXICITY AND POTENTIAL
TRIALS FOR USING PREVENTIVE
THERAPIES AND PATIENTS WITH HIGH
RISK OF THIS TOXICITY. THANK
YOU S-
>> I'M A CLINICAL INVESTIGATOR
FOR STUDIES AT ST. JUDE AND
FORTUNATE TO WORK WITH MANY IN
AUDIENCE TODAY DEVELOPING A
PROSPECTIVE MULTICENTERED STUDY.
>> TO START TO SUMMARIZE CURRENT
STATE OF KNOWLEDGE ABOUT WHAT
DELAYED TOXICITIES LOOK LIKE WE
NEED MORE INFORMATION AND WE
HEARD THROUGHOUT DAY INITIAL
FOCUS IS DESCRIBING ACUTE
TOXICITY PROFILE ESTABLISHING
EFFICACY PREVENTING RELAPSE AND
START TO SEE PATTERNS EMERGING
WITH COHORT INTEGRATING THIS IN
STANDARD OF CARE.
PRIORITIES SUPPOSED TO HAPPEN IN
BUILDING IN SPRING OF 2020
IMPACT OF INFECTIONS AND ONGOING
DELAYED CONSTITUTION AS INITIAL
PRIORITIES AND THINKING FOR MORE
OF A TRADITIONAL LATE OF
EXCELLENCE WE KNOW IT IS
IMPORTANT TO CONSIDER AND
SUBSEQUENT MALIGNANCIES WHAT
HAPPENS TO REST OF ORGANS WE
HAVEN'T HIGHLIGHTED YET AND WHAT
IT MEANS FOR PATIENTS FROM
PSYCHOSOCIAL STANDPOINT AND
STARTING WITH BONE MARROW
DISFUNCTION AREA WE ARE STARTING
TO SEE CLINICAL QUESTIONS POP
UP.
SO, WE KNOW WHEN WE GIVE LYMPHO
DEPLETING CHEMOTHERAPY FOLLOWED
BY T-CELL -- LOOKING AT PACE OF
RECOVERY IT IS BIMODAL
DISTRIBUTION MAJORITY OF
PATIENTS RECOVER IN THE FIRST
MONTH AND SMALLER SUBSET
CONTINUE TO HAVE LOW COUNTS
PERSISTING OUT MONTHS AND MONTHS
AFTER THEY RECEIVED THEIR
THERAPY DEFINITIONS USING WORD
DELAYED AND SUBACUTE AND
POPULATION HASN'T GROWN TO HAVE
LARGE COHORT IN WHAT IS TRUE
EFFECTS OF SURVIVORSHIP AND
POPULATION AND IMPORTANT
TIMEFRAME TO CONSIDER AND
LOOKING BEYOND FIRST MONTH INTO
FIRST MONTH AND 2 YEARS AFTER
THERAPY CONSIDERING TALKING
ABOUT CRYTOPINAS IN CONSTRUCTS.
WHAT WE BEGIN TO OBSERVE GOES
BEYOND THAT WHILE NO CONSENSUS
DEFINITIONS YESTERDAY WE START
WITH DIAGNOSIS SEVERE PLASTIC
ENEMIA AND THERE IS CASES WITH
PEOPLE WITH CRYTOPINAS RELATED
TO PROCESSES AUTO IMMUNE OR
DISSTRUCKTIVE AND LOOKING TO SEE
RISK FACTORS LOOKING FOR
DEVELOPING THIS CONSIDER
BASELINE CRYTOPENIAS AND
PATIENTS EXPERIENCING TREATMENTS
FOR CYTOKINE RELEASE SYNDROME
AND MANY HYPOTHESIZE PRIOR BONE
MARROW TRANSPLANT MIGHT BE RISK
FACTOR DON'T HAVE DATA TO SUPOWE
RT THAT THERE IS PREDICTIVE
SCORES VALIDATED LOOKING AT
MEASURES OF BASELINE
INFLAMMATION NOT VALIDATED IN
PEDIATRIC SETTING AND
SUMMARIZING WHEN PEOPLE ARE
DOING WITH PATIENTS IN MOMENT
LOOKING TO ACQUIRE MORE DATA
BEYOND STANDARD TRANSFUSION
SUPPORT WE PROVIDE INITIAL
QUESTION THAT COMES UP IS WHAT
IS ROLE OF GROWTH FACTORS IN
POPULATION MANY ARE HESITANT
USING FACTORS WITH CONCERN IT
MAY PROMPT OR WORSEN SYMPTOMS OF
CYTOKINE SYNDROME USED SPARINGLY
IN POPULATIONS IN INIRNL
EXPERIENCE AND CASES COMING OUT
WITH SEVERE INFECTION IN
CRYTOPENIAS GCSF IS USED AND
EARLIER USE COMING OUT AGAIN IN
ADULT LYMPHOMA SETTING SESSION.
CAUTION AND WEIGHING RISKS AND
BENEFITS FOR ANY GIVEN PATIENT
AND EMERGING AREA IS FOR
PATIENTS WITH PRIOR BONE MARROW
TRANSPLANT WITH ONGOING SEVERE
CRYTOPENIAS USING CD4 SELECTED
STEM CELL BOOST TO RECOVER
ACCOUNTS AND PEDIATRIC CASE
REPORTS COMING OUT AND SHOWING
IN PATIENTS THIS IS EFFECTIVE
WAY TO RECOVER ACCOUNTS AND
SMALL COHORT CAN GO ON TO HAVE
SUSTAINED RESPONSES AND OF
COURSE LEUKO PINA REQUIREMENT
FOR IMMUNOGOB YOU'LLANCE
SUPPLEMENTATION AND RISK IS
ONGOING AND WILL TALK ABOUT IT
IN NEXT PORTION AND MOVING TO
NEUROTOXICITY AS HANEEN
DISCUSSED WE SEE THIS RECOVER
AFTER FIRST FEW WEEKS OF
TREATMENT. HAVEN'T LOOKED TO
SEE YET WHAT PATIENTS HAVE AS
FAR AS NEUROCOGNITIVE FUNCTION
AND IMAGING CHARACTERISTICS OR
MARKERS LATE EFFECTS
EXPERIENCING TOXICITIES AND
ADULT SETTING WHERE THEY START
TODAY INCORPORATE PATIENT
REPORTED NEUROOUTCOMES PATIENTS
REPORT HIGHER INCIDENCE OF MOOD
DISORDERS COMPARED TO HEALTHY
POPULATION AND LOOKING AT
PATIENT REPORTED OUTCOMES AS
COMPARE TER REPORTING CAR TO
OTHER THERAPIES SUCH AS
TRANSPLANTS AND ADULT SETTINGS
CAR HAS FAVORABLE PROFILE AND
GROUP LOOKING HOW TO INTEGRATE
INTO UP FRONT STUDIES AND HOW TO
INCORPORATE MOVING FORWARD AND
PEDIATRIC SURVIVORSHIP COHORT
AND BLA POPULATION WE HAVE TO
THINK IMPACT OF PRIOR THERAPIES
AND PRIOR TRANSPLANTS CAN IMPACT
NEUROOUTCOMES AND WE NEED TO
COLLECT THAT DATA ALONG WITH CAR
TREATMENT RELATED INFORMATION.
OTHER ORGANS IN ACUTE PHASE WE
HAVE SEEN IMPACT ON HEART AND
KIDNEYS AND PARTICULARLY IN
PATIENTS EXPERIENCING CYTOKINE
RELEASE SYNDROME AND IN GENERAL
THIS APPEARS IN SETTING WE HAVE
NOT LOOKED WHAT IT MEANS GOING
FORWARD HIGHER INCIDENCE OF LATE
CARDIAC EFFECTS OR TOXICITIES
AND ADULT SETTINGS WE HAVE SEEN
A HANDFUL OF LATE IMMUNE EVENTS
WITH MORE AUTO IMMUNE PHENOTYPE
THAT IS NOT REPORTED IN
PEDIATRICS AND SOMETHING TO LOOK
FOR AND PARTICULAR INTEREST FROM
PEDIATRIC STANDPOINT FROM
SURVIVORSHIP LENS WHAT IS IMPACT
FROM PATIENTS IN TERMS OF ENDO
KIND GROWTH FOR WHEN PATIENT IS
DECIDING ABOUT WEIGHING RIFBLG
AND BENEFIT OF GOING TO
TRANSPLANT VERSUS CAR T AS A
DEFINITIVE THERAPY AND OVERALL
FROM SAFETY STANDPOINT WE ARE
INTERESTED IN POTENTIAL IMPACT
ON RISK OF SUBSEQUENT MALIGNANT
NEOPLASMS AND FRAMING BASELINE
POPULATION RISK IN POPULATION
FOR PATIENTS WHO ARE SURVIVORS
OF RELAPSE REFRACTORY BL
UNDERGONE A TRANCE PLANT WE
THINK OF RISK OF 4% THIS IS
HEIGHTENED IN PATIENTS WITH
KNOWN CANCER PREDISPOSITION
SYNDROMES AND INITIAL WORK
COMING OUT OF COHORT FOUND A
RATE OF 1.5% AND IN LINE WITH
WHAT IS EXPECTED IN POPULATION
BECAUSE OF UNDERLYING RATE IS SO
LOW WE NEED BIG NUMBERS TO START
TO DRAW COMPARISONS BETWEEN
THERAPIES IT IS REASSURING WHEN
YOU LOOK AT ADULT COHORT WHERE'S
NUMBERS ARE BIGGER THEIR RATES
ARE PARALLELING ANL-RELATED
RISKS THAT ARE CLOSER TO 15% IN
THEIR POPULATION AND PHENOTYPE
SEEING FOR MALIGNANCIES EXPECTED
FOR AGE-RELATED RISKS AND I WILL
CLOSE WITH VISION AND HOW WE CAN
START TO WORK TOGETHER TO BEGIN
ANSWERING QUESTIONS IN SUBACUTE
AND DELAYED TOXICITY SPACE AND
DEVELOPING STUDY PLANNING TO
INITIATE IN PILOT PHASE ACROSS 9
PEDIATRIC CENTERS LOOKING AT CAR
T-CELL RECIPIENTS HIGHLIGHTING
INTERVAL FROM 3 MONTHS TO 2
YEARS AS THERAPY IN FIRST ROUND
AND PARTNERING WITH AS MAR CELLA
DESCRIBED THIS MORNING TO TRY TO
REDUCE BURDEN OF DATA ENTRY
REDUCING PREVENTION ACROSS
MULTIPLE DIFFERENT STUDIES AND
FORMATS AND OUR GOAL WITH THE
STUDY IS THAT WE CAN LOOK NOT
JUST WITHIN A POPULATION
RECEIVING 1 CAR T-CELL PRODUCT
OR ONE INDICATION AND REALLY
DESIGNING THIS IN WAY THAT WE
CAN BUILD UPON AS WE HOPE
THERAPIES FOR MALIGNANCIES AND
SOLID TUMORS WILL GROW WITH US
OVER THE NEXT COUPLE OF YEARS
AND SO WILL INTEGRATING STANDARD
METRICS FOR COMPREHENSIVE
EVALUATION IN PATIENTS LOOKING
AT CLINICAL DATA AND BUY LOGIC
CORRELATES AND FOCUS KNOWING
COHORT IS ENRICHED FOR BLA
PATIENTS IN AREAS THAT HAVE HAD
EMERGING SIGNALS FROM INITIAL
DATA INCORPORATING EXPLORATORY
AIMS WITH SYSTEMATIC EVALUATION
OF ORGAN SYSTEM TOXICITIES
REPORTING PATIENT OUTCOMES AS
WELL TO PICK UP SIGNALS EARLIER
ACROSS EXPANDED INDICATIONS AND
OUR GOAL IS REALLY THINKING
ABOUT DOING THIS IN A SYSTEMATIC
WAY SO WE CAN GET MOST
INFORMATION FROM OUR POPULATION.
THANK YOU.
>> ALL RIGHT. WE WILL LASTLY
HAVE JOSHUA HILL FROM FED HUTCH
SPEAK ABOUT VACCINATION AND
IMMUNOCONSTITUTION IN A
PRE-RECORDED SESSION.
>> ORGANIZING COMMITTEE FOR IN
-- RECIPIENTS AND HOPE TO REVIEW
WHAT WE LEARNED IN PAST FEW
YEARS AND GAPS WE NEED TO
UNDERSTAND MOVING FORWARD AND
APOLOGIZE I CAN'T BE THERE IN
PERSON AND LOOK FORWARD TO
DISCUSSING AT END OF THE SES
SESSION.
THESE ARE MY DISCLOSURES AND
WILL TALK ABOUT IMMUNE DEFICITS
CAR T-CELL THERAPY AND WHAT WE
KNOW IN THIS AREA. MOVING
QUICKLY TIME IS LIMITED HERE
DON'T NEED TO DWELL TOO MUCH ON
FACT THIS AUDIENCE CAR T-CELL
RECIPIENTS HAVE HIGH STATE OF
IMMUNO -- IN RELATION TO
UNDERLYING HEMATOLOGIC THERAPY
AND PATIENTS RECEIVED PRECAR
THERAPY ALL CONTRIBUTE TO IMMUNE
SUPPRESSION AND FACTORS
PRIMARILY B CELL DEPLETION WE
SEE AS RESULT OF CAR T-CELLS IN
PATIENT POPULATION IN ADDITION
TO TOXICITIES CRS AND ICANS
ASSOCIATED IMMUNOSUPPRESSION WE
HEARD ABOUT IN PRIOR TALKS AND
LEADING TO THESE AND WE ARE
LEARNING TO WHAT DEGREE THIS
IMPACTS PATHOGEN SPECIFIC
ANTI-BEAUEDIES OR PATHOGEN
SPECIFIC T-CELL IMMUNE MEMORY IN
PATIENTS RECOVERING IN CARS AND
STAT JIS IMPLEMENTED IN
IMMUNOGLOBIN THERAPY AND WE WILL
TALK ABOUT ANTI-MICROBIAL
PROPHYLAXIS AND VARIETY OF
PAPERS LOOKING AT CONSTITUTION
AFTER CAR T-CELL THERAPY THAT IS
A QUICK SNAPSHOT FROM PAPER BY
FRED'S GROUP IN MOV ET AND
LYMPHOCYTE ACCOUNTS AND CD19B
CELL ACCOUNTS ORIGINATE AROUND
DAY 30 AND SLOWLY RECOVER OVER
OF A YEAR AND ABSENT IN PATIENTS
THAT RESPOND IN 6 MONTHS AND SEE
A SUBSET OF PATIENTS BEGINNING
TO HAVE RECOVERY AND TOTAL IGG
DATA SHOWS A LITTLE OF A DROP
AFTER FIRST MONTH OR SO THAT IS
PERSISTENT WITH RECOVERY A YEAR
OR FURTHER OUT. BY ONE YEAR 10%
OF PATIENTS CONTINUE TO HAVE
SOME DEGREE OF CRYTOPENIA AFTER
CAR T INFUSION FOR VARIETY OF
FACTORS WE DON'T HAVE TIME TO
GET INTO TODAY.
THIS IS A COMPLICATED SLIDE I
WILL WALK THROUGH TO MAKE KEY
POINTS AND IS A CROSS-SECTIONAL
STUDY IN INDIVIDUALS RECEIVING
CD19 OR BCMA CAR SOME AREPEDIA
THE TRICK PATIENTS A YEAR OR UP
TO 5 YEARS OUT LOOKING AT
DIFFERENT IMMUNE METRICS IN
BLOOD AND DATA IS PATIENT TIME
POINT HERE AND TOTAL IGG WE
DIDN'T HAVE PEDIATRIC PATIENTS
ON PLOT ALL RECEIVING IVG AND
MEASUREMENTS WERE CONFOUNDED AND
SEE A MIX 12 MONTHS UP TO 5
YEARS OF PATIENTS BELOW NORMAL
IGG LEVEL AND THOSE THAT ARE
ABOVE WITH AND WITHOUT IV
REPLACEMENT LOOK AT TOTAL IGA IN
BLUE SQUARES ARE PEDIATRIC
PATIENTS SEEING 12 MONTHS TO 5
YEARS OUT AND NO PATIENTS TESTED
IN COHORT HAD MEASURABLE IGA AND
SAME STORY IN BLUE SQUARES
PEDIATRIC PATIENTS FOR IGM UP TO
5 YEARS PATIENTS WE TESTED HAD
NO IGM DETECTIBLE CIRCULATION
AND SIMILARLY CELL COUNT SPREAD
IN ADULT PATIENTS SOME WITH
RECOVERY AND SEEMS TO BE
DIFFERENT AND HAVE PROLONGED
IMMUNE DEFICIENCY
CROSS-SECTIONAL STUDY WE LOOKED
AT SAME TIME POINTS AND
INDIVIDUALS 12 MONTHS OUT TO SEE
HOW WELL THEY RETAINED PRIOR
PATHOGEN SPECIFIC ANTIBODIES TO
VACCINE PREVENTIBLE INFECTIONS
THAT ARE ON X AXIS AND Y AXIS IS
PROPORTION OF PATIENTS TESTED
WITH PROTECTIVE LEVEL IN BLUE OR
CD19 CAR T RECIPIENTS ADULTS ON
THIS PLOT AND PATIENTS ARE
PROTECTED AND OTHERS YOU SUSPECT
PROTECTION IS NOT AS GOOD AND
PATIENTS CAN RETAIN PROTECTIVE
ANTIBODIES WITH CD19BC DEPLETION
AND TARGETING PLASMA CELLS WITH
THIS YOU SEE FEWER PROPORTION OF
PATIENTS HERE ARE PROTECTED
GIVING INSIGHTS YOU EXPECT
KNOCKING OUT IMMUNE CELL SUBS
AND TARGETS HAVE IMMUNE
[INDISCERNIBLE] FOR IMMUNE
SYSTEM AND LONGITUDINAL STUDY
COLLECTING SAMPLES AND INCLUDING
PEDIATRICS AND ADULTS ARE DATA
BASELINE PRECAR T INFUSION WITH
TEENS 11 TO 18 AND ADULTS 18 AND
OLDER.
WHAT YOU CAN SEE FOR THE MOST
PART IS CHILDREN AND YOUNG
ADULTS ARE SIMILAR TO ADULTS AND
IF ANYTHING THEY HAVE HIGHER
BASELINE PROTECTIVE ANTIBODY
[INDISCERNIBLE] FOR DIFFERENT
VACCINE PREVENTABLE INFECTIONS
AND NOTABLY 60 TO 70% OF
PEDIATRIC PATIENTS HAD
[INDISCERNIBLE] TO HEPATITIS TO
MUMPS TO MEASLES AND RUBELLA AND
THERE IS A LARGE CHUNK OF
PATIENTS GOING INTO CAR T
THERAPY WITHOUT PROTECTIVE
TIGHTERS AND WITH PEDIATRIC
PATIENTS WITH PROTECTIVE
TIGHTERS WE STILL DON'T
UNDERSTAND TRANL ECTRY AFTER CAR
T THERAPY.
WHAT CAN WE DO ABOUT THIS?
VACCINATION IS OBVIOUSLY AN
IMPORTANT STRATEGY IN INFECTION
PREVENTION AND TRANSPLANT
PATIENTS AND WILL BE IN CAR T
PATIENTS AS WELL AND DON'T
UNDERSTAND WELL HOW PATIENTS
RESPOND AND WHEN TO GIVE
VACCINES.
WE HAVE DONE STUDIES AND OTHERS
HAVE AS WELL TRYING TO FOCUS ON
THIS QUESTION AND LOOKING AT
PRECAR VACCINES AND POST CAR
VACCINES AND USING SARS COV2
EXAMPLE STUDY WE DID PATIENTS
WITH TWO DOSES OF THE VACCINE
PRECAR DON'T MOUNT A GREAT
ANTIBODY TIGHTER WHAT THEY MOUNT
PERSISTS IN FIRST FEW MONTHS
THAT IS IMPORTANT AND YOU CAN
GET RESPONSE VACCINATING 3 TO 6
MONTHS AFTER CAR T-CELL THERAPY
AND WHAT YOU SEE IN PRECAR T
PERIOD IS PATIENTS HAVE GOOD
RESPONSE WITH T-CELL RESPONSE
THAT DROPS AS YOU EXPECT DAY 30
THAT BOUNCES BACK AND IS
IMPORTANT AND SUPPORTS CONCEPT
FOR CERTAIN PATHOGENS GIVING
PRECAR VACCINE COULD INDUCE
MEMORY THAT CAN SUBSEQUENTLY
RECOVER AND ESTABLISH IMMUNITY
PERSISTING AFTER A PERIOD OF
TIME FOR INITIAL CAR T INFUSION
AND WE DON'T HAVE TIME TO DIVE
INTO DETAILS OF PLOT BUT LOOKED
AT VARIETY OF CLINICAL MATRIX
AND DO A GOOD JOB PREDICTING
WHETHER A PATIENT WILL RESPOND
TO VACCINE AND SHOWED THAT IN
PATIENTS WITH UNDETECTABLE IGG
LEVELS AND UNDETECTABLE B CELLS
IN PROLIFERATION THEY COULD
MOUNT OF GOOD ANTIBODY RESPONSE
AND I THINK THIS GOES TO SHOW
THESE ARE NOT GREAT MATRIX FOR
WHAT IS HAPPENING IN LYMPH NODES
AND ASPECTS OF IMMUNE SYSTEM AND
DON'T HELP STRATIFY THAT WELL
WHO WILL RESPOND TO VACCINE OR
RIGHT TIME TO GIVE A VACCINE AND
ASIDE FROM COVID VACCINES AND
PAPER WE PUBLISHED ON FLU THERE
IS NOT MUCH OWE TLUT ON VACCINES
UNTIL THIS PAPER CAME OUT FOR
FRED LOCKE'S GROUP DOWN IN MOVE
ET LAST YEAR AFTER CAR T-CELL
THERAPY AFTER ADULTS SMALL STUDY
13 INDIVIDUALS WERE VACCINATED
AND WHEN YOU COMPARED BASELINE
TIGHTERS DAY 90 AND THEY GOT
VACCINATED LOOKING AT DAY 1-80
THERE IS NO IMPROVEMENT AND ARE
A HANDFUL OF PATIENTS
VACCINATION DAY 90 AND 180 AS
WELL AND SOME DIDN'T SEEM TO
BOOST TIGHTERS EITHER AND
PATIENTS NEED MULTIPLE ROUNDS OR
IT IS TOO EARLY BUT NOT
ENCOURAGING FROM EARLY VACCINE
RESPONSE.
ASIDE FROM SARS C- CO-V2
RESPONSE AND THREE MONTHS AFTER
CAR AND GETTING MORE DATA AND
ROUTINE VACCINES WE CONSIDER
POTENTIALLY GIVING VACCINES 6
MONTHS AFTER CAR T-CELL THERAPY
AND PATHOGENS AND VACCINATING
FOR THOSE WITH VACCINES
RECHECKING TIGHTERS AND
UNDERSTANDING PATIENTS SPONTDING
OR NOT AND BASED ON THAT WE
DETERMINED TO CONTINUE
MONITORING GIVING ADDITIONAL
VACCINES WAITING 6 MONTHS AND
RE-EVALUATE AND TRYING AGAIN AND
LEADING US TO TRY AGAIN PATIENTS
DEVELOP DETECTIBLE -- AND CD4
COUNT AS ABOVE 200 AND METRICS
DIDN'T DO GREAT JOB PREDICTING
AND SUPPORTING IMMUNE RECOVERY
AND INCREASED LIKELIHOOD OF THE
VACCINE RESPONSE.
HOW DO WE MANAGE THIS? THIS IS
IMPORTANT BRANCH POINT.
WE DON'T KNOW IF THERE ARE
PATIENTS THAT DON'T NEED IT AND
HOW FREQUENTLY SHOULD WE GIVE IT
AND HOW LONG TO TARGET SPECIFIC
IGG TIGHTERS IS ONGOING AREA OF
DISCUSSION.
THIS IS AN EXPENSIVE PRODUCT AS
SUB-QIGG REPLACEMENT COULD BE
BURDEN SOME AS WELL WE HAVE LOTS
TO LEARN IN PEDIATRIC PATIENTS
ABOUT COST BENEFITS HERE AND
WHAT IVIG MIGHT BE DOING FOR
PATIENTS IN THE LONG TERM AND I
MOVED QUICKLY THROUGH THAT.
THAT IS WHERE WE ARE WITH
CURRENT STATE OF UNDERSTANDING
IMMUNE RECOVERY AND VACCINATION
AND IMMUNOGLOB YOU'LLIN
REPLACEMENT STRATEGIES AND
BETTER TO UNDERSTAND PATIENTS
AND THANKING COLLABORATORS
ACROSS UNIVERSITY OF WASHINGTON
SYSTEM AND SEATTLE AND FUNDERS
OF WORK AND LOOK FORWARD TO
CHATTING WITH YOU DISCUSS
SECTION AND THANK YOU FOR YOUR
ATTENT
ATTENTION.
>> I THINK WE HAVE TIME FOR A
COUPLE QUESTIONS IF ANYONE HAS
A
ANY.
>> THANK YOU, EVERYBODY, FOR A
GREAT SESSION.
YOU KNOW, I WAS THINKING WE SEEM
LIKE WE ARE LEARNING MORE AND
MORE THAT WE DON'T NECESSARILY
NEED INFLAMMATION AFTER CAR. AT
LEAST IN ALL. I PONDER THIS
ALSO A LOT AS WE DO BRAIN TUMOR
TRIALS AS WELL. WE GET INTO
TROUBLES STILL THAT WE ARE
WORRIED WE WILL TURN OFF THE
CAR.
I'M CURIOUS WHAT PEOPLE'S
THOUGHTS ARE OF BLUNTING
INFORMATION WITH THINGS LIKE
STEROIDS EARLY TOESEE WE HAVE
SEEN SOME ARE TARGETED FOR SOME
THINGS BUT NOT ALWAYS GOOD FOR
ALL AND CURIOUS ABOUT PEOPLE'S
THOUGHTS ABOUT THAT QUESTION.
>> I THINK, YOU KNOW,
[INDISCERNIBLE] THERE IS A FEW
TIMES WITH PATIENTS WITH 98%
DISEASE IN BONE MARROW AND WE
REALLY DON'T WANT TO GO THERE
AND WE GIVE THEM CELLS AND DAY 2
AND 3 AND 4 WE WILL DO STEROIDS
AND THEY DO FINE AND I THINK IT
WOULD BE REALLY HELPFUL FOR US
TO UNDERSTAND A LITTLE BIT MORE
HOW T-CELLS ARE RESISTANT TO
STEROIDS AND THINK YOUR FIRST
POINT THAT WE ARE LEARNING YOU
DON'T NEED FOR INFLAMMATION FOR
CAR RESPONSES AND POTENTIALLY IF
WE DECREASE INFLAMMATION MAY
IMPROVE RESPONSES.
IT IS FOR THIS IN THE LAST YEAR
AND AS WE LEARN MORE WE CAN GET
TO THAT IDEAL STATE OF LETTING
T-CELLS HAVE FUNCTIONAL RESPONSE
ABOUT ALL OF THE EXCESS
INFLAMMATORY RESPONSE.
>> MINE IS NOT DIRECTED AT ONE
SPEAKER. YOU DID GREAT. AWARE
OF BIOMARKERS THAT COULD
POTENTIALLY CORRELATE WITH
TOXICITY WHERE THERE IS NO
CLINICAL PHENOTYPE FOR EXAMPLE
CYTOKINE THAT IS ELEVATED BUT
PATIENT DOESN'T COME IN WITH
FEVER OR CSF BIOMARKER BUT NEVER
DEVELOP ICANS? WOULD BE A NICE
GOAL TO HAVE A SURROGATE TEST
THAT TRACKS THINGS ARE GOING IN
THE RIGHT DIRECTION BUT THEN THE
PATIENT IS NOT SICK.
>> I HAVE A COMMENT ON CARRIE'S
VERY GOOD INITIAL POINT. I
THINK THAT I WOULD SAY THAT I AM
NOT SURE THAT WE KNOW FOR SURE.
I DON'T KNOW. IN MY MIND THE
JURY IS STILL OUT WHETHER YOU
NEED SOME INFLAMMATION AND YOU
MIGHT NOT NEED IT FOR INITIAL
RESPONSE BUT NOT SO SURE FOR
DURABLE RESPONSE. I KNOW I
THINK WE CAN'T NECESSARILY
EXTRAPOLATE AND SOME DATA I
AGREE WITH YOU I CAN'T FOLLOW
COHORTS ON THE KITE TRIAL AND
SOME DATA FROM THERE ARE EARLY
DECKS THAT LOOKED LIKE YOU MIGHT
HAVE IMPACT ON DURABLE
REMISSIONS AND I JUST WONDER
WHETHER YOU NEED A LOOK AND FOR
PATIENTS GOING TO 10 TORS CD19
NEGATIVE AND IS THERE TOXIN THAT
INFLAMMATION IS HELPING CLEAR
THAT IN THOSE PATIENTS?
WE NEED TO STUDY IT I THINK TO
FIGURE THAT OUT.
MY QUESTION IS AND THIS IS SORT
OF ALSO A COMMENT TO COMMENTARY
AND YOU BROUGHT UP, RICK, SOEBY
IS NOT SO INTERESTED IN STUDYING
[INDISCERNIBLE] BECAUSE IT IS
LOGISTICALLY CHALLENGING AND
COSTLY AND COSTLY COMPARED TO
GAMAFANT. I THINK THERE IS --
WE DO NEED TO JUST KEEP IN MIND
THAT IT IS, YOU KNOW, VERY
INTERESTING AND IMPORTANT TO
STUDY GAMAFAN. WE HAVE TO KEEP
IN MINDS A LITTLE BIT OF COMPANY
MOTIVATION OF TRYING TO GET AN
EXPENSIVE PRODUCT TO USE MORE
THAN AN ANOTHER POPULATION.
SO, THAT IS A COMMENT ON THAT.
I WONDER WHAT YOUR THOUGHTS ARE
ON DO YOU THINK IT WILL BE
EASIER TO STUDY SOMETHING LIKE
THAT VERSUS ANAKIN RA? DO YOU
AGREE IT IS LOGISTICALLY HARD
WITH ANAKIN RA?
>> WE DON'T KNOW YET.
IN PART WE ARE A LITTLE
BEHOLDENED TO SOEBY AND WISH WE
COULD BE MORE ENTHUSIASTIC ABOUT
ANAKIN RA. [INDISCERNIBLE].
>> 1 DOSE.
>> DOSING.
>> AND I DO THINK THAT IT WILL
BE REALLY INTERESTING AND THERE
IS MORE AND MORE DATA I THINK
COMING OUT FOR VARIOUS GROUPS
AND DATA A FEW WEEKS AGO
KEYSTONE AT TANDEM AND
COLLABORATING EARLY RESULTS WE
SEE THAT ARE POTENTIALLY
INHIBITING INTERFERON GAMA MIGHT
ENHANCE YOUR EFFICACIOUS
RESPONSE AND THINK YOUR POINT
ABOUT, YOU KNOW, BEING
INFLAMMATIONS POTENTIALLY TO
SOME DEGREE FOR DURABLE RESPONSE
REMAINS TO BE SEEN AND FOR SURE
YOU NEED EXPANSION OF T-CELLS
AND YOU WILL HAVE SOME AND IS
RECRUITMENT OF MONOCITES AND
MACROPHAGES TO DO THAT.
>> YEAH. THAT WOULD BE IDEAL IF
WE COULD AND WE DIDN'T NEED
THIS.
>> YEAH.
>> HOW MUCH -- OH, GOD. I DON'T
KNOW. I THINK $50,000.
>> LIQUID GOLD.
>> 50,000? I DON'T KNOW.
>> NOT AS MUCH AS
[INDISCERNIBLE].
>> IN TERMS OF EXPERIENCE WITH
ANAKIN RA IT HAS BECOME BEST
FRIEND IN GD2 CAR I WILL HEAR
MORE FROM ROBBY LATER NOT
CHALLENGING TO USE AND WE CAN
GIVE -- YOU CAN GIVE A DRIP OR
INTERMITTENT DOSING ABOUT YOU WE
USE IT IN A STANDARD WAY. IT IS
ABOUT COST YOU KNOW AND
COMPANY'S INCENTIVE THAT IS A
SHAME THAT WE CAN'T MAKE
DECISIONS BASED ON OTHER
VARIABLES.
>> ONE LAST QUESTION?
>> GREAT TALKS BY EVERYBODY.
THIS QUESTION IS FOR HANEEN AND
GETTING TO ERA WITH BETTER
DEFINED GUIDELINES FOR GRADING
ICANS I START TO SEE IDEAS ABOUT
AS WE TRY TO MOVE TOWARDS
TREATING PATIENTS IN OUTPATIENT
SETTING POSSIBLY MONITORING
ICANS AND OTHER TOXICITY
REMOTELY THROUGH PATIENT
RESPONSES THROUGH APP OR PLUS OR
MINUS AI INCORPORATION AND IF
YOU HAVE THOUGHTS ON WHEN THIS
MIGHT BE FEASIBLE AND IF THIS IS
SOMETHING WE COULD POTENTIALLY
DO FOR PEDIATRICS OR IF THAT IS
STILL FAR AWAY.
>> I THINK THAT IS REALLY NEAT
AND THINK THAT IS SORT OF IN THE
NEXT STRATOSPHERE OF CAR LOOKING
IN TERMS OF NEUROTOXICITY THAT
IS A DIFFICULT THING TO ASSESS
FOR SUBTLE SIGNS AND ONCE IT IS
ACTUALLY STARTED YOU ARE LIKE
OKAY. WHAT DID WE MISS?
THAT IS WHAT I FEARED WOULD
HAPPEN IN TERMS OF AI TYPE OF
STRATEGY AND YOU RELY HEAVILY ON
PROBABLY NOT PATIENTS BUT MORESO
THE CAREGIVER. YOU LOSE NURSING
ASSESSMENT AND PHYSICIAN
ASSESSMENT AND KEEP PATIENTS
ADMITTED AND I'M BIASED WITH
THAT REGARDS REGARDS TO INFUSING
AND MONITORING AND WATCHING.
THAT WOULD BE PROBABLY EXCELLENT
TO GET TO A POINT TO DEVELOP AN
APP.
MAYBE I DON'T HAVE ENOUGH
FORESIGHT TO SEE THAT BUT MAYBE
NOT QUITE YET BUT WOULD BE COOL
TO SEE.
>> THANK YOU.
>> WELCOME TO
SECTION 4A. IF LOOKING FOR 4B,
PLEASE CROSS THE CORRIDOR. THIS
SECTION WE ARE LOOKING AT UNIQUE
POPULATIONS THAT A LOT OF US ARE
TRYING TO GET CAR T INTO. WE
WOULD LOVE TO DO THIS IN AN
ORGANIZED FASHION IN CLINICAL
TRIALS AND LOOK AT SOCIAL AND
ECONOMIC ISSUES SURROUNDING
ACCESS TO CAR T AND
PATIENT-REPORTED OUTCOMES AND
WOULD LIKE TO START WITH SARAH
FROM GREATER OREMAN STREET THAT
WILL TALK TO US ABOUT INFANTS
AND PATIENTS WITH DOWNSYNDROME.
>> THANK YOU VERY MUCH FOR
INVITING ME AND CURATING THIS
VERY EXCITING PART OF THE
SYMPOSIUM. DEALING WITH DOWN
SIN INFANTS AND USING
INFORMATION TO CONSIDER BROADER
GROUPS AS WELL.
IS THAT ON? THE MOUSE. GOT IT.
OKAY. CONSIDERING GENERALLY
THOUGHT MATRIX TERMS TO CONSIDER
YOU MIGHT WANT TO CONSIDER
FEASIBILITY IN RELATION TO PACE
OF DISEASE AND COMORBIDITIES
IMPACT ON ESSENTIAL INTRINSIC
DEFECTS AND UNDERSTAND DATA
EFFICACY OF SUBGROUP AND
CONSIDERING IMPACT OF
TOLLRABILITY OF EXPECTED
TOXICITIES AND WHETHER AN IMPACT
TO CONSOLIDATE ON STEM CELL
TRANSPLANTATION AROUND FOR
EXAMPLE COMORBIDITIES AND
APPLYING TO THINKING OF DOWNSIN
DROCHL AND ALL20-FOLD INCREASE
WE KNOW AND DEMONSTRATED
OUTCOMES IN GROUPS CONTRIBUTED
TO RELEVANT TOXICITIES IN TERMS
OF SEVERE INFECTIONS IMPACTING
THROUGHOUT THERAPY AND IN
SLIGHTLY DIFFERENT GENETIC
BACKGROUNDS ACTIVATING IN
PARTICULAR COHORT -- CERTAINLY
THERE ARE RELEVANT COMORBIDITIES
IN CARDIAC LESIONS AND EVIDENCE
THAT T-CELL COMPARTMENT IS NOT
SAME FOR NONDOWNSYNDROME
PATIENTS IN SMALLER NAÏVE POOL
THAT MIGHT IMPACT ON PRODUCT YOU
TAKE AND THAT YOU GENERATE AND
THERE IS QUITE SIGNIFICANT
EVIDENCE OF IMMUNE DISREGULATION
IN INNATE SYSTEM AS WELL AND ARE
SMALL STUDIES NOT WELL
CHARACTERIZING AND NOT
SYSTEMATICALLY CHARACTERIZED IN
DOWN SYNDROME PATIENT GROUPS AND
INTEREST IN TERMS WHAT IT MIGHT
MEAN IN TERMS OF PATIENT COHORTS
AND EFFICACY THERE IS TREATMENTS
AND STUDIES AND TALKING ABOUT
DATA NOW PUBLISHED AND IN TERMS
OF CONSIDERING DOWN SYNDROME
PATIENTS IN RELATION TO
TOLLRABILITY FOR EXAMPLE ABILITY
TO TOLERATE CYTOKINE SYNDROME
AND RELEASE THAT THEY MIGHT FACE
THAT IS OF IMPORTANCE AND INNATE
CHANGES NOTED MIGHT HAVE IMPACT
ON SEVERITY OF CRS ICANS COHORT
WITH RIFBLG FOR INFECTIONS THAT
IS OF CONCERN NEEDING TO BE
CONSIDERED AND PATIENTS
CONSIDERATING TRANSPLANT TAKING
INTO ACCOUNT IN TERMS OF ABILITY
WITHSTANDING CONDITIONING OR
MIGHT INDEED HAVE A TRANSPLANT
BEFOREHAND AND I GUESS THIS
WOULD BE THERAPY PERHAPS FOR
HIGH-RISK PATIENTS. WE DON'T
HAVE TO GUESS TOO MUCH. THIS
PRESENTED NICE DATA YOU THAT IS
RETROSPECTIVE DATA FROM THREE
STUDY PROTOCOLS THAT IS
INCORPORATING 17 PATIENTS AND
DOWN SYNDROME AND PATIENT NOT
INFUSED LEAVING 16 TO BE INFUSED
AND PRIOR STEM CELL TRANSPLANT
AND MEDIAN LINES CRYOTHERAPY
WERE TWO AND PERHAPS A BIT LESS
THAN WE SEE IN STANDARD COHORT
AND IN TERMS OF CR8S AND THESE
IN FIRST TWO BULLET POINTS YOU
SEE RATES ARE FAVORABLE COMPARED
TO DATA FROM NONDOWNSYNDROME
PATIENTS TREATED IN ELLI ANA
STUDY AND 13 MONTHS OVERALL
SURVIVAL NOT REACHED -- THE
PROBABILITY OF DURATION OF
RESPONSE WAS LOWER THAN IL-IANA
STUDY AND INTERVALS AND DON'T
MISS SIGNIFICANCE AND THREE ARE
DEFINED TO BE CD9 NEGATIVE AND 3
UNDEFIND AND COMPARING TO GROUP
OF ALL RESPONDERS AND KINETICS
WERE COMPARABLE. HERE ARE DATA
ON RELAPSE FREE SURVIVAL AND
OVERALL SURVIVAL AND
CHARACTERISTICS ARE SIMILAR TO
WHAT WE WOULD EXPECT FROM
PATIENTS TREATED WITH LICENSED
PRODUCT AND IN CONTEXT OF
NONDOWNSYNDROME PATIENTS ELAPSE
SURVIVAL IS LOWER AND SPEAKING
TO SLIGHTLY SHORTER DURATION OF
RESPONSE IN COHORT AND ARE SMALL
NUMBERS THAT [INDISCERNIBLE]
CAN'T BE DRAWN AND IN TERMS OF
TOXICITIES RATE OF GRADE 3 OR 4
AND EPAN GRADE 3 OR 4 SYNDROMES
EQUIVALENT IN NONDOWNSYNDROME
PATIENTS TREATED AND SEVERE
ICANS AND THIS IS EQUIVALENT TO
NONDOWNSYNDROME PATIENTS AND
RATE OF SEVERE INFECTIONS AND
SUGGESTING TOLLRABILITY OF
CRYTOPENIAS CAN'T BE MANAGED
THERE ARE FOUR DEATHS IN STUDY
AND THREE DYING OF DISEASE AND
ONE PATIENT IN CONTEXT OF CRS
CRANIOPATHY AND [INDISCERNIBLE]
AND LIKELY CELL IN CHILDREN AND
YOUNG ADULTS WITH DOWNSYNDROME
TO DELIVER RESPONSE RATE TO
LOWER OUTCOMES THAT OVERLAY
THOSE WITH NONDOWNSYNDROME
PATIENTS TREATING PROMINENT RATE
OF SEVERE INFECTIONS AND LATE
INFECTIONS IS NOT EXCESSIVE IN
THE COHORT THAT IS NOT
ENCOURAGING AND REFLECTS
INTERNALIZED EXPERIENCE WE HAVE
TREATED SUCCESSFULLY WITH
THERAPEUTIC IN CONTEXT OF
DOWNSYNDROME ALL AND GOING TO
CONSIDERATIONS OF THERAPY IN
YOUNGER CHILD AND PARTICULARLY
INFANTS WITH MLL REARRANGED
LEUKEMIAS APPLYING THOUGHT RATES
AGAIN AND SEEING PROGRESSIVE AND
HIGHLY AGGRESSIVE DISEASE AND
SORRY SOME THINGS ARE MOVING AND
THEY ARE BEING MODIFIED AND
FEASIBILITY OF A3 NEEDS TO BE
CONSIDERED AND SMALL CHILDREN
LESS THAN 10 KILOGRAMS AND THEY
DON'T HAVE RELEVANT EXPERIENCE
IN THAT AND IN OUR HANDS IS NOT
A PARTICULAR PROBLEM AND CONCERN
THAT INFANCY WOULD COLLECT
T-CELL POPULATION PREDOMINANTLY
NAÏVE AND ACTIVATED WOULDN'T BE
ABLE TO MAKE PRODUCT AND THAT
HASN'T BEEN BROUGHT OUT INTO
PRACTICAL EXPERIENCE AND
CHILDREN LESS THAN THREE YEARS
OF AGE CONTEXT OF SEVERE PRIOR
THERAPY TO TOLERATE INFECTIONS,
ET CETERA, MIGHT HAVE BEEN A
KWER AND WE HAVE RELEVANT
RETROSPECTIVE DATA TO SUPPORT
THIS AND COVERED EUROPEAN
PROPERTY OF GROUPS DATA THAT WE
PUBLISHED IN LANCET HEEM ATOLOGY
LAST YEAR AND GOT DATA FROM
CORINNE'S DATA FROM SORRY
COLLEEN'S DATA FROM PLATEAU 2
AND 5 TREATING PATIENTS WITH
INFANT ALL AND PRESENTED DATA
FROM COHORT THAT IS LOOKING AT
14 INFANTS THEY HAD IN THEIR
STUDY. IF WE LOOK AT
MANUFACTURING FEASIBILITY,
PROPORTION OF PATIENTS DIDN'T GO
ON TO HAVE PRODUCT INFUSED
BECAUSE OF PROGRESSIVE DISEASE
RATES OF NEGATIVE CR AND 6 AND
12 MONTH SURVIVAL AND OVERALL
SURVIVAL AND COMPARING TO
OUTCOMES IN RED AND LOOKING AT
OUTCOMES FROM APPLICATION AND
BOLDED STUDIES AND COLLEEN'S
DATA WITH PLATEAU 2 AND PLATEAU
5 YOU CAN SEE DELIVERABILITY AND
THE SHORT-TERM OUTCOMES IN TERMS
OF RESPONSE RATES AND LONG-TERM
OUTCOMES ARE FAVORABLE FOR
COHORT OF PATIENTS CONSIDERED AS
HAVING AGGRESSIVE DISEASE DIDN'T
RESPOND TO THERAPY AND HAS POOR
PROGNOSIS IN MOST CONTEXTS AND
LOOKING AT DETAIL IN DATA THAT
WE ARE ABLE TO PROVIDE WITH SOME
GRANULARITY AND WE ARE LOOKING
IN EUROPE OF 15 CENTERS AND
LOOKED AT ALL DATA AROUND
CHILDREN SCREENED AT ANL LESS
THAN 3 YEARS THAT IS HEAVY
PREDOMINATED BY COHORT AND
COHORT IS 5 MONTHS AND MEDIAN
AGE INFUSION IS 17 MONTHS AND
REARRANGED 80% CAUSING TO INFANT
PROTOCOLS AND MAJORITY HAVE HAD
IT PRICED IN STEM CELL
TRANSPLANT AND MEDIAN OF TWO
LINES OF THERAPY NOT INCLUDING
TRANCE PLANTS HEAVILY PRETREATED
PATIENTS DEFINITELY RELEVANT TO
INFANT CONTEXT AND DATA WE GOT
ON LEUKO FORESIS PROJECTS THAT
ARE IN 38 PATIENTS YOU CAN SEE
VAST MAJORITY OF PATIENTS
COLLECTED WITH SINGLE DAY
HARVEST AND PATIENTS REQUIRE
MORE DAYS THAN THAT WORTH
CONSIDERING ACHIEVING AND 35 OUT
OF 38 PATIENTS AND CONCERNS
WHETHER CELLS ACTIVATE THAT WAY
AND ARE TRANCE DEUCEABLE NOT
BORN OUT AND [INDISCERNIBLE]
GENERATED WAS IN MEETING OF CAR
T-CELLS EXPECTED FROM OLDER
COHORT AS WELL AND FEASIBILITY
OF LEUKO FORESIS AND OF
MANUFACTURER IS NOT AN ISSUE AT
ALL AND WE HAVE OVERALL SURVIVAL
ON LEFT AND EVENT FREE SURVIVAL
CRITERIA ON THE RIGHT AND WE HAD
RELAPSES AND WE DIDN'T HAVE ANY
INCIDENCE OF LINEAGE SWITCH
WITHIN CONTEXT OF FOLLOW UP FOR
PAPER AFTER DATA CUTOFF FOR
PAPER ONE CASE CONFINED WITH
LINEAGE SWITCH AND FURTHER CASE
LOSS CD19 EXPRESSION AND MARKERS
AND RETAINED SOME LYMPHO MARKERS
TOO WASN'T TRUE AND LINEAGE
SWITCH AND KINETICS FROM
PROGRESSION AND TWO POSSIBLE
LINEAGE SWITCHES AFTER DATA
CUTOFF AND IN CONTEXT OF FOLLOW
UP WE HAD THERE WERE NONE ON THE
STUDY AS PUBLISHED.
SO, THERE WERE 8 PATIENTS WITH
RELAPSE AND 19 POSITIVE TO
DISEASE AND ONE WITH MIXED
[INDISCERNIBLE] DISEASE AND 6
PATIENTS WENT ON TO HAVE FURTHER
THERAPY BEFORE RELAPSE.
WE LOOKED AT A MORE STRINGENT
EVENT DEFINITION WE INCORPORATED
EVENTS RELATED TO EMERGENCE OF
NID AND APPLICATION TO FURTHER
LEUK EMO THERAPY AND SURVIVAL
SHOWN HERE IF YOU LIKE THIS IS
PERHAPS CLINICALLY MORE RELEVANT
EVENT DEFINITIONS AND POINT OF
VIEW AND SCREENING AND TELLING
THEM WHAT IS LIKELIHOOD NEEDING
THERAPY BEING LEUKEMIA FREE AND
NOT ANY OTHER THERAPY AND
PARAMETERS I LIKE TO DISCUSS
WITH PATIENTS IN CONTEXT WE HAVE
TWO ADDITIONAL CASES OF
EMERGENTS BOTH WENT ON TO
FURTHERTHERAPY AND ONE WAS CD19
NEGATIVE AND ONE WAS CD19
POSITIVE AND ONGOING
[INDISCERNIBLE] AND CURVES
OVERLAY DATA.
IN TERMS OF TOXICITIES RATES OF
SEVERE CYTOKINE SYNDROME WERE
LESS SEEN ON THIS AND REAL WORLD
DATA POINTING TO FACT WE BRIDGE
MORE EFFECTIVELY REDUCING RISK
OF SEVERE CRS AND ICANS EKWIF
TLOENT RATE OF ELLI ANA STUDY
AND SLIGHT INSTANCE OF
DIFFERENCE OF CRYTOPENIAS AND IN
TERMS OF FEASIBILITY DELIVERY IN
TOXICITY PROFILE IS SIMILAR TO
OLDER PATIENTS AND TOXICITY TO
BE TAKEN INTO ACCOUNT AND
FEASIBILITY FOR DELIVERY OF
YOUNGER CHILD IS SIMILAR TO THAT
AND OLDER CHILDREN RESPONSE RATE
LONGER OUTCOMES TOXICITY RATES
SAME FOR CHILDREN IN TERMS OF
GRANULARITY FOR PATIENTS 15 OUT
OF 35 TREATED DID GO ON TO
THERAPY AND [INDISCERNIBLE] 2
PATIENTS HAD GONE ON TO HAVE
TRANSPLANT BECAUSE OF PHYSICIAN
PREFERENCE ALONE AND WITH THIS
TO WRAP UP THANKING COLLEAGUES
PROVIDING DATA FOR
[INDISCERNIBLE]. THANK YOU.
>> NEXT STOP IS DR. LEAHY WHO
WILL TALK ABOUT CYTOGENETICS.
>> ALL RIGHT. HI, EVERYONE.
I'M ALLIE LEAHY AND HAVE NO
CONFLICTS AND SLIDE WILL BE
FAMILIAR TO EVERYONE. ON LEFT
IS AGE DISTRIBUTION OF COMMON
GENETIC ABHORATIONS WE FIND IN
LEUKEMIA IN AVERIENT SETTING AND
RIGHT-HAND SIDE OF THE SCREEN
YOU SEE LIST OF CYTOGENETICS
USED TO RISK STRATIFY IN UPFRONT
SETTING IN DIAGNOSIS IN NATIONAL
AND INTERNATIONAL CONSORTIUM.
CRYTOGENETIC AND OTHER MOLECULAR
GENOMIC AB-HARRATIONS ARE KNOWN
TO HAVE PROGNOSTIC DIAGNOSIS AND
RISK ASSESSMENT IS CARRIED
THROUGH TO RELAPSE AND
SIGNIFICANCE OF DIFFERENT RISK
CATEGORIES ARE SORT OF AN OPEN
QUESTION IN THE USE OF CAR
T-CELL THERAPY. I WILL FIRST
TALK THROUGH GENERAL FINDINGS
WHEN WE DO WHAT WE HAVE TO DO IN
CAR T-CELL WORLD THAT IS LUMP
AND SPLIT IN AWKWARD CATEGORIES
AND IS WORK WE DID AT CHOC WITH
RETROSPECTIVE ANALYSIS WITH 231
CAR NAÏVE PATIENTS WITH WHOM WE
HAVE ROBUST CRYTOGENETIC AND
MOLECULAR GENETIC DIAGNOSIS OR
FROM RECENT RELAPSE AND RELAPSED
REFRACTORY CD19 POSITIVE DISEASE
TREATED ON 5 CLINICAL TRIALS
[INDISCERNIBLE] CONSTRUCT OR
HUMANIZED CONSTRUCT OR
COMMERCIALIZED CHIMERA AND BROKE
TO FOUR CATEGORIES HIGH RISK
THAT WE KNOW AND LOVE AND
INTERMEDIATE RISK STRATIFICATION
ACROSS THE UNITED STATES AND
EUROPEAN TRIALS AND FAVORABLE
GENETICS AND UNINFORMATIVE THAT
I THINK I WILL HAVE YOU HOLD ON
TO AND COME BACK LATER IN THE
DISCUSSION. THEY WERE THINGS
NOT NECESSARILY THAT COULD BE
NORMAL BUT COULD LUMP TOGETHER
COMPLEX CYTOGENETICS AND
OTHERWISE UNBUCKETABLE LESIONS.
LOOKING AT THIS WITH LENS OF DO
CYTOGENETICS DRIVE OUTCOMES
ANSWER WAS ENCOURAGING BROKE
DOWN BY FOUR BIG RISK CATEGORIES
SEEING FOR RFS OR ROS THAT WAS A
NEGATIVE FINDING AND DID
SUBANALYSIS LOOKING AT PH AND
PHLIKE AND KMT2A AND
SPECIFICALLY IN INFANTS PH AND
PHLIKE SIMILAR TO LARGE LUMP
FINDINGS AND NO DIFFERENCE
COMPARED TO OTHERS AND KM22AS I
WILL TALK ABOUT IN A SECOND AND
WE LOOKED AT MORPH FOE LOGIC
RELAPSE AND CLINICALLY
APPLICABLE MRD RELAPSE AND IN
CASE OF ANALYSIS THERE WAS NO
DITCHES USING RELAPSE IN EVENT
OF RELAPSE FREE SURVIVAL. THIS
WAS BUTT TRESSED BY
MULTIVARIABLE MODELS TAKING INTO
ACCOUNT THINGS LIKE DISEASE
BURDEN AT INFUSION.
LOOKING AT OTHER STUDIES WE
TALKED ABOUT STUDY A PARTICULAR
STUDY AND MULTICENTER CONSTRUCT
LOOKING AT 41BB CARS AND CD28
CARS AND THIS DID PULL A
PORTIONING OF PATIENTS FROM
PREVIOUS ANALYSIS TO THIS
ANALYSIS AND DUPLICATIVE PATIENT
INVOLVEMENT BROKE DOWN
CYTOGENETICS TO MORE BARE
DESCRIPTION THAN WHAT WAS
INCLUDED IN PREVIOUS DISCUSSION
AND WASN'T THE INTENDED ANALYSIS
IN THIS PAPER THAT ARE PURELY
DESCRIPTIVE CAP LYNNE MEYER
CURVES I WILL SHOW YOU HERE
UNIVARIATE ANALYSIS AND CAUTION
WITH CONCLUSIONS AND
ILLUSTRATING FROM THIS LOWER
LINE OF HYPODIPLOID PATIENTS IT
THAT IS A ROBUST GROUP OF
PATIENTS 380 WITH KNOWN GENETIC
CHARACTERISTICS AND THIS GROUP
OF 14 IS LARGE FOR NUMBERS THAT
WE KNOW WE HAVE IN THE WORLD.
THIS IS REDEMONSTRATED WHEN
BROKEN DOWN EVEN FURTHER THAT
LOWEST FOUR LINES ARE
HYPODIPLOID THAT CATEGORY OF
WHAT I WANTED YOU TO HOLD ON TO
NORMAL ETV6 RUNG AND YOU HAVE TO
LIMIT CONCLUSIONS TO DRAW FROM
THIS AND DEFINITELY INDICATES
THERE IS MORE TO PULL OUT FROM
THE POPULATIONS ADAM TALKED
ABOUT THIS EARLIER AND THOUGHT
IT WAS INTERESTING AND PULLING
ON THIS SAME KARMA CO-HORT 380
PATIENTS WITH CHARACTERISTICS
WHITTLED DOWN TO 170-ISH THAT
HAD CYTOGENETICS THAT RELAPSED
AND LOOKING AT DIFFERENCE IN
CYTOGENETICS WITH ASSOCIATION TO
RELAPSED PHENOTYPE AND HE
DISCUSSED THERE WAS NOT -- MOST
THINGS FELL OUT IN MOVE FROM
UNIVARIATE TO MULTIVARIATE
ANALYSIS AND CAPTURED TWO THINGS
HE DISCUSSED IN K2M STATUS THAT
WAS ONLY THING ASSOCIATED WITH
ANY RELAPSED PHENOTYPE AND
PREDOMINANTLY WAS ONLY QUITE
STRONG ASSOCIATION SEEN IN
PATIENTS WITH LINEAGE SWITCH AND
NICE SEGUE TO KM2A
REARRANGEMENTS AND WHAT WE KNOW
ABOUT THEM SPECIFICALLY AND THIS
IS ADAMS WORK AND WORK FROM CHOC
SIDE BY SIDE AND SEE HERE
RELAPSE FREE SURVIVAL KMT2A
GROUP REPLICATES WHAT WE SAW IN
LARGER LUMPED ANALYSIS AND NO
STATISTICAL DIFFERENCE BETWEEN
THOSE WITH KM2TA ARRANGEMENTS
AND THOSE WITH CRYTOGENETIC
CHARACTERISTICS AND TREND FOR
SIGNIFICANCE AND MULTIVARIABLE
MODEL CONTROLLING FOR KEY
CHARACTERISTICS THAT DIDN'T
REACH STATISTICAL SIGNIFICANCE
AND WE NEED LARGER SAMPLE SIZE
AND MORE EXPERIENCE WITH THIS
AND BEAUTIFUL ASSOCIATION WITH
LINEAGE SWITCH AND LOOKING AT
THIS STORY IS MORE DISMAL FOR
PATIENTS IN PART BECAUSE OF
LINEAGE SWITCH THERE WERE
SIGNIFICANT NUMBERS IN CO-HORTS
WITH OVERLAPPING PATIENTS AND
UNIFORMLY PATIENTS EXPERIENCING
LINEAGE SWITCH DIED FROM THEIR
DISEASE AND THESE PATIENTS THERE
DOESN'T SEEM TO BE SIGNIFICANTLY
INCREASED RISK OF RELANCEPSE AN
WHEN THEY DO IT IS DIFFICULT TO
SALVAGE AND WHO TO PAY THAT IS
AT HIGHER RISK OF RELAPSE AMIDST
PATIENTS AND WHAT WE CAN DO IN
POST CAR INFUSION.
LY PAUSE BRIEFLY IN THIS AND WE
LOOKED AT 13 PATIENTS DIAGNOSED
WITH INFANT LEUKEMIA AND KMT2
REARRANGEMENTS AND THERE IS 67%
RELAPSE FREE SURVIVAL AT 2 YEARS
THAT DAUNTING ASSOCIATION OF
SURVIVAL WITH 3.6 TIMES INCREASE
IN ALL CAUSE MORTGAGE ALET THAT
IS A SIGNIFICANT FINDING AND
MOVING TO POTENTIAL GENETICS OF
INTEREST. THERE ARE, AGAIN,
PULLING ON THAT OTHER
CRYTOGENETIC ABHORATION CATEGORY
THERE IS A NUMBER OF EMERGING
INTERESTING THINGS IN THE FIELD
THAT WE HAVE NOT YET STARTED TO
EVALUATE. THE WE HAVE SEEMINGLY
WHITTLED DOWN WHAT WE LOOKED AT
TO WHAT WE KNOW THAT DIAGNOSIS
IS IMPORTANT AND A GREAT
STARTING POINT AND TP53
ALTERATIONS THAT ARE RARE LIKE
MANY THINGS WE LOOK AT. THEY
ARE ASSOCIATED WITH HYPO
DIPLOIDY AND OLDER ANL AND
ARTICLES IN LYMPHOMA
INVESTIGATORS DEMONSTRATED THERE
IS CONCERN FOR DISREGULATION IN
PATHWAYS THAT CONTROL
CYTOTOXICITY OF CAR T-CELLS IN
FIRST ARTICLE THEY DEMONSTRATED
PATIENTS HAD INFERIOR OUTCOMES
IN SECOND ARTICLE THERE WAS SOME
DEMONSTRATION THAT IS USE OF
CRYTOBEEN AND SYNERGISTIC EFFECT
THAT MITIGATED THIS AND THINGS
TO THINK ABOUT GAINING MORE
INTEREST OR INFORMATION IN
GENOMIC FIELD AND THINKING ABOUT
WHAT WE WANT TO FOCUS ON FOR
ENRICHING PATIENT POPULATION
SAMPLE SIZES AND THESE ARE
SLIDES I STOLE FROM ANDRÉ'S
PRESENTATION AND OF PLANNING OF
CONFERENCE AND PLUG FOR
RETROSPECTIVE WORK THAT HE IS
INTERESTED IN DOING FOR TWO
RELATIVELY RARE LESIONS AND WE
KNOW HAVE QUESTIONABLE OUTCOMES
AND PUT TOGETHER A DELAYED GROUP
OF ALREADY PUBLISHED DATA IN
TERMS WHAT WE KNOW ABOUT
TRANSLOCATION 119 AND I ADDED
DETAILS INCLUDED IN WORK COMING
OUT OF CHOC TO THIS.
DEMONSTRATING THAT IN SORT OF
INTERNATIONAL LOOSE COHORT OF 30
WE HAVE 13 ALIVE AND 12 IN CR.
REALLY A RELATIVE POSTY OF
GRANULAR INFORMATION AROUND
PATIENTS THAT IS IMPORTANT TO
LOOK AT THAT AND DEFINITELY TO
LOOK AT 7 TAEN-19 AND LESION WE
KNOW HAS SIGNIFICANT
IMPLICATIONS FOR PATIENTS AND
AGAIN, RARE, TOTAL OF 15
PATIENTS 8 ALIVE AND POSSIBLE 8
IN CONTINUOUS CR AND ADD IING
HYPODIPLOIDY TO THIS AND DIDN'T
PULL DATA LIKE THIS AND GOING
FORWARD IN TERMS OF WHAT WE HAVE
SORT OF IN THE WORKS AND ALREADY
IN PROCESS AND ANDRÉ'S 119 AND
1719 I WOULD ARGUE FOR ADDITION
OF HYPODIPLOIDY COHORT AND
PROSPECTIVE TRIALS WE HAVE ONE
ONGOING PRIMARY INVESTIGATOR DEN
OVIA INSTITUTION AT CHOC AND
LOOKING AT LOCATIONS AND
HYPODIPLOIDY AS COHORT AND HIGH
RISKS K2A REARRANGEMENT OF
INFANTS AMONGST OTHERS. THANK
YOU.
>> [INDISCERNIBLE] FROM
CHILDREN'S HOSPITAL OF LA WILL
TALK ABOUT DRIVING CARS FORWARD.
>> >> THANK YOU, EVERYBODY.
THANK YOU ALL FOR STAYING.
>> WE KNOW THERE IS LIMITED
APPROVAL OF CAR T-CELL THERAPY
FOR PEDIATRICS TO DATE AND 2017
[INDISCERNIBLE] AND INDICATION
IS BALL IN SECOND OR LATER
RELAPSE AND LOOSE DEFINITION OF
REFRACTORY OR HOWEVER YOU WANT
TO INTERPRET IT FOLLOWING
MULTIPLE TRIALS OF DEMONSTRATED
EFFICACY AND SUBSETS THAT WE
HEARD ABOUT IN THIS SESSION AND
DOWNSTREAM INFANTS FIRST RELAPSE
AND LACK OF INDUSTRY SUPPORTER
REGISTRATIONS IN PEDIATRIC
INDICATIONS AND FOCUS ON FIRST
RELAPSE IN THIS TALK THAT ARE
PRIMARILY BONE MARROW AND CNS
AND FIRST RELAPSE IS CURRENTLY
NO. 1 UNMET NEED IN ALL. THERE
IS A LOT OF PATIENTS BECAUSE OF
THE SHEER NUMBERS IS ONE OF THE
MOST COMMON CANCERS RELAPSED ALL
AND THERAPY FOR MOST IS INTENSE
AND THERAPY OUTCOME IS DISMAL
AND PATIENTS RELAPSING EARLY
WITHIN 36 MONTHS AND THAT DON'T
RESPOND TO FIRST REDUCTION
CHEMOBLOCK AND STANDARD OF CARE
CURRENTLY FOR PATIENTS IN THE
UNITED STATES AFTER THE ALL1331
RESULTS THAT WERE PUBLISHED AND
CURRENT STANDARD OF CARE IS
REDUCTION OF CHEMOFOLLOWED BY
THIS FOLLOWED BY TRANSPLANT AND
THIS SURVIVAL IS 54% OF TUMOR
MAP OF THIS STUDY AND THERAPY
WAS TOXIC AND 4% TREATMENT
RELATED MORTALITY AND 43% RATED
3 TO 4 INFECTIONS AND DESPITE
TOXICITY 75% OF PATIENTS
REMAINED POSITIVE AFTER THIS
REINDUCTION CHEMO. WHAT IS
IMPORTANT IS 40% OF PATIENTS
DIDN'T PROCEED TO THIS AND
DIDN'T GET THROUGH THE FIRST
BLOCK OF CHEMOTHERAPY
SUCCESSFULLY TO GET TO BLINA AND
INTEND TO TREAT ANALYSIS ON
PATIENTS ON STUDY AND THIS EFS
IS 25% AND TAKING OUT PATIENTS
ENROLLING ON THE [INDISCERNIBLE]
THAT IS [INDISCERNIBLE] IT IS
STILL ONLY 30%. WHAT IS IDEAL
THERAPY OF HIGH RISK RELAPSE?
AVOID INFECTIONS AND ORGAN
DAMAGE AND WE KNOW CD19 CAR T
CAN DO THAT AND USING THIS AS A
STANDALONE VERSUS PERSISTENCE
AND WE DISCUSSED THIS THAT IS TO
BE DETERMINED AND 2EFS AND WHAT
WE HAVE HEARD ALL DAY IS ABOUT
50% OF MULTIPLY RELAPSED ALL AND
ANTICIPATE THIS IS BETTER IN
FIRST RELAPSE AND LOOKING AT
DATA ON PREVIOUS SLIDE 30% TO
IMPROVE TO 50% IS A BIG WIN AND
LOTS OF PATIENTS AND SWITCHING
GEARS A LITTLE TO ISOLATED CNS
RELAPSE AND UNMET NEEDS AND HERE
WE TALK ABOUT THE DATE ISOLATED
EXTRA MEDULLARY RELAPSE AND 18
MONTHS FROM DIAGNOSIS AND
CURRENT STANDARD OF CARE IS
INTENSIVE CHEMOTHERAPY AND LOTS
OF [INDISCERNIBLE] FOLLOWED BY
RADIATION TO YOUNG BRAIN THIS IS
NOT REALLY GOOD.
DEINTENSIFY CHEMOTHERAPY AND ADD
[INDISCERNIBLE] THAT IS NOT
SUCCESSFUL AND 2 YEAR DFS IS
ONLY 34% OWE ON THIS TRIAL.
EFFECTIVE FOR CNS RELAPSE AND
SEVERAL TRIALS I WILL QUICKLY
RUN THROUGH AND THIS IS THE
FIRST CHOC STUDY WHERE THEY
ADOPTED 5 TRIALS AND CNS
POSITIVITY WITHIN FIRST YEAR.
ON THESE TRIALS CNS YOU WANT TO
BE LEGIBLE AND SAW TOXICITY WAS
SAME AND RESPONSE WAS SAME AS
BONE MARROW RELAPSE AND STUDY
FROM CHINA LOOKED AT CNS
POSITIVITY AT SCREENING AND 30
DAYS GETTING INFUSION AND 60% OF
PATIENTS HAD CNS DISEASE AT TIME
OF INFUSION AND THEY HAVE
NUMBERS THAT WERE ABLE TO TELL
IF YOU HAD A HIGHER DISEASE
BURDEN IN CNS, RESPONSE WAS
WORSE WHETHER CNS IS 1, 2, OR 3
AND SHOWED INCREASED TOXICITY
WITH INCREASED ICANS AND DATA
FROM REAL-WORLD CONSORTIUM WITH
12 MONTH EFS IS SAME IF YOU HAVE
CNS DISEASE VERSUS NOT IS ABOUT
60% AND LAST STUDY TO SHOW HERE
IS THE STUDY FROM EUROPE WHERE,
AGAIN, 12 MONTH EFS IS ABOUT 60%
AND THEY SHOWED THERE WAS A
DROPOFF AFTER 1 YEAR IF YOU
DIDN'T RECEIVE ANY SUBSEQUENT
THERAPY.
HOW DO WE DRIVE CARS FORWARD
AFTER FIRST APPROVAL PUSHING AND
PUSHING NOT ABLE TO GET INDUSTRY
TO SUPPORT US AND MADE SLIDE A
FEW YEARS AGO OR COUPLE YEARS
AGO AND KEPT UPDATING IT AND
WANTED TO BRING IT FORTH HERE.
WE HAVE SEVERAL ACADEMIC TRIALS
SHOWING SUCH GREAT RESULTS HOW
EFFECTIVE IT COULD BE AND HOW WE
GET THIS TO OTHER PATIENTS NEED
A COUNTRY WILD WORLDWIDE AND
INDICATIONS FOR SECOND RELAPSE
WE WON'T HAVE THIS STUDY AND
THERAPIES THAT ARE AVAILABLE.
WE HAVE BEEN TRYING THROUGH
CHILDREN'S ONCOLOGY GROUP
GETTING RELAPSE STUDY OPEN
COUNTRYWIDE FOR FIRST RELAPSE
AND ARE EFFORTS AND ON TOP
APPROVED ONGOING STUDIES AND
BOTTOM NONAPPROVED NONPHARMA-AND
27 TAEN-FD APPROVED T-CELL.
SINCE BEFORE 207 TAENTO ALMOST
2022 SHANNON CAN VOUCH FOR THAT
AND HOW MANY CONVERSATIONS WITH
NEF AR TIS AND RELAPSE AND DOWN
STREAM INFANT STUDY AND EVERY
ONE WAS DENIED AND FINALLY THEY
SAID WE WILL SUPPORT STUDY BUT
PAY FOR IT AT MARKET RATE FOR
THE PRODUCT WHICH IS NOT
FEASIBLE. WE HAD HUMANIZED CAR
T DATA THAT SHANNON PUBLISHED
THAT WAS BEAUTIFUL AND NEVARTIS
BOUGHT THE RIGHTS TO IT DON'T
WANT TO DEVELOP IT AND SITTING
ON SHELF NOT DOG ANYTHING WE
TALKED TO KITE AND GILLI AD AND
TRIAL IS ONPAUSE CURRENTLY AND
WE WORKED WITH THEM TWO YEARS TO
GET A FIRST RELAPSE STUDY
THROUGH CRG AND MULTIPLE
CONCEPTS AND FINALLY THEY DENIED
THAT AND WE WERE A LITTLE FED UP
AT THIS POINT AND LET'S DO
ACADEMIC AND HAVE IT COGWIDE AND
APPLIED TO NC NEXT PROGRAM AND
HAD CONCEPTS FOR COG AND THIS
WAS DEVELOPED BY JIM AT NCI AND
SAW DATA THAT IS HUMANIZED HIGH
PERSISTENCE [INDISCERNIBLE]
TOXICITY AND NEXT PROGRAM LIKED
THE CONCEPT AND DENIED IT AND
THEY WERE LIKE YOU SHOW EFFICACY
IN FIRST RELAPSE AND THEN WHAT?
WON'T GO OUT TO KIDS IN THE
COUNTRY THAT NEED IT AND WE
WON'T LOOK AT YOUR APPLICATION
AND STARTED TO TALK TO BNS.
THIS IS GOING SOMEWHERE.
FINALLY AFTER A YEAR OF TALKING
TO BMS, THEY HAVE GOTTEN
APPROVAL FROM HIGHER UPS AND
FUNDING TO AMEND ONGOING STUDY
AND INCLUDE PATIENTS WITH FIRST
RELAPSE AS A COG COHORT WHERE WE
HAVE STATISTICS SHOWING CD19 IS
BETTER STANDARD OF CARE FOR
FIRST RELAPSE AND TRIAL WAS
DECISION MADE A COUPLE WEEKS AGO
AND SEE IF IT GOES FORWARD WITH
FINGERS CROSSED AND WE HEARD
CLAUDIA DURING LUNCH TIME WON'T
BE DECENTRALIZED APPROACH LIKE
DOING IN EUROPE USING NCI NEXT
PLATFORM IN DERISKING IT FOR
COMPANY AND WE MIGHT BE ABLE TO
GO AHEAD ON THAT TOO.
CHALLENGES AND NEXT STEPS I
DON'T KNOW HOW TO PUT THAT IN A
SLIDE OR 2 BUT WE TALK THE ABOUT
IT AND WON'T GO ABOUT IT IN EACH
DETAIL BUT WE HAVE TO
INCORPORATE EARLIER IN THE
COURSE OF DISEASE AND TALKED
ABOUT RESISTANCE AND HOW TO
OVERCOME THAT AND CAR T-CELL
LOSS AND T-CELL EXHAUSTION AND
HEARD ABOUT NEW CONSTRUCTS AND
AMAZING RESULTS WE ARE GETTING
AND HOW DO WE MONTH OF THIS
FORWARD? UNIQUE SEVERE
TOXICITIES WE TALKED ABOUT TOO
AND HAVE TO MAKE THERAPIES MORE
TOLERABLE. DEVELOPING
AFFORDABLE AND ACCESSIBLE
DELIVERY METHODS WE TALKED ABOUT
IT TOO WHETHER WE HAVE
COLLABORATIVE MODELS WITH
PHARMAOR POINT OF CARRACKDEMIC
MANUFACTURER AND CLAUDIA SAID WE
HAVE TO ALL WORK TOGETHER HOW DO
WE GET TO REST OF THE WORLD AND
LOOK AT COST AND LOW AND MIDDLE
INCOME COUNTRIES AND WHO CAN
AFFORD THIS? WE HAVE TO THINK
ABOUT THAT TOO. I WANT TO THANK
EVERYBODY LEADERSHIP AND NIRALI
AND MICHAEL HELPED ME PUSH THIS
AS A COG NEXT STUDY AND SAT IN
MEETINGS WITH EVERY PHARMA
TRYING TO EXPLAIN HOW NCI COULD
SUPPORT THEM AND WE SO FAR HAVE
A FEW BITES. I WILL SEE HOW
THAT GOES. THANK YOU.
>> NEXT HEARING FROM DR. KAREN
CHAO ABOUT ACCESS TO CAR
T-CELLS.
>> I WILL TALK ABOUT BARRIERS TO
ACCESSING CAR T THERAPY AND
POTENTIAL SOLUTIONS FOR PATIENTS
MOVING FORWARD AND STARTING IT
SUMMARIZES BARRIERS TO ACCESSING
CAR T THERAPY FROM STAKEHOLDER
PERSPECTIVES AND FROM PATIENT
PROVIDER MANUFACTURER
PERSPECTIVES AND ADDING A 4TH
PERSPECTIVE FROM RESEARCH
ENTERPRISE AND BARRIERS ARE
FAMILIAR NOT EXCLUSIVE TO CAR T
THERAPY ALONE AND ON UPCOMING
SLIDES I WILL GO INTO EACH
PERSPECTIVE IN DEPTH. PATIENT
PERSPECTIVE LARGE HURDLE
ACCESSING CAR T THERAPY IS
PHYSICAL ACCESS TO INSTITUTION
ADMINISTERING CAR T THERAPY AND
THEY ARE AVAILABLE AT FACT
CERTIFIED CENTERS AND SCENARIO
OR DEMAND GREATLY OUTSTRIPS
SUPPLY AND CERTIFIED CENTERS IN
US FOR PEDIATRIC HEM ATTOPOETIC
STEM CELL PLANT AND PROXIES
ADMINISTERING FOR PATIENTS AND
OFTEN ARE SYNONYMOUS AND THESE
FACT ACCREDITED CENTERS ARE MORE
POPULATION DENSE AREAS AND OUTER
EDGES OF THESE SERVICE LOOKING
AREAS ARE TRAVELING UP TO 3
HOURS AND CENTERS IN SOUTHWEST
AND MIDWEST AND PLAIN STATES ARE
SPARSELY RESUSCITATED AND TRAVEL
AND TRAVELING LONG DISTANCE IN
STATES AND PATIENTS TRAVELING IN
MORE RURAL AREAS AND HIDDEN
COSTS OF RECEIVING CAR T THERAPY
AND TRAVEL AND LODGING EXPENSES.
COSTS MEALS HOTEL STAYS
INCREASING DECREASE INCOME OR
LOSS OF INCOME FOR ONE OR BOTH
CAREGIVERS REQUIRING RISK
MITIGATION AND PATIENTS AND
FAMILIES HAVE TO BUDGET FOR MORE
TIME TO BE WITHIN MANDATED 30
MINUTES TO TWO HOUR DRIVING
SYSTEMS IN REFERRAL INSTITUTION
FOR ADEQUATE SAFETY MONITORING
AND TREATMENT FOR RELATED
TOXICITIES.
UTILIZATION MANAGEMENT POLICIES
ARE IMPOSED BY INSURANCE
COMPANIES AND POLICIES INCLUDE
NEED TO GET PRIOR AUTHORIZATIONS
OR STEPWISE THERAPY WHERE
PATIENTS HAVE DEMONSTRATED
FAILURE OF MULTIPLE LINES OF
THERAPY PRIOR TO AUTHORIZATION
FOR CAR AND STEPS DELAY ACCESS
TO IN-PATIENTS WHOSE NEED FOR
CAR IS TIME SENSITIVE AND
MEDICAL BILL STANDPOINT COPAYS
ARE HIGHER GIVEN HIGHER COSTS OF
CAR AND POTENTIAL COSTS OF
TOXICITY MANAGEMENT AND THERE IS
POTENTIAL TO REFER TO DEFERRAL
-- PREVIOUS COMORBIDITIES AS A
RESULT OF TREATMENT RELATED
COMPLICATIONS FOR FEAR OF
RELATED CAR TOXICITIES MEDICAL
PROVIDER AND STANDPOINT
GEOGRAPHY PLAY AZ ROLE HERE
MONITORING PATIENTS LOCALLY THAN
REFERRING TO INSTITUTION THAT IS
FURTHER.
PREVENS FOR CLOSER TREATMENT IS
DIFFICULT TO ACHIEVE TO
DISTANCED FACT CERTIFIED CENTER
LOGISTICAL DIFFICULTIES
COORDINATING FOLLOW UP FOR
PATIENTS INCLUDING MAINTAINING
EFFECTIVE COMMUNICATION BETWEEN
PRIMARY ONKOLS AND REFERRAL
INSTITUTION AND HOSPITALS THERE
IS CONSIDERATION OF
REIMBURSEMENT STRUCTURE OF CAR T
THERAPY AND ITERATIVE CHANGES
THAT HAVE HAPPENED OVER TIME AND
CURRENT REIMBURSEMENT DOESN'T
OFTEN SUFFICIENTLY COVER COSTS
OF CAR OR TREATMENT SERVICES AND
DOESN'T DISINCENTIVIZE HOSPITALS
TO PROVIDE CAR T THERAPY TO
PATIENTS ADMINISTRATION OF
THERAPY REQUIRES INSTITUTION
STAFFING HIGHLY SPECIALIZED
TEAMS PHYSICIANS AND APPS AND
NURSES AND CLINICAL SUPPORT
STAFF AND INTAKE SPECIALISTS AND
SOCIAL WORKERS AND CASE MANAGERS
AND FINANCIAL SUPPORT STAFF
HELPING WITH NEGOTIATIONS AND
[INDISCERNIBLE] --
REGRESSES FROM REFERRAL TO CAR
TO AFORESIS TO MANUFACTURING AND
LIMITED PRODUCTION SLOTS
MANUFACTURERS CREATING RATE
LIMITING STEP -- FROM AFORESIS
TO INFUSION THERE IS 3 TO 5 WEEK
TURNAROUND FOR MANUFACTURING AND
QUALITY ASSESSMENT CHECKS AND
SPECIFIC NATURE MANUFACTURING
CAR LEADS TO DIFFICULTY IN
SCALING SCALABILITY OF
MANUFACTURING PRODUCTS AND
BITECH COMPANIES SEE CHALLENGES
CAR MANUFACTURERS ARE UNDERGOING
INNOVATIVE THERAPIES IN PIPELINE
MAY BE EFFECTED COMPANIES
SHIFTING PRIORITIES TO EASIER
PATH TO COMMERCIAL VIABILITY AND
PERSPECTIVE OF RESEARCH
ENTERPRISE OUTSTANDING CLINICAL
QUESTIONS WE HAVE GONE OVER
TODAY AND MIGHT NOT BE OPEN
CLINICAL TRIALS SUCH AS ONES
LOOKING AT HUMANIZED FAST CAR OR
EARLY B CELL RECOVERY CAR
INFANTS AND CNS RELAPSE AND
AVAILABLE CLINICAL TRIALS MIGHT
NOT BE OPEN AND AVAILABLE FOR
PATIENTS WHEN THEY NEED THEM AND
PER CLINICAL TRIALS ELIGIBILITY
IS OFTEN STRICT AND LIMITED
RESOURCES TO RECRUIT PATIENTS
AND DESPITE CONCERTED AND
MANDATED EFFORT BY NIH TO
INCLUDE WOMEN AND PATIENTS IN
CLINICAL TRIALS SINCE 90S TO
DATE AND RECRUITING
REPRESENTATIVE MINORITY
PARTICIPANTS AND PIE GRAPH HAS
RACIAL AND ETHNIC BREAKDOWN IN
CLINICAL TRIALS IS SIMILAR IN
CANCER CLINICAL TRIALS INCLUDING
ONCE FOR PEDIATRIC PATIENTS AND
SOME POTENTIAL SOLUTIONS TO
IMPROVING ACCESS AS I HAVE
BROKEN THEM DOWN TO THREE MAJOR
AREAS AND FROM A FINANCIAL
STANDPOINT ADDRESSING FINANCIAL
TOXICITY OF PROCESS OF CAR
ADMINISTRATION IS IMPORTANT FOR
PATIENT AND FAMILY AND PATIENT
ASSISTANCE PROGRAMS MANY DON'T
INCLUDE INCIDENTAL COSTS RELATED
TO TRAVEL AND EXPANSION OF
PROGRAMS TO INCLUDE HIDDEN COSTS
OF GETTING CAR HELPED REMOVE
FINANCIAL DIFFICULTIES THAT SOME
PATIENTS MIGHT BASE AND CHIMERA
TRAVEL ASSISTANCE PROGRAM AIMS
TO LOW INCOME PATIENTS ELIGIBLE
WITH EXPENSES INCURRED DURING
TRAVEL FOR CAR ADMINISTRATION
AND POST CAR MONITORING PERIOD
AND IS A FEW CENTERS IN UNITED
STATES THAT WORKS WITH PATIENTS
TO OFFER FREE OR SUBSIDIZED
HOUSING TO RECEIVE CAR T
TREATMENT AND FINANCIAL
COUNSELING SERVICES FOR PATIENT
INFORMING THEM ABOUT DIRECT AND
INDIRECT COSTS OF SEEKING CAR T
THERAPY AND HELPING THEM
NAVIGATE THROUGH VARIOUS
ASSISTANCE OPTIONS AVAILABLE TO
THEM AND PROGRAMS MAY HELP
REMOVE RELIANCE ON MANUFACTURING
AND CHARITABLE ORGANIZATIONS OR
CROWDFUNDING FROM FAMILIES AND
FRIENDS THAT IS PATCHWORK AND
LARGELY UNRELIABLE SAFETY NET
FROM PATIENTS GEOGRAPHICAL
STANDPOINT AND SETTINGS WITH
CARS INCREASE ACCESS TO MANY
TREATMENT CENTERS MOVING TOWARDS
OUTPATIENT CAR INFUSION AND
EXPANDING CENTERS TO COMMUNITY
TRANSPLANT CENTERS THAT ARE NOT
FACT CERTIFIED MIGHT BE ONE
SHORT TERM SOLUTION TALKING
ABOUT TODAY AS WELL
DECENTRALIZING CAR MANUFACTURING
TO BE DEVELOPED LOCALLY WOULD
IMPROVE EFFICIENCY AND ACCESS TO
HELP DECREASE OVERALL COSTS AND
FROM BIOMEDICAL STANDPOINT
AUTOMATION WOULD HELP BOOST THIS
PROCESS AND MENTIONED MANY TIMES
TODAY AND IN OFF THE SHELF
THERAPIES DON'T REQUIRE FORESIS
WHO HELP SHORTEN MANUFACTURING
TIME AND PEDIATRIC WORLDWIDE
CONSORTIUM TWO EFFORTS AIM AT
BETTER UNDERSTANDING PATIENT
EXPERIENCE AND PATIENT PERCEIVED
BARRIERS TO CARE AND REAL WORLD
COST TO ADMINISTERING CAR IS.
THERE WILL BE THREE VERSIONS AND
PATIENT SELF REPORT FOR PATIENTS
OVER 18 PARENT CAREGIVER PROXY
FOR THOSE LESS THAN 18 YEARS OF
ANL AND NEXT OF KIN SURVEY FOR
PATIENTS THAT PASSED AND
QUESTIONS INCLUDE FOLLOW UPS AND
HOUSEHOLD MATERIAL HARDSHIP AND
AS WELL AS PERCEIVED BARRIERS TO
ACCESS AT CAR T INSTITUTION AND
WILL ALSO BE PATIENT REPORTED
OUTCOMES THAT WILL BE UTILIZING
PROMISE MEASURES ACROSS 7
DOMAINS AND OTHER EFFORT IS A
REAL WORLD FINANCIAL COST
ANALYSIS AND PREVIOUS WORK BY
LYNNE ET AL. EVALUATED COST
EFFECT AND THEY ARE CONTAINING
REGIMENTS USING FINANCIAL
MODELING TO CALCULATE QUALITY
ADJUSTED LIFE BASED ON VARIOUS
RATES OF EFS WITH 40% 5 YEAR EFS
WITH COST IS 61,000 PER EQUALI
AND 5 YEAR EFS DROPS THIS DROPS
AS WELL AND REDUCING OVERALL
COST OF CHIMERA TO HALF THAT
PRICE TAG WOULD ALLOW IT TO MEET
MORE ACCEPTABLE STAND AARD REAL
WORLD FINANCIAL COST ANALYSIS IS
PAIRING CLINICAL DATA COLLECTED
IN PRWCC AND ENCOUNTER LEVEL
BILLING CHARGE DATA THAT IS
SHARED WITH FIZZ THAT IS THE
PEDIATRIC HOSPITAL INFORMATION
SYSTEMS AND IN THE ORIGINAL 15
INSTITUTIONS MAKING UP PRWCC10
SHARE DATA WITH THIS. WE HAVE
BEEN ABLE TO PULL ABOUT 100
PATIENTS FROM DATA AND BOTH
DATABASES AND FINALIZING DATA
SET FOR ANALYSIS.
THANK YOU.
>> THANK YOU, KAREN MOVING TO
ANGELA TALKING ABOUT PATIENT
REPORTED OUTCOMES.
>> GOOD AFTERNOON I'M ANGIE AND
GRATEFUL TO TALK ABOUT PATIENT
REPORTED OUTCOMES VALUE OF
FUTURE CORRECTIONS IN CAR T-CELL
THERAPY.
THERE WE GO ALL RIGHT WE HEARD
OF TREMENDOUS WORK BEING DONE IN
CAR T-CELL THERAPY THAT IS
PEDIATRIC AND ALL IS EXCITING
AND COMMON THEME WE ARE HERE
TODAY IS TO FIND WAYS TO HELP
FIND CHILDREN WITH CANCER TO
LIVE HEALTHIER AND LONGER LIVES
AND KAPLAN MEYER CURVE WE AGREE
THIS PROVIDES SUPERIOR CARE TO
THE BLUE ARM AND WE CAN ALL
AGREE THE GOLD ARM SHOULD BECOME
THE STANDARD OF CARE AND WE KNOW
PATIENT REPORTED OUTCOMES
IMPROVE CLINICAL OUTCOMES AND
RCT WHERE ADULTS RECEIVED USUAL
CARE OR COMPLETED PATIENT
REPORTED OUTCOMES SYSTEM
ASSESSMENTS FROM STUDY WE
LEARNED PATIENT REPORTED
OUTCOMES IMPROVE QUALITY OF LIFE
AND SATISFACTION AND DECREASE
RESOURCE UTILIZATION AND
INCREASE SURVIVAL AND OTHER
STUDIES WE LEARNED THAT BASELINE
PATIENT REPORTED OUTCOMES ARE
STRONGER PREDICTOR OF SURVIVAL
THAN MANY OTHERS SURVIVORS IN
BONE MARROW TRANSPLANTS --
INDEPENDENT CRITERION FOR
APPROVAL OF NEW DRUGS TREMENDOUS
VALUE
VALUE. WHAT IS A PATIENT
REPORTED OUTCOME? WE HAVE HEARD
A LOT ABOUT THEM TODAY PATIENT
REPORTED OUTCOME OR PRO IS
MEASURE OF ASPECT OF PATIENT
STATUS OR WELL BEING COMING FROM
PATIENT NOT FROM CAREGIVER OR
CLINICIAN AND OUTCOMES USE TODAY
MEASURE CONSTRUCTS LIKE SYMPTOMS
QUALITY OF LIFE AND
PSYCHOLOGICAL DISTRESS AND
FINANCIAL WELLBEING AMONG MANY
OTHERS AND PATIENT REPORTED
OUTCOMES USE VALIDATED
INSTRUMENTS APPLYING ARIG ROUS
DATA COLLECTIONS AND METHODS AND
ANALYSIS AND UNDERSTANDING
IMPORTANT DISEASE EXPERIENCE
WHEN DO SYSTEMS PEAK AND HOW
DOES TREATMENT EFFECT
CAREGIVERS?
IN CHILDREN THIS MEANS DIRECTLY
ASKING THE CHILD AND CHILDREN
PROVIDE DISTINCTIVELY IMPORTANT
PERSPECTIVE COMPARED TO PARENTS
AND MEDICAL TEAM THAT IS
DRAMATIC FOR SUBJECTIVE
EXPERIENCES PAIN FATIGUE AND
ANXIETY PREVALENT AND
DISTRESSING -- MUCH WORK DONE IN
THIS SPHERE HAS PREDATED
IMMUNOTHERAPY.
AS OF LATE 2022, JUST 14 STUDIES
IN CAR T-CELL THERAPY INCLUDED
PROS AND VAST MAJORITY OF THESE
FOCUS ON HEALTH RELATED QUALITY
OF LIFE AS OUTCOME AND I THINK
THAT ONE PREVAILING AND VERY,
VERY PROMISING THEME AMONG
STUDIES IS CAR T-CELL THERAPY
OFFERS FAVORABLE PATIENT
EXPERIENCE AND HOWEVER JUST ONE
STUDY WAS DONE IN CHILDREN AND
ONLY FOUR WERE DONE IN PATIENTS
WITH ACUTE LEUKEMIA AND VAST
MAJORITY WERE DONE WITH PATIENTS
WITH ADULT HEEM ATOLOGIC TYPE
MALIGNANCIES AND DESPITE
GREATEST CHANGES IN WEEKS
FOLLOWING TWO STUDIES COLLECTED
DATA IN TWO WEEKS OF INFUSION
AND 5 COLLECTED DATA BEYOND ONE
YEAR AND NOTABLY 29 OF 400
CURRENTLY REGISTERED CLINICAL
TRIALS IN CAR T-CELL THERAPY
AROSE IN PRIMARY OR SECONDARY
OUTCOME AND LONE STUDY IN
CHILDREN THE STUDY COLLECTED
LONGITUDINAL MEASURES HEALTH
RELATED LIFE FOLLOWING CAR
T-CELL THERAPY AND DOMAINS OF
WELL BEING IMPROVEMENT FROM
TREATMENT FROM BASELINE
OCCURRING AS EARLY AS 1 MONTH
POST TREATMENT SUSTAINED TO
THREE YEARS POST TREATMENT AND
PHYSICAL FUNCTION SCORES SHOWED
GREATEST CHANGE AND INDIVIDUALS
RESPONDING TO TREATMENT AND 13
PATIENTS COMPLETE AD ASSESSMENTS
AT LATER TIMEPOINTS INCLUDING 3
YEAR TIME POINT.
ONE STUDY HAS COMPARED CAR
T-CELL THERAPY TO AUTO
TRANSPLANTS AND ADULTS AND
PRIMARY FINDING HERE
DEMONSTRATED BY BLUE LINE THAT I
THINK IS VERY IMPORTANT AND
PATIENTS WHO WERE TREATED WITH
CARS EXPERIENCED A LESS
SIGNIFICANT POST TREATMENT
DECLINE IN WELLBEING AND QUICKER
RETURN TO BASELINE AND THIS IS
CONSISTENT ACROSS ALL DOMAINS OF
FUNCTIONING AND LOBBYING.
ONE UNPUBLISHED STUDY REPORTED
SYMPTOMS THAT ARE EXPERIENCED
FROM CARS FROM CHILD'S
PERSPECTIVES AND DEANNA LEVINE
LENT ME DATA FROM ST. JUDE PART
OF THIS COLLECTED ON SUBSET OF
PATIENTS AND CAREGIVERS FOCUSING
ON SYMPTOMS AND QUALITY OF LIFE
AT BASELINE WEEK 2 AND 4 AT CAR
T FUSION AND GREATEST AT WEEK 2
NOT SURPRISING AND MOST
PARTICIPANTS REPORTED A HIGH
NUMBER OF SYMPTOMS THROUGHOUT
THE TREATMENT AND QUALITY OF
LIFE SCORES ON OTHER HAND
SURPRISING REMAINED CONSISTENT
OVER TIME PERIOD ANALYZED
PSYCHOLOGICAL DISTRESS FOR
PARENTS AND CAREGIVERS WERE HIGH
THROUGHOUT THE TREATMENT AND
POTENTIALLY COULD HAVE EFFECTIVE
QUALITY OF LIFE AND IS
CONSISTENT ALSO WITH WHAT WE ARE
SEEING IN LARGER PROSPECTIVE
MULTI-SITE STUDY AND SUGGESTS
PAIN AND FATIGUE AND NAUSHIA ARE
PREVALENT BOTHERSOME SYMPTOMS
WITH INFUSION AND FIND THAT
SYMPTOMS ARE NOT THAT BAD AND
QUOTE ON QUOTE COMPARED TO
THERAPY AND PSYCHOSOCIAL
STRESSORS ARE PREVALENT AND
BURDEN SOME AND THIS IS
COMPLICATED BY MANY PATIENTS
WANTING SOME DEGREE OF SYMPTOM
RELATED SUFFERING AS REASSURANCE
THAT TREATMENT IS ACTUALLY
WORKING.
FINALLY LOOKING AT LONGER TERM
OUTCOMES ADULTS WITH MIX OF HEEM
ATOLOGIC MALIGNANCIES ASSESSING
-- ASSESSMENTS WERE
CROSS-SECTIONAL COMPLETED AT 1
TO 5 YEARS INFUSION AND
NONSTANDARDIZED FASHION AND 12
PATIENTS WENT ON TO RECEIVE BONE
MARROW TRANSPLANT AFTER CAR
T-CELL THERAPY AND REPORTED IN
SIGNIFICANT NUMBER OF PATIENTS
INCLUDING THIRD REPORTING
PROBLEMS WITH MEMORY OR WORD
FINDING AND ONE QUARTER REPORTED
DIFFICULTY CONCENTRATING AND
WANT TO NOTE THIS IS NOT
DEPENDENT ON WHETHER OR NOT
PATIENT HAD TRANSPLANT ALBEIT
SMALL NUMBERS COMPLAINTS ARE
SIMILARLY PREVALENT WITH HALF
PATIENTS REPORTING CLINICAL
NEGATIVE OUTCOME HERE YOU SEE BY
NONBLUE CIRCLES.
THIS SUGGESTS A NEED FOR MENTAL
HEALTH SERVICES FOLLOWING CAR
T-CELL THERAPY AND MOST
IMPORTANT FOR GROUP IS YOUNGER
ANL AND ACUTE NEUROTOXICITY ARE
LIKELY TO BE RISK FACTORS AND
FROM STUDIES LEARNING
LONGITUDINAL ASSESSMENTS PATIENT
REPORTED OUTCOMES ARE POSSIBLE
AND INCLUDING AMONG CHILDREN AND
PROVIDING FAVORABLE PATIENT
EXPERIENCE AND THERE IS ROOM FOR
IMPROVEMENT STILL.
LOOKING FORWARD, I SEE THREE
PRIMARY FUTURE DIRECTIONS FOR
PATIENT REPORTED OUTCOME
RESEARCH IN CAR T-CELL THERAPY.
FIRST, CONSENSUS AND
COLLABORATION IS THEME FOR TODAY
THAT IS E-SEINE SHL AND WE ARE
ALL VERY FAMILIAR WITH SAMPLE
SIZE LIMITATIONS INPEDIA THE
TRICKS AND MUST WORK TOGETHER TO
DO THIS WORK COLLECTING SIMILAR
DATA AT SIMILAR TIME POINTS
FOCUSING ON OTHER PATIENT
DOMAINS SUCH AS CAREGIVER
OUTCOMES AND FBL TOXICITY AND
SECOND COLLECTION OF DATA WITHIN
CONTEXT OF CLINICAL TRIAL HAS
BENEFITS AND ARE SUBSTANTIAL
LIMITATIONS PARTICULARLY WHEN
GENERALIZING RESULTS TO
PEDIATRIC PATIENTS WHO ALL
PEDIATRIC PATIENTS RECEIVING
CARS AND FINALLY DEFINING THE
PROBLEM IS NOT ENOUGH AND
APPLICATION TO PRACTICE
IMPROVEMENT IS NECESSARY AND
DATA CAN BE USED FOR GUIDING
ANTICIPATORY GUIDANCE WE GIVE
FAMILIES WITH POTENTIAL TO BE
LEVERAGED TO IMPROVE EARLY
IDENTIFICATION AND TOXICITY OF
EVENTS IMPROVING PATIENT CARE TO
IMPROVE DAY-TO-DAY QUALITY OF
LIFE FOR CHILDREN WITH CANCER.
THANK YOU.
>> ALL RIGHT. RUNNING A LITTLE
OVER AND ONE VIRTUAL
PRESENTATION FROM LORI MUFFLY
FROM STANFORD ABOUT AYA
POPULATION.
ONLY AROUND 40% OF THOSE AYAS
ARE TREATED IN KREVENLTERS IN
ADULT CANTER TREATMENT SETTING
AND HAS IMPLICATIONS HOW
PATIENTS ARE TREATING AND
IMPLICATIONS ON CAR T-CELLS AND
IMPLICATIONS TO SURVIVAL AND
TREATMENT PARADIGM FOR AYLL AND
THAT IS POSITIVE OR RELAPSE
REFRACTORY DIFFERS AND CURRENT
PARADIGM AFTER FRONTLINE THERAPY
AND IN ADULT WORLD WE CAN'T
AGREE WHETHER THAT IS AFTER
INDUCTION OR CONSOLIDATION
THERAPY AND MOST TYPICALLY FOR
PATIENTS RECEIVING CLEARANCE OF
MRD AND TRANSPLANTATION FOR
CONSOLIDATION AND RELAPSE
REFRACTORY B CELL ALL IS USED IN
COMBINATION WITH [INDISCERNIBLE]
CHEMOTHERAPY AND BLINA IS FOR
THOSE WITH MRD POSITIVE RELAPSE
AND LATE 2021 I WILL TALK ABOUT
WE HAVE [INDISCERNIBLE].
HOWEVER, THERE IS SERIOUS
CHALLENGES GIVING COMMERCIAL CAR
T-CELLS IN ADULT TREATMENT
SETTING AND CHALLENGES THAT
PEDIATRICIANS FACE AS WELL AND
INSURANCE APPROVALS AND TIMING
OF T-CELL COLLECTION HAS BEEN AN
ISSUE AND WE HAVE NO MECHANISM
FOR PRE-EMPTIVE T-CELL PRIOR
PRESERVATION AND THEY DON'T TAKE
THESE T-CELLS FOR MANUFACTURING
AND IN ADULT ALL WORLD THIS
TRANSPLANT REMAINS PROVEN
[INDISCERNIBLE] AND THERE IS A
BIG QUESTION AS TO WHETHER CAR
T-CELLS ARE A DEFINITIVE THERAPY
ON THEIR OWN.
NOW, WHY DOES THE TREATMENT
PARADIGM DIFFER FOR AYAS TREATED
ON PEDIATRIC AND ADULT TREATMENT
SETTING AND IN PART HAS TO DO
WHEN DRUGS ARE APPROVED AND
ADULT PARADIGM OR WORLD I'M
TALKING ABOUT PATIENTS 18 OR
OLDER WE HAVE RELAPSED
REFRACTORY IN 2014 GOT
EXPERIENCED USING THIS
IMMUNOTHERAPY AND APPROVED IN
2016 AND 17 AND WASN'T APPROVED
UNTIL LATE 2021 AND FIRST TIME
ADULT PRACTITIONERS GOT HANDS ON
COMMERCIAL CAR T-CELL FOR ALL
AND PEDIATRIC TIMEFRAME LOOKS
DIFFERENT AND APPROVED FOR
PATIENTS UP TO THE AGE OF 26 AND
ALL THE WAY BACK IN 2016 OR 17
AND PEDIATRICIANS HAVE USED CAR
T-CELLS FOR A LONG TIME AND
RECENTLY STARTED TO USE THEM AND
HOWEVER THERE IS OTHER REASONS
AND THIS IS -- THESE FIGURES CAN
WORK FROM A SYSTEMATIC REVIEW I
WAS PART OF WHERE WE LOOKED AT
16 DIFFERENT STUDIES OF CAR
T-CELLS FOR ADULT B CELL ALL AND
INCLUDING ALMOST 500 PATIENTS.
YOU SEE HERE PROGRESSION FREE
SURVIVAL AT 12 MONTHS IS AROUND
37%. LOOKING AT CURVES THEY
DON'T LOOK ALL THAT EXCITING
PARTICULARLY FOR PROGRESSION
FREE SURVIVAL AND THERE IS A BIG
QUESTION ABOUT HOW ROBUST ARE
CAR T-CELLS FOR ADULT ALL?
NOW, ZUMA3 IS STUDY CONDUCTED BY
KITE AND BRECHLA CELL PREVIOUSLY
CALLED [INDISCERNIBLE] THAT LED
TO APPROVAL OF AGENT FOR
PATIENTS 18 OR OLDER YOU SEE ON
DIAGRAM TO THE RIGHT OF 71
PATIENTS ENROLLED 55 PATIENTS
ENFUSED AND PATIENTS REPORTED ON
AND USED AD LYMPHO DEPLETION YOU
CAN SEE DOSING OF CAR T-CELLS
AND 7 DAY MINIMUM
HOSPITALIZATION AND ARE RESULTS
OF SDOOUMA 3 AND 55 PATIENTS
INFUSED COMPOSITE CRR RATE 71%
AND 16% OF PATIENTS HAVE NO
RESPONSE AND RIGHT YOU SEE
MEDIAN RELAPSE SURVIVAL FOR
PATIENTS AND CRI WAS 14 MONTHS
FOR ALL TREATED PATIENTS WAS
APPROXIMATELY 1 YEAR AND YOU SEE
OVERALL SURVIVAL BELOW AND
FACTOR THAT SEEMED TO INFLUENCE
WHETHER OR NOT PATIENTS
RESPONDED TO THERAPY WAS
PERCENTAGE OF BONE MARROW BLASTS
AND PATIENTS WITH PACKED BONE
MARROW WITH PEDIATRIC RESPONSE
HAD MUCH LOWER RATE RESPONSES
AND QUITE A BIT OF TOXICITY IS
POST STIMULATORY CAR AND LEAD
CRITERIA FOR CRS AND YOU SEE 24%
[INDISCERNIBLE] AND NEUROTOX
THIS IS REALLY BEFORE ASCTC
GUIDELINES ARE ROUTINELY USED
AND GRADE 34 RATE OF NEUROTOX
WITH 25 P RS WITH ONE DEATH FROM
NEUROTOXICITY AND PEAK EXPANSION
WAS 15 DAYS AND DETECTED IN 20%
-- PCR AND 18% OF THE STUDY
POPULATION ACHIEVING CR
UNDERWENT ALOE TRANSPLANT AND
RELAPSE 2/3 OF PATIENTS RETAINED
[INDISCERNIBLE] WITH 1/3 LOSING
CD19 NEGATIVE RELAPSE AND LABELS
OF CELLS YOU SEE ARE DIFFERENT
IMPLICATIONS FOR AYAS WITH AGE
GROUPS THAT COULD GO BOTH WAYS
AND THEY HAVE A WIDE OPEN LABEL
ADULT PATIENTS 18 OR OLDER WITH
RELAPSE REFRACTORY B CELL AND
REQUIRES PATIENTS TO BE UP TO
AGE OF 25 AND NO OLDER THAN 25
AND THIS IS EITHER REFRACTORY OR
SECOND OR LATER RELAPSE AND
BRECHLA CELL COULD BE GOOD
OPTION FOR PATIENTS WITH FIRST
RELAPSE MIGHT NOT BE ABLE TO GET
TO THE CELL. IN ADULT A WILL.
L TREATMENT WORLD AND CELL
THERAPY TREATMENT WORLD WHAT ARE
WE EXCITED ABOUT? PUBLICATION
BY COLLEAGUES AND THIS IS ON
FAST CAR AND WE ARE EXCITED
ABOUT HERE IS NOT ONLY DO CURVES
LOOK GOOD BUT TOXICITY PROFILE
IS QUITE EXCITING WITH REALLY NO
GRADE 34CRS AND ONLY 15% IS
REPORTED IN EARLY PHASE STUDY
AND PHASE 1, B2 FELIX IS LIKELY
TO REPORT OUT BY NEXT YEAR'S
ASCO. WE ARE VERY MUCH HOPING
THIS IS A CAR THAT WILL GAIN
APPROVAL WITHIN THE NEXT COUPLE
YEARS.
WE ALSO HAVE BARRED OFF THE
WONDERFUL WORK THAT
PEDIATRICIANS YOUR GROUP HAS
DONE WITH CAR CONSORTIUM AND
OTHER CONSORTIUMS AND HAVE
OUTCOMES COLLABORATIVE OF RT AND
ADULT ALL CALLED ROCHA AND 14
CENTERS ARE INVOLVED AND
COUNTING AND STANFORD IS HOME
CENTER AND SUBMITTED THE FIRST
76 PATIENT EXPERIENCE TO POST
CARTITIS AND WE ARE EXCITED
ABOUT THE OPPORTUNITY AND HAVE
SEVERAL ABSTRACTS PLANNED FOR
ASH TAKING ON WONDERFUL WORK
THAT PEDIATRICIANS HAVE DONE AND
IN SUMMARY CURRENTLY TREATED IN
ADULT RATHER THAN PEDIATRIC
SETTING AND THIS IS NOT
UNIFORMLY CONSIDERED A
DESTINATION THERAPY AND
TREATMENT PARADIGMS B CELL ALL
DIFFER BETWEEN PEDIATRIC AND
ADULT CANCER TREATMENT SETTINGS
AND ADULT PRACTITIONERS TO FEEL
COMFORTABLE WITH DESTINATION
THERAPY WE NEED LONG-TERM DATA
AND DURABLE POST CAR REMISSIONS
WITHOUT USE OF CONSOLIDATIVE
TRANSPLANT AND IS ACCESS
DIFFERENT FOR AYAS TREATED ON
ADULT TREATMENT SETTINGS?
COULD BE. IS INSURANCE
DIFFERENT?
MIGHT BE. WHICH OF THESE ARE
LIMITING ACCESS AS WELL AND
PEDIATRIC CENTERS CONSIDER
TAKING YOUNG ADULTS WANTING CAR
T-CELL THERAPY AND ADVOCATES IN
THE PAST THE CENTERS SHOULD
TREAT YOUNG ADULTS OUTCOMES ARE
BETTER AND WE HAVE BEEN ABLE TO
SHOW THIS AND REACHING AYA
PATIENTS IN NEED AND FOR EXAMPLE
POOR RISK BIOLOGY WE KNOW ARE
REPRESENTED IN CLINICAL TRIALS
AND IMPORTANT AYA CENTRIC CAR
T-CELL QUESTIONS THAT I'M
EXCITED FOR US TO LOOK AT AND
DIFFERENTIAL TOX TIS I ACROSS
THE ANL SPECTRUM AND FERTILITY
AND LATE EFFECTS IS A NEW FIELD
AND SO MUCH MORE TO ANSWER AND
MOST EXCITING TO ME IS NOW WITH
APPROVAL OF BRECHLIS IS RISE IN
COMMERCIAL CAR T-CELL USE AMONG
AYAS AND USING THIS OPPORTUNITY
TO STUDY CAR T-CELL AS CROSS
THIS CONTINUUM AND REAL WORLD
CONSORTIUM AND YOU HAVE ONE IT
IS FUN TO PAIR DATA AND WORK
TOGETHER ON SOME OF THE
QUESTIONS AND WITH THAT I WILL
END MY TALK. I DON'T KNOW IF I
CAN TAKE QUESTIONS BUT WOULD BE
MORE THAN HAPPY TO. AGAIN, I'M
REALLY SORRY TO HAVE MISSED THIS
EXCITING EVENT.
THANK YOU.
>> >> ALL RIGHT. WE ARE 6
MINUTES OVER AND HAVE A BREAK
NOW. IF ANYONE WANTS TO STICK
AROUND AND TALK TO SPEAKERS OR
ASK QUESTIONS PEOPLE WOULD BE
OPEN TO STICKING AROUND BUT FEEL
FREE TO TAKE YOUR BREAK IF YOU
NEED TO.
>> WE ARE GETTING STARTED ON THE
LAST SESSION OF THE DAY. FIRST
SPEAKER TODAY IS RAIN ROUS WHO
WILL TALK TO US ABOUT TCALL.
>> HELLO. GOOD AFTERNOON.
I WILL START WITH T-CELL
MALIGNANCIES. THESE ARE MY
DISCLOESH YURZ. WE TALKED A LOT
ABOUT GREAT SUCCESSES WE HAVE
SEEN TARGETING B CELLS LEUKEMIAS
AND LYMPHOMAS WITH T-CELLS AND
THERE IS UNIQUE CHALLENGES
TRYING TO TARGET T-CELL
MALIGNANCY WITH CAR T-CELL AND
MANUFACTURING AND GENERATING
CELLS TARGETING ANCONTINUALEN
AND RESULT IN REALLY REMARKABLE
IN ANTITUMOR ACTIVITY THEY HAVE
A UNIQUE SET OF ISSUES THAT CAN
OCCUR AND ONE IS [INDISCERNIBLE]
CAR T-CELLS CAN ACTUALLY TARGET
THEMSELVES AND THEY CAN LIMIT IN
VITRO EXPANSION AND CAN ALSO
LIMIT IN VIVO ANTITUMOR ACTIVITY
AND T-CELLS CAN RESULT IN T-CELL
APLASIA AND THEY ARE TARGETING
T-CELL ANCONTINUALENS AND IT IS
MUCH LESS ACCEPTABLE SIDE
EFFECT.
LOOKING AT IDENTIFYING AN TIJEN
TARGETING CD7 MAINLY AND CD5 AND
CD30 AND AS PEDIATRICIANS WE SEE
PREMATURE NEOPLASMS AND GROUP
WAS INTERESTED IN SURINGLY
IDENTIFYING AN TIJANTIGENS.
>> WHETHER EDITED OR UNET ITDED
I WILL TALK ABOUT THIS. BECAUSE
OF SPECIFIC RISK OF
[INDISCERNIBLE] YOU HAVE TO
OFTEN EDIT OUT CD7 BY KNOCKING
IT OUT TO ALLOW CELLS TO EXPAND
IN VITRO. WE HAVE SEEN
REMARKABLE CLINICAL RESPONSES
THAT I THINK ARE GREATER THAN
WHAT ANY OF US EXPECTED WITH
NUMBER OF MRD NEGATIVE CRS AND
IN PATIENTS WITH IMMATURE --
ALSO IMPATIENT WITH MORE MATURE
T-CELL LYMPHOMAS AND IMPORTANTLY
TRIALS ARE DESIGNED TO SERVE AS
A BRIDGE TO TRANSPLANT BECAUSE
OF RISK OF T-CELL APLASIA HE WE
HAVE SEEN PATIENTS IN ALL TRIALS
PUBLISHED AND PRESENTING
INFORMATION WITH ONGOING
COMPLETE REMISSIONS DESPITE NOT
PROCEEDING TO TRANSPLANT AND WE
HAVE LEARNED QUICKLY THAT IT IS
CHALLENGING TO CREATE CAR
T-CELLS TARGETED T-CELL ANTIGEN
FROM PATIENTS AND RISK IS DUE TO
FACT THAT WE DON'T WANT TO
TRANCE DEUCE MALIGNANT BLASTS
AND HAVING CIRCULATING
PERIPHERAL BLASTS AND SEVERAL
HAVE USED STEM CELL TRANSPLANT
DONOR DERIVED CAR T-CELLS
GENERATING FROM PRIOR TRANSPLANT
DONOR AND THIS CAN'T ACCOUNT FOR
PATIENTS UNABLE TO PROCEED TO
TRANSPLANTS AND OTHERS USE
HEALTHY DONORS AND STUDIES ARE
FROM CHINESE GROUPS THAT READ
REALLY REMARKABLE CLINICAL
RESPONSES WITH A NUMBER OF
PATIENTS BEING ABLE TO GO ON TO
TRANSPLANT AND SOME REMAINING IN
REMISSION EVEN WITHOUT
TRANSPLANT AND OUR GROUP FOCUSED
ON TARGETING CD5 AND STARTED
STUDY OUT WITH ON TOLL GAUS
STUDY AND WE ARE ABLE TO
GENERATE CELLS FROM VAST
MAJORITY OF PATIENTS AND
PATIENTS DESPITE BEST EFFORTS
UNABLE TO GENERATE SALES FROM
AMENDING PROTOCOL TO ALLOW US TO
GENERATE CD5 CAR T-CELLS FROM
TRANSPLANT DONOR AND SINCE THAT
TIME 2 OUT OF 3 PATIENTS WE
RETREATED ACHIEVED CDR AND ONE
WAS A PEDIATRIC PATIENT ABLE TO
GO ON TO TRANSPLANT AND PICTURES
WORTH 1,000 WORDS AND RECEIVING
LYMPHO DEPLETION STANDARDS AND
SINGLE INFUSION OF CD5 CAR
T-CELLS AND COMPLETE RESPONSE
AND REMARKABLE RESPONSES THAT WE
HAVE SEEN AND WE LEARNED LESSONS
AND LEARNED THAT RISKS ARE REAL
WHEN TARGETING T-CELL ANTIGENS
WITH CAR AND SAFETY PROFILE IS
OVERALL MANAGEABLE WITH LOW
GRADE CYTOKINE SYNDROME RARELY
SEE ANYTHING ABOVE GRADE 3 AND
INFECTIONS ARE REAL ISSUE
RELATED TO T-CELL APLASIA IN CD5
AND 7 T-CELLS AND WE HAVE SEEN
EBB POSITIVE LYMPHO
PROLIFERATIVE DISEASE AS RESULT
OF EBV REACTIVATION AND HAVE TO
MODIFY STUDIES TO SPECIFICALLY
ADDRESS THIS RISK AND COUPLE OF
GROUPS IN CHINA HAVE HAD TO DO
SO AND SEEN CRYTOPENIAS THAT ARE
SIMILAR TO SEEING CELLS THAT YOU
WILL SEE SOMETIMES OUT TO 4 OR 5
WEEKS AND MAIN ISSUE HAS BEEN
RISK OF TC APLASIA THAT HAS
CAUSED US TO PROPOSE SOLUTIONS
TO ESTABLISHED RISKS AND STUDIES
FOR NOW WILL REMAIN AS BRIDGE TO
TRANSPLANT THAT IS MAINLY A
SAFEGUARD AND IF YOU HAVE T-CELL
APLASIA AND ARE IN REMISSION AND
RECEIVING CONDITION IN
CHEMOTHERAPY MOST LIKELY THING
IS THAT CONDITIONING CHEMOWILL
ERADICATE T-CELLS AND
[INDISCERNIBLE] IS A MECHANISM
WE USED NOT JUST FOR CRS AND FOR
JUST FOR REFRACTORY CRS AND
INFLAMMATION BUT SPECIFICALLY WE
HAVE SEEN IT CAN KILL CAR
T-CELLS AND INCORPORATING
FREQUENT VIRAL PCR MONITORING
SIMILAR TO MEDIA TRANSPLANT
PERIOD I SUSPECT AS WE CONTINUE
TO TRY TO EVOLVE WITH STUDIES
FDA WILL BECOME SAVVY AND
REQUIRE YOU TO HAVE THINGS
TARGETING TC ANCONTINUALEN AND
ABENDED TRIALS AND IN ANY
PATIENT THAT IS EVV POSITIVE WE
GET THIS PRIOR TO GIVING PRIEFR
T-CELLS AND WE ENSURE THAT WE
HAVE IMMEDIATELY AVAILABLE
PARTIALLY HLA MATCH OFF SHELF
VIRUS T-CELL PRODUCT AVAILABLE
FOR EBV AND WE HAVE HAD PATIENTS
WITH EXTENSIVE EBV POSITIVE PLTD
THAT IS REFRACTORY TO STANDARD
TREATMENTS WE USE AND THERE IS A
BIT OF REGULATORY COMPLEXITY
USING GENE EDITING AND SEVERAL
STUDIES I HAVE SHOWN ACTUALLY
EDIT THEIR CAR T-CELLS TO ALLOW
FOR CELLS TO EXPAND IN VIVO AND
WHEN USING GENE EDITING IT ADDS
REGULATORY COMPLEXITY.
ONE OF THE STRATEGIES THAT OUR
GROUP USED THAT IS FROM THIS
WITH OUR GROUP IS MANUFACTURING
FUNCTIONAL T-CELL ANTIGEN
TARGETING T-CELLS WITHOUT GENE
EDITING RELATIVELY SIMPLE ADDING
CHEMICAL INHIBITION AND THIS TO
THE IN VITRO CULTURE THAT IS
ACTUALLY ENABLING CAR T-CELLS TO
STILL EXPAND AND TRANSLATES TO
ENHANCED TUMOR KILLING ALLOWING
US TO OPEN CD7 CAR T-CELL
WITHOUT USING CRISPER TO
KNOCKOUT CD7 AS WE ORIGINALLY
PLANNED AND WE LEARN THAT
STARTING PRODUCTS MATTER AND
TALKED ABOUT OFF THE SHELF
STRATEGIES NO THE JUST TALKING
ABOUT ACCESS BUT GETTING
THERAPIES TO ALL PATIENTS AND
GROUP HAS LONG HISTORY OF USING
VIRUS SPECIFIC T-CELLS TO TARGET
VIRUSES AND EBV PROLIFERATIVE
DISEASE AND FORTUNATE BENEFITS
ABOUT VIRUS SPECIFIC T-CELLS IS
THEY HAVE RELATIVELY LOW RISK OF
GRAPH VERSUS HOST DISEASE AND
T-CELL REPERTOIRE IS NARROW AND
DEFINED TO VIRUSES YOU CAN USE
THIS AS A PLATFORM AND WE
RECENTLY HAVE AN OPENED AND
CLINICAL TRIAL HAVING A CD30 CAR
ON THIS BASE IN THIS CASE EBV
AND LESS RISK OF GBHD AND TARGET
TUMORS TO CAR AND TARGET EBV
POSITIVE TUMORS AND HODGE KINES
LYMPHOMA FOR EXAMPLE POSITIVE
FOR EBV AND CAN POTENTIALLY
REJECT ALOREACTIVE T-CELLS THAT
UP REGULATE CD30 AND IS OPEN AND
ONGOING TRIAL AND I WANT TO TALK
ABOUT THE LESSONS LEARNED IN
FUTURE DIRECTIONS. WE HAVE
TRULY LEARNED THAT MANUFACTURED
CHALLENGES TRYING TO CREATE OT
OL GAUS PRODUCTS FOR REFRACTORY
T-CELL PATIENTS HAVE WIDESPREAD
USE LIMITED NUMBER OF HEALTHY
T-CELLS STARTING OFF WITH RATIO
OF HEALTHY T-CELLS TO
CONTAMINATING CIRCULATING BLASTS
THAT ARE [INDISCERNIBLE] AND
MOLECULE GENERATING T-CELLS MAY
IMPACT FRAT TROE CRIED MORE THAN
PERSISTENCE WHEN USING CAR
T-CELLS TYPICALLY AS BRIDGE TO
TRANSPLANT AND GENE EDITING OR
CHEMICAL INHIBITION MIGHT BE
NECESSARY AND NOT THE ONLY GROUP
TO USE A [INDISCERNIBLE] WITHIN
A CULTURE MECHANISM. WE KNOW
THIS CAN LEAD TO HAVING T-CELLS
THAT ARE A BIT LESS EXHAUSTED
AND MORE OF A CENTRAL MEMORY
PHENOTYPE LIKE WE TALKED ABOUT
EARLIER THAT ARE STRATEGIES THAT
HAVE TO OFTEN BE ENGAGED WHEN
CREATING PRODUCTS UP FRONT AND
CONSERVATIVE RISK MITIGATION
PLANNING IS KEY AND LOOKING AT
RISK OF INFECTIOUS COMPLICATIONS
AND I SUSPECT FOR ALL FUTURE
ITERATIONS OF CAR T-CELL TRIALS
AND MALIGNANCIES WE WILL BUILD
IN RIFBLG MITIGATION TO AVOID
CATASTROPHIC EVENTS AND EARLIER
THIS IS KEY AND RANGE RS TRUE
FOR ALL DISEASES WE TREAT AND
ALTERNATIVE DONORS ARE REALLY
THE FUTURE AND UNFORTUNATELY
MANY GROUPS INCLUDING OURS ARE
TRYING TO BRING THE FUTURE TO
NOW AND GENERATE PRODUCTS FROM
ALTERNATIVE DONORS AND I WILL
NEVER DO A PRESENTATION AGAIN
WITHOUT INCLUDING A SLIDE ABOUT
ACCESS AND IF WE CAN BUILD IT WE
CAN ADVOCATE FOR ACCESS WITH
FANCIEST CAR AND ENGINE CAN'T
REACH DESTINATION IF ALL ROADS
ARE CLOSED AND DON'T HAVE TO
BELABOR TO GROUPS AND PATIENTS
STRUGGLE WITH ACCESS TO
THERAPIES AND SOMETIMES MEDICAL
AND HEALTH CARE SYSTEMS HAVE TO
CATCH UP TO SCIENCE AND ACCESS
BARRIERS ADDRESSED AT EVERY
SINGLE STEP AND TRIAL CONCEPTION
AND IMPLEMENTATION AND TRIAL
ACCRUAL HAS BEGUN AND INFORMED
PARTICIPATION REQUIRES ALL
EDUCATION FOR ALL INVOLVED AND
SCIENTISTS PATIENTS REFERRING
PROVIDERS AND CLINICAL TRIAL
STAFF AND EQUAL ACCESS IS LANE
AND HOV PASS THAT IS NOT NEEDED
AND COMMITTEES FOR TCT AND
POLICY WORKING GROUPS AND WE
TALKED TO CONGRESS VERY OFTEN
AND CNS AND MEDICAID AND WE CAN
REALLY MAKE WAYS. I WILL BE
HAPPY TO TAKE QUESTIONS AND THAT
IS TEAM SCIENCE AND EPITOME OF
TEAM SCIENCE THAT I HAVE TO
THANK WONDERFUL PEOPLE AND
FUNDING SOURCES AND PATIENTS AND
FAMILIES AND CIGT ALUMNI THAT
ARE DOING GREAT THINGS IN THE
AUDIENCE. THANK YOU.
>> [APPLAUSE].
>> THANK YOU VERY MUCH FOR
INVITATION TO SPEAK HERE AND
TALKING ABOUT CARDIO PEDIATRIC
AML AND BACKGROUND WILL BE
FAMILIAR YOU TO AND I WILL FOCUS
ON FACT THAT AS YOU ARE FAMILIAR
WITH MULTIPLE SHARES THAT
TARGETS 33 AND 123 ARE BEST
KNOWN AND WE WILL TALK ABOUT A
COUPLE TRIALS THAT ARE USING
THOSE.
THERE ARE -- THERE IS OBVIOUSLY
A NEED FOR NEW THERAPIES IN AML
SPACE AND AS YOU KNOW IT IS
INTENSIVE AND 50% OF PATIENTS
RELAPSE AND OUTCOMES FOR
PATIENTS FOR RELAPSE ARE POOR.
AML SPACE WE ARE INSPIRED WITH
WORK IN ALL SPACE AND.
THAT MEANS A DURABLE RESPONSE
AML CAUSES BONE MARROW APLASIA
THAT IS LIFE THREATENING NOT AN
OPTION TO STEP INTO AND NEED
TRANSPLANT TO RESCUE PATIENTS
AFTERWARDS CONSOLIDATING AND
TRIALS AND CAR SPACE AND THIS IS
PLAYING AN IMPORTANT ROLE
VIS-À-VIS RESPONSES WE ARE
SEEING THAT WE ARE NOT SEEING IN
A WAY THAT WOULD BE COMPARABLE
TO THE AML OR ALL SPACE. AS I
PREPARED FOR THIS TALK I WENT ON
CLINICAL TRIALS.GOV AND FOUND 18
TRIALS ENROLLED IN CHILDREN AND
LIST OF TARGETS THERE AND 5
TRIALS ARE FOR CHILDREN IN US.
I WILL FOCUS ON SUMMARIZING
TRIALS AND PIS OF TRIALS AND GOT
INFORMATION FOR THEM ABOUT
TRIALS THAT I WILL PRESENT FROM
THIS POINT FORWARD.
GENERALLY SIMILAR AND TRIALS
THAT ARE OPEN ONLY TO OLDER
CHILDREN THAT ARE REALLY RELATED
TO FDA APPROVAL ISSUES THAT WERE
NOTED BEFORE.
FIRST TRIAL IS CDC33 MULTI-SITE
TRIAL AND CD28 CONSTRUCT THAT
ENROLLS UP TO 34 PATIENT AND
INCLUDES CHLA, DENVER SEATTLE
AND DANA FASHER AND STANDARD 3.3
DESIGN AND KRUNT DOSE LEVEL --
AS SINGLE INFUSION AND 22
PATIENTS ENROLLED WITH 19
PATIENTS INFUSE THE AND 1 OUT OF
5 VALUABLE PATIENTS DOES ELT AND
6TH PATIENT IS IN MIDDLE OF
THERAPY AND 2 OUT OF 4 PATIENTS
AVAILABLE AT DOSE LEVEL WITH
MOLECULAR CR AND ENROLLED IS
NEGATIVE MRD ENROLLMENT NOT
AVAILABLE FOR RESPONSE AND
CONFIDENCE INTERVAL OF THIS AND
DOES NOT INCLUDE ZERO THAT FOR
US IS IMPORTANT TAKE-HOME
MESSAGE AND TAKING OFF WHAT
RAINSAID. WE ARE HOPEFUL THAT
FDA WILL ALLOW US TO AMEND THIS
AND WILL BE INTERESTING TO SEE
HOW IT PLAYS OUT.
I BELIEVE WE TREAT THE THREE
PATIENTS AND NOW ARE OPEN FOR
PEDIATRIC ENROLLMENT THIS IS
INITIALLY PRESENTED BY TODAY
LAST YEAR AND 123 TRIAL AND CD28
CONSTRUCT AND CD20 SAFETY SW
SWITCH.
NO DLTS TO DATE AND ONE CR DOSE
LEVEL TO 2 AND PATIENT INFUSED
STUDY AND VERY IMPORTANT STUDIES
THAT HAVE COME OUT OF THIS.
THEY ARE A GROUP THAT AT ST.
JUDE'S HAS BEEN GENEROUS SHARING
WITH US IN CD3 TRIAL AND
INDICATING THAT CELLS ARE
PREDOMINANTLY REFACTORY CELLS
AND PICTURE IS WORTH 1,000 WORDS
AND THIS IS PREAND POST IMAGING
STUDY FOR A PATIENT THAT
EXPERIENCED A COMPLETE RESPONSE
TO THEIR CAR WHICH IS A VERY
EXCITING CLINICAL RESPONSE.
THERE IS CD123 TRIAL AT CHOC AND
BASED ON THIS CONSTRUCT THAT IS
DEVELOPED AT UNIVERSITY OF
PENNSYLVANIA AND 12 PATIENT
ADULT TRIAL THAT IS COMPLETED
AND IN PROCESS OF BEING WRITTEN
FOR PUBLICATION AND ARE PATIENTS
ON TRIAL THAT HAVE COMPLETE
MOLECULAR RESPONSES THAT LED TO
12 PATIENT TRIAL BEING OPEN AT
CHOC.
THIS IS A SINGLE DOSE LEVEL AT
2 x 10 TO THE 6 THAT IS MANDATED
BY FDA TOXICITY IS SEEN ON ADULT
TRIAL AND 6 VALUABLE PATIENTS
WITH NO DLTS AND ONE PATIENT HAD
A TRANSIENT DECREASE AND
PERFORMED BLAST AND TRANSFUSION
INDEPENDENCE AND NO MOLECULAR
RESPONSES AND ONGOING AMENDMENTS
TO INCREASE CELL DOSE ON THIS
TRIAL AND IS DERIVATIVE FROM 33
EXPERIENCE WHERE WE HAD TO GET
TO 1 x IT ENTO THE 7TH BEFORE WE
SEE CLINICAL EFFICACY AND BELOW
THAT DOSE LEVEL HERE IS THE NEXT
STEP FOR THIS TRIAL.
TEXAS CHILDREN'S HAS CLL TRIAL
AND TREATING UP TO 18 PATIENTS
WITH PEDIATRIC PATIENTS AT TEXAS
CHILDREN'S AND GREATER THAN 18
YEARS OF AGE AND PATIENTS
EVALUATED AT DOSE LEVEL OF 1.
4 OF THE 6 ARE AVAILABLE AND
SPECIFIC RESPONSE AVAILABLE
RESPONSE INFORMATION IS NOT
AVAILABLE AND WITH THAT THANK
YOU FOR ALLOWING ME TO PRESENT
THIS DATA OF PRIMARILY OTHER
PEOPLE'S WORK.
>> NEXT IS ROBBY WHO WILL TALK
TO US ABOUT CNS TUMORS.
>> HI, EVERYONE. NICE TO SEE
YOU AT THE MEETING. THANK YOU
TO NIRALI FOR ORGANIZING
FANTASTIC MEETING OF CAR T BRAIN
TRUST FROM BOTH SIDES OF THE
ATLANTIC. GREAT TO SEE. THESE
ARE MY DISCLOSURES PRACH IT IS
FUNNY I'M DOING THIS. I KNOW
NOTHING EXCEPT THAT BRAIN TUMORS
SUCK. INCURABLE INVERSE ALLEY
FATAL AND OTHER DISEASES APPENDO
MOEMA AND MEDIO BLASTOMA THEY
ARE TREATABLE UNTIL THEY ARE
RELAPSED AND THEY ARE
UNIVERSALLY FATAL AND WORK TO DO
IN THIS SPACE AND TALKING ABOUT
THIS SLIDE FOR A SECOND. I WANT
TO POINT OUT FIRST CAR T-CELL
EVER IN A CHILD WAS CARRIED OUT
BY MALCOLM BRENNER'S GROUP AND.
I THINK IT TAKES SOMETHING TO
BE BOLD ENOUGH TO DO SOMETHING
LIKE THIS -- HAD TWLEE OUT OF
11CRS AND FIRST GENERATION CAR
THAT HAS LED TO MULTIPLE NEW
ITERATIONS AND WAS A REALLY BIG
DEAL AND SHOWS WHAT ACADEMICS
CAN DO WHEN THEY ARE BOLD AND
TRY TO DEVELOP DRUGS
SPECIFICALLY FOR CHILDREN. THIS
IS A TARGET ALMOST IRRELEVANT IN
ADULT STUDIES.
CAR T-CELLS MAKE SENSE FOR BRAIN
TUMORS.
THEY ARE ABLE TO GET THROUGH
BLOOD BRAIN BARRIER. WE KNOW
THIS FROM EXPERIENCE WITH CD19
ON CAR AND ON LEFT YOU HAVE DATA
TREATING PATIENTS WITH PRIMARY
CS AND IN PEDIATRIC SPACE WE SEE
CAR T-CELLS TRAVEL FROM THIS
GROUP ALL THE TIME AND BLAST
COUNTDOWN AND BLACK LINES YOU
GET T-CELLS AND CNS BLASTS GO
AWAY QUICKLY AND MAKES SENSE TO
GIVE AWAY CAR T-CELLS THAT
TRAVEL ACROSS CNS.
I WILL JUST SHOW -- YEAH. ALL
RIGHT. OKAY. SO, THIS IS
PRECLINICAL DATA THAT WE
DEVELOPED OF GD2 CAR IN
PRECLINICAL MODELS AND
DISCOVERED THAT GD2 PEDIATRIC
TARGET FROM NEUROBLASTOMA
EXPRESSED ON BRAIN TUMOR THAT IS
DRIVEN BY EPIGENETIC MUTATION
AND IT WAS GREAT IN PRECLINICAL
MODELS AND SOME DIED EARLY ON IN
THE PRECLINICAL STUDIES.
WHAT YOU CAN SEE THERE IS IT
HAPPENS DURING DAY 7 TO 10
DURING PERIODS OF PEAK
INFLAMMATION AND WE FOUND IN
NERVE CELLS INCLUDING IN BRAIN
WASN'T DUE TO DESTRUCTION OF
NEURONS YOU FOUND ON MICE
HYDROCEPHALUS AND THEY WERE
DYING BECAUSE OF LOCATION OF THE
TUMORS AND BASED ON PRECLINICAL
STUDIES WE DESIGNED A CLINICAL
TRIAL I WON'T GET INTO MUCH OF
IT HERE.
WE TRIED TO USE WHATEVER WE CAN
GET FROM MOUSE TO GUIDE OUR
DEVELOPMENT AND MOST IMPORTANT
DECISION MADE WAS ALL PATIENTS
WOULD HAVE OING MIA PLACED TO
ACCESS CNS AND RELIEVE PRESSURE
BY REDUCING CSF AND BY REMOVING
CSF AND LOWER PRESSURE.
PUBLISHED AND PRESENTED TO READ
THE PAPER AND RESULTS FROM FIRST
TWO DOSE LEVELS WHERE WE TREATED
ABOUT 12 PATIENTS WITH 1 MILLION
SELLS PER KILOOR 3 MILLION CELLS
PER KILOAND WILL TURN YOUR
ATTENTION TO A COUPLE THINGS
THIS IS CRITERIA NOT PERFECT FOR
ASSESSING BRAIN TUMOR RESPONSES
AND WE HAD A PATIENT ON THE
RIGHT THERE AND SOME HAD PARTIAL
RESPONSES AND HIGHLIGHTING THESE
HERE THIS MALE RECEIVED FIRST IV
DOSE AND HAD PARTIAL RESPONSE TO
THAT DOSE AND WE HAVE FOLLOWED
IT UP WITH MULTIPLE ICV INFU
INFUSION.
I DON'T HAVE TIME TO GET TO IT
NOW STUDYING DIFFERENCE BETWEEN
IV AND ICV ADMINISTRATION AND
PATIENT HAD HUGE REDUCTION OF
TUMOR AND LEFT WITH BIOPSY TRACK
THERE AND LEFT WITH LOTS OF
CLINICAL IMPROVEMENTS ALSO AND
ACROSS PATIENTS THAT WERE
TREATED AND PATIENT WITH FIRST
YOUNG CHILD WITH DPD THAT WE
TREATED ON THIS TRIAL AND SHOW
HERE SHE HAD A VOLUMETRIC
INCREASE IN HER TUMOR AND PARTS
OF TUMOR RESPONDED.
YOU SEE HERE SHE HAS MID BRAIN
INVOLVEMENT AND SHE KEEPS HAND
IN SPAS TICK FLEXION AND CAN'T
REALLY USE IT AND WITHIN A MONTH
OF TREATMENT YOU CAN SEE THAT IN
THE CORNER OF THE MICKEY MOUSE
HERE YOU HAVE CLEARANCE OF TUMOR
AND SHE OPENS HER HAND AND
SPONTANEOUSLY USES IT IN PLAY
AND CLINICAL IMPROVEMENTS THERE
ARE LOTS OF AT SAME TIME AND
VIDEO TELLS IT THE BEST AND WHEN
SHE CAME INTO CLINIC FOR
ENROLLMENT SHE HAD TO WALK WITH
PARENTAL ASSISTANCE AND THIS IS
HER AFTER 2 MONTHS OF INFUSION.
THIS LASTED A COUPLE MONTHS
UNTIL SHE EVENTUALLY PROGRESSED
AND TRIED TO TREAT HER WITH ICV
AND HAS BEEN UNSUCCESSFUL AND
OKAY WITH PATIENTS ON TRIAL AND
TRANSIENT BENEFIT LASTING
SEVERAL MONTHS AND TELLS YOU WE
ARE STARTING AND UNBELIEVABLE IT
WORKS AS WELL AND MEDIATING
RESPONSE AND WE ARE CLEARLY NOT
THERE AND NOT CURING OR COMING
CLOSE TO CURING ANY PATIENTS AND
WE ARE NOT ONLY ONES IN THE
CLINIC DOING CAR T-CELLS AND
THERE IS AT LEAST THREE OTHER
GROUPS ACTIVELY EXPLORING THIS
IN PEDIATRIC DISEASES AND ARE
GROUPS AND SLIDES FROM MINA HEG
DAY AND GROUP FROM BAYLOR AND
THIS IS STEVE GOD CHALK
PUBLISHING AND YOU SEE RESPONSE
HERE IN PATIENTS THAT WERE
STABLE PROGRESSIVE DISEASE ON
TRIAL AND NEXT GENERATION
VERSION OF TRIAL GOING FORWARD
IN MULTITENOR TRIAL BRINGING
THIS TO PATIENTS WITH PEN DAH
MOEMA THAT IS BEST PLACE TO GO
THIS THROUGH PBTC IS OPENED NOW
AT MULTIPLE CENTERS.
THIS IS WORK FROM CITY OF HOPE
TWO CAR T-CELLS WITH RESULTS OF
REPORTING IN NEW ENGLAND JOURNAL
5 OR 6 YEARS AGO INCLUDING A
COMPLETE RESPONSE WITH ADULTS
WITH [INDISCERNIBLE] AND TAKING
OPPORTUNITY TO ASK AN IMPORTANT
QUESTION AND THEY ARE ADDING
LYMPHO DEPLETION AND HAVE DONE
PATIENTS WITHOUT LYMPHO
DEPLETION AND WE ARE NOW IN
COHORT WITH LYMPHO DEPLETION AND
RESULTS OF FIRST THREE PATIENTS
YOU HAVE IN BLUE A PEN DAH MOEMA
PATIENT. THIS IS A
[INDISCERNIBLE] PATIENT AND THIS
IS A DAH MOEMA PATIENT AND
LOOKING FORWARD TO SEEING DATA
SOON WITH LD. THIS IS
INCREDIBLE PORTFOLIO OF TRIALS
FROM SEATTLE CHILDREN'S. THESE
SLIDES AND UP IN BLUE YOU CAN
SEE THERE ARE MANY TRIALS THEY
ARE DOING IN BRAIN TUMORS AND
PUSHING THE ENVELOPE FOR KIDS
HERE. I WILL SHOW DATA FROM
PUBLISHED DATA AND FIRST THEY
PUBLISHED HER 2 CAR THREE
PATIENTS IN NATURE MEDICINE AND
SEE THEY ARE SHOWING DURING
INFUSION YOU SEE EVIDENCE OF
LOCAL INFLAMMATION AND CELLS ARE
TRAVELING THERE AND DOING
SOMETHING. PATIENT EVENTUALLY
PROGRESSED AND IN RECENT
PUBLICATION OF P7H3 CAR WHERE
THEY GIVE LOCAL ADMINISTRATION I
WILL SEE ABOUT 20% SHRINKAGE OF
SIZE OF TUMOR OF IT THIS PATIENT
AND THEY ARE MOVING ON FROM
TRIALS AND NOW STARTING
MULTIANTIGEN TARGETING APPROACH
AND PROVEN HER 2 -- ALSO ADDING
TO THAT IL-7 TAENRECEPTOR TOO.
AN TIJENS WILL BE IMPORTANT IN
HETEROGENOUS DISEASES HOW AM I
DOING ON TIME?
OKAY. LY SAY A COUPLE WORDS
ABOUT THIS NEW ACCESS OF
TOXICITY.
ONE THING WE FOUND WE TREATED
PATIENTS WITH BRAIN STEM TUMORS
GETTING INFLAMMATION IN BRAIN
TUMOR AND TAUGHT US IT IS THE
BRAIN AND IT ACTUALLY DOES STUFF
AND YOU SEE SYMPTOMS BASED ON
WHERE THE TUMOR IS IN THE BRAIN
AND YOU SOMETIMES SEE WORSENING
OF BASELINE DEFICITS PATIENT HAS
AND CRANIOPATHY GETS WORSE AND
SELF-RESOLVES NOT SOMETHING TO
DO SOMETHING ABOUT AND THIS CAN
PRESENT AS LIFE THREATENING
HYDROCEPHALOUS AND DOES CLINICAL
WORK ON GROUND TAKING CARE OF
PATIENTS THAT DEVELOPED GRADING
SCALE FOR TN THAT WILL BE
PUBLISHED SOON IN NATURE
MEDICINE DOING COLLABORATIVE
EFFORT WITH GROUPS FROM AROUND
THE WORLD TREATING PATIENTS WITH
TNS MODELS.
CONCLUDING CAR T-CELLS REALLY
THERE IS A STRONG OPPORTUNITY
FOR THEM TO SHOW EFFICACY IN
PEDIATRIC BRAIN TUMORS WHERE
NOTHING ELSE WORKED AND MOST
THINGS DON'T GET TO CNS. TNS
EMERGED ACCESS TO TUMOR LOCATION
AND MULTIPLE CLINICAL TRIALS
HAPPENING AT MULTIPLE CENTERS
POINTING OUT THIS MORNING THAT
THERE IS A NICE JOB SHOWING HUGE
LANDSCAPE OF CAR T-CELLS GOING
ON IN BIOTECH LOCATED IN
BACKYARD IN PALO ALTO AND
PUSHING COMPANIES TO DO
PEDIATRIC TRIALS AND AGREE WITH
THEM ADDING MOST COMPANIES WON'T
DO PEDIATRIC TRIALS WHATEVER YOU
TELL THEM. THEY ARE VENTURE
BACKED AND DOESN'T MAKE SENSE
FOR THEM TO DO IT.
THERE IS 3 IMMUNOTHERAPIES
APPROVED AND CHIMERA DID
[INDISCERNIBLE] AND EVERY SINGLE
ONE OF THOSE I WANT TO REMIND
EVERYONE WERE DERISKED IN
ACADEMIA AND INITIAL TRIALS WERE
RUN IN ACADEMIA SHOWING ACTIVITY
IN IT AT THAT POINT SHOWING
BIOTECH AND LARGER PHARMA CAME
IN AND SHOWED DRUGS AND
RESPONSIBILITY ON US IS ACADEMIC
PEDIATRIC ONCOLOGIES RUNNING
PHASE 1 TRIALS IN ACADEMIA
PROVING BENEFIT THERE AND
DRIVING INVESTMENT.
AND HOPEFULLY WE WILL HAVE MORE
EFFICACIOUS CARS AND LEARN FROM
CLINICAL TRIALS AND CONTINUE TO
DEVELOP THEM AND I LOST
ACKNOWLEDGEMENT SLIDE AND
ACKNOWLEDGING AMAZING GROUP AT
STANFORD DRIVING CLINICAL WORK
AND OF COURSE OUR PATIENTS ARE
FAMILIES AND OTHER GROUPS
CONTRIBUTING THOSE SLIDES AND
ARE DOING EXCELLENT CLINICAL
WORK ALSO.
>> LAST SPEAKER FOR SESSION DR.
ROSA WIN WILL TALK TO US ABOUT
SOLID TUMORS.
>> GOOD AFTERNOON, EVERYONE.
I'M ROSA. THANK YOU FOR GIVING
ME THE OPPORTUNITY TO CONTRIBUTE
TO THIS SESSION. I'M PART OF
POB TEAM AND RUN A LAB HERE AND
TRANSLATE FINDINGS FROM LAB TO
CLINIC. WASN'T TASKED TO TALK
ABOUT EXPANDING USE OF CAR
T-CELLS AND SOLID TUMORS THAT
FOR 8 MINUTES IS A LOT AND HOPE
YOU CAN USE PROMPTERS FOR TALK
IN FURTHER DISCUSSION. WHEN I
PUT THIS TOGETHER I REVIEWED
CURRENT TRIALS THAT HAVE BEEN
COMPLETED AND LISTED THEM ALL
HERE. WHAT BECOMES VERY CLEAR
IS THAT MOST OF THE SOLID TUMOR
TRIALS THAT HAVE BEEN COMPLETED
HAVE BEEN DONE IN PATIENTS WITH
NEUROMRAFTOMA AND HANDFUL OF
DIFFERENT SAR COMBAS AT BOTTOM
AND MAIN TARGET PEOPLE HAVE
LOOKED AT IS GD2. YOU HAVE
DIFFERENT ITERATIONS OF CARS
RANGING FROM MUIRIN TO HUMANIZED
CRVS TO DIFFERENT GENERATIONS
AND PLATFORMS AND WANT TO POINT
OUT HERE THAT IF YOU LOOK AT
RESPONSES AND NUMBERS THEY WILL
FIRST OF ALL ALTER OR BE
DIFFERENT COMPARED TO ABSTRACTS
WHEN YOU PULL PAPERS AND LOTS OF
PATIENTS ARE INCLUDED IN TRIALS
THAT HAVE NO DISEASE OR
MEASURABLE DISEASE AT TIME
INFUSION THAT IS A LITTLE BIT
DIFFICULT TO SEE WHAT EFFECT OF
CAR T-CELLS WOULD BE AND
NARROWED IT DOWN TO JUST
MEASURABLE DISEASE THAT YOU CAN
SEE THAT IN FACT WE REALLY ONLY
HAD 2CRS THAT IS VERY
CONTRASTING AND DIVERGIENT IF WE
THINK ABOUT ALL OF THE SUCCESSES
IN B CELL HEEM ATOLOGIC
MALIGNANCY WORLD AND POINTING
OUT ALSO TWO CRS ARE MAINLY IN
TWO PATIENTS WITH VERY LIMITED
DISEASE BURDEN ONLY TO BONY
LESIONS.
LOOKING AT TRIALS THAT ARE
CURRENTLY OPEN, IN THE US AND IN
EUROPE. I LEFT OUT ASIA. JUST
THESE TWO REGIONS YOU SEE A
MULTITUDE OF DIFFERENT TRIALS
AND AGAIN A LARGE REPRESENTATION
OF GD2 AND DON'T KNOW IF SOME OF
YOU HAVE ATTENDED THE EUROPEAN
HEMATOLOGY ASSOCIATION MEETING
LAST MONTH WHERE ITALIAN GROUP
PRESENTED FINDINGS AND I THINK
THAT THE PAPER IS ACCEPTED IN
NEW ENGLAND JOURNAL OF MEDICINE
AND REPORTED TWO-YEAR EVENT
SURVIVAL OF 44% AND AMAZING
CAN'T WAIT TO READ PAPER SEEING
WHAT DIFFERENCES ARE IN THIS
TRIAL COMPARED TO WHAT WE KNOW
ABOUT G2 AND WHAT HAS BEEN
REPORTED.
WE WILL USE THE REST OF THE TIME
ACTUALLY TO TALK ABOUT UNIQUE
CHALLENGES OF CAR T-CELLS AND
SOLID TUMORS AND WHY WE HAVEN'T
BEEN SUCCESSFUL COMPARED TO
COLLEAGUES IN LUKE WORLD AND
LISTED FOUR IMPORTANT ONES HERE.
WE HAVE TUMOR HETEROGENEITY THAT
I ARGUE WE DEAL WITH IN LUKEMIA
AND IN THIS CONTEXT IS REALLY
SPATIALLY CONFINED WHEN T-CELLS
COMELE INTO THE PATIENT BODY AND
HOME TO TUMOR SITE THEY ARE
OUTNUMBERED BY TUMOR CELLS AND
IF THEY GET INTO THE TUMOR
MICROENVIRONMENT THEY ARE
NUTRIENT DEPRIVED AND CYTOKINE
DEPRIVED AND ENCOUNTER IMMUNE
CHECK POINTS AND DIFFICULT FOR
THEM TO SURVIVE AND FUNCTION AND
BIG QUESTION IS HOW TO OVERCOME
CHALLENGES OF CURRENT CAR T-CELL
THERAPIES AGAINST SOLID TUMORS
AND MOST WORK HAS BEEN DONE OR
IS ONGOING IN PRECLINICAL REALM
THAT HASN'T BEEN TRANSLATED YET.
I WILL JUST PUT UP A COUPLE OF
EXAMPLES TO STIMULATE THE
DISCUSSION AND ONE OF THE
STRATEGIES IS LOOKING AT THE
SCARCITY OF OR LACK OF TUMOR
SPECIFIC ANTIGENS THAT IS
ACTUALLY THIS STORY HERE THAT IS
GPC2 AND THIS IS A GLOPOKIN AND
THREE UPCOMING TRIALS AT
STANFORD AND NCI AND GPTC2 IS A
HEAVY ONCO FETAL PROTEIN
DOWNREGULATED AND MATURE TISSUES
YOU WILL FIND IN TESTES AND SOME
SKIN CELLS AND IT IS SPECIAL IN
THAT IT IS FAIRLY -- IT IS TUMOR
ASSOCIATED BUT REALLY MOSTLY
ABSENT IN NORMAL TISSUE. IN OUR
NC ISTORY HERE, OUR SCF TARGETS
PREDOMINANTLY AXON 3 AND 10
OCCURRING IN ISOFORM THAT YOU
SEE IN TUMORS THAT IS NOT
EXPRESSED AND NORMAL TISSUES AND
THEREFORE ARE MORE TUMOR
SPECIFIC AND HAVE BEEN EFFORTS
THAT LOOK AT NEW TUMOR ANTIGENS
AND ONE STORY HERE IS REALLY
PARADIGM SHIFTING PUBLISHED IN
NATURE LAST YEAR BY CHOC GROUP
WHERE THEY DEVELOPED A PEP TICK
CENTRIC CAR THAT, AGAIN IS 2B
PEPTIDE PRESENTED THROUGH HLA
AND IS A TRANSCRIPTION FACTOR
AND NEUROBLASTOMA THAT IS
OPENING A WHOLE NEW, YOU KNOW,
AREA FOR DEVELOPMENT BUT KNOWING
A LITTLE BIT ABOUT THE HISTORY
OF THE DEVELOPMENT AND IT WAS
DIFFICULT TO FIND THE KIND THAT
TOOK ALMOST A DECADE AND
CERTAINLY IS PARADIGM SHIFTING.
ANOTHER WAY THAT PEOPLE HAVE
ADDRESSED THIS ALSO IS, YOU
KNOW, TO COME UP WITH NEW
[INDISCERNIBLE] NOT TALKING
ABOUT MANIPULATING DIFFERENT
COMPONENTS OF CARS AND COMING UP
WITH GAINING STRATEGIES AND ONE
CAME OUT FROM THE LAB AT UCSF
THAT IS A RECEPTOR WHERE
BASICALLY THROUGH THAT SYNAPSE
RECEPTOR CELL SENDS FIRST
ANTIGEN AND INDUCES EXPRESSION
OF THE CAR AND WITH THAT CONCEPT
T-CELL SHOULD SPARE SINGLE
ANTIGEN AND KILL DUAL ANTIGEN
CELLS AND THEREFORE HAVE LESS
TOXICITY THAT HAS BEEN TRIED TO
-- THIS HAS BEEN INCORPORATED IN
SEVERAL DIFFERENT CONCEPTS FOR
EXAMPLE G2BH27 [INDISCERNIBLE]
FROM CHLA IF NOT MISTAKEN AND
[INDISCERNIBLE] CARS BUT HAVE
BEEN UNSUCCESSFUL IN UPSCALING
FOR CLINICAL USE OR USING IT IN
HUMAN CELLS.
AND WHEN WE TALK ABOUT
STRATEGIES TO OVERCOME IMMUNE
SUPPRESSIVE TME THERE ARE A
VARIETY OF APPROACHES THAT
PEOPLE HAVE UNDERTAKEN. I WOULD
SAY THAT ONE OF THE STRATEGIES
HAVE BEEN TO USE CYTOKINES TO
ARMOR CELLS WHETHER IT IS AS
TRUCKS WHERE CAR T-CELLS WILL
THEN COME TO THE TME AND SECRETE
CYTOKINES MODULATING TMC AND
ARMORED HAVING CYTOKINES
TETHERED TO THEIR SURFACE AND
STIMULATING EACH OTHER IN
AUTOKINE AND PAIRO CYANMANNER
AND MOST COMMON CYTOKINES USED
FOR THIS PURPOSE ARE FROM FA M
MLY OF CYTOKINES WE KNOW THEY
HAVE POSITIVE EFFECTS ON T-CELL
BIOLOGY AND K CELL BIOLOGY AND
SO ON AND SO FORTH AND IN THIS
CONTEXT IT IS IMPORTANT TO -- TO
CONSIDER AND TO THINK ABOUT THE
TOXICITIES THAT COULD BE
ASSOCIATED WITH THAT. SO, I
THINK THAT THE PUSH IN THE FIELD
NOW IS TO ALSO MOVE TOWARDS
CONDITIONALLY EXPRESSED CYTOKINE
SYSTEMS AND WE HEARD FROM
CLAUDIA ABOUT NFAT18 PRODUCT
THAT WILL OPEN IN GERMANY AND
ANOTHER WAY TO DO THAT IS USING
THAT APPROACH THAT I TALK ABOUT
BEFORE WITH IL2 THAT HAS BEEN
DONE AT UCSF AND IN PRECLINICAL
MODELS AND I THINK THAT REALLY
CAR T-CELLS HAVE LIMITED
ANTITUMOR ACTIVITY LOOKING AT
PREVIOUS TRIALS THAT HAVE BEEN
RECORDED AND IS IMPORTANT THAT
WE COME UP WITH NEW APPROACHES
TO OVERCOME UNIQUE CHALLENGES I
MENTIONED THAT NOT ONLY
INCORPORATE CREATIVE CAR DESIGN
NOT TALKING ABOUT ITERATIONS OF
CAR COMPONENTS AND GAINING NEW
STRATEGIES AND THEN ALSO LOOKING
AT FINE TUNING CAR FUNCTION AND
CHALLENGE RING PRECLINICAL
MODELS USING ORTHOGONAL
APPROACHES SUCH AS TRANSGENIC
CYTOKINES AND I HAVEN'T TOUCHED
UPON WHETHER OUR CURRENT
CONDITIONING REJIMMEN HAS TO BE
OPTIMIZED USING WHAT LUKEMIA
COLLEAGUES USED IN TRIALS AND
TRANSPLANTED IT INTO SOLID
TUMORS AND THERE IS CERTAINLY
ROOM WITH NEWER APPROACHES LIKE
TARGETED RADIO THERAPY FOR
EXAMPLE TO TARGET NOT ONLY
LYMPHOOCYTES IN THE SPACE BUT
[INDISCERNIBLE] ITSELF AND
LASTLY THIS CONCEPT CAME UP
ALREADY AND NOT JUST CELLULAR
WITH CELLULAR BUT SYNTHETIC
APPROACHES SUCH AS
IMMUNOCYTOKINE AND NEXT
GENERATION CYTOKINES THAT ARE
MODULATED JUST TO YOU KNOW
STIMULATE CERTAIN CELL
POPULATIONS OF LYMPHOOCYTES.
WITH THAT I END. THANK YOU.
>> [INDISCERNIBLE].
>> YEAH. I THINK THIS IS AN
IMPORTANT POINT. MOST
PRECLINICAL CAR T STUDIES ARE
DONE IN HUMANIZED MODELS WHERE
WE HAVE ONLY T-CELLS AND PDXS
AND PUSH AND REASON FOR GOING
THERE IS BECAUSE WE USE A TUMOR
THAT IS CLOSE TO THE CLINIC. IF
YOU REALLY WANT TO MODEL THIS
AND STUDY IT YOU NEED RELIABLE
MODELS WHERE YOU HAVE ENTIRE
IMMUNE SYSTEM OR HUMANIZED
MODELS THAT ARE VERY CHALLENGING
AND BRINGING UP MR. G MICE
DEVELOPED AT YALE WHERE YOU
BREED THEM AND INJECT WHEN THEY
ARE LITTLE INTO THE LIVER AND
THEY GROW UP AND STILL NO
T-CELLS YOU DON'T IMPLANT A
THYMUS. THEY DON'T SURVIVE THAT
LONG BECAUSE OF ANEMIA. YOU
KNOW?
SO, I THINK THAT HUMANIZED MOUSE
WORLD STILL HAS WAYS TO GO TO
COME UP WITH LONG-LASTING
HUMANIZED MODELS AND BEST WE CAN
DO NOW IS [INDISCERNIBLE] AND I
THINK THAT TRANSPLANTABLE MODELS
IS WAY TO GO WHERE YOU CAN DO IT
ORTHOTOPICALLY FOR SOLID TUMORS
AND ENROLL THEM NOT ON ROLLING
BASIS. THAT IS LOGISTICALLY
VERY CHALLENGE RING AND TIME IT
AND TRY THAT.
>> I THINK ALL MODELS ARE
HORRIBLE AND WE HAVE TO DO
CLINICAL TRIALS AND THINK WE ARE
GOING TO DO AND WE TRY TO DO
STRONG CORRELATIVES IN TRIALS TO
SEE WHAT WE CAN LEARN AND TEST
HYPOTHESES. YOU CAN'T TEST
EVERYTHING IN A HUMAN OBVIOUSLY
AND AT A KEYSTONE RECENTLY AND
CRYSTAL GAVE KEYNOTE AND
MYELODEPLETION -- DALIA FROM FDC
CHILDREN'S GAVE A TALK IN MODEL
WHERE OPPOSITE IS TRUE AND LOSE
EFFECT OF CAR T-CELLS.
THERE IS ONLY ONE WAY
UNFORTUNATELY TO FIND OUT AND SO
I DON'T KNOW HOW TO DEAL WITH
THAT EXACTLY WE SAY AND I WRITE
IN GRANT AND ALTERNATIVE TO DO
IN A MODEL AND I WON'T DO IT AND
DON'T WANT TO SET ONE UP BUT NOT
SURE IF THEY REPRESENT HUMANS.
>> GOOD ANSWER.
>> NOT FOR-NIH.
>> [LAUGHING].
>> I WAS GOING TO ASK A QUESTION
BUT NOW WOULD MUCH RATHER MAKE A
COMMENT.
SO, FIRST I COULDN'T AGREE MORE
AND I WOULD LIKE TO LET YOU ALL
KNOW THAT MAYBE SOME PEOPLE
DON'T KNOW. FIRST STUDY THAT
MALCOLM BRENNER DID WITH A
BLASTOMA WAS DONE WITHOUT
KILLING A SINGLE MOUSE AND WENT
FROM IN VITRO DIRECTED TO
CLINICAL TRIAL AND WISH WE COULD
DO IT AGAIN.
>> WHICH FDA PERSON DID YOU
KIDNAP? WHAT DID YOU DO?
>> I DON'T KNOW. WE WENT FOR IT
AND COMPLETELY AGREED AT THAT
TIME AT HOUSTON AND AT THAT TIME
THERE WAS NO MICE KILLED WE SAID
THEY DON'T REPRESENT THE
SITUATION IN HUMANS AND IS HOW I
WAS RAISED.
>> YEAH.
>> JUST LOVE YOU REMIND US OF
THAT AGAIN.
CAN I ASK MY QUESTION STILL?
WE WANT TO SOLVE THAT
REQUIREMENT PROBABLY.
WHY DO WE GET AWAY WITH
TARGETING GD2 SO EFFECTIVELY?
DO YOU THINK IT IS A THRESHOLD
ISSUE ALONE?
ANYTHING THAT PROTECTS GD2
EXPRESSING BRAIN CELLS ANYTHING
ON TOP OF THRESHOLD?
WHAT DO YOU THINK?
YOU PROBABLY DON'T KNOW ABOUT.
>> YEAH. GREAT QUESTION.
FIRST, IF YOU LOOK ON HUMAN OR
NORMAL BRAIN VERSUS DIPG BY IHC
THERE IS 100 FOLD INCREASE
INTENSITY FOR GD2 STAINING AND
PART HAS TO BE THRESHOLD AND
BELIEVE AT ONE POINT WE MAKE
EFFICIENT ENOUGH GD2 CAR NOT
EXHAUSTED AND POTENT ENOUGH TO
RECOGNIZE LOW LEVELS OF GD2 AND
LOW LEVELS OF TOX TIS I AND NOW
SEEM TO BE IN THERAPEUTIC WINDOW
AND THAT SAID NOT SURE IT IS
TRUE.
YOU KNOW, GD2 ANTIBODY MEDIATED
PAIN IS STILL POORLY UNDERSTOOD
AND WE GET NONE IN A MOUSE
DESPITE FACT THAT GD2 IS
EXPRESSED IN MOUSE AND DON'T GET
IT CELLS AND HAPPENING
CROSS-LINKING OF GD2 ANTIBODY
POTENTIAL ON FIBERS DOESN'T SEEM
TO BE IMMUNE ATTACK ON CELLS
WHEN DRAWING ANTIBODIES,
PATIENTS ARE FINE. I DON'T
KNOW.
>> ARE WE ASKING OUT OF
CURIOSITY? I'M AFRAID OF SEEING
NEUROTOXICITY ONE DAY WHEN WE
GET THEM SUFFICIENTLY EFFECTIVE
TO REALLY CURE THE DISEASE.
>> YEAH.
>> SAME CONCERNS.
>> I THINK IT IS AMAZING.
>> AND IF IT IS BRAVE AND JUST
DO IT AND I WOULDN'T HAVE BEEN.
>> YOU DID IT WITHOUT EVER
TESTING IN A MOUSE.
>> NOT IN CNS COUNTER. YEAH.
>> PERIPHERAL NEUROPATHY.
>> JUMPING IN AT ONE POINT
SARAH RICHMOND'S PAPER SHOWED
CLEARLY WITH MUCH BETTER BINDER
COMPLETE NEUROTOXICITY AND ALL
YOUR MICE ARE DEAD.
>> CONTROVERSIAL FINDING I WOULD
SAY.
>> IT IS CONTROVERSIAL.
>> YOU KNOW, WE HAVE MADE THAT
BINDER AND TRIED.
WE HAVE USED IT IN MANY, MANY
MODELS AND KRYSTAL USES IT AS
MODEL OF EXHAUSTION AND LOTS OF
POE 10CY ENHANCEMENTS AND SITES
ARE SIMILAR AND BRAIN EXPRESSED
HIGHER LEVELS OF COMPLEX GANG
LEEE CITES AND CROSS-REACTIVITY
WITH THOSE AND WOULDN'T CHANGE
WHY WE GET IT OR DON'T SEE IT.
>> THAT IS INTERESTING. SHOWING
THE SAME THING.
SO, I GUESS THERE IS A NICE
LITTLE CONTEXT.
>> DAVID AT MSK SEES IT IT MUST
BE NORTHEAST THING VERSUS
CALIFORNIA I DON'T KNOW.
>> THANKS FOR ROBUST DISCUSSION.
BEING EXITED OFF STAGE AND ONE
MORE ROUND OF APPLAUSE FOR
SPEAKERS, PLEASE.
>> [APPLAUSE].
>> FOR CONCLUDING SESSION
STARTING WITH DR. KRYSTAL MCHLTD
WHO IS A PROFESSOR OF PEDIATRICS
IN MEDICINE AT STAN FORWARD AND
FOUNDING DIRECTOR AT CANCER CELL
INSTITUTE AND DIRECTOR OF PARKER
INSTITUTE AT STANFORD WITH
NUMEROUS ACCOLADES IN
GROUNDBREAKING WORK.
SHE ENDED TERM AS CHIEF OF POB
AND IMMUNOLOGY SECTIONS AND
COMING TO STANFORD I RECOGNIZE
HER TO BE A TRANSLATIONAL AND
REVERSE TRANSLATIONAL MASTERMIND
IN PEDIATRICS ROBBY PRESENTED
GD2 TRIAL AND I WENT ON
MATERNITY LEAVE. BEFORE GOING
ON LEAVE THERE WAS NO BRAIN
TUMOR TRIAL AND AFTER COMING ON
LEAVE THERE WAS A BRAIN TUMOR
TRIAL SHE BUILDS INFRASTRUCTURE
AS A REGULATORY EXPERTS UNMASKS
THERAPY AND CRYSTAL THANK YOU.
>> GOOD GOOD AFTERNOON. SORRY
NOT ABLE TO BE THERE IN PERSON.
IT IS HARD TO PROVIDE CLOSING
REMARKS OR MEETING THAT YOU WERE
NOT YET SEEN AND HOPE THEY ALIGN
IN SOME WAYS WITH ISSUES RAISE
THE EARLIER TODAY AND CAN
PROVIDE SOME FOOD FOR THOUGHT
AND I ENTITLED THIS DELIVERING
ON PROMISE OF CAR T-CELLS FOR
CHILDREN'S CANCERS AND
DISCLOSURES ARE SHOWN THERE.
SO, TO LEVEL SET IN FEBRUARY
2023, I THINK THERE IS EVERY
REASON TO BE OPTIMISTIC ABOUT
THE PROGRESS MADE AND USE OF CAR
T-CELLS WITH TREATMENT OF CANCER
AND TO BELIEVE THAT THIS IS
STILL THE TIP OF THE ICEBERG.
WE HAVE 12 APPROVALS FOR 6
PRODUCTS AND THREE TARGETS
SPANNING 5 COMPANIES.
ONE, YAY, IS FOR PEDIATRIC
INDICATION. I THINK THAT EVEN
THOSE OF US WHO ARE ALREADY
BELIEVERS IN 2010 WHEN FIRST
PATIENT WAS TREATED FOR LYMPHOMA
AT NIH AND KNEW IT WOULD BE
SOMETHING REALLY EXCITING, CAR
T-CELLS ABOUT FORM OR OUTSTRIP
EXPECTATIONS OF EVEN MANY OF
THOSE OF US WHO ARE ALREADY
BELIEVERS.
IF WE WANT TO LOOK BACK AT HOW
WE GOT HERE, IT IS IMPORTANT TO
UNDERSTAND THAT WHILE IT LOOKS
LIKE SOME OF THE STUFF HAPPENED
OVERNIGHT, IT DIDN'T.
ESSENTIALLY, ANY NEW THERAPY
THAT HAS VALUE IN THE CLINIC, IF
YOU GO BACK AND LOOK, IT MOST
LIKELY HAS EARLY DEVELOPMENTAL
ROOTS 2 OR 3 DECADES BEFORE
CLINICAL SIGNAL IS SEEN AND CAR
T-CELLS ARE NO EXCEPTION THERE
AND RECENT REVIEW COMING OUT
THIS WEEK IN NATURE, WE TRIED TO
SUMMARIZE AT A VERY HIGH LEVEL
HOW WE GOT TO WHERE WE ARE
TODAY.
IT REALLY STARTED IN 1989 WITH
AMAZING CREATIVE IDEA FROM
[INDISCERNIBLE] THAT YOU COULD
GET OUT FROM UNDER THE IMAGE
RESTRICTION OF A T-CELL WITH
SO-CALLED T BODY OR RECEPTOR
THAT LINKS UP T-CELL ACTIVATION
MACHINERY WITH BINDER IT THAT IS
NOT MAC RESTRICTED AND REMAINS A
CONCEPT THAT IS NOT QUITE
ACCEPTED FOR A FEW YEARS AND THE
FIRST ITERATION WAS PRETTY CRUDE
AND NOT PRETTY WEAK.
AFTER 5 OR 6 YEARS, YOU KNOW,
CONCEPT WAS APPROVED AND
THERAPEUTIC WAS NOWHERE NEAR
READY FOR CLINICAL TESTING THAT
REQUIRED ANOTHER DECADE OR SO OF
PROTOTYPE ITERATION.
ALONGSIDE JUST GENERAL
UNDERSTANDING OF HOW YOU EXPAND
T-CELLS EX-VIVO.
WHICH COSTIMULATORY DOMAINS ARE
USEFUL AND IDEA THAT YOU HAVE TO
INCLUDE A COSTIMULATORY DOMAIN
AND LEARN TO PREPARE HOST TO
RECEIVE T-CELL THERAPIES.
IT WASN'T REALLY UNTIL AROUND
2010 THAT WE SAW REAL AND TRUE
EVIDENCE OF CLINICAL PROOF OF
CONCEPT.
AND I THINK THAT THE REAL
TIPPING POINT ARGUABLY HAPPENED
IN 2012 WHEN BIOPHARMADECIDED TO
INVEST IN CAR T-CELL THERAPIES
AND UP TO THAT TIME DOGMA HAD
BEEN YOU COULDN'T COMMERCIALIZE
IN THERAPY. IT WOULD BE
IMPOSSIBLE TO DO AND FAST
FORWARD WITH COMMERCIALLY
SUPPORTED APPROVED CELL
THERAPIES AND IT SEEMS TO BE
EVER INCREASING AND IF YOU LOOK
AT PHASES, WE HAD A CONCEPT
PHASE OR PROTO TYPE ITERATION
PHASE AND WE HAD PHASE OF
CLINICAL PROOF OF CONCEPT AND
ARE NOW DEEP INTO THE
COMMERCIALIZATION PHASE.
AND TO PROVIDE MORE BASIS FOR
THAT NOTION. IF YOU LOOK AT THE
AMOUNT OF INVESTMENT HAPPENING
IN THE PRIVATE SECTOR IN THE
FIELD OF CELL AND GENE THERAPY,
IT IS JUST TRULY MIND BOGGLING.
THESE ARE A BIT OUTDATED AND ARE
DRAWN FROM 2021 REPORTS.
THERE HAS BEEN A DOWNTURN IN THE
MARKET SINCE THAT TIME.
NONETHELESS, IF YOU LOOK IN
AUGUST OF 2021, THERE WAS $14
BILLION.
14 BRS DLL INVESTED IN CELL AND
GENE REGENERATIVE THERAPIES AND
5 MILLION INVESTED BY VENTURE
CAPITALISTS INTO SMALL EARLY
STAGE PRIVATE STAGE BIOTECH AND
IS AMOUNT OF MONEY AROUND SAME
TIME AND IF YOU SAY AROUND HOW
MANY COMPANIES ARE THERE? I
DON'T KNOW WHAT ANSWER IS TODAY.
IN 2019 ACCORDING TO THIS MARKET
WATCH THERE IS 100 CELL AND GENE
THERAPY COMPANIES WORLDWIDE.
END OF 2020 IT INCREASED TO OVER
1,000.
THAT IS REMARKABLE GROWTH AND AT
THAT TIME MORE THAN 500 WERE
US-BASED COMPANIES AND IF YOU,
YOU KNOW, YOU LOOK AT YEAR 2022
TODAY WAS TRYING TO GET MORE
UPDATED NUMBERS ON AMOUNT OF
INVESTMENT, CURRENT ESTIMATE IS
THAT THE MARKET IS ABOUT $8.5
BILLION MARKET IN 2022. IT WILL
GROW AT AN ASTONISHING ANNUAL
GROWTH RATE OF 25% PER YEAR AND
ESTIMATED TO BE AROUND 20
BILLION BY 2026. REMARKABLE
GROWTH RATE. IN FACT TAKING
DEEP DIVE INTO THIS YOU CAN BUY
A GLOBAL MARKET REPORT AND 250
PAGE BOOK LOOKING AT PROJECTED
GROWTH IN THE SPACE. THIS BOOK
WILL SET YOU BACK ONLY $5,000.
TO JUST SHOW YOU HOW INTERESTED
THE PRIVATE SECTOR IS IN
UNDERSTANDING HOW THEY CAN GET
INVOLVED IN THIS DRAMATIC GROWTH
FIELD.
IT IS NOT JUST THE COMMERCIAL
SPACE THAT IS BREEDING THE
ENTHUSIASM.
CLEARLY THERE HAS BEEN DRAMATIC
PROGRESS IN ARENA OF SYNTHETIC
BIOLOGY AND CREATING NEWER AND
BETTER MORE EFFECTIVE RECEPTORS
FROM ORIGINAL PROTOTYPES THAT WE
ALL KNOW AND LOVE.
AND THIS IS FROM RECENT REVIEWS
SHOWING JUST, YOU KNOW, HOW MUCH
WE HAVE LEARNED. WE KNOW A LOT
ABOUT SINGLE CHAIN OF FEE PLAYS
AND WHAT ROLE HINGE AND SPACE
AND TRANSMEMBRANE DOMAINS AND
COSTIMULATION AND SIGNALING
THROUGH MODULATING CD3 AND EVERY
PART OF PROTOTYPE RECEPTOR CAN
BE ENGINEERED IN ORDER TO MAKE
THE CELL BEHAVE IN A WAY THAT IS
MORE LIKELY TO BENEFIT YOUR
PATIENT.
AND BEYOND THAT, WE ALSO
UNDERSTAND THAT THIS PROTOTYPE
CAR T-CELL AND, AGAIN, WE ARE
COMFORTABLE WITH TODAY IS LIKELY
TO BE OUTDATED IN NOT TOO
DISTANT FUTURE BETWEEN CREATING
MULTISPECIFICITY CARS AND IF
THEN GATES WHERE YOU HAVE TWO
SIGNAL LOGIC GATE AND TRUE END
GATE AND NEW LINK CAR COMING OUT
OF ROBBY'S LAB AND ALLOWING YOU
TO REQUIRE RECOGNITION OF TWO
IDS ALLOWING CELL TO FIRE AND
ADAPTOR AND REGULATABLE CARS AND
ONE CALLED SNIP CAR CAME OUT OF
LAB AND DRUG REGULATED WITH
PROTEASE SYSTEM ALLOWING TO USE
A SMALL MOLECULE FDA APPROVED
AND TO REGULATE CAR WE HAVE CARS
CREATED TO GO OUT UNDERNEATH
RADAR OF HUMAN SYSTEM
POTENTIALLY ALLOWING CARS TO BE
DELIVER AND PERHAPS PERSIST AND
IS IMMENSE AMOUNT OF
TRANSCRIPTIONAL PROGRAMMING
UNDERWAY AND ENTIRELY NEW WAYS
THINKING ABOUT MAKING SYNTHETIC
IMMUNE RECEPTORS AND MANY LOOK
LIKE ENDOGENOUS TC RECEPTOR AND
HARNESS BENEFITS OF THEM AND
ANTIGEN DENSITY AND LESS
SUSCEPTIBILITY TO EXHAUSTION AND
SIGNAL 3 IS AREA WHERE THERE IS
IMMENSE WORK TRYING TO DELIVER
CYTOKINE SIGNAL THAT IS IN A WAY
BOTH EFFECTIVE AND SAFE AND ONE
COULD ARGUE STOP CALLING
CHIMERIC ANTIJ YEN RECEPTORS
CALLING THEM -- BECAUSE OF THE
GREAT VARIABILITY IN THE
DESIGNS.
BEYOND DIFFERENT PLATFORMS ARE
INCREASING ARRAY OF ENHANCEMENTS
BY WHICH YOU CAN MODIFY BIOLOGY
OF MOSTLY T-CELLS BUT MANY OF
THE ENHANCEMENTS COULD BE USED
FOR IN K CELLS OR MACRO PHAGES
OR DELTA T-CELLS OR OTHER CELLS
YOU MIGHT WANT TO DRIVE.
YOU CAN SEE DIZZYING ARRAY OF
ENHANCEMENTS DEMONSTRATED IN
PRECLINICAL MODELS TO BE ACTIVE
AND SOME IN CLINIC SHOWN IN BOLD
THERE AND GUARANTEE YOU THIS
LIST IS OUT OF DATE AND EVERY
MONTH IS ANOTHER SET OF NEW WAYS
YOU CAN MAKE CELLS MORE POTENT
OR MORE REGULATABLE AND
THEREFORE POTENTIALLY MORE
EFFECTIVE. THIS IS AMAZING
MOMENTUM BY ANYBODY'S ACCOUNT.
GIVEN ALL THAT, WHAT COULD GO
WRONG. WHAT KEEPS SOME OF US UP
AT NIGHT. WELL, I THINK ONE
THING THAT IS A REAL PROBLEM
FACING OUR FIELD IS HOW IN THE
WORLD WILL WE ADDRESS THESE AND
FIGURE OUT WHICH ENHANCEMENTS
ARE RIGHT ONES TO STUDY AND HOW
WILL WE AVOID MISSING PERHAPS
THE BEST ONE AND IN CHASING THE
WRONG ONE AND I THINK THAT THE
FIRST THING CLEAR TO ME IS THAT
EVERY ONE OF THE ENHANCEMENTS
DEMONSTRATE TODAY BE EFFECTIVE
IN A MYRIAD MODEL CAN'T BE
TESTED CLINICALLY DON'T HAVE
ENOUGH PATIENTS OR MONEY OR
ENOUGH MANUFACTURING.
IT IS JUST NOT PRACTICAL TO BE
ABLE TO CONDUCT DIFFERENT
CLINICAL TRIAL TO TEST EVERY ONE
OF THE ENHANCEMENTS.
I THINK WE SHOULD THINK ABOUT
THESE PRECLINICAL STUDIES.
THEY NOT ONLY SHOULD THEY BE USE
TODAY CREATE NEW ENHANCEMENTS
BUT SOMEONE NEED TODZ CONDUCT
RIGOROUS PRECLINICAL STUDIES
NEED TODAY COMPARE ITERATIONS TO
PRIORITIZE.
THAT SOUNDS SIMPLE AND WE KNOW
HOW TO CERTAINLY DO THIS TYPE OF
WORK AND ARGUE THAT INCENTIVES
IN ACADEMIA AND IN INDUSTRY
DON'T REWARD COMPARISON STUDIES.
NOT AN EXTENT YOU DON'T SEE
COMPARATIVE STUDIES OUT THERE.
WHEN YOU DO THEY ARE WEIGHTED
TOWARDS ONE OR THE OTHER
ENHANCEMENTS BECAUSE OF BIAS OF
THE INVESTIGATORS.
I THINK THAT THE ACADEMIC ARENA
IN PARTICULAR IS -- HAS
HYPERFOCUS ON NOVELTY IN
ACADEMIC STUDY SECTIONS AND
GETTING GRANT FUNDED AND
DECIDING WHETHER PAPER IS
PUBLISHED AND EMPHASIS IS ON NEW
AND DIFFERENT AND THEMLE FASIS
MINIMIZES THE IMPORTANCE OF
CAREFUL COMPARATOR STUDIES THAT
WILL ADVANCE THE FIELD OVERALL
AND ALLOW US TO BE BETTER AT
PRIORITIZATION.
NOW, EVEN IF WE PRIORITIZE TO,
YOU KNOW, REALLY A LOT, WE HAVE
TO STILL BE ABLE TO HAVE GREATER
THROUGHPUT IN HUMAN TEXTING.
CAN'T DO THAT. WE DON'T HAVE
ACCESS TO VECTOR AND CLINICAL
NUCLEIC A** ID VIRAL PLATFORM
AND MONEY TO RUN CLINICAL TRIALS
WE OFTEN DON'T HAVE CAPACITY TO
DO MANUFACTURING NEEDED TO TEST
MULTIPLE ITERATIONS AND IF WE
HAD ALL OF THAT, CURRENT
REGULATORY PRACTICES DON'T ALLOW
ADMINISTRATION OF MIXED PRODUCTS
AS AN EXPERIMENTAL QUESTION IN
ORDER TO COMPARE FITNESS IN
HUMANS AND MIXED PRODUCTS ARE
PART OF WHAT WE ARE ALWAYS
ADMINISTERING AND I ARGUE THAT
ADMINISTERING MIXED PRODUCTS TO
WHAT WE CALL A BAKE OFF TO PICK
THE WINNER IS PROBABLY BEST WAY
TO REALLY KNOW WHICH CELLS ARE
MORE EFFECTIVE IN HUMANS.
SO, I THINK THAT WE NEED TO MAKE
THE CASE TO THE REGULATORS THAT
HETEROGENEITY IN AND OF ITSELF
IS NOT LIKELY TO INCREASE RISKS
SUBSTANTIALLY AND WE ADMINISTER
HETEROGENOUS PRODUCTS AND
ABILITY TO TEST SEVERAL OR MANY
ITERATIONS IN INDIVIDUAL
PATIENTS IS PART OF INDIVIDUAL
GRAPH WOULD BE INCREDIBLY
VALUABLE AND THIS NEXT
GENERATION CLINICAL TRIAL DESIGN
IN CORRELATIVE TESTING IS
CRITICAL TO ADDRESS THIS
CHALLENGE. WHAT ELSE COULD GO
WRONG?
WELL, THE OTHER POINT THAT KEEPS
ME UP AT NIGHT AND THIS ONE I
THINK IS NEAR AND DEAR TO HEARTS
OF EVERYBODY PARTICIPATING TODAY
IS BIOPHARMAMODEL THAT IS
DOMINATING THE SPACE AND MOVING
INTO FACE OF COMMERCIALIZATION
THAT CARIES WITH IT SUBSTANTIAL
RISK THAT CAR T-CELLS FOR RARE
INDICATIONS INCLUDING PEDIATRIC
CANCERS WILL JUST NEVER BE
DEVELOPED AND WHY DO I WORRY
ABOUT THIS?
LOOK AT CD22 CAR.
THIS IS CREATED, OPTIMIZED AND
TESTED ALL IN ACADEMIA AND
[INDISCERNIBLE] LED WORK IN MY
LAB AND THEY DID ALL OF THE HARD
WORK THAT IS COMPARING VARIOUS
ITERATIONS TO PICK WINNER IN
TERMS OF BINDER AND EPITOEP AND
A DESIGN.
TERRY FROOI AND NCI DID HARD
WORK RUNNING EARLY PHASE TRIALS
SHOWING THAT THIS HAD REAL
EFFICACY AND THIS WAS FOR
PATIENTS WHO LARGELY FAILED CD19
CAR THERAPY AND MANY WERE CD19
DIM AND YET 70% HAD CR MOST MRD
NEGATIVE THAT LED TO
BREAKTHROUGH THERAPY
DESIGNATION. THIS IS EXCITING
BUT DESPITE PROMISING DATA WE
ARE NOW 10 YEARS FROM THE
ORIGINAL PUBLICATION AND
REGISTRATIONAL TRIALS HAVE NOT
YET BEEN LAUNCHED BY BIOPHARMA.
I WILL TELL YOU FROM PERSONAL
EXPERIENCE THIS IS NOT FROM LACK
OF TRYING AND IT WILL GET
LAUNCHED AND WE WILL GET
REGISTRATION IN PEDIATRICS BUT
NOT AT SPEED AND PACE THAT
THERAPEUTIC DESERVED.
WHAT ABOUT SOLID TUMORS?
WE KNOW THAT IS WHERE GREATEST
NEED IS IN PEDIATRIC CANCERS WE
NEED BREAKTHROUGHS IN DISEASES
AND IN SUMMARY OF I THINK MOST
PROMISING DATA THROUGHOUT FOR
CAR T-CELLS AND SOLID TUMORS ARE
9 DIFFERENT STUDIES THAT ARE
NOTED. OF THESE, 4, COUNT THEM
4 ARE IN PEDIATRIC INDICATION.
AND 7 OF THE 9 ARE ACADEMIC
STUDIES.
AGAIN, HIGHLIGHTING CRITICAL AND
EFFECTIVE ROLE THATTACDEMIA CAN
HAVE IN DEVELOPING AND
DELIVERING NOVEL THERAPEUTICS
WHEN COMING TO SELLING GENE
THERAPY.
SO, WHAT CAN GO WRONG? IT IS
THAT BIOPHARMAMODEL DOMINATING
THE SPACE CARIES WITH IT THIS
RISK THAT RARE INDICATIONS WILL
NOT GET DEVELOPED.
AND THIS IS EASY TO UNDERSTAND.
THE HIGH COSTS AND HIGH RISKS IN
BIOPHARMAFOR DEVELOPING CELL AND
GENE THERAPIES DIMINISH FOCUS ON
RARE DISEASES AND TRUTH IS 500
COMPANIES IN THE US, EVERY ONE
OF THEM HAS TO SURVIVE. IF THEY
INVEST PRECIOUS DOLLARS IN RARE
INDICATIONS CHANCE OF GETTING
GREATER INVESTMENT SUSTAINING
RUNWAY DIMINISHES. THIS IS NOT
UNIQUE TO CAR T-CELLS FOR SOLID
OR LIQUID TUMORS AND SIMILAR
MARKET FAILURE IS OCCURRING IN
DEVELOPMENT OF CELL AND GENE
THERAPIES FOR NONMALIGNANT
DISEASES OCCURRING IN CHILDREN
AND FOR MOST PART THESE ARE
RARE. THIS HAS BEEN REALLY
CHALLENGING FOR DEVELOPMENT OF
GENE THERAPY AND
IMMUNODEFICIENCIES AND NEUR
LOGIC DISEASE AND IN ADDRESSING
THIS PROBLEM IS DEVELOPMENT OF
NEW INITIATIVE IN UK
AGORAINITIATIVE GOAL TO BRING
GENE THERAPIES TO MARKET FOR
RARE DISEASE USING NEW MODELS
AND PUBLIC AND PRIVATE
PARTNERSHIPS, ET CETERA. IF
INTERESTED IN THIS I ENCOURAGE
YOU TO READ IN RECENT ARTICLE IN
NATURE MEDICINE AND JUST A WEEK
OR 2 BACK. DISCUSSING THIS
INITIATIVE. I THINK THAT YOU
KNOW SCIENTIFIC PROGRESS THAT
HORSE IS OUT OF THE BARN AND
THIS WILL CONTINUE TO ADVANCE.
WHAT WILL BE DIFFICULT IS
FIGURING OUT WHICH OF THOSE
GREAT PRECLINICAL MANUSCRIPTS
MERIT CLINICAL TESTING AND HOW
DO WE INCREASE THROUGH PUT OF
CLINICAL TESTING TO LEARN MOST
FROM LEAST NUMBER OF PATIENTS?
HOW DO WE PREVENT PEDIATRICS
FROM BEING LEFT OUT OF THIS
REMARKABLE SUCCESS STORY THAT IS
CAR T-CELLS AND CELL GENE
THERAPIES WRIT LARGE. LOOK
FORWARD TO WORKING WITH YOU STAY
TUNED WHAT IS NEW IN PEDIATRICS
AND WHAT WILL BE CRITICAL I HOPE
IN MAKING SURE KIDS DON'T GET
LEFT OUT AND THANKS FOR
OPPORTUNITY TO GIVE CLOSING
REMARKS AND HOPE THEY WERE OF
INTEREST. THANK YOU. BYE, BYE.
>> [APPLAUSE].
>> KRYSTAL, DO WE HAVE ANY
COMMENTS TO MAKE? MIGHT GO
RIGHT TO THE NEXT SPEAKER.
I WILL GO AHEAD. I HAVE
PLEASURE OF INTRODUCING STEVEN
GOD CHALK. BEFORE JOINING ST.
JUDE IN 2017 CHAIR OF DEPARTMENT
-- HE ACTIVELY CONDUCTS
INVESTIGATOR INITIATED EARLY
PHASE CLINICAL TRIALS AND
OVERSEES PHD RESEARCHERS WORKING
ON MULTIPLE RESEARCH PROJECTS
OVERCOMING LIMITATIONS FOR
ADOPTIVE CELL THERAPY FOR CANCER
AND CO-LEADS TRANSLATIONAL
COTHERAPY AT ST. JUDE OF
SCIENTISTS AND ACADEMIC
PHYSICIANS AND WILL HEAR ABOUT
HIS TALK OF PONDERING FUTURE OF
CAR T-CELLS.
>> THANK YOU. I WOULD LIKE TO
THANK ORGANIZER PARTICULARLY TO
ORGANIZE MEETING AND INVITE ME
GIVING TITLE SHE TOLD ME AS LONG
AS PONDERING IS POSITIVE I CAN
GIVE TALK IS.
AT ANY RATE THEY ARE MY
DISCLOSURES AND.
SO, YOU KNOW, IT HAS BEEN 30
YEARS SINCE I PUT UP THE SLIDE
AND TWO GROUPS FROM INVESTIGATOR
DESIGNS THAT WE CURRENTLY KNOW
IT AND TOM BROKER AND OVER THE
YEARS THERE HAS BEEN CONTINUOUS
RESIGN OF MOLECULES THAT I THINK
ARE STILL -- I WOULD SAY
NOVELTIES THAT COME UP AND ARE
VERY EXCITING AND ONE STORY IS
ROBBY'S STORY REPLACING THE
SINGLE DOMAIN SHOT CIRCUITING
THE SINGLING MACHINERY AND WE
RECENTLY PUBLISHED ARTICLE
ADDING PBC BINDING DOMAIN
DRAMATICALLY ENHANCING SIGN UPS
WITH CARS AND FIRST CHIME ERIC
RECEPTOR CONSISTING OF TWO GENES
WAS REALLY CREATED BY
[INDISCERNIBLE] GROUP AND WAS
QUITE AMAZING AND 1987 AND THREE
YEARS AFTER T RECEPTORS ARE
CLONED AND BRINGING UP BECAUSE
YOU SHOULD LOOK AT DESIGN AND
SAY THIS SOUNDS FAMILIAR.
RECENTLY RECEPTORS ARE
REINTRODUCED AGAIN BY JEN'S
GROUP AND ALSO MICHELLE'S GROUP
AND NOWADAYS OR TODAY WE NOT
ONLY HAVE STANDARD CAR BUT HAVE
MULTIPLE SYNTHETIC MOLECULES
THAT IN THE END TAKE ADVANTAGE
OF THE ENTIRE T-CELL RECEPTOR
COMPLEX AND PROBABLY THE BIGGEST
ADVANTAGE OF THESE DESIGNS ARE
THAT THEY HAVE INCREASED
ANCONTINUALEN SENSITIVITY AND TO
MY KNOWLEDGE ONLY GROUP THAT
CAREFULLY MANAGED THAT IS
MICHELLE AND LOOKS LIKE
RECEPTORS ARE 10 FOLD MORE
SENSITIVE THAN COMPARABLE CAR
FOR DETECTING SAME ANTIGEN ON
CELL SURFACE OF TARGET CELLS AND
RIGHT NOW TO MY KNOWLEDGE THERE
IS NONE OF THESE NOVEL T-CELL
RECEPTOR DESIGNS BEING EXPLORED
IN PEDIATRIC SPACE.
IF YOU LOOK AT SOLID TUMOR CAR
T-CELLS PEDIATRIC CANCER WE LIVE
IN WORLD WHERE MAJORITY OF
STUDIES CONDUCT TARGETED ANTIGEN
AND IS TREMENDOUS NEED TO
DISCOVER ANCONTINUALENS AND
THESE ARE ALREADY MENTIONED AND
WE THOUGHT TO TAKE A LITTLE
DIFFERENT APPROACH. WE PUT
TOGETHER PROBABLY ONE OF THE
LARGEST COHORTS OF PEDIATRIC
SOLID TUMORS AND BRAIN TUMORS
DEVELOPING A PIPELINE TO NOT
ONLY LOOK AT DIFFERENTIALLY
EXPRESSED ANCONTINUALENS BUT
ALSO ASKED QUESTIONS ARE THERE
CANCER SPECIFIC ISOFORMS THAT
COULD BE TARGETED?
AND YOU KNOW WITH HELP RUNNING
COMPUTATIONAL BIOLOGY DEPARTMENT
TEAM DEVELOPED A VERY NICE
PIPELINE FOR US AND IN END WE
ENDED UP MAINLY DIFFERENTIALLY
EXPRESSED GENES AND ALSO SEVERAL
9 GENES WE DISCOVERED AND
DETECTED CANCER SPECIFIC
ISOFORMS LOOKING AT VERY HIGH
LEVEL USING A HEAT MAP FOR TIER
1 TARGETS IS NOT ALL CLEAN AND
CLEARLY A LOT OF THE TARGETS ARE
HIGH EXPRESSING SOLID TUMORS AND
BRAIN TUMORS AND SOME TARGETS
ARE REALLY VERY INTERESTING AND
ARE NOT REALLY CELL SURFACE
TARGETS THAT I EXPRESSED IN
EXTRA CELLULAR MATRIX INCLUDING
A1 SPLICE VARIANT OF
[INDISCERNIBLE] PUBLISHING WORK
ON TARGETING SPLICE VARIANT OF
HOOIFERMECTIN AND THESE ARE
SECRETED AND LOTS HAVE RGD
DOMAINS THAT BIND INTEGRIN
BINDING BACK TO TARGET CELLS AND
ARE THERE FOR SENSITIVE TO CAR
T-CELLS TARGETING SPECIFIC
ISOFORMS AND WE HAVE SHOWN THAT
THESE CELLS HAVE SIGNIFICANT
ANTITOMB ERIC ACTIVITY AND TUMOR
VASCULAR ACTIVITY IN PRECLINICAL
MODEL.
FOR COALO LEVEL A1, WE REALLY
ARE INTRIGUED BY THIS PARTICULAR
ECM PROTEIN. IT IS VERY CLEAN
AND THERE IS ALMOST NO
EXPRESSION IN NORMAL TISSUE THAT
IS HIGHLY EXPRESSED IN OSTEOSAR
COMBA AND TARGETS LOOKING IN
LITERATURE YOU CAN FIND THEM
COALO LEVEL A1 IS EXPRESSED IN
STROMA OF BREAST CANCER AND P
DABBING AND ARE QUITE LUCKY AND
THERE IS COMPANY DEVELOPED WITH
DIAGNOSTIC ANTIBODY TO PROTECT
THIS LEVEL OF A1 USED TO
GENERATE A CAR AND THESE T-CELLS
IN PRELIMINARY ANALYSIS
RECOGNIZE PEDIATRIC -- AND ALSO
HAVE SIGNIFICANT ANTI-TOMB ERIC
ACTIVITY IN SOME PRECLINICAL
MODELS.
AS ALREADY MENTIONED CAR T-CELLS
ARE BEING NOW EXPLORED TO TARGET
PEPTIDES IN CONTEXT OF HLA
MOLECULE AND MUST ADMIT I AM
ALWAYS SKEPTICAL AND AS LONG AS
WE GET HOA RESTRICTION BACK WE
CANNOT DO THESE STUDIES IN
PEDIATRIC CANCER AND GOOD
EXAMPLE IS BY TCR STUDY AND FOR
THIS SAR COMBA THAT IS HLA
RESTRICTED AND KRYSTAL WILL TELL
YOU TO INVOLVE ONE PATIENT PER
YEAR AND AT LEAST THESE ARE
GENERATED AND PEPTIDES ACTUALLY
ARE SVS RECOGNIZE PEPTIDES IN
CONTEXT OF MULTIPLE HA TYPES AND
IF THAT CAN REALLY BE APPLIED TO
MORE PEPTIDES I THINK THESE TYPE
OF APPROACHES WILL BE FEASIBLE
IN THE PEDIATRIC SPACE AND ARE
NOT RESTRICTIVE TO A SINGLE HOA
MOLECULE AND OF COURSE THERE ARE
SYNTHETIC APPROACHES USING THESE
AND ALSO THE FOREMENTIONED I
WOULD CALL IT SEQUENTIAL OR
ZENGATE THAT IS A BEST EXAMPLE
RIGHT NOW THAT IS A SYSTEM.
WHAT ABOUT ADDITIONAL GENETIC
MODIFICA
MODIFICATION.
TAKING CELLS EX-VIVO RECURSIVELY
EXPOSE IT TO T-CELLS INVARIABLY
T-CELLS CONTRACT AND WE WANT TO
BE IN SPACE WHERE THERE IS
CONTINUING ANTIGEN DEPENDENT
T-CELL EXPANSION.
CONCEPTUALLY YOU CAN DO TWO
THINGS, DO SCREENS AND TRY TO
DELETE NEGATIVE REGULATORS OR
OVEREXPRESS MOLECULES LIKE
TRANSCRIPTION FACTORS CYTOKINES
OR CHIM ERIC CYTOKINE RECEPTORS
TO ENHANCE AND PUT PEDAL TO THE
METAL AND TRY TO EXPAND
YOURSELVES AND WE HAVE BEEN VERY
INTERESTED IN EPIGENETIC
MODULATION AND THERE IS NO DOUBT
IF YOU LOOK ACROSS MIRRORING
HUMAN STUDIES NOW T-CELL
PLASTICITY IS DRIVEN BY HISTYOEN
MODIFICATIONS AND DNA
MODIFICATION AND HAVE BEEN
PARTICULARLY INTERESTED IN DMT3A
THAT HAS TO DO REALLY WITH
COLLABORATORS THAT WHEN HE WAS A
POST DOC IN LAB DEMONSTRATED IF
YOU KNOCK OUT IN T-CELLS YOU CAN
PREVENT TERMINAL EXHAUSTION AND
THESE CELLS ARE SENSITIVE TO
CHECK POINTS AND DEVELOPING
MULTIPOTENCY BASE WHERE NAÏVE
CELLS GET SCORE OF 1 AND
TERMINALLY DIFFERENTIATED CELLS
GET SCORE OF 0 AND TOGETHER WITH
THEM THERE IS A SAMPLE OF CD9
CAR T-CELL THERAPY THAT WAS
DEVELOPED BY AMY TELURE TO ASK
WHAT HAPPENED TO METHYLATION
PROGRAMS AFTER INFUSION OF
T-CELLS.
FIRST OF ALL LOOKING AT
MULTIPOTENCY INDEX OF PRODUCT TO
MY SURPRISE CELLS ARE NOT TOO
SHABBY AND INTERESTINGLY
MULTIPOTENCY INDEX CORRELATED
WITH PEAK EXPANSION OF INFUSED
CELLS.
NOW LOOKING AT WHAT HAPPENED IN
VIVO USING PCA ANALYSIS AND
FIRST TO ORIENT YOU ON THESE
CELLS AT BOTTOM THAT ARE
EXHAUSTED CELLS AND IN THE
MIDDLE ARE PRECURSOR EXHAUSTED
T-CELLS THAT ARE CALLED T PACKS
AND Z CELLS IN MODELS AND KNOW
HUMAN STUDIES THAT HAVE BEEN
IDENTIFIED AS CRITICAL SUBSET.
T PECHL CAN GIVE RISE TO
FUNCTIONAL EFFECTOR CELLS WHILE
IF YOU EXHAUST EVEN CHECKPOINT
LOCATED DOES NOT HELP YOU
ANYMORE.
IF YOU NOW LOOKING WHERE YOUR
CELLS ARE TO GNP PRODUCT IS
CLOSELY TO NAÏVE CELLS AND WITH
INFUSION OVER TIME WEEK 1, 2,
AND 3 SAMPLES, YOU GET A
PROGRESSIVE DECLINE.
IN PLASTICITY OF THE CELLS AND
BASED ON THESE RESULTS WE ARE
NOW ACTUALLY DEVELOPING A STUDY
KNOCKING OUT IN LEUKEMIA
SPECIFIC CAR T-CELLS AND WE WILL
EVALUATE THEIR FUNCTION.
LAST BUT NOT LEAST, I THINK THAT
ROBBY ALREADY MENTIONED IT AND
COMBINATORY THERAPY AND I
STRONGLY BELIEVE YOU HAVE TO
TEST SOME OF THESE IN
PRECLINICAL MODELS AND CLINICAL
STUDIES ARE JUST TOO EXPENSIVE
AND I JUST AS A TEASER I WANT TO
REALLY SHOW WORK FROM DALIA THAT
ROBBY MENTIONED IS IN
[INDISCERNIBLE] WHEN SHE WAS IN
LAB AND IS A QUESTION WHAT
REALLY HAPPENS DEPLETING
MICROPHAGES AND USING CSF
INHIBITOR AND IN GS
[INDISCERNIBLE] MODELS AND
INHIBITORS WORK NICELY AND WITH
REDUCTION OF TUMOR ASSOCIATED
MACROPHAGES AND THEN IF SHE
TESTED SEVERAL APPROACHES EITHER
CO-COMMITIENTLY GIVING INHIBITOR
OR PRETEACHING WITH INHIBITOR IN
ALL OF THE MODELS WHAT SHE FOUND
IS THAT ACTUALLY IS THE DRUG
DESTROYS OR IS DEPLETING
MACROPHAGES THAT IS INSTRUMENTAL
TO FUNCTIONS IN THIS MODEL AND
THEREFORE I STRONGLY BELIEVE
THAT CAR T-CELLS MIGHT REQUIRE
SUPPORT FROM IMMUNE CELLS AND I
THINK THAT IS IF YOU NOW LOOK AT
CHECKPOINT WORLD THAT IS
ACTUALLY WELL ESTABLISHED FOR
INSTANCE IN COLON CANCER NICK
PUBLISHED THAT AND CALLS IT
IMMUNITY HUB AND MYELOID CELLS
INTERACT IN T-CELLS AND PATIENTS
THAT HAVE IMMUNITY HUBS ARE
SENSITIVE TO CHECK POINTS.
IN CONCLUSION TO MAKE T-CELLS
BROAD APPLICATOR WE HAVE TO HAVE
A BETTER UNDERSTANDING OF CAR
T-CELL BUY OL IN HUMANS AND
RELEVANT PRECLINICAL MODELS
TARGETING MULTIPLE ANCONTINUALEN
AND DO THESE CELLS BEYOND TARGET
SPECIFICITY AND WE HAVE TO
DEVELOP EVIDENCE-BASED
COMBINOTORY THERAPY AND SPEAKERS
MENTIONING IN SYMPOSIUM THERE IS
A NEED TO ADJUST REGULATORY
REQUIREMENTS AND WITH THAT I
WANT TO THANK ST. JUDE AND MY
TEAM WHICH OVER THE LAST FIVE
YEARS I WOULD SAY REALLY HAVE
BUILT A GOOD TRANSLATIONAL CELL
THERAPY PROGRAM FOR CHILDREN
WITH PEDIATRIC CANCER. THANKS
SO MUCH.
>> [APPLAUSE].
>> OKAY. THANK YOU, STEVE. I
HAVE THE PRIVILEGE INTRODUCING
THE LAST SPEAKER OF THE DAY LISA
WARD THAT YOU WILL SEE VERY SOON
IS A WOMAN OF COMPASSION AND
AMAZING ENERGY AND WOMAN OF
ACTION. SHE IS MOTHER OF BROOK
AND BLAKE AND LOVING ATTENTIVE
SUPPORTIVE MOTHER OF JAYS WARD
WHO CAME TO ASK FOR TREATMENT OF
-- WITH GD2 T-CELL THERAPY. I
WALKED INTO JAYS'S ROOM ONE
AFTERNOON HE WAS LYING IN BED
WITH A DOLL HE WAS PROBABLY THE
COOLEST ANLER ANYBODY EVER MET I
SAID WHY THE DOLL DID HE HE WAS
MAKING A VIDEO OR DEMO WHAT IT
WAS LIKE TO HAVE OMIA ACCESSED
SO YOUNG CHILDREN COMING ON
TRIAL WOULDN'T BE AFRAID --
MAKING THE PANEL EASIER FOR
OTHERS IN SAME HOSPITAL BED IS
WHERE THIS SORT OF ORGANIZATION
EMERGED THAT WE WILL HEAR ABOUT
FROM LISA BASICALLY TO CARRY
DIPG COMMUNITY AND THE OTHER
BRIEF ANECDOTE IS ABOUT THE
TRIAL AND AS WE HEARD FROM ROBBY
INTENT WAS TO GIVE ONE DOSE OF
-- WE SAW PATIENTS EFFICACY
ABOUT THESE PERSISTING AMENDING
TRIAL TO GIVE MULTIPLE DOSES
DIRECTLY INTO VENTRICLES JAYS
WAS PATIENT NO. 2 ON TRIAL --
AND AS WE HEARD FROM PATRICK IT
IS NOT EASY TO BE PATIENT NO. 1
AND EMILY WHITEHEADS WITH NEXT
GENERATION CARS AND JAYS HAD
COURAGE AND TO SORT OF MOVE THE
FIELD FORWARD. LET'S HEAR FROM
LISA. THANK YOU.
>> [INDISCERNIBLE].
>> UNDERSTAND THIS MOMENT IS
EASY AND UNDERSTAND
[INDISCERNIBLE] TOGETHER.
HELPING FOUNDATION
[INDISCERNIBLE] IN MY LIFETIME.
DAILY DIPG FIGHTS TO TAKE MY
SIGHT, MY VOICE, MY MOBILITY,
AND FINALLY MY LIFE.
[INDISCERNIBLE] DOESN'T KNOW WHO
IT IS MESSING WITH.
[INDISCERNIBLE] STAND UP AND
STAND BY AND KICK THE HELL OUT
OF IT.
>> SO OFTEN IN THE JOURNEY WITH
CANCER, SOMEONE WOULD SAY TO US,
I REALLY CAN'T EVEN IMAGINE WHAT
YOU ARE GOING THROUGH RIGHT NOW.
AND THAT THEY WERE RIGHT. THEY
REALLY COULDN'T MANL. THOSE OF
US IN THE MIDST OF IT CAN'T
IMAGINE AND IN PLACE NOT SURE
HOW YOU GOT THERE AND DISEASE
PROGRESSION THAT DO NOTHING AT
ALL AND DO NOTHING WITH
POTENTIAL HARM IS NOT REALLY
EVEN A CHOICE.
BUT I CAN'T IMAGINE WHAT YOU AS
RESEARCHERS OR CLINICIANS OR
POLICY MAKERS GO THROUGH EITHER.
I CAN'T IMAGINE THE CONCERN YOU
FEEL WITH EVERY NEW TRIAL OR
AMENDMENT TO THE TRIAL. WITH
EVERY CHOICE THAT DOESN'T PROVE
TO BE A HOME RUN. I OFTEN THINK
OF OUR TEAM WHO WE LOVED SO
MUCH.
WHO TREATED JACE AND CHILD AFTER
CHILD WHO HAVE NOW PASSED AWAY.
EVEN THOUGH THEY ARE ALSO
TREATING SOME THAT ARE STILL
RESPONDING SO VERY WELL.
I KNOW WITH EACH LOSS THERE IS A
HEAVINESS AND KNOW WITH EACH NEW
AMENDMENT THAT DID NOT WORKING
AS PLANNED THERE IS SO MUCH
CONCERN ABOUT MAKING THE WRONG
DECISIONS.
ALL I KNOW TO SHARE WITH YOU IS
YOU HAVE TO KEEP GOING. WE
BELIEVE IN YOU. YOU GAVE OUR
CHILD A CHANCE. YOU ALLOWED OUR
FAMILY TO LIVE WITH LESS REGRET.
THERE WERE TIMES TUMORS SHRUNK
AND SYMPTOMS SUBSIDED AND YOU
GAVE MORE TIME TO THESE
FAMILIES.
YOU EXPLAIN POTENTIAL OUTCOMES,
GOOD, BAD, AND SO MANY UNKNOWN.
WE KNOW THAT YOU TRIED WITH THE
BEST KNOWLEDGE OF THAT DAY TO
GIVE US MORE TIME, A CHANCE AT A
CURE, AT THE LIFE WE MANL FOR
OUR CHILD. FOR THAT, WE ARE
ETERNALLY GRATEFUL AND FOR THAT
WE LIVE WITHOUT REGRET. KEEP
GOING. PUSH THE ENVELOPE. BE
TRANSPARENT WITH US.
KNOW THAT EVEN WHEN WE SO WISH
THAT, THAT CHILD HAD NO EVIDENCE
OF DISEASE ONE DAY WAS OUR OWN.
WE CHEER FOR EVERY SINGLE
VICTORY IN ANY OTHER CHILD AS IF
IT WAS.
YOU ARE DOING WHAT 1,000
DESPERATE PARENTS CANNOT DO. WE
ARE BEYOND GRATEFUL TO YOU.
>> THANK YOU SO MUCH FOR WHAT
YOU DO FOR FAMILIES LIKE MINE.
I CAN'T DO WHAT YOU DO.
SO, WHY AM I HERE?
I HAVE LIVED A PORTION OF THE
SAME EVOLUTION YOU HAVE SPENT
YOUR LIFE'S WORK ON FROM A
DIFFERENT ANGLE. SO, JACE'S
BATTLE WITH DIPG IS DEFINED IN
MY MIND BY THREE MOMENTS IN TIME
THAT ARE SEERED INTO MY
EVERY-DAY LIVING.
MAY 17TH, 2019, I STOOD WITH
JACE IN A SMALL OFFICE IN KANSAS
CITY. THE WORDS INOPERABLE,
MALIGNANT, AGGRESSIVE FLOODED
THE ROOM. NO TREATMENT BUT
RADIATION. IT WILL KILL YOU.
THERE IS NO TREATMENT. GO HOME
AND MAKE MEMORIES.
JACE RESPONDED, HOW LONG DO I
HAVE? THE DOCTOR WITH THE
KINDEST EYES LOOKED INTO MINE
AND SAID, NO, NO, NO. I'M NOT
AFRAID TO DIE. I WANT TO KNOW
HOW LONG I HAVE TO MAKE AN
IMPACT BEFORE I DO. I NODDED
AND DOCTOR SAID 6 TO 9 MONTHS.
HE WAS 20 YEARS OLD. AUGUST 20,
2020, A ZOOM CALL WITH STANFORD
BRAND NEW CAR T-CELL TREATMENT
PATIENT NO. 2 WAS BEING OFFERED
TO JACE AND NOT MUCH THEY COULD
TELL US ABOUT PATIENT NO. 1 AT
ALL. THIS IS A TRIAL THAT
SEEMED TO WORK IN MOST MICE.
IT COULD CURE HIM, IT COULD KILL
HIM, IT COULD DO SOMETHING
IN-BETWEEN. THEY WOULD DO
EVERYTHING THEY COULD TO HANTDLE
THE SIDE-EFFECTS.
THEY HAD GONE OVER EVERYTHING
THEY COULD POSSIBLY THINK OF.
THERE WAS A LOT OF UNKNOWNS.
AND JACE KNEW WHAT HE WANTED TO
DO AT THE END OF THE CALL.
BUT, HE CALLED AN AD HOC
NATIONAL TUMOR BOARD OF 6
DOCTORS THEY MET ALONG THE WAY
AND ASKED IF HE WOULD JUMP ON A
ZOOM CALL THE NEXT DAY AND HE
LINE THE OUT GENOMICS AND
IMAGING AND CLINICAL RECORDS AND
HE ASKED: WHAT WOULD THEY DO IF
HE WAS THEIR CHILD? THIS IS A
HARD DECISION TO MAKE WE CAN'T
MAKE FOR YOU. WE WILL TELL YOU
THIS IS PROBABLY THE MOST
PROMISING THERAPY WE JUST CAN'T
TELL YOU IF IT WILL WORK.
DECISION HAD BEEN MADE.
HE WAS GOING FORWARD.
I'M HAVING A LITTLE TROUBLE WITH
MY SLIDE.
AM I HITTING THE WRONG BUTTON?
I'M SORRY I WILL KEEP GOING.
IT IS LATE IN THE DAY.
>> THANK YOU. SHOWING UP HERE
FOR A MOMENT.
>> I KNOW.
>> NOT CONNECTING.
>> OKAY.
>> HE SAID I'M GOING FOR IT. IT
HAS A CHANCE TO CURE ME. THERE
IS NOTHING ELSE THAT DOES. WE
KNOW WHAT HAPPENS IF I DO
NOTHING. AND IF IT DOESN'T,
THEY WILL LEARN LOTS FROM ME.
I'M OLDER AND I CAN EXPLAIN
THINGS.
MOM, COULD YOU IMAGINE WHAT A
DAD OF A 5 YEAR OLD WOULD GO
THROUGH IF THEY PICK THIS
THERAPY AND IT KILLS THEM
IMMEDIATELY?
CAN YOU EVEN MANL WHAT IT WOULD
FEEL LIKE WHEN I COULD GO FIRST?
AND HE WAS PROUD OF THAT
DECISION.
THE LAST MOMENT THAT IS SEERED
INTO MY BRAIN IS JULY SECOND,
2021. FOR TWO DAYS WE WERE
UNSURE WHETHER SOME ONSET OF
SYMPTOMS BACK HOME IN ST. LOUIS
AREA WERE THE CAUSE OF THE CAR
T-CELLS RAMPING UP OR SOMETHING
DIFFERENT. HE WASN'T STABLE
ENOUGH TO DO AN MRI.
HE HAD SEVERE HEADACHES AND NO
LONGER COULD SPEAK AND NO
MOBILITY AND HIS HANDS COULDN'T
WORK. HE COULD STILL SPELL.
THAT IS HOW WE COMMUNICATED.
DOES IT START WITH A THROUGH M
OR M THROUGH Z? A, B, C, D.
STARTS WITH D. HE AND I WERE
GREAT SPELLERS AND DAD WASN'T.
THAT WAS THE PROBLEM. HE KNEW
WHAT HE WANTED.
AFTER THE MRI WHEN STANFORD TEAM
WAS CLINGING SO CLOSE TO US FROM
AFAR, WE KNEW THERE WAS NOTHING
MORE WE COULD DO. NONE OF THE
ABILITIES WOULD EVER RETURN. IT
WAS PROBABLY THE HARDEST THING I
HAVE EVER DONE TO LEAN INTO HIM
AND TELL HIM HOW MUCH I LOVED
HIM.
AND TO WATCH HIS EYES AND TO
TELL HIM WE HAD COME TO THE END
OF THE FIGHT, 25 MONTHS. THERE
WAS NOTHING MORE THAT WE COULD
DO.
AND MY EYES WERE FILLED WITH
TEARS. HIS EYES WERE FILLED
WITH SOMETHING ELSE. THEY WERE
FILLED WITH FURY AND FILLED WITH
THAT DESIRE TO KEEP FIGHTING AND
BATTLING EVEN THOUGH HIS BODY
HAD LONG WARN OUT AND WAS
FUELING THE SAME THING THAT
FUELS YOUR WORK. THERE HAS TO
BE AN ANSWER. HE DID NOT WANT
THIS TUMOR TO WIN. AS OUR EYES
LOCK THE, THAT FURY TRANSFERRED
TO ME AND CONTINUES TO DRIVE OUR
WORK.
YOU KNOW, JACE HAD GREAT FAITH.
HE WAS NOT AFRAID WHAT HIS NEXT
CHAPTER WOULD BE. HE DID NOT
WANT TO GIVE UP FOR THOSE LITTLE
ONES WHO HAD NOT FINISHED
KINDERGARTEN OR PROM OR PLAYED
FOOTBALL UNDER THE LIGHTS. HE
WANTED TO BE THERE WHEN HE WAS
ABLE TO RING THE BELL AND MORE
IMPORTANTLY WATCH ALL OF THE
OTHER KIDS HE HAD MET ALONG THE
WAY. HE WAS SO, SO DETERMINED.
YOU KNOW, SINCE THEN WE HAVE MET
-- DID WE HAVE ANY LUCK ON THE
SLIDES?
THE SLIDES DIDN'T COME THROUGH.
OKAY. OKAY. PERFECT. THAT IS
PERFECT. SO, ALONG THE WAY WE
HAVE MET 361 FAMILIES.
DIPG IS NOT RARE.
AND AS OF LAST NIGHT, NO. 362 BY
PHONE. IT IS ALWAYS THE SAME
PHONE CALL.
MY CHILD WAS JUST DIAGNOSED. I
HEARD YOU ARE A REALLY GOOD
PERSON TO TALK TO ABOUT THE
OPTIONS.
I JUST CAN'T IMAGINE THAT THERE
IS NOTHING THAT WE CAN DO. WE
GO THROUGH THOSE. YOU CAN
IMAGINE THAT THE ANSWER IS LET'S
FIND SOMETHING TO KEEP YOUR
CHILD STABLE UNTIL WE FIND A
TREATMENT THAT CAN WORK. TO
THINK OF ANYTHING ELSE IN THOSE
EARLY MOMENTS IS JUST THE
UNTHINKABLE FOR ANY OF US.
YOU ARE DOING WHAT WE CAN'T DO.
WE ARE SO, SO GRATEFUL. YOU ARE
PUSHING THAT EDGE OF SCIENCE.
AS FAMILIES, WE ARE PUSHING
RIGHT WITH YOU.
I KNOW THAT MANY OF YOU,
PROBABLY ALL OF YOU, TOOK AN
OATH TO DO NO HARM.
IN A CANCER-LIKE DIPG TO DO
NOTHING IS TO DO HARM.
WE KNOW WHAT THAT TRAJECTORY
LOOKS LIKE. TO BE TRANSPARENT,
TO SAY HERE IS WHERE WE ARE AND
WE KNOW WE HAVE TO GET HERE AND
WE ARE NOT EXACTLY SURE WHERE
THE ROAD GOES.
IF YOU WANT TO WALK WITH US,
THERE IS ROOM.
THAT IS TO DO SOMETHING.
YOU MAY BE TIRED AND WARN. I
KNOW THAT EVERY ONE OF YOU IS
EVERY BIT AS DETERMINED AND
RESILIENT AS LITTLE CHILDREN
THAT YOU SAW IN THE VIDEO. I
INSTEAD TO SUGGEST TODAY THAT
YOU USE THE FAMILIES IN THE
FIGHT WITH YOU.
USE THEM IN YOUR ARSENAL TO WIN
THIS BATTLE.
YOU SEE, WE CAN NAVIGATE
PATIENCE YOUR WAY. IF YOU KEEP
US UP TO DATE ON THE WINS AND
ADJUSTMENTS IN YOUR WORK. I
KNOW THAT THERE IS A LOT OF
INFORMATION THAT YOU ARE KEEPING
TO PUBLISH. THAT IS TOTALLY
UNDERSTANDABLE.
THERE ARE SOME THINGS YOU CAN
TELL US THAT HELPS US TO ADVISE
IN A WAY THAT DOES NO THE FEEL
COMPLETELY LIKE BLINDED RUSSIAN
ROULETTE WITH YOUR CHILD. LET
US AMPLIFY TO THE PATIENT
COMMUNITY HOPE IN ACTION. IN A
REAL PARENT TO PARENT WAY.
BECAUSE THEY ARE LOOKING FOR
THAT ON FACEBOOK ANYWAY.
HELP PARENTS IN YOUR COMMUNITY
BE INFORMED WITH INFORMATION
THAT THEY ARE SHARING.
ASK US FOR FEEDBACK.
ASK US WHAT THE FACEBOOK AND
INSTAGRAM COMMUNITY IS SAYING
ABOUT YOUR CAR T-CELL TRIALS OR
ADVANCED THERAPY TRIALS. THERE
IS ALWAYS OPINIONS OUT THERE.
ASK US WHAT NEW SUPPLEMENT OR
THERAPY IS THE NEXT THING TO
MAKE ROUNDS AND THAT SOMEBODY IS
TAKING NOT TELLING YOU IN YOUR
TRIAL. I'M AN EDUCATED PERSON I
WILL ADMIT THERE WAS A TIME I
STOOD IN A PET FILE TO LOOK FOR
DE-WORMER. MY SON CALLED AND
SAID WHAT ARE YOU DOING?
LOOKING AT DE-WORMER. DOES OUR
DOG HAVE WORMS? NO. I BET IT
COULD HELP YOU WITH YOUR CANCER.
GET OUT OF THE AISLE. YOU ARE
NOT A DOCTOR AND WILL NEVER BE
AND TRUST THOSE THAT ARES. I
UNDERSTAND THE PLIGHT OF PARENTS
AND ALLOW US TO HELP IF YOUR
PATIENTS NEED FINANCIAL OR
EMOTIONAL OR PALLIATIVE SUPPORT
THAT IS NOT ABLE TO BE REACHED
QUICKSLY IN YOUR INSTITUTIONS.
WE HAD NUMBERS OF TIMES THAT
PATIENTS NEEDED TO GET HOME FOR
A TRIAL ACROSS THE COUNTRY FOR
PALLIATIVE CARE OR THERE IS NO
MONEY TO BURY A CHILD OR GET
THEM TO THE TRIAL OR BRING THEIR
DAD TO THE TRIAL OR BABY BROTHER
TO THE TRIAL. THAT IS THE PLACE
THAT WE CAN HELP. IN SOMETHING
THAT MOVES AS QUICKLY AS DIPG
WHICH IS WHAT I KNOW THE MOST
ABOUT, WE KNOW WE CAN'T WAIT FOR
LONG APPLICATIONS AND TIME FOR
THE SOCIAL WORKER TO MAKE IT TO
THE ROOM SOME TIME IN THE NEXT 2
OR 3 WEEKS.
INSTEAD, USE FAMILY SUPPORT LIKE
WE HAVE TO MAKE THAT ONE CALL
AND EXPLAIN THE NEED AND ASK THE
FAMILY TO CONTACT US. WE WILL
SEND IT THROUGH VENMO OR FILL
OUT THE APPLICATION FOR THEM.
WE WILL HAVE THEM DOCU SIGN IT.
WE WILL SEND IT ON TO THE
FOUNDATIONS THAT TRUST US AND WE
WILL HAVE FUNDS THE NEXT DAY.
BECAUSE WE KNOW WHAT IT IS LIKE
TO SIT IN AN EMERGENCY ROOM AND
WATCH THE NEXT MOTHER NOT HAVE
ANYTHING TO EAT. BECAUSE SHE
CAME WITHOUT HER PURSE OR HER
BANK ACCOUNT IS OVERDRAFT AND
FOR THE EMERGENCY ROOM DOCTOR TO
SAY, I'M SORRY WE ONLY SERVE
PATIENTS.
WE KNOW WHAT THOSE DAYS FEEL
LIKE. WE DON'T WANT THAT TO ANY
OTHER FAMILIES AND WE WANT YOU
TO DO YOUR JOB THAT WE CAN'T DO.
SO, DON'T EVER FEEL BAD ABOUT
ASKING FAMILIES TO HELP DO WHAT
YOU -- WHAT WE CAN DO. IT IS AN
HONOR AND IT IS A PRIVILEGE AND
IT IS A WAY OF CONTINUING THE
PURPOSE OF OUR CHILD IN THE
FIGHT. WE KNOW AS WELL AS
ANYONE WHAT THAT FEELS LIKE. I
WILL SHARE A COUPLE WINS REAL
QUICK ALONG THE LINES YOU
WOULDN'T EXPECT. A MOTHER IN
CINCINNATI AND CHILD TREATED FOR
DIPG FOR TWO YEARS REAL WIN IN
OUR WORLD TWO YEARS THIS CHILD
ANL 8 AND BELOW BELOW POVERTY
LINE CLEARLY RECEIVED 2 $25 GAS
CERTIFICATES AND SHEPHERDS PIE
FROM NEIGHBOR BEFORE I TOOK
PHONE CALL WE PROVIDED CHRISTMAS
AND FILLED PANTRY AND
REFRIGERATOR AND HOSPICE NURSE
CAME AND ON HER OWN TIME SHE
TOOK IT TO A JEWELRY STORE AND
HAD THE JEWELRY MAKER MAKE A
RING OF THE FINGER PRINT AND
PROVIDED CHRISTMAS GIFTS AND
MOTHERS GOT OUT OF BED AND
STARTED TO TAKE LESS MEDICATION
AND STARTED TO RELY LESS ON
NONPRESCRIPTION ASSISTANCE AND
TOOK THE LITTLE BOYS CASE TO A
TUMOR BOARD THAT LED TO
RE-RADIATION AND ADMISSION INTO
A NEW TRIAL. SHE TEXTED ME LAST
WEEK AND SENT ME A PICTURE OF
THE LITTLE BOY WHOSE COLORING
FOR THE FIRST TIME IN 20 MONTHS
AND WAS OUTSIDE PLAYING ON HIS
SWING SET.
WE JUST DON'T KNOW; RIGHT?
WHAT IT TAKES FOR THE NEXT
PARENT TO TAKE THE NEXT STEP
WITH THEIR CHILD. WHAT MADE ME
EVEN HAPPIER WAS THURSDAY SHE
SENT ME A PICTURE OF SHE AND HER
SON TAKING A PUPPY THAT THEY
BREED AND RAISE TO ANOTHER
LITTLE BOY THAT THEY MET LOCALLY
ALSO WITH DIPG. SHE WAS HAPPY
TO PAY IT FORWARD TO THE NEXT
FAMILY. THAT IS A STORY I WILL
ALWAYS HANG ON TO. ANOTHER ONE
IN FLORIDA A YOUNG MOM WHO IS 26
WHO HAS A 6 AND 8 YEAR OLD AND 6
YEAR OLD HAS DIPG AND 6 YEAR OLD
TOOK A TURN DOWNHILL AND NEEDED
A WHEELCHAIR AT HOSPITAL AND
MANY OF YOU KNOW PEDIATRIC
WHEELCHAIR IS NOT SOMETHING YOU
CAN FIND OVERNIGHT SOMETIMES AND
WE KNEW A MOTHER WHO HAD ONE AND
WHOSE SON PASS AD WAY EARLIER
THIS FALL. I SAID RACHEL IS
THERE ANY WAY THAT YOU WOULD
WANT TO LET ELIA'S WHEELCHAIR
AND MOM IN THE HOSPITAL IN MIAMI
THAT COULD USE IT AND IF YOU
WOULDN'T MIND YOU CAN JUST BRING
IT TO THE HOSPITAL AND THEY WILL
MAKE SURE IT IS TO THE RIGHT
ROOM AND I CAN MAKE SURE OF
ARRANGEMENTS AND SHE SAID THAT
IS BEST AND NOT READY TO MAKE
MOMS OR KIDS AND I UNDERSTAND
AND WHEN SHE GOT THERE I WOULD
LIKE TO MEET MOM I DID SPENT
TIME TALKING AND SHE WAS HELPING
TO PLAN THE 6 YEAR OLD'S
BIRTHDAY PARTY AND TAKING THEM
GROCERY SHOPPING ON 26 YEAR OLD
MOMLE'S CAR BROKE DOWN AND 26
YEAR OLD'S MOTHER WHO WAS 42 HAD
AN ANNURISM AND WAS IN ICU FIVE
DAYS BEFORE PASSING AWAY. DO
YOU KNOW WHO TOOK CARE OF THE
KIDS? RACHEL, THE MOM WHO LOST
HER CHILD IN NOVEMBER.
THAT IS SOMETHING THAT THEY KNEW
TO DO. THE 6 YEAR OLD HAD AN NG
TUBE. SHE SOMETIMES NEEDED
SUCTION AND WASN'T COMFORTABLE
LAYING IN EVERY DIRECTION AND
YOUNG MOM COULDN'T TRUST HER TO
ANYONE ELSE THAT SHE KNEW.
RELY ON THE FAMILIES.
SOMETIMES A HOSPITAL -- A DOCTOR
OF A HOSPITAL WILL CALL AND SAY
THERE IS A PATIENT I'M CARING
FOR THAT DOESN'T KNOW ANYONE
ELSE WITH DIPG OR DMG. I CAN'T
TELL THEM THAT THERE IS A
PATIENT IN THE NEXT ROOM. YOU
PROBABLY KNOW WHO THAT PATIENT
IS. IS THERE A WAY THAT IF THEY
CALL YOU YOU WOULD BEL TO
CONNECT THEM WITH ANYONE ELSE
THAT MIGHT BE IN THE AREA?
ABSOLUTELY. THAT IS HOW THOSE
FRIENDSHIPS HAVE FORMED AND MORE
OFTEN THAN NOT WE KNOW FAMILIES
IN THE AREA THAT WILL PROVIDE A
MEAL OR A CAR OR PLACE TO STAY
OVERNIGHT BECAUSE THEY HAVE BEEN
IN THAT SAME PLACE. WE DON'T
NEED LOTS AND LOTS OF
REGULATIONS AND COMPLICATED
PROGRAMS TO DO THIS. WE JUST
NEED ONE PARENT TELLING ANOTHER
ONE WHERE TO FIND HOPE. YOU
NEED SOMEBODY YOU CAN TRUST AND
ROOI LIE ON TO ANSWER THOSE
CALLS WHEN YOU MAKE THEM.
I CAN ALSO TELL YOU THAT COUNT
ON US TO BE INFORMED ADVOCATES
AS YOU CHOOSE TO HELP WITH
FUNDING RESEARCH OR CHANGES IN
REGULATION OR SHARING OF TISSUE
AND DATA. WE KNOW HOW IMPORTANT
THOSE ARE AND WILL COME AND WE
WILL HELP WHEN WE CAN. I WILL
GIVE YOU A GLIMPSE OF WHAT WE
HAVE DONE IN THE LAST YEAR SO
YOU CAN KNOW QUICKLY WHAT IS
POSSIBLE.
WOULD YOU RELY ON A MOM WHO
DIDN'T KNOW THEY HAD A PONS FOR
ADVICE AND THEY SHOULDN'T AND
WITH HELP OF CHAD AND DIPG AND
20 OTHER FOUNDATIONS WITH HE
FUNDED DIPG NAVIGATOR A NURSE
NAVIGATION SYSTEM THAT PROVIDES
EDUCATION AND ANSWERS QUESTIONS
AND HELPS PATIENTS TO FIND
CENTERS OF EXCELLENCE WITH
TRIALS THAT STAY UP TO DATE ON
HOW THE TRIALS COMPASSIONATE USE
AND ADJUNCTIVE THERAPIES ARE
GOING AND NOW THERE IS FOUR
FULL-TIME NURSES THAT THEY
SERVED 196DIPG DNG PATIENTS
SINCE MAY AND CAN CASE LLOYD
CONTINUES TO GROW. WE WENT BACK
THINKING ABOUT THE AD HOC 2
BOARD AND HOW MUCH RELIEF IT
GAVE NOT SCROLLING THROUGH
CLINICAL TRIALS.GOV TO PICK WHAT
WAS NEXT FOR JACE. WE PICKED
THE CREAM OF THE CROP IN THE
DIPG WORLD AND ACROSS THE
COUNTRY WOULD YOU DO A ZOOM CALL
TWICE A MONTH AND PROVIDE
OPTIONS FOR YOUR PEERS FOR OTHER
PROVIDERS? NOW A FAMILY
PROVIDER AND ONE OF THE
[INDISCERNIBLE] NAVIGATORS CAN
HELP A PATIENT SIGN UP AND
RECORDS WILL ALL GO TO THE TUMOR
BOARD. THEY GET ON A ZOOM CALL.
ANY PROVIDER IN THE COUNTRY.
ACTUALLY, IN THE WORLD CAN
LISTEN IN TO WHAT
RECOMMENDATIONS ARE BEING GIVEN
AND WHY SOME TRIALS THAT THE
PATIENT WOULD BE INELIGIBLE FOR
AND WHY THEY WOULD BE ELIGIBLE
FOR AND TREATMENTS THAT ARE NOT
MAYBE THE BEST PRACTICES EVEN AS
A STANDARD OF CARE HASN'T
CHANGED IN 60 YEARS AND WE ARE
SEEING REAL WINS AND SEEING
PROACTIVE STEROID USE GO DOWN.
WE ARE SEEING ADJUNCTIVE
THERAPIES GO UP AND SEEING GAINS
IN OUTSIDE SURVIVAL AND EVEN
PROGRESSION-FREE SURVIVAL JUST
BECAUSE OF THE CHANGES IN HOW
THEY ARE TREATING THE
SIDE-EFFECTS IS IMPACTING THE
QUALITY OF LIFE AND FOR SOME
REASON THE LENGTH OF LIFE.
WE ARE EXCITED ABOUT THAT.
WE ALSO STAYED TOGETHER THEN, 68
FOUNDATIONS, AND STARTED
FUNTDING RESEARCH. IN FIRST 5
MONTHS FUNDED $1.1 MILLION IN
RESEARCH FOR DIPG/DMG. WE HAVE
ANOTHER ROUND OPEN NOW THAT WILL
FUND IN APRIL. SO, INSTEAD OF
WRITING GRANTS TO A WHOLE BUNCH
OF LITTLE FOUNDATIONS, YOU CAN
WRITE IT AT ONE PLACE. IT IS
REVIEWED BY A WONDERFUL MEDICAL
ADVISORY COUNCIL LED BY MICHELLE
MANJAY AND THOSE ACROSS THE
COUNTRY KNOWING ADVANCED
THERAPIES WELL THAT IS THE
DIPG/DMG RESEARCH FUNDING
ALLIANCE AND YOU CAN LOOK AT ANY
TIME. WE KNEW IT WAS IMPORTANT
TO CONTINUE CONVERSATIONS LIKE
THIS WITH RESEARCHERS,
CLINICIANS AND FAMILIES IN THE
FIGHT AND ADVOCATES AS WELL AS
POLICYMAKERS SO WE BUILD ON CURE
FAST THAT IS IN SEPTEMBER IN
WASHINGTON, DC EVERY YEAR.
WE ASK THOSE THAT ARE LEADING
NEW IDEAS WHETHER IT BE IN
PALLIATIVE CARE OR ALTERNATIVE
THERAPY OR TRIALS OR BASIC
RESEARCH TO COME TOGETHER FOR
WHAT IS NOW CALLED THE
BRAINSTORM SUMMIT. IT IS WIDER
THAN DIPG/DMG. IT IS ALL
PEDIATRIC BRAIN TUMORS. IF ANY
OF YOU ARE INTERESTED IN
PRESENTING NEXT YEAR, PLEASE
REACH OUT. WE WILL MAKE SURE
AND LOOK TO SEE WHETHER WE CAN
FIT YOU IN. LAST YEAR, WE HAD
500 PEOPLE PARTICIPATE.
SO, WHAT CAME OUT OF IT THAT WAS
REALLY INTERESTING. LIKE A
HOSPITAL ON THE EAST COAST
CALLING AND SAYING, DO YOU THINK
THE REASON THAT PEOPLE ARE NOT
ENTERING OUR TRIAL IS IF IT
DOESN'T WORK THEY CAN'T DO
ANYTHING ELSE UNTIL PROGRESSION?
YEAH. THAT IS PROBABLY A BIG
PART OF IT.
AS EXPLAINED BY A 13 YEAR OLD AT
THE TOUGH TOGETHER BREAKFAST.
SO, NOW THAT TRIAL IS AMENDED.
IF IT DOESN'T WORK, THEN THEY GO
STRAIGHT TO ONG201 COMPASSIONATE
USE BEFORE PROGRESSION. THERE
IS JUST THINGS LIKE THAT, THAT
WE CAN HELP WITH.
AND WE CAN NEVER TAKE YOUR
PLACE. TO THE EXTENT THAT WE
CAN MAKE YOUR WORK FASTER,
EASIER, MORE WELFUNDED, PLEASE
LEAN ON US IN WHATEVER TYPE OF
PEDIATRIC CANCER YOU ARE WORKING
WITH.
WE SOMETIMES STUMBLE UPON THINGS
THAT ARE INTERESTING TO US.
FOR YEARS, THOSE PARENTS THOUGHT
THAT THEY WERE CONSENTING TO
SHARING THEIR DATA JUST ASSUMED
WHEN ASSIGNING ALL CONSENT WILL
YOU SHARE YOUR DATA WITH
CHILDREN'S BRAIN TUMOR NETWORK
AND OTHERS THAT, THAT WAS
HAPPENING AND WE LEARNED THAT IN
2020 THAT JACE SAID HOW MANY
TUMORS THAT ARE FULLY SEQUENCED
DO YOU USE AT CBTN AND FOR DIPG?
THE ANSWER WAS WE HAVE ABOUT
480.
WE HAVE SEQUENCED I WANT TO SAY
IT WAS 69 OR 70 AT THE TIME.
WHY HAVEN'T YOU SEQUENCED THE
REST?
IT IS EXPENSIVE AND ABOUT $1500
A PERSON. THEY SAID, SO, WHO
MAKES THE PHONE CALLS?
WHAT PHONE CALLS?
WHO CALLS THE PARENT AND SAYS
THANK YOU FOR YOUR CHILD'S
BRAIN, BUT YOU FORGOT THE
PROCESSING FEE. IT IS IN THE
FREEZER. THAT IS KIND OF GROSS.
DON'T YOU THINK?
HE SAID, YEAH. DON'T WORRY. I
WILL GO GET IT RAISED. HOW MUCH
DO WE NEED?
(1) 500-0000.
SO, WITH COUNT ME IN AND BROAD
INSTITUTE AND [INDISCERNIBLE]
THOSE TUMORS WERE SEQUENCED THIS
LAST FALL AND CBTN CAME HERE TO
THE NIH WRITING A GRANT TO
SEQUENCE 6500 MORE SAMPLES OF
ALL TYPES OF PEDIATRIC BRAIN
TUMORS.
SO, AS THAT COMES IN AND BECOMES
HARMONIZED AND IS ABLE TO BE
ANALYZED, IT SEEMED TO US THAT
IMAGING AND CLINICAL RECORDS
SHOULD PROBABLY BE THERE TOO;
RIGHT?
THEY ARE NOT. NOT IN WIDE
SCALE.
SO, WE BROUGHT TOGETHER THROUGH
FUNDS AT CANCER MOON SHOT AMAZON
AND WEB SERVICES WITH
INFRASTRUCTURE UNDER WHICH MANY
OF YOU WORK AND CHILDREN'S BRAIN
TUMOR NETWORK AND FOUR OTHER
PARTNERS.
TOGETHER, THEY ARE WORKING ON AN
OBSERVATIONAL TRIAL THAT IN A
SHORT AMOUNT OF TIME WILL HAVE
THE CLINICAL RECORDS OF OVER
500DIPG/DMG PATIENTS AND 400 OF
WHICH ARE DECREASED AND 100 IN
THE FIGHT AND HOW IS THAT A
SHORT PERIOD OF TIME?
THEY ARE ON MY PHONE AND THEY
ARE ON MY FRIENDS LIST. ALL WE
HAVE TO DO IS ASK THE PARENT ARE
YOULE TO SHARE YOUR CHILD'S DATA
TO HELP THE NEXT CHILDREN?
AND THEY ARE GOING TO SAY YES.
I KNOW 361 PARENTS AND I
GUARANTEE 350 AT LEAST ARE
SAYING YES.
BECAUSE WHATEVER WE CAN DO TO
HELP IS WHAT WE WANT TO DO. WE
WANT TO BE ABLE TO PROVIDE THAT
IN A WAY THAT HELPS YOU THE MOST
THOUGH WHICH IS WHAT REQUIRES IT
THAT CONSTANT CONVERSATION. WE
WANT TO USE REPUTABLE GROWTH TO
FLOW INTO THE CCI AND WE CAN'T
WAIT. DIPG WON'T WAIT WE KNOW
IF WE TAKE SHOTS ON THE RIM YOU
NEED TO KNOW WHO HAS THE BALL
AND WHERE THE RIM IS AND WILL
TAKE WORK IN TRANSLATIONAL
SCIENCE. SO, THESE ARE THINGS
THAT WE FIND TO BE OUR HONOR AND
PRIVILEGE. WE CAN'T DO WHAT YOU
CAN DO.
YOU ARE GIVING OUR CHILD A
CHANCE. FOR THAT I AM
INTERNALLY GRATEFUL AND IS A
PRIVILEGE TO THANK YOU TODAY AND
TO SHARE WITH YOU WHAT MY VERY
GOOD FRIEND ADAM AT CBN SENT ME
IN A TEXT THAT IS A GREAT WAY TO
END THE DAY. I HAVE ZERO DOUBT
AND COMPLETE CONFIDENCE IN THE
ULTIMATE OUTCOME. OUR JOB IS TO
DO IT MUCH FASTER.
AS FAST AS POSSIBLE ON BEHALF OF
THE LEGACIES OF THOSE WHO
SACRIFICED AND THOSE THAT COME
AFTER THAT WILL NOT SUFFER. FOR
THAT MOMENT WHEN HUMANITY IS NO
LONGER AFRAID OF WHAT CANCER CAN
DO TO ITS CHILDREN BUT
CELEBRATES WHAT GROUPS OF
PASSIONATE PEOPLE DID WHEN THEY
CAME TOGETHER AND WHAT THEY
ACHIEVED TOGETHER ON BEHALF OF
CHANGING HISTORY. SO, ON BEHALF
OF NEUROCAR T-CELL PIONEER MARY
THE GIRL SCOUT YOU MET TURNING 7
IN APRIL AFTER 2 FULL YEARS OF
CAR T-CELL THERAPY, PLEASE BE
BRAVE. TRY TO BE NICE. THANK
YOU.
>> >> I THINK ALL OF THE
CHALLENGES WE HAVE TALKED ABOUT
OVER THE DAY WE SOLVED THEM FOR
DIPG. THANKS FOR YOUR POWERFUL
WORDS AND THANKS TO ALL OF THE
SPEAKERS AND CHAIRS AND TO
NIRALI FOR ARCHITECTING THIS
ENTIRE EVENT IN LIEU OF TIMING
WE WILL FOREGO CLOSING REMARKS
AND SAY SEE YOU AT INSPIRED 2.0.
>> THANK YOU, EVERYBODY. THANK
YOU TO THE AV TECH WHO STAYED
LATE. WE APPRECIATE YOU GUYS
MAKING THIS