>> THANK YOU ALL FOR COMING, AND
HAVING I THINK A REALLY EXCITING LECTURE.
YOU'RE IN FOR A TREAT.
I OF COURSE KNOW THIS INTIMATELY
BECAUSE I'M INTRODUCING ONE OF
MY BEST FRIENDS AND COLLEAGUES
AT THE CCR NCI WYN WILSON.
IT'S REALLY SPECIAL BECAUSE I
THINK WYNDHAM IS SPECIAL AND
EPITOMIZES WHAT WE SHOULD BE
DOING AS A CLINICAL SCIENTIST, I
WOULD SAY.
YOU KNOW, NOTICE I DIDN'T
JUST -- SO WE'RE -- WHAT WORKS
VERY WELL IN THE TEAM IS THAT
WYNDHAM BEGAN AS I DID AS AN
MD/PHD AT STANFORD.
I WAS AT PENN, AND DID, YOU
KNOW, VERY SOLID
LABORATORY-BASED WORK, AND HE
THEN FOUND THAT HE GOT MORE
GRATIFICATION OUT OF THINKING
ABOUT CLINICAL PROBLEMS.
I, ON THE OTHER HAND, RAN THE
OPPOSITE DIRECTION AND AFTER A
YEAR OF CLINIC, I HAD IT, I JUST
HAD IT.
BUT THE POINT IS I MET WYNDHAM,
HE HAD BEEN HERE IN THE NCI FOR
SOME TIME, HAD GREAT MENTORS,
DAN LONGO, BRUCE CHADNER, BUT I
MET HIM AT A P.I. RETREAT.
SO ADVERTISEMENTS FOR THE P.I.
RETREAT, AND SOMEBODY SAID YOU
REALLY GOT TO MEET THIS GUY,
WYNDHAM WILSON, AND I WAS JUST
DEVELOPING SOME MOMENTUM ON
STUDYING THE GENOMICS OF
ESPECIALLY DIFFUSE LARGE B-CELL
LYMPHOMA WHICH WYNDHAM WILL TALK
ABOUT.
THE REST IS HISTORY.
THAT'S WELL OVER 23 YEARS OR SO
THAT WE'VE WORKED TOGETHER.
I WILL LET WYNDHAM TELL A LOT OF
THE RECENT STORIES, BUT I DID
WANT TO HIGHLIGHT SOME
INTERESTING THINGS THAT TELL YOU
ABOUT HIM.
SO, ONE THING IS HIS VERY
UNCONVENTIONAL AND INTEREST IN
EXPLORING THE UNEXPLORED, I
WOULD SAY.
SO, HE WOULD DO THINGS -- HE
WOULD HAVE RARE PATIENTS WITH
LYMPHOMAS, SUCH AS THOSE WITH AN
EBV-DRIVEN PROCESS CALLED
LYMPHOMATOID GRANULOMATOSIS,
THAT LED HIM TO DEVELOP OVER A
VERY LONG TIME FRAME, 30 YEARS,
A SUCCESSFUL TREATMENT THAT
PREVENTED PATIENTS WITH SORT OF
LOW-GRADE DISEASE FROM
PROGRESSING TO HIGH-GRADE
DISEASE THAT WOULD KILL, AND AT
THAT TIME THAT WAS VERY
EXPERIMENTAL.
THAT WAS INTERFERON.
AND HIS HYPOTHESIS WAS SIMPLY
THIS IS AN IMMUNE-MEDIATE
DEFICIT AND INTERFERON WOULD DO
IT, AND IT DID.
MIND YOU, THIS IS STARTING IN --
WHAT WAS IT, 1997?
1990, YEAH.
SO, THIS IS WELL BEFORE ALL THE
BUZZ AROUND IMMUNOTHERAPY.
ANOTHER-- I WANT TO HIGHLIGHT
THAT WYNDHAM'S WORK CHANGES
PRACTICE, SO HE DEVELOPED A
CONCEPT THAT YOU COULD GET A
BETTER CELL KILL WITH
CHEMOTHERAPY BY INFUSING THE
CHEMOTHERAPY I.V., ESPECIALLY
THE CONCEPT OF ESSENTIALLY IN
VIVO PHARMACODYNAMICS.
THAT IS, WITH EACH CYCLE OF
CHEMOTHERAPY, YOU GO UP A NOTCH,
AND YOUR MEASURE OF HITTING THE
MARK IS NEUTROPENIA, SO BY DOING
THIS YOU ESCALATE THE DOSES TO
JUST WHAT THE PATIENT CAN
TOLERATE, AND THAT IS CALLED
DOSE ADJUSTMENT, AND THAT HAS
BECOME A MAINSTAY IN LYMPHOMA
THERAPY WORLDWIDE FOR THE
TREATMENT OF ESPECIALLY THE MOST
AGGRESSIVE SUBTYPES OF LYMPHOMA.
AND THE FINAL ONE I WANT TO
EMPHASIZE WHICH WILL BE A LITTLE
BIT AT THE BEGINNING OF
WYNDHAM'S TALK WILL BE STUDYING
NEW DRUGS IN THE SPACE OF
LYMPHOMA.
AND I HAD BY CHANCE ENCOUNTER AT
AN ACR MEETING BEEN APPROACHED
BY A COMPANY WHO HAD A MOLECULE
TARGETING BTK THAT THEY -- I
FORGET WHAT THEY CALLED IT, PCI
2765, I CAME BACK WYNDHAM HAD I
WOULD SAY A HEALTHY SKEPTICISM
BUT NOT THAT PREVENTED HIM FROM
DOING THE EXPERIMENT, AND THAT
IS IN UNBELIEVABLY SHORT TIME BY
TODAY'S STANDARDS, MY EDITORIAL
REMARK, BETWEEN 3 AND 6 MONTHS
WYNDHAM WAS TREATING THE FIRST
PATIENT WITH DIFFUSE LYMPHOMA
EVER WITH ABRUTINIB MODEL
THERAPY.
AND THE PLAN WAS, WELL, LET'S
JUST SEE IN 10 PATIENTS, AND WE
GOT GOOD RESULTS IN 10 PATIENTS.
AND THAT LED TO A NATIONAL
STUDY, WYNDHAM WILL TELL YOU
ABOUT THAT.
SO I THINK IT'S THAT
FEARLESSNESS THAT I'VE REALLY
ENJOYED, HIS OPENNESS TO IDEAS.
SO YOU'LL HEAR A LOT OF OTHER
STUDIES THAT ARE EVEN FARTHER
THERE.
SO I WANT TO LEAVE SOME TIME, I
DON'T WANT TO TAKE THE WHOLE
TIME.
YOU'VE DONE A LOT IN YOUR
CAREER, MAN.
SO MY PLEASURE TO INTRODUCE
WYNDHAM WILSON.
[APPLAUSE]
>> WELL, I'M GLAD THE LIGHTS
AREN'T TOO BRIGHT BECAUSE I
DON'T WANT YOU TO SEE ALL MY
REDNESS HERE.
OKAY.
SO, I'M GOING TO -- BECAUSE WE
HAVE A VERY DIVERSE AUDIENCE --
TAKE YOU THROUGH A 24-YEAR
JOURNEY FROM THE START OF WHEN
LOU AND I FIRST STARTED TO WORK
TOGETHER, ALL THE WAY THROUGH
WHERE WE CURRENTLY ARE.
AND THAT IS HOW LONG IT ACTUALLY
TOOK TO GET US TO WHERE WE ARE
NOW.
BUT I THINK THERE ARE MANY, MANY
LESSONS THAT WE CAN LEARN FROM
GOING THROUGH THIS.
SO, FOR THOSE THAT -- THOSE OF
YOU WHO, YOU KNOW, JUST TO PUT
LARGE CELL INTO PERSPECTIVE,
IT'S THE FIFTH MOST COMMON --
NOT LARGE CELL BUT LYMPHOMA IS
THE FIFTY MOST COMMON, LYMPHOMA
THE LARGEST.
WHERE ARE WE IN TERMS OF THIS
TUMOR?
WE CAN ACTUALLY CURE THIS.
AND WE'VE BEEN ABLE TO CURE
LARGE CELL SINCE THE EARLY
1970s USING JUST CHEMOTHERAPY
ALONE.
IN THE 1970s, ONLY AROUND 25
TO 30% OF PEOPLE COULD BE CURED.
BUT NOW WITH THE USE OF
IMMUNOTHERAPY, IN THIS CASE IT'S
RITUXIMAB, WE'RE CURING
SOMEWHERE IN THE -- SOMEWHERE
AROUND 60% OVERALL.
THIS MEANS THAT 30 TO 40% ARE
NOT CURED.
SO, WE NEED BETTER THERAPY, BOTH
FOR UP-FRONT THERAPY, BUT ALSO
ONCE SOMEBODY RELAPSES, THE
ABILITY TO CURE THEM IS VERY,
VERY LOW.
AND SHOWN HERE IS -- SO THIS IS
SHOWING WHAT THE CURE RATE OF
RELAPSE REFRACTORY LARGE CELL IS
USING STANDARD THERAPY AND OFTEN
BONE MARROW TRANSPLANT.
YOU CAN SEE YOU'RE ONLY CURING
IN THE RELAPSE STATE AROUND 12%.
SO, THE STATE OF THE ARCH WAS
VERY, VERY POOR.
I THINK WE'VE ALL BEEN VERY
EXCITED BY CAR T CELLS AND WE'RE
NOW SEEING IT BEING USED
EVERYWHERE.
BUT THE REALITY IS THERE'S A LOT
OF SELECTION GOING ON WHEN YOU
BRING PEOPLE IN FOR CAR T CELL
THERAPY.
WE'RE NOW FINDING THAT THERE'S
EMERGING LATE-TERM CHRONIC
TOXICITY INCLUDING INSERTIONAL
MUTAGENESIS, WHICH IS STILL RARE
BUT DOES LEAD TO PEOPLE DYING,
AND YOU CAN SEE THAT WE'RE ONLY
CURING AROUND 32% OF PEOPLE
USING CAR T CELLS.
SO THAT'S CERTAINLY BETTER THAN
12 BUT WE STILL HAVE A LONG WAY
TO MOVE THE FIELD.
NOW, I'M GOING TO TAKE US ALL
THE WAY BACK TO 2000 WHEN LOU
AND I FIRST STARTED TO WORK
TOGETHER.
AND THIS IS WHERE LOU LED THE
FIELD IN TRYING TO UNDERSTAND
WHAT THE MOLECULAR BASIS FOR
LARGE CELL IS, UP TO THIS POINT
LARGE CELL WAS SIMPLY DEFINED AS
BEING A B CELL TUMOR THAT WAS
RELATIVELY LARGE, AND IT GREW IN
A DIFFUSE PATTERN.
IT MOSTLY GREW WITHIN LYMPH
NODES, ALTHOUGH IT ALSO COULD GO
INTO OTHER SITES AS WELL.
WHEN YOU SAY DLBCL, DIFFUSE
LARGE CELL, I THINK IT DOESN'T
TAKE A ROCKET SCIENTIST TO
REALIZE THIS IS SO GENERAL THAT
IT'S PROBABLY NOT A SINGLE
DISEASE.
OF COURSE WE KNEW THAT
CLINICALLY BECAUSE SOME PEOPLE
WOULD DO VERY WELL, SOME PEOPLE
WOULDN'T, AND WE DIDN'T
UNDERSTAND WHY.
SO LOU REALLY I -- I THINK THE
FIRST MICROARRAY IN CANCER,
CERTAINLY THE FIRST MICROARRAY
IN LYMPHOID TUMORS, WHAT HE DID,
HE ARRAYED SEVERAL HUNDRED LARGE
CELLS AND ALSO ARRAYED NORMAL B
CELLS, TONSILS, ET CETERA, TO BE
ABLE TO ASK THE QUESTION WHETHER
OR NOT YOU COULD DIVIDE LARGE
CELL INTO DIFFERENT TUMORS,
BASED ON THEIR STAGES OF
DIFFERENTIATION WHERE YOU USED
AS YOUR GOLD STANDARD THE NORMAL
CELL.
AND THIS ACTUALLY WAS THE WHOLE
START OF THE FIELD OF TARGETED
THERAPY IN LARGE CELL.
AND THIS STUDY FROM "NATURE" WAS
PUBLISHED BY LOU IN 2000.
AND THE KEY HERE IS HE
IDENTIFIED TWO MAJOR GROUPS, ONE
WAS CALLED THE ABC, ACTIVATED B
CELL, AND THIS IS A TUMOR THAT
IS DERIVED FROM A POST-GERMINAL
CENTER, B CELL, THE OTHER MAJOR
GROUP IS GCB, GERMINAL CELL
B-CELL TUMOR DERIVED FROM CELLS
THAT STILL HAVE DIFFERENTIATION
STATE, MORE OR LESS, OF THE
GERMINAL CENTER.
AND SOMETHING WE'RE NOT GOING TO
BE DISCUSSING NOW IS ANOTHER
TOPIC, PRIMARY MEDIASTINAL, THIS
COMES FROM A THYMIC B CELL.
SO, UNDERSTANDING NOW WE HAVE
THESE TWO MAJOR GROUPS, ONE FROM
THE POST-GERMINAL CENTER, AND
ONE FROM A GERMINAL CENTER CELL.
BUT IF YOU REALLY WANT TO HAVE
TARGETED THERAPY, YOU WANT TO
UNDERSTAND WHAT THE CRITICAL
DRIVING SIGNALING OF PATHWAYS
ARE.
THE FIRST HINT OF THIS ALSO CAME
FROM LOU'S WORK WHERE HE LOOKED
AT EXPRESSION OF NF-kappaB
TARGET GENES, AS YOU KNOW
NF-kappaB IS A VERY POTENT
SURVIVAL FACTOR, AND WHAT HE
FOUND WAS THAT ABC HAD HIGH
EXPRESSION OF THESE NF-kappaB
TARGET GENES, WHEREAS GERMINAL
CENTER DID NOT.
SO, THIS THEN LED INTO
UNDERSTANDING THE BEGINNING OF
THE DISSECTION OF WHY IS
NF-kappaB INCREASED IN ABC
LARGE CELL, AND IT TURNS OUT
THAT IT IS INCREASED BY
CONSTITUATIVE B CELL RECEPTOR
SIGNALING AND YOU CAN SEE THE
CASCADE HERE.
AND WHAT WAS EVENTUALLY WORKED
OUT IN NUMBERS OF THESE CASES BY
LOU WAS THAT YOU HAVE ACTUAL
ACTIVATING MUTATIONS, HERE THIS
IS THE B CELL RECEPTOR ITSELF,
YOU HAVE ACTIVATING MUTATIONS
WITHIN THE RECEPTOR ITSELF, AND
THEN A COLLABORATING TOLL LIKE
RECEPTOR, 88, CAR 11, NOW A 20,
A TUMOR SUPPRESSOR, WHICH
INHIBITS NF-kappaB.
AND SO THIS WAS THE BEGINNING OF
UNDERSTANDING ALL THESE
MUTATIONS WERE ACCUMULATED
WITHIN MANY OF THE ABC TUMOR
CELLS, BECAUSE THEY WERE
ENHANCING B CELL SIGNALING,
ULTIMATELY NF-kappaB.
SO, THIS ACTUALLY TAKES TO US
WHERE LOU LED OFF THIS MORNING,
THAT HE WENT TO A CONFERENCE
WHERE THEY PRESENTED SOME DATA
WITH IBRUTINIB THAT INHIBITED
TYROSINE KINASE, BTK IS RIGHT
HERE, LOU HYPOTHESIZED IF WE
EXPOSED PATIENTS TO THIS DRUG,
THAT WE WOULD SEE TUMOR
REDUCTIONS IN ABC BECAUSE THAT'S
THE GROUP THAT HAD THE
NF-kappaB, CONSTITUATIVE BCR
SIGNALING, WHEREAS WE WOULDN'T
SEE IT WITHIN THE GERMINAL
CENTER.
I SAID, OH, YEAH, RIGHT, RIGHT,
RIGHT.
I MEAN, I HAD ALREADY TESTED
MANY, MANY DRUGS BEFOREHAND,
CAMTOTHECINS, TAXOL, SO MANY
NEVER PANDEMIC OUT.
THIS WAS ONE OF THE FIRST
TARGETED AGENTS I HAD EVER
WORKED WITH.
SO I SET UP A CLINICAL TRIAL
WITH LOU.
IT WAS A SMALL PILOT STUDY WHERE
WE BROUGHT IN RELAPSED
REFRACTORY LARGE CELL AND WE
EXPOSED THEM TO IBRUTINIB AND
THEN WE'RE CHARACTERIZED WHETHER
OR NOT THEY WERE OF THE ABC OR
GERMINAL CENTER TYPE.
AND THIS IS WHAT WE FOUND.
THIS IS WHAT'S CALLED A
WATERFALL PLOT, PERCENT CHANGE
IN TUMOR SIZE, AND ANYTHING
BELOW THIS LINE MEANS TUMOR
SHRINKS, DOWN 50% IS HERE, DOWN
100% HERE.
WHEREAS THIS MEANS THE TUMOR
GROWS.
AND I DON'T KNOW IF YOU CAN
APPRECIATE THAT, BUT IN GENERAL,
THERE WERE CERTAINLY FEWER OF
THESE GERMINAL CENTER TYPES THAT
SHRANK WELL ACTIVE TO THE ABC
TYPE.
BUT WHEN WE ACTUALLY GO TO
IDENTIFY WHETHER OR NOT WE
CONSIDER IT TO BE A CLINICALLY
MEANINGFUL CHANGE, WE REQUIRE IT
TO BE AT LEAST A 50% OF
REDUCTION IN TUMOR SIZE.
SO WHEN WE USE THAT CRITERIA,
WHAT WE FOUND WAS THAT THE ABC
TYPE HAD 15 OUT OF 39 PATIENTS
HAVE AT LEAST A 50% SHRINKAGE
AND ALMOST HALF OF THOSE HAD A
COMPLETE RESOLUTION OF THEIR
TUMOR.
WHEREAS IN THE GERMINAL CENTER
TYPE, THERE WAS ONLY ONE OUT OF
20, SO THIS REALLY WAS THE FIRST
VALIDATION CLINICALLY THAT THIS
DRUG MIGHT BE PREFERENTIALLY
USEFUL WITHIN THE ABC TYPE.
NOW, LOU AND I WENT ON FURTHER
AND ASKED THE QUESTION AS TO
WHETHER OR NOT THERE WERE
CERTAIN TYPES OF ABCs THAT
MIGHT BE MORE OR LESS SENSITIVE
TO THIS DRUG, AND WE KNEW THAT
THERE WERE ALL THESE MUTATIONS
THAT I'VE ALREADY POINTED OUT,
MYD88, AND THE BCR RECEPTOR, AND
WE FELT THAT IF A TUMOR IN FACT
HAD BOTH OF THESE THEY WOULD
HAVE BEEN HYPER-ADDICTED TO B
CELL RECEPTOR SIGNALING.
AND SO WHEN WE ACTUALLY LOOKED
AT -- THESE WERE RELATIVELY
SMALL NUMBERS BUT YOU CAN SEE
AMONG THOSE TUMORS FIVE CASES
THAT HAD BOTH A MUTATION WITHIN
THE BCR RECEPTOR ITSELF AS WELL
AS MyD88, THE RESPONSE RATE
WAS 4 OUT OF 5.
WE ALSO FOUND THAT IF IT WAS
ONLY MyD88 ALONE, OR A WILD
TYPE, THAT THEY ALSO RESPONDED
BUT AGAIN NOT AS VIGOROUSLY AS
IF THEY HAD BOTH OF THESE.
SO WE IDENTIFIED THIS GROUP AS A
GROUP THAT WAS HYPERADDICTED TO
B CELL RECEPTOR SIGNALING.
ONE THING I WANT TO POINT OUT,
AND THIS IS CRITICAL, WHEN
YOU'RE DEALING WITH TUMORS THAT
HAVE MULTIPLE DIFFERENT
MUTATIONS, LIKE LARGE CELL DOES,
AND EVEN THOSE THAT ARE OF THE
SINGLE TYPE SUCH AS ABC, THERE
ARE MULTIPLE POINTS THAT THE
TUMOR IS ABLE TO HIT IN ORDER TO
INCREASE NF-kappaB AND SO IF
YOU HAVE A SINGLE DRUG THERE'S
LIKELY TO BE A WORKAROUND BY THE
TUMOR CELLS, MEANING IF WE
SIMPLY LOOK AT A KAPLAN-MEIER
CURVE, WHETHER OR NOT WE HAVE
DURABLE RESPONSES TO THESE
DRUGS, YOU CAN SEE AS A SINGLE
AGENT, ALTHOUGH IBRUTINIB MADE
THE TUMOR SHRINK IN 40% OF ABC
TYPES, THESE WERE NOT DURABLE.
A SINGLE AGENT WAS NOT CURATIVE.
I WILL SAY THERE WAS LIKE ONE OR
TWO PATIENTS THAT WENT ON TO
STAY IN REMISSION FOR YEARS AND
YEARS, BUT THAT WAS BY FAR A
VERY RARE EVENT.
IF WE LOOK AT THE GCB TYPE, WE
SEE NONE.
I'M GOING TO NOW JUMP AHEAD TO
ANOTHER CLASSIC PAPER THAT LOU
PUBLISHED IN 2018 WHERE HE THEN
FURTHER SUBDIVIDED LARGE CELLS
INTO GENETIC TYPE BASED ON
PROFILE.
IT TURNS OUT ABC TYPE CAN BE
DIVIDED INTO MULTIPLE TYPES, AND
THE GERMINAL CENTER TYPE
SIMILARLY.
WHAT I WANT TO POINT OUT IS THAT
THE MCD TYPE, THIS ONE UP HERE,
IS CHARACTERIZED BY HAVING THESE
MUTATIONS WITHIN MyD88 AND
CD79B, SO THIS IS WHAT WE
CONSIDER TO BE THE POSTER CHILD
FOR FOR HYPERADDICTED LARGE
CELLS TO B CELL RECEPTOR
SIGNALING.
SO, HOW COULD WE FURTHER TEST
THIS IDEA THAT INHIBITING BTK
COULD BE ESPECIALLY ACTIVE
WITHIN THAT GROUP?
WELL, TURNS OUT THERE IS A TYPE
OF TUMOR WHERE THE CHANCE OF
HAVING BOTH MyD88 AND CD79B IS
VERY, VERY HIGH.
IF YOU LOOK ACROSS YOUR
CONVENTIONAL ABCs, AND AGAIN
MOST TUMORS, LARGE CELL, GROW
WITHIN NODES THAT YOU CAN SEE
THAT AMONG SO-CALLED NODAL LARGE
CELL, THAT'S ABC TYPE, HAVING
BOTH IS RELATIVELY RARE.
BUT IT TURNS OUT THAT IF YOU
LOOK AT EXTRA-NODAL TUMORS,
FOCUSING ON PRIMARY CNS, 37% OF
THESE TUMORS HAVE BOTH OF THESE,
AND THIS TUMOR TYPE IS HIGHLY
ENRICHED FOR MCD TYPE.
SO, WE ASKED THE QUESTION, OKAY,
WE THINK THIS DRUG SHOULD WORK
REALLY, REALLY WELL THERE, BUT
NOBODY HAD EVER TESTED IT.
SO, WE WENT AHEAD AND DID
ANOTHER CLINICAL TRIAL.
THIS IS A LITTLE DIFFERENT
STUDY.
IN THIS CASE WE ALSO TOOK
RELAPSED REFRACTORY TUMORS, THEY
WERE ALL OF THESE PRIMARY CNS
TYPES, AND WE DID A WINDOW USING
IBRUTINIB ALONE FOR A TWO-WEEK
PERIOD AND ADDED THAT TO
CHEMOTHERAPY.
THE REASON WE DID THAT IS
BECAUSE THESE ARE HIGHLY LETHAL
TUMORS.
ONCE YOU RECUR, THE CHANCE OF
DYING FROM THEM IS ESSENTIALLY
100%.
AND SO WE FELT THAT GIVEN THE
WORK WE HAD DONE WITH IBRUTINIB
WE WERE HOPING THE IBRUTINIB
WOULD SHRINK TUMORS DOWN BUT
DIDN'T THINK IT WOULD ERADICATE
THEM.
I WON'T GO INTO THE ENTIRE
CLINICAL TRIAL.
THE THERAPY IS CALLED TEDDY-OR,
A PROGRAM MARK IS LEADING BUT
I'M SHOWING THE WATER FALL PLOT
FROM THIS TWO-WEEK WINDOW.
EVERY PATIENT BUT ONE HAD
SIGNIFICANT SHRINKAGE OF TUMOR.
TWO IN FACT ACHIEVED A COMPLETE
REMISSION WITH THIS DRUG.
SO THIS REALLY WAS A VERY
EXCITING FINDING THAT
HYPERADDICTED ABC TUMORS WOULD
BE HYPERSENSITIVE TO INHIBITING
ABRUTINIB TYROSINE KINASE.
WE DID A LARGE INTERNATIONAL
PHASE 3 TRIAL ADDING IBRUTINIB
IN PATIENTS WITH NON-GCB LARGE
CELL.
THIS WAS UNTREATED, RANDOMIZED
STUDY, PATIENTS WERE RANDOMIZED
IN A BLINDED FASHION TO GET
R-CHOP STANDARD OF CARE PLUS OR
MINUS IBRUTINIB THERAPY.
I'M NOT GOING INTO WHY WE HAVE
THIS BASED ON AGE BUT TURNED OUT
IBRUTINIB IS TOXIC IN PEOPLE
THAT ARE OLDER BUT YOU CAN SEE
THOSE PATIENTS WITH ABC TYPE AND
PATIENTS UNDER 60 ALL HAD
SIGNIFICANT CLINICAL BENEFIT AND
INCREASED CURE WHEN EYE
IBRUTINIB WAS ADDED TO R-CHOP.
MCD IS HYPERADDICTED, AND 100% OF THOSE PATIENTS THAT RECEIVED
R-CHOP PLUS IBRUTINIB ARE CURED
VERSUS ABOUT 40% OF THOSE WHO
RECEIVE R-CHOP ALONE.
SO, THIS IS ALL BUILDING ON THIS
IDEA THAT THE BCR RECEPTOR
SIGNALING CASCADE IS SOMETHING
THAT WE SHOULD BE FOCUSING ON TO
DEVELOP A TARGETED THERAPY.
SO, JUST TO KIND OF BRING US ALL
AT THE SAME POINT HERE, WE'VE
SEEN THAT LARGE CELL IS NOT A
SINGLE DISEASE TYPE.
IT IS A VERY COMPLEX DISEASE
TYPE WITH MANY DIFFERENT TYPES.
IT'S SIMPLY DEFINED BY BEING
LARGE, B, AND GROWING IN A
DIFFUSE WAY.
AND THAT HITTING THE BCR
SIGNALING IS EFFECTIVE,
ESPECIALLY IN THOSE THAT ARE
HYPERADDICTED TO IT, AND THAT
THERE ARE MULTIPLE MUTATIONS
ALONG THE BCR SIGNALING THAT ARE
ENHANCING NF-kappaB.
SO, HOW DO WE THINK ABOUT THIS
IN TERMS OF TRYING TO COME UP
WITH A WAY TO HIT MULTIPLE
POINTS IN THIS CASCADE AND TO
CURE PEOPLE WITH THIS TUMOR?
AND SO, AGAIN, I GO BACK TO THIS
HERE, AND YOU CAN SEE AGAIN ALL
THE DIFFERENT MUTATIONS, AND SO
THIS IS WHERE WE WERE WHEN LOU
AND I AND THE TEAM BEGAN TO
THINK ABOUT HOW DO WE COME UP
WITH A BETTER THERAPY, BETTER
TARGETED THERAPY.
FIRST OFF, THE STATE OF THE ART
WAS THAT TARGETED THERAPIES WERE
CONVENTIONALLY GIVEN AS SINGLE
AGENTS, WE ACTUALLY STARTED SOME
OF THAT BY HAVING GIVEN
IBRUTINIB AS A SINGLE AGENT.
AND THEY WERE GIVEN CHRONICALLY
AND ONLY GIVEN AS A SINGLE OR A
DOUBLET BECAUSE IF YOU TRIED TO
GIVE THESE KINDS OF AGENT,
MULTIPLE AGENTS CHRONICALLY, YOU
SIMPLY CAN'T DO IT.
RUN INTO INTO MANY SIDE EFFECTS
THAT LIMIT YOUR ABILITY TO KEEP
GIVING THEM, ET CETERA.
AND THIS APPROACH IS SIMPLY NOT
CURATIVE IN LARGE CELL.
SO, WE KNEW FROM LOOKING AT ALL
THE MUTATIONS THAT WE WOULD HAVE
TO HIT MULTIPLE POINTS IN ORDER
TO COME UP WITH A THERAPY THAT
WOULD BE CURATIVE.
AND SO THE PRINCIPLES WE HAVE TO
THINK OF HERE IS THAT
COMBINATIONS OF DRUGS IDEALLY
SHOULDN'T JUST BE ADDITIVE BUT
SYNERGISTIC, ESPECIALLY IF
YOU'RE HITTING MULTIPLE POINTS
IN A CASCADE YOU CAN IMAGINE
FROM A FIRST PRINCIPLE POINT OF
VIEW EXPECT MORE THAN EACH ONE
ALONE.
YOU WANT YOUR COMBINATIONS TO BE
SYNERGISTIC.
BUT IN ORDER TO DO THAT, YOU
HAVE TO GIVE ALL THE DRUGS AT
THE SAME TIME.
AND YOU ALSO WANT TO MAKE SURE
THAT YOU GIVE AS HIGH A DOSE AS
YOU CAN, BECAUSE IF YOU GIVE TOO
LOW A DOSE RESISTANCE COMES UP,
OR YOU'RE SIMPLY NOT AT ADEQUATE
DOSE IN ORDER TO ACTUALLY
INHIBIT YOUR TARGET.
AND YOU NEED TO COME UP WITH
DRUGS THAT HAVE WHAT ARE CALLED
NON-OVERLAPPING SERIOUS
TOXICITY.
IF YOU COMBINE A BUNCH OF DRUGS
THAT ALL HIT THE MARROW, THEN
YOU'RE LIMITING YOUR ABILITY TO
GIVE THEM BECAUSE YOU'RE SIMPLY
WIPING OUT MARROW FUNCTION, AND
WE ALL KNOW THAT WHEN YOU GET
DOWN TO VERY LOW NEUTROPHIL
COUNTS YOU GET INTO ISSUES WITH
FEVER, NEUTROPENIA, AND DEATH.
SO IN ORDER TO DO THAT, YOU NEED
TO LIMIT CYCLE TIMES.
YOU NEED TO HAVE BREAKS.
AND YOU DON'T GIVE THE DRUGS
CHRONICALLY.
SO, WITH THESE PRINCIPLES, WE
LOOKED TO SEE WHAT DRUGS ARE
THERE OUT THERE THAT WOULD HIT
DIFFERENT POINTS OF THE BCR
RECEPTOR CASCADE.
WE SPENT A LOT OF TIME TALKING
ABOUT IBRUTINIB.
WELL, IT ACTUALLY TURNS OUT
PREDNISONE INHIBITS BCR
SIGNALING UPSTREAM OF BRUIN
TYROSINE KINASE, EFFECTS ON
DECREASING BCR AND SAR KINASE, A
FREEBIE.
IF YOU GIVE IN LIMITED CYCLES
THEY ARE WELL TOLERATED AND
DON'T HAVE BAD SIDE EFFECTS.
WHAT CAME OUT OF THE WORK WE
WERE DOING HERE WAS THE FIRST
EVIDENCE THAT IN FACT STEROIDS
WAS A POTENT WAY TO INHIBIT BCR
SIGNALING.
SO, THAT ACTUALLY CAME OUT OF
THIS WORK.
AND THEN FINALLY WORK THAT LOU
DID WAS LOOK AT LENALIDOMIDE,
AND THIS INHIBITS DOWNSTREAM OF
BRUTIN TYROSINE KINASE BY
INHIBITING IRF 4 AND SPE-B, AS A
RESULT NF-kappaB AND BY
TURNING THOSE OFF BECAUSE THEY
TURN OFF INTERFERON BETA, IT
GOES UP, TOXIC TO LARGE CELLS.
SO WE'RE NOW HITTING THE BCR
SIGNALING AT THREE DIFFERENT
POINTS.
WELL, WE ALSO WANTED TO INHIBIT
BCL-2 AS WELL, BCL-2 IS HIGHLY
EXPRESSED WITHIN ABC TUMORS, AND
SO WE ASSUMED IT PLAYED A
CRITICAL ROLE BASICALLY BLOCKING
APOPTOSIS, WE HAD THE DRUG
VENETOCLAX AND USED ANTI-CD20
ANTIBODIES, THIS IS ONE OF THE
NEWER ONES, AND THESE DRUGS HAVE
A NUMBER OF IMMUNE EFFECTS, AND
KILL TUMOR CELLS ADCC AND
COMPLEMENT MEDIATED
CYTOTOXICITY.
SO THIS WAS THE DRUGS IN OUR
ARMAMENTARIUM THAT WE HAD TO
PLAY WITH.
AND SO, AS I SAID, YOU WANT
THESE DRUGS TO SHOW SYNERGY, SO
IN FACT IN THE LAB USING ABC
LINES WE CAN SEE VENETOCLAX AND
IBRUTINIB SHOW TREMENDOUS
SYNERGY HERE.
THIS IS A NUMBER OF LIVE CELLS,
AND THE VENETOCLAX DOSE, AND YOU
CAN SEE THE CURVE SHIFTING TO
THE LEFT.
SIMILARLY, STEROIDS IN THIS CASE
WE USED DEXAMETHASONE, AND
IBRUTINIB, ALSO SHOWED SYNERGY
AS DID COMBINATIONS OF IBRUTINIB
AND LEN.
WHEN YOU LOOK AT THE SAME TIME
YOU CAN SEE EACH OF THESE DRUGS
ARE AS SINGLES, AND WHEN WE
COMBINED ALL OF THEM YOU CAN SEE
THIS CASPASE ASSAY WOULD GET
VERY LARGE CELL KILL.
SO, THIS REALLY WAS THE
LABORATORY EVIDENCE BASED ON THE
CLINICAL WORK WE HAD DONE THAT
COMBINING THESE DRUGS, IF WE
COULD, WOULD POSSIBLY CURE
RELAPSE REFRACTORY LARGE CELL.
AND SO BASED ON THOSE PRINCIPLES
THAT I WENT OVER WITH YOU, THIS
IS THE WAY WE DECIDED TO
SCHEDULE.
FIRST, WE ONLY GAVE THE DRUGS
FOR SIX CYCLES.
SO YOU WOULD GIVE THEM IN
PACKETS OF THREE WEEKS, AND YOU
WOULD HAVE TWO WEEKS ON
ESSENTIALLY AND ONE WEEK OFF.
AND YOU CAN SEE HERE, I DON'T
NEED TO GO OVER THE ACTUAL
SCHEDULING, BUT YOU CAN SEE THAT
THESE DRUGS ARE MOSTLY GIVEN FOR
THE FIRST TWO WEEKS, THEN YOU'VE
GOT A BREAK, AND WE DO THIS FOR
SIX CYCLES AND STOP.
AGAIN, QUITE DIFFERENT FROM THE
WAY SINGLE AGENTS OR DOUBLETS
ARE GIVEN IN LARGE CELL BECAUSE
THEY ARE NOT CURATIVE, THEY
DON'T STOP THEM UNTIL THE TUMORS
GROW.
WITH LARGE CELLS TUMORS GROW
RELATIVELY SOON, SO, YES,
SOMETIMES THEY CAN WORK VERY,
VERY WELL, BUT ONLY IN A VERY
SMALL NUMBER, AND ALMOST NEVER
CURE.
SO, THIS IS WHERE WE STARTED,
AND THIS IS THE VIPOR THERAPY
THAT I'M GOING TO SHOW YOU.
SO WE DID A STUDY, THIS WAS ALL
RELAPSE CASES, TOTAL OF 50
CASES.
MEDIAN AGE WAS 61, WITH A RANGE
OF 29 TO 77.
LARGE CELLS DO OCCUR MOSTLY IN
MEN, IN THIS CASE 66%.
AND THIS IS JUST GIVING YOU A
BREAKDOWN AGAIN BY THE
HISTOLOGY, BY THIS NOMENCLATURE
FOR THE NON-GCB, 36%, FOR GCB IT
WAS 24%.
AND SOMETHING I'LL BE DISCUSSING
IN A BIT IS SOMETHING CALLED
HIGH GRADE B-CELL LYMPHOMA
DOUBLE HIT.
THESE ARE MOSTLY GCB TUMORS, BUT
THEY HAVE TRANSLOCATIONS ABOVE
MYC AND BCL-2.
AND AMONG THE GCB TUMORS THEY DO
VERY, VERY POORLY.
CONVENTIONAL CHEMOTHERAPY DOES
NOT WORK WELL.
IT EPOCH SCATTER MOST EFFECTIVE
THERAPY BUT ONLY THERE CURING
65% OF CASES.
THIS GROUP AGAIN THESE ARE ALL
RELAPSE CASES, 68% HIGH RISK,
THREE PRIOR THERAPIES, 40%
THROUGH CAR T CELL.
WHEN YOU GIVE CAR T CELL, AND
YOU'RE NOT CURED, AGAIN 70% ARE
NOT CURED, AS PART OF THE CAR-T
CELLS YOU GIVE FLEWDEROBINE AND
CYCLOPHOSPHORIDE TO MAKE ROOM,
THAT'S CRITICAL.
WHEN YOU WIPE OUT NORMAL T CELL
REPERTOIRE, YOU CAUSE SEVERE
LONG-TERM TOXICITY TO IMMUNE
FUNCTION, BONE MARROW FUNCTION,
AND IT'S VERY DIFFICULT TO GIVE
THERAPY AFTER CAR-T CELLS AND IN
FACT IN A NUMBER OF STUDIES THE
CURE RATE AFTER CAR T CELL IS
LIKE 5%, MOST PEOPLE DIE WITHIN
SIX MONTHS.
WE FOUND OUT IT'S A REAL
CHALLENGE TO TAKE THESE CAR T
CELL FAILURES BUT EVERYONE IS
GETTING CAR-T CELLS, AND SO THEY
SHOULD, BECAUSE COMPARED TO
STANDARD THERAPY IT IS A BETTER
OPTION.
BUT, AGAIN, YOU'RE LEFT WITH
SOME VERY SEVERE ISSUES.
NOW, ONE THING THAT WAS VERY
GRATIFYING, WE'RE COMBINING ALL
THESE DRUGS, YOU WORRY ABOUT
SIDE EFFECTS, BUT BECAUSE OF THE
WAY WE SCHEDULED IT, BECAUSE OF
THE TYPES OF DRUGS WE ACTUALLY
CHOSE, IT TURNED OUT THAT THE
THERAPY WAS EXTREMELY WELL
TOLERATED.
GENERALLY SPEAKING WHEN YOU
TREAT RELAPSE REFRACTORY
PATIENTS THEY ALREADY HAVE
PRETTY BEAT UP MARROW FUNCTION,
AND SO HEME TOXICITY IS
RELATIVELY HIGH.
WE FOUND GRADE 4, MUCH LESS
CONCERNED ABOUT GRADE 3, WAS
ONLY SEEN IN 8% OF CYCLES FOR
PLATELETS, AND NEUTROPENIA ONLY
SEEN IN 10% OF CYCLES, AND WHAT
WAS MOST GRATIFYING IS THAT
FEVER AND NEUTROPENIA, WHICH
MEANS YOU HAVE A WHITE COUNT
BELOW 500, YOU'RE AT RISK OF
GETTING A BACTERIAL INFECTION,
USUALLY DUE TO SEEDING FROM THE
GUT, WITH STANDARD CHEMOTHERAPY
UP FRONT IT'S AROUND 15% OF
PEOPLE GET FEVER AND
NEUTROPENIA.
IN THE SALVAGE SETTING IT CAN
APPROACH 40%.
AND IN THIS STUDY WE SAW 1%.
SO, IT WAS NOT CAUSING BONE
MARROW DYSFUNCTION THE WAY
STANDARD CHEMOTHERAPY DOES.
AND SO THIS IS ACTUALLY SHOWING
THE WATERFALL PLOT OF THE LARGE
CELLS THAT WE TREATED.
I JUST WANT TO POINT OUT THIS IS
THE 50% MARK HERE.
AND THIS IS GERMINAL CENTER,
NON-GERMINAL CENTER, THIS IS THE
GERMINAL CENTER WITH THE MYC
TRANSLOCATION, WHICH IS THE
SO-CALLED DOUBLE HIT.
I THINK I'M MISSING SOME THINGS
HERE, BUT THAT'S OKAY.
LET ME NOW ZONE ON THE ACTUAL
RESPONSE RATES WITHIN THIS
CLINICAL TRIAL.
IF WE LOOK AT ALL COMERS, AND
AGAIN WE WERE FOCUSING ON BCR
RECEPTOR SIGNALING HERE, SO OUR
HYPOTHESIS WAS AS WE SHOWED WITH
IBRUTINIB IN THE VERY FIRST
TRIAL, THAT IS UNLIKELY THAT
VIPOR WAS GOING TO CURE GERMINAL
CENTER TUMORS.
IF WE LOOK AT ALL COMERS,
GERMINAL CENTER, NON-GERMINAL
CENTER AND DOUBLE HIT MOST WHICH
WERE GERMINAL CENTER, WE SAW A
COMPLETE REMISSION RATE OF 38%.
IF WE FOCUS DOWN ON NON-GERMINAL
CENTER TYPE, THE GROUP THAT IS
ENRICHED FOR THESE TUMORS THAT
HAVE B CELL RECEPTOR SIGNALING,
WE NOW SEE THAT THERE'S A 62%
COMPLETE REMISSION RATE.
THIS WAS A VERY GRATIFYING
FINDING, NUMBER ONE, THAT IT WAS
SO MUCH HIGHER THAN WE THOUGHT
WE WOULD SEE.
BUT WHAT WAS NOT EXPECTED AND
I'M GOING TO SHOW WHY WE THINK
IT'S THE CASE, AND THIS IS WHY
WHEN YOU DO A CLINICAL TRIAL
UNLESS YOU KNOW FOR SURE YOU
INCLUDE ALL COMERS BECAUSE
UNEXPECTED THINGS CAN SHOW UP.
WE FOUND AMONG THESE DOUBLE HIT
CASES, GERMINAL CENTER TYPES,
THAT HAVE A TRANSLOCATION OF
BOTH BCL-2 AND MYC, THIS
COMPLETE REMISSION RATE WAS 53%.
SALVAGE THERAPY OF THESE DOUBLE
HITS IS RARELY EFFECTIVE.
AND SO MOST OF THESE CASES USING
STANDARD CHEMOTHERAPY DO VERY
POORLY, AND AS IT TURNS OUT
CAR-T CELLS IN SOME CLINICAL
TRIALS DON'T SEEM TO DO WELL
WITH THIS GROUP EITHER.
AND THEN THESE OTHER TWO I'M NOT
GOING TO REALLY FOCUS ON.
OH, SO FINALLY, WHAT DID WE SEE
WITHIN GERMINAL CENTER?
THIS IS GERMINAL CENTER
EXCLUDING THESE DOUBLE HIT,
EXCLUDING GERMINAL CENTER TYPES
THAT HAVE THE TRANSLOCATION OF
MYC AND BCL-2.
RESPONSE RATE 33%.
C.R. RATE ZERO, MEANING IT IS
UNLIKELY WE WERE CURING A SINGLE
ONE.
AND THIS IS JUST KIND OF SHOWING
YOU WHAT HAPPENS WHEN YOU HAVE A
VERY EFFECTIVE THERAPY.
THIS IS A MIDDLE AGE MAN,
NON-GERMINAL CENTER LARGE CELL,
HAD FAILED SIX PRIOR THERAPIES,
HAD CHEMOTHERAPY, CAR T CELLS,
BI-SPECIFICS, CAME IN MASS
DISEASE EVERYWHERE, BONES
EVERYWHERE, WITHIN ONE CYCLE YOU
CAN SEE TREMENDOUS SHRINKAGE,
WITHIN TWO CYCLES IT WAS ALMOST
ALL GONE.
SO WHEN THESE DRUGS WORK, THEY
WORK VERY, VERY QUICKLY.
SO, ARE THESE DURABLE?
AND WHAT I CAN TELL YOU WITH
LARGE CELL IS THAT IF YOU DON'T
RECUR BY 18 MONTHS, THE CHANCES
THAT YOU'RE CURED IS 90%-PLUS.
AND SO I'M JUST SHOWING YOU THIS
IS FOR ALL COMERS.
GCB, NON-GCB, DOUBLE HIT, BLAH,
BLAH, BLAH.
OVERALL WE'RE SITTING HERE AT
34%, AT 24 MONTHS.
THIS ONE TICK HERE IS
UNFORTUNATELY A POOR SOUL THAT
WAS IN REMISSION AND DIED FROM
COVID.
SO WE'VE NOT SEEN A SINGLE
RECURRENCE AFTER 18 MONTHS.
BUT IF WE LOOK AT USING VIPOR
EARLIER ON, SHOWN WITH CAR T
CELL AS WELL, THIS IS LOOKING AT
VIPOR AFTER PEOPLE WHO HAD ONE
PRIOR THERAPY, CAN YOU SEE THE
DURABLE C.R. RATE, ALL COMERS
INCLUDING GERMINAL CENTER, WAS
60%.
SO WHEN YOU MOVE THESE THERAPIES
EARLIER ON, THEY TEND TO HAVE
BETTER OUTCOMES AND THAT'S TRUE
WITH CAR-T CELLS AND LOOKS TO BE
TRUE WITH VIPOR.
WHEN YOU GO INTO A C.R. 78% OF
PATIENTS STAYED THERE.
SO DURABLE, CURATIVE, IN 78% IN
THIS PARTICULAR GROUP OF
PATIENTS THAT WENT INTO C.R.
AND SO WHEN WE LOOK AT THE
CURVES BASED ON GCB, NON-GCB AND
DOUBLE HIT, GCB, THE NON-GCB,
THE DOUBLE HITS, AND THE T CELL
RICH, WHICH MARK OUT AS NON-GCB,
HAVE LONG-TERM PFSs AND
PROBABLY CURES IN 38 TO 47%
RANGE.
LOOK AT GERMINAL CENTER, WHICH
IS THE NON-DOUBLE HIT, IT IS NOT
CURATIVE.
AND ACTUALLY TURNS OUT THAT THIS
THERAPY IS HIGHLY TARGETED, IT'S
MUCH MORE EFFECTIVE IN
NON-GERMINAL CENTER TYPE
COMPARED TO GERMINAL CENTER
TYPE, AND IN DOUBLE HIT GERMINAL
CENTER TYPE VERSUS GERMINAL
CENTER TYPE.
AND IF WE LOOKED AT ITS USE IN
CAR T CELLS, AGAIN THIS IS A
DEATH DUE TO COVID, 30% OF ALL
COMERS WITH POST CAR T FAILURE
HAVE REMAINED IN C.R., AGAIN
SMALL NUMBERS, BUT THE DATA
SEEMS TO BE HOLDING UP.
AND SO FINALLY WE ALSO DID CTDNA
AS WELL, TO MAKE SURE THAT THERE
WEREN'T SMALL NUMBERS OF CLONES,
AND SO WHAT WE SHOW HERE IS THIS
IS ACTUALLY SHOWING
QUANTITATIVELY THE ctDNA
AMOUNT AS BASELINE STATUS POST
CYCLE 1, 2, AND OF TREATMENT,
THIS IS LOOKING AT ALL COMERS,
I'M GOING TO BE REMINDING YOU
THAT WE HAD ABOUT 38% COMPLETE
REMISSION RATE, BY PET, AND YOU
CAN SEE LOOKING AT MRD NEGATIVE
IT'S AT 38%.
BUT I THINK TELLS YOU A LITTLE
BIT MORE HERE IS IF WE SIMPLY
LOOK AT PATIENTS THAT WENT INTO
C.R., WHAT I WANT TO POINT OUT
IS THAT BY CYCLE 1, 73% OF THE
PATIENTS THAT ACHIEVED CLINICAL
C.R. WERE MRD NEGATIVE BY CYCLE
1.
THIS IS EVIDENCE OF HIGHLY
EFFECTIVE AND HIGHLY SENSITIVE
TUMORS TO THIS PARTICULAR
THERAPY, IT INCREASED SOMEWHAT
BY CYCLE 2, AND BY THE END OF
TREATMENT 93% OF THE C.R.s
ARE ctDNA NEGATIVE AND STAYED
THAT WAY AMONG THOSE THAT HAVE
NOT RECURRED AFTER 18 MONTHS.
AND SO I'M JUST GOING TO SHOW
YOU SOME KAPLAN-MEIER CURVES.
THIS IS FOR ALL CASES.
AMONG THOSE PATIENTS THAT BECAME
MRD NEGATIVE BY CYCLE 2 YOU CAN
SEE 70% OF THOSE HAVE DURABLE
C.R.s, AND THAT THIS IS JUST
SHOWING END OF THERAPY.
SO, MY FINAL THING IS GOING TO
BE WHY IS VIPOR EFFECTIVE IN
THESE DOUBLE HITS?
I WANT TO FOCUS ON HERE AS PART
OF THIS GENOMICS THAT LOU DID
THERE'S A GROUP CALLED EZB,
MUTATIONS WITHIN THOSE PATHWAYS,
YOU CAN GIVED THEM INTO MYC
PLUS, TRANSLOCATED VERSUS MYC
NEGATIVE.
AND IF YOU GO TO THE OLD
LITERATURE, YOU'LL SEE THAT MYC
IS A DOUBLE-EDGED SWORD.
ON ONE HAND IT PROMOTES SURVIVAL
AND PROMOTES PROLIFERATION, BUT
ON THE OTHER HAND IT ACTUALLY
SETS THE TUMORS UP FOR
APOPTOSIS, AND IN FACT WHEN YOU
LOOK AT BURKETT LYMPHOMA,
CHARACTERIZED BY HAVING A MYC
TRANSLOCATION, HIGH RATE OF
SPONTANEOUS RATE OF APOPTOSIS.
MAYBE WHAT'S GOING ON BCL-2,
TRANSLOCATED IN THESE TUMORS,
ARE CRITICAL TO BLOCK THAT
APOPTOTIC SIGNAL AND THEREFORE
ALLOWING THESE DOUBLE HIT TUMORS
TO ACTUALLY PROLIFERATE AND
SURVIVE.
SO, WE ASKED THE QUESTION,
WHETHER OR NOT AS A SINGLE AGENT
THIS WOULD BE MORE ACTIVE IN GCB
TUMORS THAT HAVE Bcl TWO AND
MYC TRANSLOCATION, WITH
VENETOCLAX, AS A SURROGATE FOR
WHETHER OR NOT INHIBITING BCL-2
WOULD CAUSE THOSE TUMORS TO
ACTUALLY DIE.
AND THIS IS WORK DONE BY JIM
PHALEN, AND I'M JUST GOING TO
SHOW YOU HERE THESE ARE MULTIPLE
DOUBLE HIT LINES.
VENETOCLAX KILLS THEM.
WE THINK THIS IS PROBABLY A
MAJOR REASON WHY VIPOR TURNED
OUT TO BE HIGHLY EFFECTIVE IN
DOUBLE HITS, NO IDEA GOING INTO
THIS.
FINALLY, LAST SLIDE, LOTS OF
DRUGS AND YOU ALL MIGHT SAY OH
MY GOD, YOU KNOW, THESE DRUGS,
THEY COST $120,000 FOR A YEAR'S
WORTH.
THIS MUST COST A FORTUNE.
AND THE ANSWER IS NOT REALLY.
I MEAN, IT'S STILL COSTLY BUT
COMPARED TO GIVING SINGLE
AGENTS, ON A CHRONIC BASIS, EVEN
CAR-T CELLS, IT'S ACTUALLY A
BARGAIN, SIX CYCLES OF THIS
COSTS $169,000, AND THESE ARE
USING THE VENETOCLAX AS A SINGLE
AGENT, IBRUTINIB, R SQUARED,
THIS IS BENOTUZOMBAB, GIVING
THEM THE OLD-FASHIONED WAY WHERE
YOU DON'T GET CURES IT COSTS --
MANY OF THESE ARE YEARLY COSTS,
THESE DRUGS ARE GIVEN FOR
MULTIPLE YEARS.
SO I WANT TO HIGHLIGHT THAT THIS
CLINICAL TRIAL WAS DONE BY MY
COLLEAGUE CHRIS MELANI WHO DID A
FANTASTIC JOB AND CONTINUES TO
DO A WONDERFUL JOB WITH THIS
THERAPY.
I'VE NOT GONE INTO IT BUT WE'RE
DOING IT IN MANTLE CELL, ALSO A
TUMOR THAT'S HIGHLY DEPEND ON
BCR SIGNALING, AND THERE BELIEVE
IT OR NOT LOOKS TO BE MORE
EFFECTIVE IN LARGE CELL.
I ALSO WANT TO -- OKAY, GOOD.
AND ALSO WANT TO HIGHLIGHT MARK,
OUR CLINICAL DIRECTOR, AND PLAYS
A PIVOTAL ROLE IN HELPING WITH
THIS, AND OUR CLINICAL AND ONE
OF OUR CLINICIANS, RAUL, WHO
ALSO WORKS WITH MARK AND CHRIS
AND ME, AND THEN FINALLY ALL
THIS WORK COULD NOT HAVE BEEN
DONE WITHOUT A VERY CLOSE
COLLABORATION BETWEEN LOU AND
MYSELF, I DON'T KNOW WHY THIS
KEEPS ON DOING THIS.
AND SO LOU HAS PLAYED A CENTRAL
ROLE HERE, AND SO HAS JAMES
PHALEN AND GEORGE WRIGHT, AND
YANDAN AND DA WEI AND WORKING
WITH NCATS, CRAIG THOMAS, WHERE
MANY OF THESE SYNERGY ASSAYS
WERE BEING DONE.
THANK YOU VERY MUCH.
[APPLAUSE]
>> QUESTIONS FOR WYNDHAM?
>> THANK YOU VERY MUCH FOR YOUR
TALK.
VERY EXCITING.
MY QUESTION IS ABOUT THE -- ONE
OF THE INGREDIENTS IN VIPOR, ONE
OF THE DRUGS I BELIEVE YOU
MENTIONED A STEROID THAT HAD
MILDER TOXICITY.
DO YOU HAVE -- WERE THERE ANY
OTHER DRUGS THAT HAD KIND OF
MILDER TOXICITY AMONG THOSE THAT
YOU USED?
AND HAVE YOU THOUGHT IF THERE'S
MORE THAN ONE, USING THEM DURING
THAT INTERVAL WHEN CURRENTLY
NOT TREATING WITH ANYTHING,
DURING THE GAP?
>> RIGHT.
WE ARE LIMITED BY DRUGS THAT
ACTUALLY AFFECT PATHWAYS, AND
THERE IS ANOTHER DRUG CLASS
WHICH IS CALLED PI3 KINASE THAT
CAN ALSO AFFECT DIFFERENT
ASPECTS OF THAT PATHWAY.
UNFORTUNATELY, THAT TURNS OUT TO
BE AN EVEN MORE TOXIC DRUG.
SO, I THINK THAT WE TRY TO FIND
DRUGS THAT BOTH HIT THE PATHWAY
BUT WERE THE BEST TOLERATED.
AND SO YOU BRING UP A VERY GOOD
POINT BUT I THINK THAT'S WHAT WE
DID HERE.
WE WOULD LOVE TO USE PI3 KINASE
BUT THAT'S JUST A VERY SPICY
DRUG.
>> SO, THIS IS A QUESTION THAT
PERHAPS MORE PHILOSOPHICAL.
BUT THESE SPECTACULAR RESULTS
THAT YOU AND LOU AND THE TEAM
HAVE OBTAINED RESTS ON A LOT OF
FANTASTIC STUDIES OF B CELL
BIOLOGY.
AND DISSECTION OF THE PATHWAYS.
TO WHAT EXTEND DO YOU THINK THIS
APPROACH WOULD BE GENERALIZABLE
TO OTHER TUMORS?
IS IT THAT B CELLS, IMMUNE CELLS
ARE REALLY SPECIAL?
OR IS IT THAT WE UNDERSTAND
THEIR PATHWAYS MUCH BETTER AND
THAT IF WE HAD EQUIVALENT
UNDERSTANDING OF SIGNAL, DIVERSE
SIGNALING IN OTHER SORTS OF
TUMORS, THAT THE SAME SORTS OF
APPROACHES COULD BE APPLIED?
>> SO, I WOULD ANSWER THAT BY
SAYING THAT EVEN IN SOLID
TUMORS, IDENTIFYING WHERE THE
PATHWAYS ARE AND USING MULTIPLE
DRUGS IS GOING TO TRANSLATE INTO
A BETTER OUTCOME.
BUT WHERE WE'RE LUCKY WITH
LYMPHOID TUMORS, IS AS YOU KNOW,
BECAUSE OF THE WAY SELECTION
GOES ON, THEY ARE REALLY -- THEY
ARE RELATIVELY EASY TO PUT INTO
APOPTOSIS, BUT YOU JUST NEED THE
RIGHT -- NEED TO SHUT DOWN THE
RIGHT PATHWAYS.
I DON'T THINK THAT'S NEARLY AS
CLEAR WITH A LOT OF SOLID
TUMORS.
YES AND NO.
WE'RE LUCKY WE HAVE RELATIVELY
SENSITIVE TUMORS BUT IN ABSENCE
OF DRUGS LIKE WE'RE DOING YOU
CAN SEE MOST PEOPLE WHEN THEY
RECURRED DIED, SO I DON'T THINK
WE'RE GOING TO FIND THAT
NECESSARILY WITH SOLID TUMORS
BUT THE EXCITING THING IS
IMMUNOTHERAPY SEEMS TO BE, YOU
KNOW, EFFECTIVE IN BOTH.
SO MAYBE WE'LL FIND OUT OTHER
PATHWAYS IN SOLID TUMORS THAT
ENHANCE OUTCOME.
CERTAINLY THEY ARE NOW USING A
NUMBER OF THESE TARGET AGENTS IN
ADJUVANT SETTING IN SOLID
TUMORS, WHERE THE TUMOR LOADS
ARE RELATIVELY LOW AND FINDING
THEY ARE INCREASING CURE RATE.
WELL, THEY ARE DECREASING THE
CHANCE OF SOMEONE RECURRING.
SO, I THINK YOU'VE JUST GOT TO
MOVE EARLIER.
BUT THE ANSWER IS YES, YOU WOULD
IMPROVE IT, BUT I DON'T THINK
THEY ARE GOING TO BE QUITE AS
EFFECTIVE AS WE HAVE FOUND.
>> I'M GOING TO TAKE THE
PREROGATIVE TO ASK ONE QUESTION.
THE QUESTION, WYNDHAM AND I HAVE
THOUGHT ABOUT AND WONDERED WHERE
HIS CURRENT THINKING IS.
YOU'RE DEALING WITH A TUMOR THAT
CAN BE CURED IN THE UP-FRONT
PREVIOUSLY UNTREATED SETTING
WITH CHEMOTHERAPY.
YOU HAVE A NEW THERAPY THAT HAS
A HIGH CURE RATE, AS YOU JUST
GOT THROUGH SAYING, MAYBE EVEN
HIGHER IF YOU MOVE IT EARLY.
SO, IS THERE A PATH TO TAKE A
TUMOR FOR WHICH THERE'S A GOOD
THERAPY BUT NOT 100% THERAPY,
AND CHANGE IT UP AND USE --
>> THE ANSWER IS YES.
WITH THE RIGHT INFORMED CONSENT.
SO, THE WAY WE WOULD, NUMBER
ONE, I THINK THAT FOR THE TUMORS
THAT THIS APPEARS TO BE VERY
EFFECTIVE FOR, I THINK YOU COULD
EASILY JUSTIFY GIVING VIPOR AS
THE PRIMARY THERAPY.
AND WHAT I'VE SHOWN YOU IS THAT
WHEN IT WORKS, THE TUMOR GOES
AWAY WITHIN ONE CYCLE.
AND WHAT I THINK YOU WOULD DO
HERE IS THAT YOU WOULD MONITOR
THE TUMOR, MONITOR THE ctDNA,
A GOOD QUANTITATIVE WAY TO TELL
YOU HOW MUCH TUMOR THERE IS
ACTUALLY THERE, AND IF THE TUMOR
GOES DOWN TO ZERO, I THINK YOU
COULD COMPLETE SIX CYCLES OF THE
VIPOR AND STOP AND WATCH THEM
VERY, VERY CLOSELY.
IF THE TUMOR DOESN'T GO AWAY OR
YOU HYPOTHESIZE IF IT'S NOT BY
ctDNA GONE WITHIN TWO CYCLES,
YOU WOULD THEN MOVE THEM TO
CONVENTIONAL CHEMOTHERAPY.
YOU COULD MOVE THIS UP FRONT BUT
AS I SAID YOU HAVE TO HAVE VERY
CAREFUL INFORMED CONSENT BECAUSE
YOU WOULD TELL THE PEOPLE YOU'RE
DOING SOMETHING VERY NOVEL,
SOMETHING THAT YOU KNOW WILL
CURE SOME OF THEM BECAUSE WE CAN
CURE THEM IN THE RELAPSED STATE,
AND THAT WE'RE GOING TO DO
EVERYTHING WE CAN BASED ON THIS
ALGORITHM TO MAKE SURE THAT THEY
ARE CURATIVE, IF THEY ARE
CURATIVE.
SO THAT IS IN FACT A CLINICAL
TRIAL THAT WE ARE ACTUALLY
PLANNING.
LET ME ALSO SAY WE'VE NOW GOTTEN
ALL THE COMPANIES TO AGREE TO
GIVE US THE DRUGS TO DO A LARGE
CONFIRMATORY OF VIPOR IN
RELAPSED REFRACTORY NON-GCB AND
DOUBLE HIT IN THE COOPERATIVE
GROUPS.
>> WELL, THANK YOU, BECAUSE THAT
MEANS THAT YOU'RE NOT GOING TO
RETIRE FOR AT LEAST 15 MORE
YEARS.
>> OH, NO WAY.
>> TWENTY, TWO KNOWS, BECAUSE
YOU WANT TO FINISH THE STORY,
RIGHT?
>> OH, YEAH.
>> SO LET'S THANK WYNDHAM.
>> THANK YOU.