TRACO 2015: Ovarian Cancer – Immune Checkpoint Air date: Monday, September 21, 2015, 4:00:00 PM Category:TRACO Runtime: 01:40:24 Description: …
TODAY OUR SPEAKER IS
CHRISTINA ANNUNZIATA, SHE GOT
HER M. D. AT UNIVERSITY OF
GEORGETOWN MEDICAL SCHOOL,
SUBSIDIARY WENTLY SHE JOINED NCI
AND WORKED IN LOU SPOUT AND WORK
WIDE ELEASE COHN, NOW SHE'S HEAD
OF TRANSLATIONAL GENOMICS
SECTION, HER TITLE OVARIAN
CANCER IN THE GENOMIC ERA.
>> OKAY, THANK YOU VERY MUCH SO
I WAS JUST LOOKING BACK AT MY
PREVIOUS PRESENTATIONS AND I
REALIZED THIS IS THE EIGHTH YEAR
THAT I'M GIVING THIS LECTURE BUT
IT WAS NOT'VE'VE I WAS RNLT
ALWAYS CALLED THE GENOMICS ERA.
>> YEAH, SO THIS IS DEFINITELY
UPDATED BECAUSE IT WASN'T
PREVIOUSLY GENOMICS.
ANYWAY, SO THANK YOU FOR
INVITING ME BACK TO SPEAK AGAIN.
I WANTED TO FOCUS ON THE TOPIC
OF GENOMICS AND FUNCTIONAL
GENOMICS.
TO START OUT WITH AND I'LL GET
TO OVARIAN CANCER IN A LITTLE
BIT.
SO WHAT IS CANCER GENOMICS.
GENOMICS IN MY VIEW IS THE STUDY
OF THE WHOLE GENOME SO NOT
INDIVIDUAL GENES OR INDIVIDUAL
MUTATIONS BUT STUDY OF THE
GENOME IN GENERAL, EITHER
CHROMOSOMES, GENE EXPRESSION OR
SOME SORT OF GLOBAL ANALYSIS.
SO I WOULD SAY THE GENOMICS ERA
FULLLY STARTED BACK IN 1959,
WITH NOWELL AND HUNG ERFORD AND
THEY IDENTIFIED A ABNORMALITY
CALLED THE PHILADELPHIA
CHROMOSOME THAT WAS OCCURRING IN
PATIENTS WITH THIS CHRONIC FORM
OF ALUALU KEEPIA.
AND THIS IS WHAT IT LOOKED LIKE.
SO IN 1959 THEY LOOKED THE
CHROMOSOME FROM MULTIPLE
PATIENTS WITH THIS CHRONIC FORM
OF LEUKEMIA AND THEY NOTICE THAD
EVERYBODY HAD OR MOST OF THE
PATIENT HIS THIS LITTLE THING
HERE WITH THE ARROW.
WHERE'S MY THINGY.
I DON'T KOW WHERE THE–THERE.
A LITTLE EXTRA CHROMOSOME.
IT LOOKED LIKE AN EXTRA
CHROMOSOME, SO THEY STUDIED
THIS, EVENTUALLY IN 1973, JANET
ROWELY DISCOVERED THAT THIS
LITTLE CHROMOSOME WAS A
RECIPROCAL TRANSLOCATION BETWEEN
HROMOSOMES NINE AND 22 IN ALL
THESE PATIENTS WHICH WAS AT THAT
POINT CALLED ROGGIC MILEOG NOWS
LEUKEMIA OR CML.
AND THEN IN 1984, GROFFEN ET AL,
WAS A CHROMOSOME REFUSION AT 22,
AND ACTUALLY AT 19 BUT HERE HE
FOUND IT WAS A RECURRENT FUSION
BETWEEN BCR AND ABLE.
SO THE GENE BCR, BREAK POINT
CLUSTER REGION AND A KINASE, AND
THEN IT WASN'T UNTIL 1996 THAT
WE ACTUALLY CAME UP WITH A DRUG
CALLED AMAT NIB WHICH HERE IT'S
CALLED CGP 57148 WITH A DRUG
THAT BLOCKS THE ABLE KINASE
FUNCTION.
SO THAT WAS QUITE A TIME BETWEEN
1950–WHAT DID I SAY 1959 AND
1996 BEFORE WE CAME UP WITH
SERRA PINE FOR THIS PARTICULAR
PHASE.
SO, THAT POINTS US TO WHAT IS
ACTUALLY FUNCTIONAL.
SO, THE THERAPIES WE USE ARE
BLOCKING A FUNCTION OF
SOMETHING.
SO HOW CAN WE USE FUNCTIONAL
GENOMICS, NOT JUST OBSERVATIONAL
DENATIONAL LIBRARY OF MEDICINICS
LIKE THEY DID IN 1959, CAN WE
USE SORT OF A FUNCTIONAL GENOMIC
EXPERIMENT TO FIND OUT WHAT PART
OF THE GENOME IS ACTUALLY DOING
SING.
WHAT IS CAUSING AN EFFECT AND
WHAT CAN ACTUALLY TRANSFORM
NORMAL CELLS O CANCER, THESE
SO CALLED DRIVER ALTERATIONS.
SO IN 1981, I THINK SHIH ET AL,
PERFORMED THIS RESEARCH.
AND THEY FOUND TRANSFORMING
GENES OF CARCINOMA AND NEURAL
BLASTOMA INTO MOUSE FIBROBLAST.
SO THEY TOOK THE ENTIRE DNA OF
NEUROBLASTOMA, THAT'S WHY IT'S
CALLED NEW, CHOP TODAY UP PUT IT
I NONTRANSFORMED FIBROBLAST AND
SAW WHICH PART OF THE GENOME
CAUSED AN EFFECT WHICH WAS TO
TRANSFORM THE CELLS INTO CANCER
CELLS.
THAT COULD ACTUALLY FORM TUMORS
IN MICE.
SO THEY FOUND A GENE THEY HAD
CALLED NEW AND THEN IN 1984
SCHECHTER THE NEU GENE WAS
CLOSE TO THE EGFR.
THIS IS A SOUTHERN BLOT.
IN 1985, COUSSENS AND GROUP
FOUND THAT THIS WAS ON
CHROMOSOME 17 AND IT WAS
AMPLIFIED AND CAN YOU SEE ON
THAT BLOB ON THE SIDE THAT THERE
MEANS THERE'S A TON OF, SO
THERE'S A LOT OF IT.
SO IT'S AMPLIFY INDEED IN REGION
OF CHROMOSOME 17.
AND THEN OF COURSE IN 1987
DENNIS SLAMON DISCOVERED IT WAS
A IN BREAST CANCER CASES AND
THIS IS CHROMOSOME 17 IN ALL OF
THIS REGION OF CHROMOSOME 17 IN
ALL OF THESE BREAST CANCER CASES
AND IN SOME OF THEM IT IS
EXTREMELY AMPLIFIED AND THAT
EVENTUALLY LED TO–AND THAT
EVENTUALLY LED TO THE
DEVELOPMENT OF AN ANTIBODY TO
BLOCK THIS RECEPTOR AND THE
APPROVAL OF HERSEPTORSIN OR THE
DUG THAT WE USE TODAY IN BREAST
CANCER THAT ARE KNOWN TO HAVE
HERTWO AMPLIFICATIONS FELT SO
THIS IS THE FIRST FUNCTIONAL
GENOMIC EXPERIMENT.
SO WHAT ABOUT OVARIAN CANCER,
CAN WE USE GENOMICS TO STUDY
OVARIAN CANCER AND DO WE HAVE
ANY DRIVERIN OVARIAN CANCER.
SO NOW I'LL INTRODUCE OVARIAN
CANCER SO GETTING TO THE ACTUAL
TUB JECT OF THIS PARTICULAR
TRACO LECTURE.
OVARIAN CANCER AS YOU MAY KNOW
IS THE MOST LETHAL GYNECOLOGIC
MALIGNANCY IN THE UNITED STATES.
IT CAUSES GREATER THAN 16,000
DEATHS PER YEAR AND THE FIFTH
MOST COMMON CAUSE OF DEATHS IN
WOMEN.
THIS IS BECAUSE 70% OF WOMEN ARE
DIAGNOSE WIDE OVARIAN CANCER.
IT'S UNUSUAL TO FIND OVARIAN
CANCKENER EARLY STAGES.
LESS THAN 35% OF THE ADVANCED
STAGE PATIENTS ARE ALIVE AT FIVE
YEARS.
AND THIS IS WHAT WE MEAN BY
STAGE, STAGE ONE IS EARLY STAGE
AND THAT OCCURS IN ABOUT 20% OF
THE CASES BUT THE SURVIVAL IS
QUITE GOOD, THE SURVIVAL IS 90%.
IF YOU CAN FIND STAGE ONE
CONFINED TO AN OVARY, THE
SURVIVAL IS QUITE GOOD.
STAGE TWO IS–HAS LEFT THE OVARY
BUT IS STILL IN THE PELVIC
REGION.
STAGE THREE AS SPREAD OR TO
LYMPHNODES AND THAT LIKE I SAID
IS THE MOST COMMON STAGE AND
UNFORTUNATELY THIS LEVEL IS
TRANSPIRED TO 45% AT FIVE YEARS.
AND THEN STAGE FOUR, THE
SURVIVAL IS EVEN WORSE, LES THAN
FIVE% AT FIVE YEARS.
SO HA IS THE TREATMENT FOR NEWLY
DIAGNOSED OVARIAN CANCER, OF
COURSE THE FIRST ONE IS COMPLETE
SURGICAL STAGING AND I WILL SHOW
A BIT ABOUT THAT. OPTIMAL
REDUCTIVE SURGERY WHICH WE'LL
TALK ABOUT FOLLOWED BY CHEMO
THERAPY AND THEN OF COURSE
CLINICAL TRIALS.
SO COMPLETE SURGICAL
STAGING–SORRY, COMPLETE
SURGICAL STAGING INVOLVES
LOOKING THROUGH THE ENTIRE PARO
TONEM AND FOR LYMPHNODES AND
LOOKING–AS CAN YOU IMAGINE THE
PELVIS AND ABNORMALITIES DOMIN
ARE SORT OF CONTIGUOUS, SO THE
DIFFERENCE BETWEEN STAGE TWO AND
STAGE THREE AND DIFFERENT
ANATOMICAL INTRUSIONS AND NOT A
FULL HARD LINE OF SEPARATION.
AND THE PERO TON EEL FLUID
CIRCULATES FREELYY THROUGHOUT
THE ABDOMEN.
SO THE SURGICAL STAGING NEEDS TO
INCLUDE EVERYWHERE IN THE
ABNORMALITIES DOMIN BECAUSE OF
THE WAY THE PERO TONIEL FLUID
IS.
THAT IS THE GOAL AND NOW THE
GOAL IS ACTUALLY TO LEAVE AS
LITTLE AS POSSIBLE BECAUSE AS
CAN YOU IMAGINE THE SURVIVAL OF
OVARIAN CANCER IMPROVES WITH THE
LESS AND LESS DISEASE LEFT AT
THE TIME OF SURGERY.
SO THE BEST SURVIVAL OF OVARIAN
PATIENTS IS IF THEY CAN GET TO
ZERO DISEASE VISIBLE IN THE
ABDOMEN.
CHEMO THERAPY, THE BASIS OF
CHEMO THERAPY IS PLATINUM IN
COMBINATION OF ATTACKSAIN AND
PERO TONEAL, AND OPTIMAL MEANING
LESS THAN 1 CENTIMETER AT THE
TIME OF SURGERY.
THE COMBINATION OF PLATINUM AND
TAX AN, CAN YOU SEE THE
INTRODUCTION OF VARIOUS CHEMO
THERAPY AND FIVE YEAR SURVIVALOT
BOTTOM.
OF ADVANCED STAGE DISEASE, THIS
IS STAGE THREE AND FOUR ONLY.
AT THE TIME OF THE INTRODUCTION
OF ALCOLLATING CHEMO THERAPY IN
1960S THERE WAS BASICALLY NO ONE
WHO LIVED BEYOND FIVE YEARS IF
THEY WERE DIAGNOSED WITH STAGE
THREE OR FOUR OVARIAN CANCER.
WHEN PLATINUM WAS INTRODUCED IN
THE 1970S, THAT WAS THE FIRST
SORT OF BIG REVELATION, BIG JUMP
UP TO FIVE% OF PEOPLE ALIVE AT
FIVE YEARS IN THE 70S.
SO THEN IN THE 80S PEOPLE
DECIDED WELL, WE SHOULD COMBINE
THEM WITH PLATINUM AND ACTUALLY
THAT WAS BETTER.
GOT UP TO 15%.
FIVE YEAR SURVIVAL IN THE 1980S
AND THEN IN THE 1990S WAS THE
INTRODUCTION OF THE P A XATOXA
TAXLE OR DOSATTACKSLE, IN THE
1990S, ANOTHER BIG JOB WITH THE
P A CLITAXEL AND CARBOPLATIN, UP
TO 35% AND THEN IN THE 2000S, IT
WAS ACTUALLY NOT NEW CHEMO
THERAPY AGENTS BUT A NEW WAY OF
INTRODUCING THEM SO INSTEAD OF
GIVING THEM IVs THAT WAS TO
GIVE IT INTERPERO TON EEL
BECAUSE THAT'S WHERE THE BULK OF
THE TUMORS ARE.
SO WHEN THEY DID THAT, THE
SURVIVAL WENT UP TO 40% IN THE
2000S.
SO THIS IS SURVIVAL OUTSIDE THE
EARTH.
BUT FROM A MOLECULAR STANDPOI,
I THINK WE STILL DON'T KNOW VERY
MUCH ABOUT OVARIAN CANCER IT IS
A VERY HETEROGEANIOUS DISEASE
AND IT'S HETEROGENEOUS AT THE
POINT OF LOOKING AT IT.
SO IF YOU THINK OF OVARIAN
CANCER HISTOLOGY, OVARIANCE
CANCER AND MADE UP OF FIVE
DISTINCT HISTOLOGIC SUBTYPES.
THE MOST COMMON OF HERE IS THE
THEORIST, SO THE HIGH GRADE
OVARIAN CANCER, THE MOST COMMON
AND ALSO THE WORST PROGNOSIS,
AND THAT IS A PARTICULAR TYPE OF
OVARIAN CANCER WHICH IS SHOWN IN
A AND THEN HAVE YOU A LOW GRADER
HERE WHICH IS MORE PAP
ILLEGALSAR CHE IS SHOWN IN B AND
THEN IN C, YOU HAVE ENDOMEET
RIOID CANCER.
AND D, HAVE YOU A MUSEINOUS
CANCER AND THEN IN E, YOU HAVE
THE CLEAR CELL CANCERS.
SO YOU HAVE AT LEAST FIVE
DISTINCT HISTOLOGIC SUBTYPES.
SO IF THEY LOOK THIS
DIFFERENTLYOT MICROSCOPE, YOU
WOULD THINK THEY ARE PROBABLY
VERY DISTINCT AT LEAST AT A
MOLECULAR LEVEL AS WELL.
RIGHT?
SO WE'RE TREATING THEM ALL THE
SAME WAY BUT MAYBE WE COULD
IMPROVE IF WE FIGURE OUT WHAT IS
ACTUALLY DIFFERENT BETWEEN THEM.
THE TISSUE OF ORIGIN IS ALSO
POTENTIALLY DIFFERENT BETWEEN
THESE CANCERS, RECENT WORK HAS
SHOWN THAT PERHAPS SEROUS
CANCERS ARISE FROM THE FALLOPIAN
TUBE.
THE ENDOMEDE RIIDENTITY COULD
GIVE WAY TO THE SUBTYPE AND THE
EXTRA UTERINE EPITHELIUM MIGHT
GIVE RISE TO MUSNOWS OR OTHER
TYPES OF OVARIAN CANCER.
SO VERY HETEROGENEOUS TO THE
POINT OF A CELL OF ORIGIN.
SO THE HYPOTHESIS IS THAT IF WE
INCREASE UNDERSTANDING ABOUT
BIOLOGICAL AND BIOCHEMICAL
EVENTS UNDER LYING OVARIANCE
CANNER PROGRESS, YOU CAN TREAT
THEM, MAYBE WE SHOULD GIVE THEM
ALL THE SAME CHEMO BUT GIVE THEM
ADDITIONAL AGENT SPECIFIC TO
THEIR MUTATIONAL STATUS.
CAN WE USE GENOMICS TO FIGURE
THIS OUT.
SO I'M GOING TO START WITH AN
OVERVIEW OF EACH TYPE OF CANCER
AND SHOW YOU WHERE WE ARE SO
FAR.
I HAVE–I CAN TELL YOU THE PUNCH
LINE IS WE DON'T HAVE SPECIFIC
THERAPIES AS OF YET BUT WE'RE
GETTING THERE.
SO LET'S START WITH CLEAR CELL
OR ENDOMEET RIOID CANCERS THAT
ARE RELATED FROM THE CELL OF
ORIGIN STANDPOINT.
CLEAR CELL CANCERS ARE IN FACT
10% AS I MENTIONED WHERE SEROUS
IS MORE COMMON.
70%.
THEY DO HAVE A WORSE RESPONSE TO
STANDARD CHEMO THERAPY WITH THE
PLATINUM AND THE TAXAIN.
AND OF COURSE THOSE ARE
ASSOCIATED WITH ENDOMETRIOSIS IN
40% OF CASES SO THIS STUDY BACK
IF 2010, LOOKED AT WHAT ARE THE
GENOMICS OF CLEAR CELL OVARIAN
CANCER SO THEY STARTED OUT BY
SEQUENCING RNA FROM 18 CASES OF
CLEAR CELL OVARIAN CANCKENER ONE
CELL LINE IN A DISCOVERY PHASE.
AND THEN THEY WENT ON AND THEY
SEQUENCED AXONS FROM 210
ADDITIONAL SAMPLES.
101 CLEAR CELLS, 76 SEROUS,
NEGATIVE COMPARISON, AND ANOTHER
CLEAR CELL LINE.
AND THEN THEY IMMUNOSTAINED,
THEY DID IMMUNOSTAINING FOR
INTERESTING THINGS IN ANOTHER
455 SAMPLES.
SO A PRETTY BIG STUDY.
AND WHAT THEY FOUND WAS THAT
THEY FOUND ARID–THEY
ACTUALLY–STAY SPAN THE ENTIRE
GENE SO THEY'RE NOT IN 1
RECURRENT LOCATION BUT IT'S THE
GENE ITSELF ANYWHERE IN THE GENE
IS MUTATED SO IT'S SORT OF–IT'S
NOT PARTICULAR KINASE LOCATION
FOR EXAMPLE, IT'S ANYWHERE IN
THE GENE THAT CAN BE MUTATED.
SO WHAT IS ARID1 A AND THIS
GIVES US A CLUE AS TO WHY IT'S
NOT IN A SPECIFIC LOCATION.
SO ARID1A IS IN A CHROME TIN
COMPLEX, IT'S FOUND IN BREAST
CANCER AND LUNG CANCER PREVIOUS
TO THIS PUBLICATION IN 2010.
IT OCCURS IN CHROMOSOME 1 P 36
AND IT'S DELETED IN ALL–IN 6%
OF ALL CANCERS ACROSS THE BOARD.
SO THIS SUGGESTS A MUTATIONAL
SPECTRUM ACROSS THE GENE
SUGGESTS IT'S PROBABLY A TUMOR
SUPPRESSOR GENE, SO IT'S NOT AN
ONCA GENE, IT'S A LOSS OF
MUTATION, IT'S A LOSS OF
FUNCTION OF THE ARID1A GENE.
SO THEY DID CONFIRM THAT ARID 1A
EXPRESSION WAS LOST HERE ON THE
THIS IT SAYS THE LOSS OF 215A,
AND IT'S THE LOSS OF THE
PROTEIN.
SO THE PROTEIN WAS LOST IN 73%
OF CLEAR CELL CANCERS AND WITH
THE ARID1A MUTATION AND IT WAS
LOST IN 50% OF ENDOMEET RIOID
OVARIAN CANCER CASES THAT WERE
ALSO ARID MUTATIONS BUT 0
CANCERS.
SO THIS SUGGESTS, OKAY, IT IS
SOMETHING THAT'S CLEAR CELL
ENDOMEETRIOL SUBTYPES IN
CANCERS.
SO, SUMMARY, TO SUMMARIZE, ARID
1-A WAS MUTATED OR LOST IN OVER
40% OF CANCERS AND THESE ARE
OVARIAN CANCERS AND LESS THAN 1%
OF SEROUS CANCERS HOWEVER SINCE
THERE'S TUMOR SUPPRESSOR, WE'RE
NOT SURE OF WHAT TO DO WITH THIS
IATION WE DON'T HAVE A WAY
OF WHICH PATHWAY IS EFFECTED AND
THERE'S THERAPIC DIRECTION
HERE WITH THE LOSS OF A TUMOR
SUPPRESSOR, IT'S DIFFICULT TO
TARGET THAT IN A WAY.
BUT AT LEAST WE ARE LEARNING
THAT THERE ARE SPECIFIC
MUTATIONS HERE.
SO WE HAVE POTENTIALLY
DIAGNOSTIC UTILITY BUT I WOULD
ARGUE THAT THIS WAS–THIS IS AN
INTERESTING FINDING BUT IT
DIDN'T GIVE US THERAPEUTIC
DIRECTION BECAUSE IT WAS NOT
IDENTIFIED WITH A FUNCL
EXPERIMENT SO THERE WAS NOTHING
WHERE WE PUT IN THE GENE, PUT IN
ND AN EFFECT.
AS SOMETHING FROM THE GENOME AND
NO, WE'RE JUST SEQUENCING AND
WE'RE MAKING AN OBSERVATION AT
EXPERIMENT SO THAT WE'RE LEFT
WITHOUT A FUNCTIONAL OUTCOME.
OKAY, SO WHAT ABOUT MUSE NOWS
CANCERS, THEY HAVE A WORSE OVER
ALL SURVIVALS COMPARED TO
NONMUCINNOUS CANCERS AND THIS IS
A SURVIVAL PLOT SINCE YOURS OF
DIAGNOSESI OF MUSE NOWS VERSES
NONMUCINOUS OVARIAN CANCERS.
AND THEN IN 2006 THIS, IS AN
OVERVIEW OF GENE EXPRESSION
EVENT THAT LOOKED AT SEROUS LOW
GRADE, HIGH GRADE AND MUCINOUS
CANCERS EITHER GRADE 1 OR GRADE
2 ASK THEY DISCOVERED THAT
MUCINOUS, WERE SURPRISINGLY OR
NOT SURPRISINGLY WERE DIFFERENT.
FROM A GENE EXPRESSION STAND
POINT, A EARLY GENE EXPRESSION
ARRAY, 10,000 GENES ON IT, IT
WAS 1 OF THE EARLY 1S IN 2006,
BUT STILL WITH LIMITED
INFORMATION YOU COULD SEE THAT
THE MUCINOS CANCER VS A
COMPLETELY DIFFERENT GENE
EXPRESSION PROFILE THAN THE
CANCERS, SO, OKAY, THAT IS GOOD.
WE FOUND–WE DIDN'T FIND, THEY
FOUND THAT PERHAPS KRASE MODEL
WAS MORE COMMON THAN IN MUTATED
CANCERS COMPARED TO SEROUS
CANCERS.
AGAIN THIS IS AN EXTREMELY SMALL
TODAY, AND SIMILARLY IN LOW
GRADE SEROUS CANCERS WHICH ARE
DISTINCT FROM HIGH GRADE CANCERS
AGAIN, KRASE MODEL AND BRAF WERE
FOUND TO BE MUTATED SO BRAF WAS
STUDIED AT CODON 599 AND CODONS
IN 12 OR 13 WHICH ARE THE COMMON
SITES OF MUTATION, AND WAS FOUND
INTERESTINGLY THAT 68% IN THIS
SMALL STUDY OF LOW GRADE CANCERS
AND 61 OF SEROUS BORDER LINE
TUMORS WHICH ARE KIND OF A
PRECURSOR TO LOW GRADE SEROUS
CANCERS WERE–HAD 1 OF THESE 2
MUTATIONS BUT NONE OF THE HIGH
GRADE SEROUS CANCERS THAT THEY
STUDIED HAVE THIS MUTATION, SO
ANOTHER CLUE, SAYS POINTING UP
TOWARDS MUSNOWS OR LO GRADE
CANCERS PERHAPS WE CAN TARGET
KRAS, O THE RS PATHWAY.
THIS A GRAPHICAL REPRESENTATION
OF WHAT I JUST SAID, THIS IS THE
LOW GRADE CANCERS WERE MORE
COMMONLY MUTATED THAN THE HIGH
GRADE SEROUS CANCERS ENDOMEET
RIOID OR CLEAR CELL.
THERE YOU GO.
SO HOW CAN WE TARGET RAS
SIGNALING.
I THINK EVERYBODY HEARD OVER THE
RAS PATHWAY BECAUSE WE HAVE THE
HUGE RAS INITIATIVE AT THE NCI.
HOW DO WE TARGET IT?
IT'S DOWN STREAM AT RAS, THAT IS
AT THE POINT OF–AT THE POINT OF
NYC.
SO RAS, SIGNALS TO RAF, TO MEK,
AND GOES TO ERK AND CHANGES GENE
EXPRESSION.
SO PARTICLE FARLEY, ET AL,
DECIDED WE SHOULD TRY THIS IN
WOMEN WITH LOW GRADE CANCER SO
THEY TREAT THE POO PATIENTS, 8
RESPONSES AND 34 PATIENTS WITH
STABLE DISEASE GREATER THAN 4
MONTHS.
SO THAT SOUNDS PROMISING BUT IF
YOU LOOK, THEN AT THE MUTATIONAL
STATUS OF THESE WOMEN THE PUNCH
LINE HERE IS THAT THERE WERE
RESPONSES IN 5 PATIENTS WHO HAD
NO ZRAF OR KRAS MUTATIONS AND
ONLY 2 RESPONSES IN MUTATIONS SO
ACTUALLY THE RESPONSES WERE NOR
COMMON IN PEOPLE WITH THE
MUTATION THAN WITHOUT THE
MUTATION.
SO THAT DIDN'T QUITE GO AS
PLANNED.
SO WHERE DO WE GO FROM HERE, SO
AS I SHOWED YOU BEFORE THE RAS
PATHWAY WAS NEATLY DESCRIBED AS
GOING FROM RAF, TO RAS AND BECK
TO ERK, HOWEVER THAT IS NOT THE
CASE THIS CANCERS OR OTHER CELLS
AS WELL.
IT PROBABLY DOESN'T CARE TO MUCH
ABOUT MEK BECAUSE IT AS A LOT OF
WAYS OF GETTING AROUND THAT SO
THAT'S PROBABLY WHY IT DIDN'T
WORK SO IT'S NOT A DRIVER.
SO AGAIN WE FOUND THIS MUTATION
BY SEQUENCING, SO WE DID NOT
FIND THE MUTATION BY VIEWING A
FUNCTIONAL EXPERIMENT.
WE JUST SAID, WOW, THERE'S A
K-RAS MUTATION BUT THERE WERE NO
FUNCTIONAL EXPERIMENTS TO SAY
THAT THE RAS WAS ACTUALLY A
DRIVER.
AND EVEN IF IT WAS A DRIVER, MEK
IS NOT THE DRIVER.
AS I MENTIONED 70% OF CASES ARE
DIAGNOSED AS HIGH GUIDE SEROUS.
SO BACK IN 2011 PUBLISHED AS
PART OF THE FIRST TIME GENOMEAT
LAS PINTAS, IT WAS THE SECOND OR
THIRD CANCER THAT WAS PRECEPTED
IN THE CANCER GERONTOLOGYSTS
GENOME ATLAS, AND IDENTIFIED
MOLECULAR ABNORMALITIES THAT
INFLUENCED, WELL, THE GOAL WAS
TO IDENTIFY MOLECULAR
ABNORMALITY PATHOPHYSIOLOGY AND
EFFECT A POTENTIAL THERAPEUTIC
TARGET.
SO WHAT THEY DID WAS
ANOTHER–WHAT I CALL
OBSERVATIONAL STUDY, WAS 489
HYBRID CANCERS LOOKED AT
MICRORNA EXPRESSION, DNA COPY
NUMBER, PROMOTER METHYLATION AND
THEY DID WHOLE EXOME SEQUENCING
ON 316 OF THOSE SAMPLES.
SO SAMPLE ENCLIEWGZ OF COURSE,
THEY HAD THE NEWLY DIAGNOSED
PATIENTS, NO PRIOR TREATMENT AND
COMPANION NORMAL TISSUE, ADJAC
EPT NORMAL TISSUE, OR PERIPHERAL
LYMPHOCYTES OR PREVIOUSLY
EXTRACTED GERM LINE DNA.
SO THAT WAS THIS EXPERIMENT
WHICH WAS THE COPY NUMBER
ANALYSIS.
SO WHAT THIS IS SHOWING YOU IS
ON THE Y-AXIS OR CHROMOSOMES, SO
CHROMOSOMES 1-22, AND ON THE
X AXIS IS INDIVIDUAL CASES.
SO THESE ARE 489 CASES, AND
THEY'RE SHOWING YOU HERE, HYBRID
THEORIES OF OVARIAN CANCER
COMPARED TO THE PREVIOUSLY
STUDIED TCGA SAMPLES, AND THAT'S
WHAT GBM IS.
SO WHAT CAN YOU SEE HERE, WELL,
AND THEN THE SCALE IS THAT RED
IS AMPLIFIED AND BLUE IS
DELETED.
SO WHAT CAN YOU SEE HERE IS THAT
IN GLIAL BLASTOMA THERE WAS A
RELATIVELY QUIET GENOME AND
THERE WERE DISTINCT AREAS OF
EITHER AMPLIFICATION OR
DELETION.
BUT IN HYBRID CANCER, THE
AMPLIFICATIONS AND DELETIONS ARE
KIND OF ALL OVER THE PLACE, SO
YOU SEE DISTINCT AREAS OF
AMPLIFICATION OR DEREGION, AND
ALL THE CHROMOSOMES, THERE ARE
SOME DISTINCT 1S BUT IT'S REALLY
NOT POINTING THERE.
SO THE CONCLUSION FROM THIS IS
THAT THERE WAS A HIGH AMOUNT OF
GENOMIC DISARRAY OR CHAOS IN
OVARIAN CANCER THAT IS NOT SEEN
IN OTHER CANCERS.
SO IS THIS A PROBLEM WITH DNA
REPAIR?
THAT'S LEADING US TOWARDS
SOMETHING INTERESTING?
SIGNIFICANTLY MUTATED GENES, P53
OF COURSE WAS THE MOST COMMONLY
MUTATED.
BRCA 1 OR 2 WAS THE NEXT MOST
COMMON, BRCA WAS ON THE TOP AND
BRCHOT BOTTOM, SO YOU COMBINE
THEM TOGETHER IN THE SAME
PATHWAY WAS THE NEXT MOST COMMON
PATHWAY.
AND THEN A NUMBER OF OTHER 1S
BUT AS YOU CAN SEE, NOTHING
REALLY SORT OF JUMPS OUT AT YOU.
AS ANYTHING BESIDES
[INDISCERNIBLE].
I DIDN'T PRESS THE BUTTON FIRST.
OKAY, SO, IF YOU FOCUS THERE ON
THIS IDEA OF GENOMIC DISAWRY
REGISTERED INVESTMENT ADVISER
AND HOMOLOGOUS RECOMBINATION
WITH KHI IS A WAY OF FIXING
GENOMES, WE THAN BRCA IS ALTER
INDEED 33% OF CASES, EITHER BY
DELETION, MUTATION OR
METHYLATION.
SO IF YOU LOOK AT THE SURVIVAL,
THE BRCA MUTATED CASES ACTUALLY
DO BETTER, INTERESTINGLY.
SO THE BRCCASE MUTATED HERE ON
THE LEFT IS IN THE RED, AND THE
METHALATED AND WILD-TYPE IS IN
THE BLACK.
SO, THE THOUGHT WAS THAT WITH
ALL THIS GENOMIC DISARRAY, AND
THE RECURRENT BRCA MUTATIONS,
MAYBE THERE IS A COMMON THEME IN
OVARIAN CANCER AS DEFECTS IN DNA
REPAIR.
SO THEY LOOKED AT WHERE ELSE DO
WE HAVE MUSEUMITATIONS THAT
WE'VE SEEN, AND WHERE ELSE ARE
ALTERATIONS AND WE CAN SAY THAT
MAYBE IN 51% OF CASES NOT JUST
THE 1S WITH THE BRCA MUTATIONS
IN 51 OVERALL WE MAY BE CONFINED
OF SPECIFIC DEFECT IN HOMOLOGOUS
RECOMBINATION OR DNA REPAIR.
THEN THIS IS ANOTHER REPAIR, DNA
CASES HAVE DNA REPAIR OR CELL
CYCLE PROBLEMS IN FOX M-1
SIGNALING.
SO WE HAVE DNA REPAIR AND CELL
CYCLE, MAYBE THAT ACCOUNTS FOR
OVARIAN CANCER.
WHO KNOWS?
SO WHAT NEXT.
WHAT DO WE DO WITH THIS
INFORMATION.
IT WAS–NOW THE FUNCTIONAL
EXPERIMENT BUT MAYBE WE CAME UP
WITH POTENTIALLY FUNCTIONAL
THERAPEUTIC TARGETS WITH RESPECT
TO HOMOLOGOUS RECOMBINATION
DEFECTS AND 1 OF THOSE DRUGS IS
INHIBITORS AND COMMONLY
DEREGULATED PATHWAYS POETIC
SENTIALLY WAS P A RP ININCREASE
IN BODYITORS, FOR THE FIRST TIME
IN 1990 BY HALL AND KING ET AL,
WHO DISCOVERED THAT THERE
WERE–THERE WAS A PARTICULAR
PART OF THE GENOME THAT WAS
ALTERED IN A FAMILIES WHERE
THERE WAS THIS RECURRING BREAST
CANCER THROUGHOUT.
SO IF YOU LOOK AT THIS PEDIGREE,
YOU CAN SEE THAT THE SOLIDS ARE
FEMALES AND THE SQUARES ARE
MALES AND THE SOLIDS ARE
EFFECTED WITH THE CANCER.
SO CAN YOU SEE THERE'S A
RECURRING HEREDITARY BREAST
CANCER IN EACH OF THESE FAMILY
WHICH IS EFFECTS ABOUT HALF OF
THE WOMEN.
SO THESE PEOPLE IDENTIFIED
EVENTUALLY THE BRCA GENE AS THE
OCUESAL LOCUST AT THAT POINT.
THE BRCA GENE THAT WAS MUTATE
INDEED THESE FAMILIES.
IN HYBRID SERIES CANCER, THE
BRACA LIKE I MENTIONED WAS ABOUT
10 OR 15%, THE BRACA IN THE GERM
LINE, BUT THEN ALSO BRACA CAN BE
MUTATE INDEED THE CANCER ITSELF.
AND NOT MUTATED IN THE IN THE
PERIPHERAL DNA IN THE GENOME.
IT CAN ALSO BE METHYLATED BUT
THEN OTHER THINGS IN THE DNA
REPAIR PATHWAY, SUCH AS THE EMCY
AMPLIFICATION OR OTHER
HOMOLOGOUS RECOMBINATION DEFECT
AND THIS IS WHERE WE THINK THAT
IN ABOUT HALF OF THE CASES, WE
CAN FIND GENETIC EVIDENCE FOR
DEFECTS IN HOMOLOGOUS
RECOMBINATION.
INTERESTINGLY INSTEAD OF JUST
LOOKING AT COPY ALTERATIONS
NUMBERS AND FOUND THAT THERE
WERE 230 COMMON GENES THAT MIGHT
PRESENT A SIGNATURE OF A SMALL
RECOMBINATION DEFICIENCY, AND
THIS IS ACTUALLY LOOKING IN
BREAST CANCER PATIENTS WITH
HOMOLOGOUS RECOMBINATION
DEFICIENT AGAIN HAD A BETTER
SURVIVAL HOMOLOGOUS RECOMBIN
INTACT.
AND IF YOU LOOK IN OVARIAN
CANCER CELL LINES, EVEN THE CASE
OF 2 DIFFERENT CELL LINES 1 WITH
HOMOLOGOUS INTACT SIGNATURE AND
1 WITH HOMOLOGOUS DEFICIENT, THE
DEFICIENT 1S IS MORE SENSITIVE
TO THE PERP INHIBITORS.
SO WHAT OUR P A RP INHIBITORS?
THEY ARE INHIBITORS OF SINGLE
STRAND DNA REPAIR.
AND THIS IS A SPECIFIC CARTOON
OF HOW WE THINK IT WORKS IN
BRCMUTATED CANCER.
SO IN A NORMAL SITUATION, YOU
HAVE THE DNA SUFFERED SINGLE
STRAND BREAKS BY VARIOUS
PROCESSES SUCH AS CELLULAR
METABOLISM, EXPOSURE TO THE
ENVIRONMENT, ET CETERA.
SO WHAT HAPPEN SYSTEM THAT THE P
A RP COMES IN AND MARKS THESE
ARE REPAIR, SO IF YOU BLOCK THE
P A RP, IN REPLICATING THE CELLS
THE SINGLE STRAND GETS CONVERT
WIDE WITH THE DNA, SO GETS
CONVERTED TO A DOUBLE STRAND
BREAK WHICH IS DEPENDENT ON
HOMOLOGOUS RECOMBINATION OR
REPAIR THAT USES THE BRCA 1 OR
BRCA 2 GENE IN THIS PATHWAY.
IF YOU HAVE CELLS THAT ARE
DEFICIENT IN BRCA, THEY CANNOT
REPAIR THIS AND THEY GET SORT OF
OVERWHELMED BECAUSE THEY DON'T
HAVE A HOMOLOGOUS RECOMBINATION
PATHWAY IN FACT, THEY HAVE HUGE
AMOUNTS OF DOUBLE STRAND BREAKS
BECAUSE OF THE P A RP INHIBITOR
AND THEY WOULD SELECTIVELY DIE.
THAT IS THE HYPOTHESIS.
SO A P A RP INHIBITOR THAT WE'VE
DONE TRIALS WITH IS AZD, 2281.
THIS IS A ORALLY AVAILABLE P A
RP INHIBITOR AND HAS BEEN SHOWN
IN THE SYNTHETIC LEATHALLITY IN
THE CELL LINES AND IT'S BEEN
APPROVED FOR THIRD LINE
TREATMENT OF WOMEN WITH BRCA
MUTATION AND RECURRENT OVARIAN
CANCER.
OUR STUDY WAS TO TAKE IT FURTHER
SO GOING FROM SINGLE AGENT TO
COMBINATION WITH CHEMO THERAPY
AND THE IDEA HERE IS THAT THE
CARBOPLATIN WILL INDUCE A LOT
MORE BREAKS THAN JUST
ENVIRONMENTAL EXPOSURES AND
CELLULAR METABOLISM SO WE WILL
GIVE PEOPLE CARBOPLATEIN SO WE
CAN CAUSE SINGLE STRAND BREAKS
AND WE WILL GIVE THEM THE
IBT–INTEGRATE HICKITTOR AND IF
THEY DON'T HAVE A HOMOLOGOUS
COMBINATION BECAUSE OF A BRCA
MUTATION OR BECAUSE OF 1 OF THE
OTHER 35% OF WOMEN WHO DON'T
HAVE BRCA MUTATION THAT HAVE
EVIDENCE OF DEFECTS IS
HOMOLOGOUS RECOMBINATION SO
COHORT 1 WAS BRCA MUTANT BREAST
OR OVARIAN CANCER AND THAT WAS
PUBLISH INDEED JMCI 2014 AND
COHORT 2 WAS TRIPLE NEGATIVE
BREAST CANCER IN RECENT TCGA
ANALYSIS HAVE SIMILARITIES IN
THE DEFICIENCY, SIMILAR TO
WHAT'S FOUND IN OVARIAN CANCER,
NONBRCA MEAN.
AND THIS COHORT 3 AND SEROUS
OVARIAN CANCER AGAIN WITH THE
THOUGHT THAT EVEN WITH A NORMAL
BRCA, THERE'S STILL A 35% CHANCE
THAT YOU MIGHT HAVE A DEFECT IN
HOMOLOGOUS RECOMBINATION AND
THESE WERE BOTH PRESENTED BY
LABORATORY 2 IN OUR GROUP, AT
AZR 2014 AND THEN ALSO RECENTLY
IN ASCO THIS PAST YEAR.
SO WE WERE ABLE TO DOSE ESCALATE
AND WE FOUND A SAFE DOSE OF OLA
P A RIB, IN THE CARRIER WHICH IS
IS COMPARABLE TO WHAT WE FOUND
IN THE NONMUTATION CARRIERS
EITHER BREAST OR OVARIAN CANCER.
SO AS I MENTIONED PHASE 1 STUDY
WAS RECENTLY PUBLISH INDEED
2014, AND WE ENROLLED 45
PATIENTS, 35 OVARIAN AND ONLY IN
THE BRCA MUTATION COHORT.
THOSE DOSE ESCALATION AND DOSE
ESCALATION, AND PHASE 1 B
EXPANSION TOLERATED DOZE IN
ADDITIONAL 15 PATIENTS.
AND HAPPILY WOO FOUND WE HAD HIT
ON SOMETHING QUITE INTERESTING.
SO THIS IS THE COLORS ARE THE
DOSE LEVELS BUT YOU CAN SEE AT
ALL DOSE LEVELS WE HAVE PEOPLE
RESPONDING TO THIS DRUG, EVEN
THOUGH THEY HAD PREVIOUS NOT
RESPONDED TO PLATNIM ALONE, SO
WITH ADDITION, TO THE PLATNIM WE
WERE GETTING GOOD RESPONSES,
DEEP RESPONSES.
WE HAD 3 PATIENTS THAT HAVE BEEN
ON STUDY FOR MORE THAN 5 YEARS
THAT HAVE ON THIS PARTICULAR
COHORT.
SO THIS WAS VERY EXTREMELY
PROMISING.
THIS IS JUST TO SUMMARIZE THAT
WE HAD–THIS [INDISCERNIBLE] BUT
SINCE THEN WE HAD THE COMPLEAT
RESPONSES.
WE HAD IN THE OVARIAN CANCER
COHORT, A PATE RESPONSE, PATE
RESPONSE RATE OF 44% AND STABLE
DEDISEASE OF 38% SO OVERALL 82%
WITH CHEMO REFRACTORY DISEASE,
WHO HAVE BEEN GIVEN THE
CARBOPLATIN AND FUNCTIONAL THAT
WE CAN WORK WITH.
SO THE CONCLUSIONS WERE FROM
THAT TRIAL THAT IT'S ABOUT
TOLERATED IN COMBINATION OF
CARBOPLATIN AND HIGHLY ACT AND I
HAVE ADVANCE REFRACTORY BRC
EFFICIENT CANCERS MORE ACTIVITY
OF THE HIGHER DOSE, AND A
POSITIVE PROOF OF CONCEPT THAT
WE HAVE ACTIVITY AND
TOLERABILITY IN THIS NEGATIVELY
DEFINED TARGETED WITH THE BRCA
MUTATED CANCER.
WE DID PRESENT THE RESULTS OF
THE HIGH GRADE CANCER AT THE
ASCO 2015 MEETING AND DON'T HAVE
THE RESULTS HERE BUT THOSE
WERE–THOSE WERE VERY PROMISING
AS WELL.
SO THAT BRINGS US TO EXPLORATION
OF NEW TARGETS.
SO HOW CAN WE NOW GO FROM USING
THE OBSERVATIONAL SORT OF GENE
EXPRESSION MUTATIONAL ANALYSIS,
TO GOING TOWARD THE MORE
FUNCTIONAL EXPERIMENT, HOW CAN
WE SORT OF RECAPITULATE WHAT WAS
DONE BACK IN WHAT DID I SAY 1981
WITH THE HER2 NEW?
LET'S JUST STEP BACK AND SAY
THERE ARE A LOT OF TESTS THAT
ARE BEING MARKETED OUT THERE FOR
THESE ACTIONABLE MUTATIONS.
BUT WHEN YOU HEAR THIS, THIS
DOES NOT THINGS THAT HAD BEEN
FUNCTIONALLY VALIDATED.
THESE ARE THINGS THAT MIGHT
POTENTIALLY BE TARGETS OF OF
THERAPIES THAT EXIST, AND YOU
SEE THEM BEING SOLD BY–FROM
PLACES LIKE [INDISCERNIBLE] OR
FOUNDATION 1 AND YOU GET BACK A
REPORT THAT HAVE YOU THIS KRASE
MODEL MUTATION FOR EXAMPLE, THAT
IS POSSIBLY SENSITIVE TO DRUG
XYZ, OR YOU HAVE SOMETHING THAT
IS UNLIKELY TO BENEFIT FROM DRUG
ABC.
SO YOU'RE GETTING THESE REPORTS
THAT ARE MORE OBSERVATIONAL THAN
FUNCTIONAL.
WHAT WE HAVE ONGOING RIGHT NOW
IN THE NCI AND ALSO AROUND THE
COUNTRY ARE BASKET CLINICAL
TRIALS TO TEST THESE HYPOTHESIS
THAT IF HAVE YOU THIS MUTATION,
ARE YOU ACTUALLY SENSITIVE TO
DRUG X, Y, OR Z.
SO WHAT THESE PEOPLE ARE DOING
IS THEY'RE GOING TO C-CLEANSE
THESE AND THESE ARE NOT TESTED
AND THEY'RE NOT DEFINITIVE GOING
TO RESPOND.
TYPICALLY AS I MENKZED THERE'S
NO FUNCTION ALGORITHMS LINK
OTHER THAN WE INTRODUCE THIS
MUTATION TO A CELL LINE AND HALF
OF THEM HAD A RESPONSE.
SO WHAT ARE ACTIONABLE
MUTATIONS?
THIS IS AN EDITORIAL,
INTERESTING, BY REDIG AND JANNE,
WHICH IS QUITE APROPOE.
SO THEY SAY ACTIONABLE MUTATIONS
DEPENDS IN LARGE PART ON THE
STRENGTH OF THE DATA LINKING THE
TARGETS AND THE TARGETED
THERAPY.
THR THIS TRIAL DESIGNED TO WORK
2 KEY CONDITIONS MUST BE MET.
NUMBER 1 THE TARGET MUST
DEPENDOT TARGET PATHWAY AND
NUMBER 2, THE TARGET THERAPY
MUST RELIAISONNABLY INHIBIT THE
TARGET.
DO YOU SEE WE HAVE A LOT OF
INFORMATION MISSING.
WE DO NEED TO DO THESE CHILDS TO
FIGURE OUT WHAT WORKS IN WHAT
SITUATION.
BUT A LOT OF THE INFORMATION IS
STILL MISSING, WHICH I THINK
THESE 2 KEY CONCEPTS, SORT OF A
HURD TOLL WHAT NEEDS TO BE
ADDRESS INDEED IN WHOLE QUEST
FOR PERSONALIZED MEDICINE.
ACHIEVING BOTH GOALS CAN BE A
MATTER OF SOME COMPLEXITY IN
THESE.
SO HOW DO WE GET ACTIONABLE
TARGETS?
FROM A EXPERIMENTAL STANDPOINT I
THINK WE NEED A FUNCTIONAL
EXPERIMENT.
SO HOW DO WE USE FUNCTIONAL
GENOMICS.
SO 1 WAY THAT CAN BE DONE IS 2
THIS HAPPENED AND 6 BY DR. LOU
STOUT AT THIS INFORMATION IS A
FUNCTIONAL APPROACH USING AN RNA
LIBRARY, ASTERISKS SHRNA
LIBRARY, SO WHAT THEY DID WAS
THEY HAD A LIBRARY CONTAINING
SHRNAs BETWEEN 6 AND 12,
SHRNAs TARPGETTING 2500
DIFFERENT HUMAN GENES.
THEY SAID THAT I HAVE 3 CONTACTS
PER GENE BUT SINCE THEN I KNOW
THEY'VE UPDATEDITOUS 6-12 PER
GENE SO THERE'S 15A THOUSAND
CONSTRUCTS IN IN LIBRARY, ALL
SEQUENCE VERIFIED AND THEY
CONTAIN A BAR CODE SO THEY CAN
IDENTIFY WHICH TARGET SEQUENCES
HAVE BEEN LOST FROM THE POOL.
THE LIBRARY CONTAINS PROTEIN 3
KINASES, D-UBIQUITINNING
PATHWAYS AND OTHER GENES OF ANY,
SO WHAT DOES LIBRARY SCREEN DOES
IS IT GETS INFECTED INTO THE
CANCER CELLS AND IT'S INDUCIBLE
SO CAN YOU INDUCE IT IN HALF
YOUR POPULATION AND CAN YOU
LEAVE IT OFF IN THE OTHER HALF
AND THEN YOU LOOK FOR GENES THAT
ARE OR BAR CODES THAT ARE LOST
IN YOUR INDUCED POPULATION AND
PRESENTIENT IN YOUR NONINDUCED.
SO YOU'RE REALLY LOOKING FOR
THINGS THAT ARE SPECIFIC TO THIS
CANCER CELL GROWTH AND SURVIVAL
IN CULTURE.
SO WE DID THIS LIBRARY IN 4
OVARIAN CANCER CELL LINES.
WE LOOKED AT 2 SEROUS AND 2
NONSEROUS OVARIAN CANCERS AND WE
FOUND THERE WERE A NUMBER OF
GENES, 55 GENES THAT WERE COMMON
TO AT LEAST 3, 3 OR 4 OF THESE,
OF THESE CELL LINES.
COULD THESE BE DRIVERS?
I DON'T KNOW.
WE HAVE A LIST OF GENES THAT ARE
COMMON TO SEROUS CANCERS WE ALSO
HAVE A LIST OF GENES THAT ARE
COMMON TO NONSEROUS CANCERS AND
WE ARE FOLLOWING UP ON EACH OF
THESE TO SEE IF WE HAVE ACTUALLY
IDENTIFIED A FUNCTIONAL TARGET.
LIKE I SAID WE'RE FOLLOWING UP
IN 6 ADDITIONAL CELL LINES
TWORKS DIFFERENT RNAi
CONSTRUCTS AND WE'RE SELECTING
THE TARGETS THAT DO HAVE DRUGS
DESIGNED FOR THESE GENES.
IN ADDITION WE'RE DOING
FUNCTIONAL SCREENS AND WE FOCUS
ON THE NF-kappaB SIGNALING
PATHWAY AS WHAT MIGHT BE A
TARGETABLE TAUGHT WAY.
SO IF YOU GO BACK TO THE CANCER
DENOME ATLAS, 1 OF THE OTHER
THINGS THAT THEY LOOKED AT WAS
BY GENE EXPRESSION KWE IDENTIFY
SUBGROUPS OF OVARIAN CANCER THAT
SYRIAN CANCER THAT HAVE BEEN
COMMON.
AND 1 OF THE THINGS THAT WE
BECAME INTERESTED IN WAS AN
IMMUNO REACTIVE SUBGROUP SO IT
LOOKED LIKE THERE WERE A LOT OF
GENES THAT WERE POTENTIALLY
EVOLVED IN IMMUNE INFLAMMATION
OR IMMUNE REGULATION.
ASK WHEN YOU PUT THAT IN THE
ANALYSIS, YOU COME UP WITH THE
COMPLEX REGULATING THOSE GENES
THAT'S WHY WE FOCUS ON NFCAP B
TARGET.
SO WHAT IS NF-kappaB, AND IT'S
A SIGNALING PATHWAY THAT
PROMOTES SURVIVAL AND
PROLIFERATION OF LYMPHOID CELLS
AND CANCER CELLS THIS, IS AN
EXAMPLE OF 1 SIGNALING PATHWAY
OF NF-kappaB, THAT'S IN THE
NUCLEUS THAT PROMODE SURAL AND
PROLIFERATION GENES BUT THEY'RE
HELD CYTOPLASM IN THE INACTIVE
STATE BY THE IKKs–SORRY THE
ICAPPA B, IT'S BIND AND RETAIN
THE TRANSSCRIPGZ FACTOR IN THE
NUCLEUS UPON STIMULATION OF A
MOLECULE SUCH AS TMK IS YOU GET
PHOSPHORYLATION OF THE ICAPPA BS
IN THE PROTEOSOME AND THEN SO
WHAT WE DID IS WE ACTUALLY
LOOKED AT IKK BETA AND EPSILON
AS REGUTORS OF THIS PATHWAY TO
SEE IF WE CAN COME UP WITH A
FUNCTIONAL EXPERIMENT TO TARGET
THAT AREA IN OVARIAN CANCER.
SO WE USE THE LIBRARY IN
COMBINATION OF EITHER I KKHI, OR
EPSILON LOW AND WE LOOKED AT
OVARIAN CANCER CELL LINES AND WE
LOOKED FOR THINGS THAT WERE
SPECIFIC WITH THE EPSILON WAS
LOW.
INTERESTINGLY WE FOUND CHECK 1
WCH WAS HIGHLY SINNER GESTIC
WITH THE LOSS OF CHECK 1 AND
VICE VERSA EXPRESSION OF CHECK 1
WAS VERY SINNER GESTIC IN
PROMOTING SURVIVAL OF IGF 1
CANCER HIGH, INTERESTINGLY CHECK
1 PEAKED OUR INTEREST
SPECIFICALLY IN OVARIAN CANCER
BECAUSE WE FOUND THAT IT WAS
OVEREXPRESSED IN CANCER GENOME
ATLAS IN ALMOST A HUNDRED% OF
OVARIAN CANCERS.
SO PERHAP ITS HAS SOMETHING TO
DO WITH THE PATHWAY OF GENOMIC
DSARRAY.
IN RESPONSE TO DNA DAMAGE.
SO DNA DAMAGE IT ACTIVATES IN
ONCE SENSE ATM WHICH ACTIVATES
CHECK 1 OR 2, TO EVENTUALLY HALT
THE CELL CYCLE AT THE G2 M CHECK
POINT.
IF YOU DON'T HALT IT THERE, IT
GOES THROUGH IT'S CELL CYCLE AND
THEN THE DEC KIND OF AMPLIFIES
AND YOU GET ADDITIONAL DNA
DAMAGE AND THE CELL WILL DIE.
SO CAN YOU IMAGINE THAT CELLS
WITH A VERY MESSED UP RESPOND
WILL HAVE ELEVATED CHECK 1 OR 2
TO BLOCK THAT RESPONSE AND ALLOW
THE CELL TO SORT OF IMPERFECTLY
REPAIR THE D NA ENOUGH SO THEY
GO THROUGH THE CELL CYCLE
WITHOUT GOING TO APOPTOSIS.
SO IT MAKES SENSE IN THIS TYPE
OF CANCER.
AND REPRESENTING OTHER
HISTOLOGY, AND WE ACTUALLY DO
HAVE A CLINICAL TRIAL ONGOING
WITH AND INTERESTINGLY WE ARE
SEEING HIGHER RESPONSES IN
PEOPLE WITHOUT A BRCA MUTATION
SUGGEST THANKSGIVING CHECK 1
MIGHT BE MORE IMPORTANT IN WOMEN
WITHOUT BRC MUTATION.
THIS WAS HIGHLIGHTED AS I
MENTIONED HERE BY FUNCTIONAL
APPROACH INSTEAD OF JUST AN
OBSERVATIONAL SCREEN.
SO IN SUMMARY THIS IS WHAT I
WENT THROUGH QUICKLY THIS, IS
DIVIDED INTO EPITHELIAL AND
NONEPITHELLIAL, EPITHELIAL ARE
HIGH GRADE, LOW GRADE, CLEAR
CELL, SEROUS AND WE HAVE EACH OF
THESE ON THE HOMOLOGOUS
COMBINATION DEFECTS IN THE HIGH
DEGREE OF OVARIAN CANCER WITH
SOME MODERATE SUCCESS.
SO, JUST TO TIE IT ALL UP, 1981,
THE DISCOVERY OF HER2 WAS A
FUNCTIONAL GENOMIC APPROACH BY
THROWING GENES INTO MOUSE
FIBROBLASTS AND SEEING WHAT
WORKED.
WE'VE DONE SHRNA LIBRARY SCREEN
AND THROWN THAT IN THERE AND SEE
WHAT WORKS WHEN YOU KNOCK IT
OUT.
WHAT KILLS THE CELL WHEN YOU
KNOCK IT OUT.
ROBBER SO FUNCTIONAL DENATIONAL
LIBRARY OF MEDICINIC SCREEN AND
THEN IT IS CLINICAL MARKERS AND
WE'VE TAKE 10 TO CLINICAL TRIALS
WITH THAT SUCCESS.
WITH THAT I WILL STOP AND TAKE
ANY QUESTIONS.
[ APPLAUSE ]
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> SO THE QUESTION WAS WHY DID
LOSS OF BRCA FUNCTION RELATE TO
OVARIAN AND BREAST CANCER AND
NOT OTHER CANCER SINCE ALL CELL
TYPES NEED HOMOLOGOUS
RECOMBINATION AND THAT IS A
FASCINATING QUESTION AND I'VE
ALWAYS–I'VE THOUGHT ABOUT THAT
FOR THE LAST 10 YEARS.
BECAUSE, YOU WOULD THINK THAT
YOU WOULD HAVE ANY TYPE OF
CANCER, KIND OF LIKE TAKING FROM
ANY PATIENT WHO IS HAVE MULTIPLE
DIFFERENT TYPES OF CANCERS.
SO, I MEAN, 1 THOUGHT IS THAT
THE–THE BREAST AND OVARIAN
CELLS BECAUSE OF THE WAY THEY'RE
CYCLING WITH THE HORMONAL SORT
OF INFLUENCE, THEY MIGHT DEPEND
MORE ON THE BRCA RELATED
HOMOLOGOUS COMBINATION AS OPPOSE
TO OTHER DOUBTS.
THIS IS ALL HYPOTHESIS.
THE OTHER THOUGHT IS WHEN
LEUKEMIA–SORRY IN BLOOD CELL
FIST YOU LOSE BOTH BRCA GENES
IT'S LETHAL SO IT WILL LOOSE THE
FUNCTION OF BRCA, SO IT CANNOT,
IT JUST DIES, LIKE THE CELLS IN
THE BLOOD AND THE BONE MARROW
MIGHT BE GETTING, YOU KNOW
THEY'RE LOSING BOTH COPIES OF
BRCA, THEY CAN'T FORM A CANCER
BECAUSE THEY'RE GOING TO JUST GO
AWAY.
SO THEY MIGHT HAVE THE ABILITY
TO SURVIVE, NOT THAT THEY'RE
EFFECTED BY THE BRCA BUT THEY'RE
THE ONLY 1S THAT CAN SURVIVE
WITHOUT IT BECAUSE THEY HAVE
OTHER WAYS TO OPERATE AND OTHER
DNA REPAIR MECHANISMS LIKE
NONHOMMOLOGIOUS ENJOIN TAG CAN
ALLOW THEM TO GROW EVEN THOUGH
THEY HAVE THIS LOSS OF
HOMOLOGOUS RECOMBINATION.
YES?
>> SO THE QUESTION IS WHY IS
OVARIAN CANCER DIAGNOSED IN LATE
STAGES AND WHAT CAN WE DO?
THAT HAS BEEN A DELL
IMPEDIMENTSA FOR MANY, MANY
YEARS.
WHY IT'S DIAGNOSED SO LATE IS
BECAUSE IT DOES NOT PRESENT WITH
OBVIOUS SYMPTOMS.
AND IT'S REALLY HARD TO EXAMINE
THAT AREA, SO IF YOU THINK OF
BREAST CANCER, THE WOMEN CAN DO
A SELF-BREAST EXAM AND NOTICE
THEY HAVE A MASS IN THE BREAST.
WITH OVARIAN CANCER, THE
SYMPTOMS, YOU CAN'T REALLY FEEL
THE MASS UNTIL IT'S ENORMOUS,
THESE SYMPTOMS ARE BIG, THEY'RE
SORT OF GI TYPE SYMPTOMS,
NAUSEA, BLOATING, DIARRHEA,
CONSTIPATION, THE OVARIAN GOES
FOR A LONG BECAUSE THERE ARE
NONSPECIFIC SYMPTOMS.
PEOPLE LOOK FOR MARKERS BUT THE
MARKERS ARE PERO TON EEL
IRRITATION, NOT SPECIFIC TO
ANY–ANY AND NOT BECAUSE OF
CANCER ITSELF.
SO THE MARKER S&P CAC125 IT CAN
BE ELEVATED FOR CONDITIONS LIKE
LUNG DISEASE OR YOU KNOW
PANCREATIC DISEASE OR ANY IRTAGS
OF THE BOWEL.
WHEREAS SO IT'S NOT SPECIFIC BUT
THEN ALSO NOT VERY SENSITIVE
BECAUSE WITH 50% OF CANCERS THAT
DON'T HAVE ALLOCATED AT 125, SO
WE'RE LOOKING FOR MARKER BUS IT
IS DIFFICULT.
THE BIG QUESTION NOW IS JUST
AWARENESS THAT PELVIC AND GI
SYMPTOMS LOOK FOR A CAUSE.
THE OTHER REASON IS BECAUSE THE
BIOPSY IS THE KIND OF INVASIVE
SO IT'S HARD TO [INDISCERNIBLE]
BUT OVARIAN BIOPSIES WILL BE
MORE OF AN OPEN SURGICAL
PROCEDURES.
>> YES?
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> YEAH, SO, THAT'S ANOTHER
INTERESTING POINT THEY WAS GOING
TO TALK B. I KNOW WE TALKED A
LOT THAT IT SPREADS–SORRY, THE
QUESTION WAS WHAT ABOUT THE
RAPID PROGRESS OF THE DISEASE.
CAN THAT–DOES THAT CONTRIBUTE
TO THE LATE STAGE?
>> AND I THINK IT'S NOT
NECESSARILY THE RAPID
PROGRESSION OF THE DISEASE BUT
THE WAY IT SPREADS.
SO A LOT OF CANCERS WOULD SPREAD
THROUGH THE BLOOD AND THE
LYMPHNODES, OVARIAN CANCER
WILL–BEFORE IT GET INTERESTS
THE BLOOD STREAM WILL SHUT, SO
IT JUST SHEDS FROM THE SOURCE OF
THE OVARY SO IT'S EASY FOR IT TO
GO AND LANDOT LIVER AND GO AND
LAND ON THE DIAPHRAGM.
SO IT'S VERY EASY FOR IT TO
FLOAT AROUND AND TAKE UP A NIGH
HOLE.
SO I THINK THAT HAS TO DO WITH
IT.
YES?
>> YEAH, SO QUIET IS ANY
RADIOLOGIC MODALITIES PLAY A
ROLE IN SCREENING.
THERE WAS A RECENT STUDY, WHICH
LOOKED AT IMAGING STUDIES EITHER
CT, ULTRASOUND OR TRANSVAGINAL
ULTRASOUND AND IN COMBINATION OF
CA-125, SO WITH A SERUM MARKER
AND THAT DID SHOW–DID SHOW SOME
PROMISE IN SCREENING FOR OVARIAN
CANCER BBUT DID NOT HAVE A HUGE
IMPACT AS 1 WOULD HOPE.
THE REASON FOR THAT AGAIN IS A
LOT OF FALSE-POSITIVES WITH THE
SCREENING, DETECTING A MOUSE,
THAT'S NOT NECESSARILY CANCER
AND YOU HAVE A LOT OF
INTERVENTION GOING ON FOR
SOMETHING THAT'S NOT CANCER.
THE EARLY STUDIES OF THAT
ACTUALLY SHOWED AN INCREASE IN
DIAGNOSIS BUT IT WAS IN THE
DIAGNOSIS OF LATE STAGE CANCER
NOT EARLY STAGE CANCER SO THATTA
WHY THEY MOVED TO NOT LOOKING AT
A PARTICULAR CUT OFF AT 125 BUT
LOOKING AT THE RATE OF RISE OF
THE CA-125 MARKER BUT THERE'S
LOTS OF IDEAS OUT THERE, SO THE
TAKE HOME POINT IS THAT THE
IMAGING HAS A LOT OF
FALSE-POSITIVES AND SO IT'S KIND
OF HARD TO USE AS A GRADE.
OKAY, YOU'RE WELCOME.
>> OKAY, I HAVE 1 MORE
ANNOUNCEMENT AND THAT BEING,
I'LL BE SENDING ALL THE
REGISTRANTS AN E-MAIL THIS WEEK
ABOUT THE TUMOR BOARDS AND THE
CORE FACILITIES.
SO THIS IS ALL VOLUNTARY IF YOU
WOULD LIKE TO LEARN MORE ABOUT
WHAT GOES ON AT NCI, WE HAVE 3
TUMOR BOARDS, MEDICAL ONCOLOGY,
ERO LOGIC ONCOLOGY OR PEDIATRIC
ONCOLOGY TUMOR BOARDS AND THEN
WE'LL ALSO HAVE A TOUR OF THE
PATHOLOGY FACILITY AND THE SMALL
MOLECULE CORE WHERE THEY USE
ROBOTICS TO DEVELOP NEW SMALL
MOLECULES FOR CANCER.
SO OUR NEXT SPEAKER IS STEPHANIE
GOFF, SHE DID A SURGICAL
RESIDENCY AT COLUMBIA, WENT TO
THE BRIGHAM WOMEN'S HOSPITAL AT
MASS GENERAL SHE'S NOW IN THE
SURGERY BRANCH.
SHE WILL TALK ABOUT A HOT NEW
AREA, CHICK POINT MODULATION.
>> YEAH, I AM, THANK YOU.
SO BEFORE I GET STARTED HOW MANY
OF YOU ARE IMMUNOLOGIST OR IN
THE IMMUNOLOGY FIELD?
YOU MIGHT KNOW MORE ABOUT T-CELL
ACTIVATION THAN I DO BUT WE'LL
GET STARTED.
SO TO UNDERSTAND CHECK POINT
MODULATION YOU HAVE TO
UNDERSTAND HOW THE T-CELL WORKS
AND WHY WE THINK CANCER
IMMUNOTHERAPY MIGHT MAY BE A
GOOD IDEA.
SO THE OBJECTIVES I WILL GO OVER
TODAY IS TALKING ABOUT THE
MECHANISM OF ACTION OF BLOCKADE,
AND I WILL TALK ABOUT THE EARLY
CLINICAL EXPERIENCES I HAD HERE
I WAS ABLE TO PARTIC 8 IN AS A
FELLOW WHEN I WAS HERE BEFORE
AND HOW WE DISCOVERED WHAT
IMMUNE RELATED ADVERSE EVENTS
WERE AND HOW IT CHANGED, HOW WE
HAD TO THINK ABOUT CLINICAL
TRIALS USING IMMUNE MEDIATED
MEDICINE.
THERE ARE NOW 3 FDA APPROVED
CHECK POINT MODULATORS AND I GO
THRGH THE CLINICAL DATA THAT
LED TO THOSE APPROVALS AS WELL
AS CHECK POINT MODULATORS AS
WELL AS DEVELOPMENT OF A FOURTH
THAT'S NOT ON THE LIST.
SO TO KNOW WHERE I GOT STARTED
HAD I MADE THE SLIDE 5 YEARS
AGO, IT WOULD HAVE HAD 3 PILLARS
AND THOSE WOULD HAVE BEEN
SURGERY WHICH DATE BACK TO THE
EGYPTIANS, THEY FOUND HIROUGH
ATOM GRIEF SHOWING THEM TAKING A
BREAST CANCER OUT OF A PATIENT.
NEXT WOULD BE RADIATION WHICH
GOT START INDEED THE LATE 1800S
AND 1900S, INCIDENTALLY, AND
THEN CHEMO THERAPY AND
ACTIVITIES AND PROJECTS CHE GOT
STARTED AT THE DANA-FARBER AND
WAS MORE FINE TUNED HERE IN THE
NCI IN THE EARLY 70S. AND CHEMO
THERAPY GOES BACK TO 1940.
BUT IN THE LAST FEW YEARS,
PARTICULARLY IN 2012 AND SINCE
THEN, THEY'VE BEEN HOW TO TREAT
PATIENTS WITH CANCER.
WE WILL GO THROUGH THAT TODAY.
SO THERE ARE 3 MAIN WAYS CANCER
IMMUNO THERAPY AND ACTIVITIES
AND PROJECTS KEWORK, THE FIRST
IS NONSPECIFIC STIMULATING
THE'MUNE REACTION OF THE BODY.
WE CAN EITHER SIMULATE EFFECTOR
CELLS, WE'VE DONE THIS IN THE
PAST USING HIGH DOSES OF THE
HORMONE INTERLEUKIN 2, WE CAN
INHIBIT THE REGULATORY FACTORS
BY TURN BEING OFF CHECK POINT
BLOCK AID.
WE CAN ACTIVELY IMMUNIZE
PATIENTS TO GET A MORE SPECIFIC
ANTITUMOR REACTION AND THAT'S A
VAST MAJORITY TO GO OUT AND READ
WHAT'S HAPPENING AT PLACES OTHER
THAN HERE AND WE CAN PASSIVELY
TRANSFER FOCUSED ON ANTITUMOR
ACTIVITY, AND WHICH S&P REALLY
HERALDAD HERE BY DR. ROSENBERG
AND CONTINUES TO MOVE FORWARD AS
KIND OF A SALVAGE THERAPY.
BUT WE FOCUS ON TODAY IS ERNE
HICKITTING REGULATORY FACTORS OR
CHECK POINT BLOCKADE.
SO IF YOU KNOW HOW A T-CELL GETS
ACTIVATED.
IT'S A 3 STEP PROCESS, REQUIRES
FIRST SIGNAL 1 WHICH PROVIDES
THE T-CELL WITH THE SPECIFICITY.
WHEN HAVE YOU A PROTEIN WHETHER
IT IS SELF-OR NONSELF, IT'S
EATEN UP BY THE PROTEOSOME ON
THE PROCESSED, PLACED ON A MAJOR
HISTOCOMPATIBILITY COMPLEX CHRKS
IS A POCKET AND MAKES ITS WAY
OUT TO THE E. R. AND BACK OUT ON
TO THE SURFAC OF THE CELL.
SO ANY PEPTIDE THAT YOU MIGHT
THINK COULD APPEAR IN THE
CYTOSOL OF THE CELL, COMES OUT
AS THE SMALL 9-10 PEPTIDE
RESIDUES, SIT NOTHING THE POCKET
OF AN MHC.
OUR BODIES HAVE THE ABILITY TO
MANIPULATE OUR GENES TO CREATE A
VAST ARRAY OF DIFFERENT T-CELL
JOINING REGIONS AND WE JOIN WITH
SPECIFIC T-CELLS THAT CAN
CONNECT TO THIS PEPTIDE IN THE
POCKET OF THIS MHC.
THAT'S WHAT'S CALLED SIGNAL 1 OR
T-CELL ACTIVATION.
IT CAN HAPPEN WITH ENDOGENOUS
PROTEIN, IT CAN HAPPEN WITH
ENDOSIGNIFYITOSED PROTEIN WHICH
IS GENTLEMENLY GET PRESENT
INDEED THE CONTEXT OF MHC 2.
ALL NUCLE88ED CELLS HAVE MHC 1
AND THEY HAVE THE ABILITY TO
REACH IN AND PULL OUT AND PUT A
9 OR 10 IN THE T-CELL TO FIND.
DENDRITIC CELLS HAVE THIS
ABILITY TO DEAL WITH PEPTIDES TO
GET ENDOIITOSED WHETHER THESE
ARE CANCER, VIRUSES, THE FLU YOU
GOT LAST WEEK, IT BRING ITS OUT
AND GIVE ITS TO A CD4 OR
TRADITIONAL LIMITED PARTNERRER
CELL WHICH THEN GIVES THE
SPECIFIC T-CELL ACTIVATION.
THAT'S ONLY THE FIRST STEP OF
THE PROCESS, THIS T-CELL WON'T
GO AND DO ANYTHING UNTIL YOU GET
FURTHER.
SOLET NEXT STEP IN T-CELL
ACTIVATION IS THAT THERE HAS TO
BE A CO LIGAND.
SO WHEN THE TCR NEXT TO THE CD3
WHICH IS THE MARKER OF THE IMP O
SITE GETS ACTIVATE TODAY
REQUIRES 1 OF THESE SECOND
SIGNALS.
SOME OF THESE SECOND SIGNALS ARE
POSITIVE THAT LEAD TO DOWN
STREAM ACTIVATION BUT SOME OF
THESE AS YOU SEE PICTURED HERE
IN RED ARE NEGATIVE SIGNALS.
CTLA 4 WHICH IS 1 FORM OF
BE IS 1 IF THAT GETS
ACTIVATED THAT WILL SHUT DOWN A
CELL, PD1 WILL SHUT DOWN A CELL.
THIS DETERMINES IF IT'S ACTIVE
OR AMERGEY, WHICH DOES NOTHING
UNTIL EVENTUALLY APOPTOSIS.
THE THIRD SIGNAL WHICH NOT AWELL
ELABORATED AS THE OTHER 2 IS THE
PRESENCE OF CYTOKINES IN THE
AREA AFTER T-CELL HAS BEEN
ACTIVATE TODAY CAN POLARIZE TO 1
TYPE OF A HELPER CELL OR A
T-EFFECTOR CELL AND THAT IS
HEAVILY DEPENDENTOT MICRO
ENVIRONMENT IN WHICH IT ASHES
RIFES.
SIGNAL 3 IS SOMETHING THAT'S
BEING WORKED OUT THESE ARE
THINGS THAT WOULD BE MORE OF THE
TRUGGABLE TARGET SMALL MOLECULE,
WE WILL TALK ABOUT TODAY IS WHAT
HAPPENS AT SIGNAL 2.
WHAT IS THE ROLE OF THE SIGNAL
2, WHY DO WE HAVE THEM, WHY ARE
THEY IMPORTANT.
IT SEEMS LIKE ALL THEY'RE DOING
IS TELLING US ABOUT CANCER, IT
PREVENTS US FROM HAVING
AUTOIMMUNE RIA ACTIONS FROM THE
T-CELLS THAT FIND NORMAL PIECES
OF OUR BODY.
SO, INITIAL RESPONSE TO AN
ANGIOMA WILL OCCUR IN THE ORGAN,
NOW THOSE CAN BE THE LYMPHNODE
WHICH IS WE HAVE ALL OVER OUR
BODY, TONSILS SPLEEN, AND THE
GUT, MUCOSEIS ASSOCIATED
LYMPHOID TISSUE RIGHT UNDER THE
SURFACE OF THE STOMACH AND THEY
ALLOWS US TO RECOGNIZE WHAT IS
OUR CELLS SO WE DON'T START TO
DESTROY IT.
THE IMMUNE CHECK POINTS ALSO
LIMIT COLLATERAL DAMAGE, AND
IT'S SOMETHING THAT'S ACTIVATED
AND TURNED ON, AND THEN IT GOES
TO THE SIDE OF SAY THE SPLINTER
YOU JUST GOT IN YOUR HAND FROM
RUNNING YOUR HAND DOWN THE STAIR
WELL, IF YOU LEFT THAT T-CELL
RESPONSE GOING ON AND ON YOU
COULD DESTROY YOUR ENTIRE FINGER
BECAUSE ONCE IT TURNS OUT
TDOESN'T KNOW HOW TO TURN OFF.
SO THESE IMMUNE CHECK POINTS
STOP THE COLLATERAL DAMAGE BY
SHUTTING DOWN THE RESPONSE AFTER
IT'S GOTTEN THERE IS ENGAGED.
SO IN THE CONTEXT OF CANCER, WE
HAVE 2 OPPORTUNITIES TO BREAK
THE TOLERANCE TO SELF-ANTIGEN.
BECAUSE FOR THE MOST PART
CANCERS WERE THE SOMETHING WE
GET.
IT'S NOT A VIRUS, IT'S NOT
SOMETHING THAT OUR BODY CAN SAY,
HEY THAT'S NOT YOUR DNA, LET'S
ATTACK IT.
IT IS YOUR DNA, IT IS PART OF
YOU AND HAVE TO TRICK YOUR
IMMUNE SYSTEM INTO DOING IT AND
THAT THERAPIST IS 1 OF THE WAYS
TO DO IT.
THIS IS THE FIRST CHECK POINT
BLOCKADE THAT WAS INVESTIGATED
BY DR. ALLISON WHO WON THE
LASKER AWARD, I DONE FINISH
YOU'RE AWARE OF THAT. BEING
PROMINENT IN THE IMMUNOTHERAPY
COMMUNITY.
THE REASON IS ONCE THIS T-CELLS
GETS ENGAGED WITH SIGNAL 1, THE
IT, CR ENGAGED WITH THE PEPTIDE
AND THE CONTEXT OF MHC, GETS
TURN OFFICE OF DIVERSITY BY
ACTIVATING CD-28.
NOW DEPENDING ON THE AFFINITY OF
THIS COMPLEX, IF THIS IS A HIGH
BINDER IT WILL INCREASE THE
CTLA-4 THAT GOESOT SURFACE AND
ONCE IT GOES TO THE SURFACE, IT
ACTUALLY BIND THIS IS LIGAND
WITH MORE AFFINITY THAT CD28 SO
IF YOU DID SOMETHING THAT TURNS
ON, THE OFF-SIGNAL COMES ON AND
IT'S STRONGER AND IT PULL ITS
AWAY.
AND IT TURNS THE T-CELL OFF.
SO THIS IS HAPPENING IN THE
PERIPHERY WHEN A T-CELL FIRST
ENCOUNTERS AN ANTIGEN.
IT HELPS SHUT IT DOWN.
IT HAS A DAMPENING EFFECT SO
THAT ONCE THEY GET STARTED THEY
DON'T GET OUT OF CONTROL.
IN MICE THAT ARE DOUBLE KNOCK
OUT FOR THIS, THEY DON'T DIE IN
UTERO BUT THEY DIE QUICKLY OF
LIM FOE PROLIFERATIVE AUTOIMMUNE
DISORDER WITHIN A FEW WEEKS.
TD1 IS ANOTHER LIGAND, EXCUSE
ME, AND THIS IS OUT ONCE THE
CELL HAS BEEN ACTIVATED AND MAKE
ITS WAS TOY WHERE IT WANTS TO
ACT.
SO HAVE YOU A T-CELL, ENGAGED
PEPTIDE IN THE CONTEXT OF MHC.
IT'S BEEN TURN OFFICE OF
DIVERSITY BY CD28 OR ITOS, 1 OF
THE OTHER POSITIVE STIMULATORS,
IT GETS TO WHERE IT WANTS TO BE,
IT STARTS THE INFLAMMATORY
PROCESS, THIS PROCESS MAKES THE
TARGET CELL, EXPRESS PD-1 WHICH
THEN SHUTS OFF THE T-CELLS.
AND THE SITE WHERE THE T-CELLS
ACTIVATING TO SHUT IT DOWN.
SO ANY INFLAMMATION CAN
UPUPREGULATE CD1 AND IT LIMITS
COLLATERAL DAMAGE WHEN YOU GET
AN INFECTION OR A SPLINTER, IT
STOPS FROM GOING TOO FAR.
SO HOW DOES THE PD1, PDL1 SYSTEM
WORK IN CANCER.
THERE'S SOME CANCERS GLEE O
BLASTOMA IS 1 EXAMPLE R THE
PATHWAY WITHIN THE CELL
UPREGULATES CDL-1 ON ITS OWN, IT
DOESN'T REQUIRE A SIGNAL FROM
THE OUTSIDE TO TURN ON.
THERE'S BEEN A MUTATION THAT
MAKE ITS UPREGULATE CDL-1.
BUT ANOTHER WAY WE FOUND IS THAT
WHEN THE SYSTEM WORKS, WHEN WE
START FEEL KILLING THE CANCER IT
RELEASES INTERFERON-GAMMA AND
THAT INTERFERON-GAMMA
UPREGULATES PDL 1 AND STARTS TO
SHUT IT OFF AGAIN.
SO WE GET SOME SUCCESS, THE BODY
SAYS, WE ARE GOING TO SHUT IT
DOWN BEFORE IT GETS OUT OF
CONTROL.
UNFORTUNATELY WE WANT TO GET OUT
OF CONTROL BECAUSE IT NEEDS MORE
TO KILL THE TUMOR SO, WE HAVE TO
FIND A WAY TO BLOCK THIS
RESPONSE TO INTERFERON-GAMMA.
SO WITH CHECK POINT WHERE SHOULD
WE START.
WHERE DID WE DECIDE WE NEED TO
GET STARTED.
WE START WIDE OTHER TUMORS THAT
WERE KNOWN TO RESPOND TO
IMMUNOTHERAPY SO THE FIRST IS
MELANOMA.
THE PATIENTS THAT NEED HELP ON
THE METASTATIC DISEASE, THEY GET
INTO TROUBLE, MEANING IT'S GONE
ELSEWHERE IN YOUR BODY, HAVE YOU
A 16% SURVIVAL RATE.
THE DOCTOR ACROSS THE STREET IN
BUILDING 10, CAN PROVIDE A
CURABLE CURE, THIS ISN'T
SOMETHING THAT WE SAY IN CANCER
VERY OFTEN, 4% DURABLE CURE RATE
IN PATIENT WHO IS HAD A WIDE
SPREAD METASTATIC DISEASE.
THE OTHER CANCER THAT'S KNOWN TO
WORK WITH IMMUNE MODULATION IS
KIDNEY CANCER.
THERE'S AN ESTIMATED 15,000
DEATHS PER YEAR, AGAIN ONCE YOU
DEVELOP THAT WIDE SPREAD
METASTATIC DISEASE, THE YOUR
VUCIPHAL IS 5% AND AGAIN THESE
PATIENTS AT BUILDING 10, DURABLE
YOU'RE IN 7%.
SO THIS IS WHAT WE STARTED WITH,
THIS WAS THE CHECK POINT
BLOCKADE, AGAIN IN
DR. ROSENBERG'S GRANTS.
ANTICTLA 4, MONOCLONAL ANTIBODY
THAT BLOCKS THAT SIGNAL 2, IT'S
CALLED IPILIMUMAB, IT'S
MONOCLONAL ANTIBODY PLUS PEPTIDE
AGAINST GP100 WHICH IS A MARKER
OF MEL AN OHM A. ONLY 14
PATIENTS ENROLLED.
TWO COMPLETE RESPONDERS AND 1
PARTIAL RESPONSE.
HOWEVER THE ACCRUAL GOT FOR
TOXICITY AND WE START TO SEE
THESE, DERMA TITIS WHERE THEY
WOULD FLUFF THEIR SKIN.
COLITIS, BLOODY DIARRHEA,
SOMETIMES OPERATIONS,
HYPOTHICITIS WHICH IS PROBLEMS
WITH THE PITUE TARY AND THE
PATIENTS WOULD LACK ADRENAL
FUNCTION AND LACK TESTOSTERONE
AND BE ON STEROID REPLACEMENT.
SO WHILE IT HAD GREAT EFFECTS
YOU SEE THIS IS A LESION IN THE
LUNG HERE AND CAN YOU SEE IT'S
GONE HERE.
BUT WHAT WE WERE SEEING THIS, IS
SKIN AND THESE DARK BLUE DOTS
THOSE ARE ALL NUTRIFILLS
INFILTRATING THE SKIN.
THIS IS BIOPSY OF COLON, ALL
THESE SMALL ROUND CELLS THAT
SHOULD NOT BE THERE.
LYMPHOCYTES THAT SHOULD NOT BE
THERE AND WHEN YOU STAIN FOR
CD3, THAT'S WHAT ALL THESE BROWN
DOTS ARE AND THIS IS THE PATIENT
WITH HEPATITIS AND IT'S
DIFFICULT TO SEE IN THIS MAG
FIELD FUNCTIONSFICATION BUOY SEE
THIS DESTROYING THE TRIBE AND
DESTROYING THE DUCT AND THE
BILLIARY SYSTEM AND YOU STOP IT
AND HAD TO FIGURE OUT WHAT WAS
GOING ON.
HOWEVER, THIS HAPPENED.
AFTER WE STOPPED THE TRIAL, WE
KEPT WATCHING THESE PATIENTS, 2
OF THESE PATIENT HIS EVERY
SINGLE BET OF DISEASE THEY HAD
DISAPPEAR.
SO WE STARTED TO INVESTIGATE,
WHY IS THIS HAPPENING.
SO WE CAUTIOUSLY, STARTED THE
TRIAL AGAIN.
WE DRONE THE DOSE, 1 MILLIGRAM
PER KILOGRAM.
WHAT WE FOUND WAS IF YOU HAD 1
OF THESE AUTOIMMUNE EVENTS YOU
HAD A HIGHER LIKELIHOOD OF
DEVELOPING A RESPONSE, IN
PATIENTS WITH MELANOMA IF THEY
HAD A GREATER THAN GRADE 3
ADVERSE EVENT, YOU HAD A 36%
CHANCE OF DEVELOPING A RESPONSE
WHEREAS IF YOU DID NOT, CAN YOU
A 5% CHANCE OF DEVELOPING A
RESPONSE.
IN RENAL CELL CANCER, THE SAME
THING, NO PATIENT THAT DID NOT
HAVE A GRADE 3 ACE, DEVELOPED A
RESPONSE.
SO THEN WE DECIDED WE WOULD
LOWER THE DOSE, LET'S RAISE THE
DOSE.
WE THINK THAT CAUSING THESE
IMMUNE REACTION FIST WE CAN GET
THE PATIENT THROUGH THEM WHICH
WE COULD.
ALL OF THIS COULD BE REVERSED BY
STEROIDS FWE CAN GET THEM
THROUGH THE TOXICITY.
IF IT CURES THEM ARE THEY
WILLING TO PUT UP WITH THAT AND
THE ANSWER OF COURSE IS THEY'RE
WILLIAMING TO PUT UP WITH
TOXICITY IF WE CAN RESCUE THEM
FROM IT.
AND SO THEN WE STARTED THE DOSE
ESCALATION TRIAL.
WHAT WE FOUND THAT WAS THE COLIT
ISOTOPE AGAIN WITH BLOODY
DIARRHEA SOMETIMES REQUIREDDA AN
OPERATION WAS THE MOST COMMON
GRADE 3-4 IMMUNE RELATED ADVERSE
EVENT AND WE DID GIVE STEROIDS
TO MANAGE THESE AND WHILE WE
WORRIED BECAUSE THE STEROIDS
SHUT DOWN THE SYSTEM
TEMPORARILY, THEY DID NOT STOP
THE PATIENT FROM HAVING A
RESPONSE.
SO IF YOU DIDN'T HAVE ANY IMMUNE
ADVERSE EVENT AT ALL THERE WAS 1
PATIENT THAT DID GET A RESPONSE.
BUT FAR GREATER NUMBERS IF YOU
DEVELOPED IMMUNE RELATED ADVERSE
EVENT.
SO WHAT DID WE DO HERE AT THE
NCI FOR THAT.
WE GOT TO THE POINT WHERE NOW IT
NEEDED TO GO OUT IN THE WORLD
AND HAVE A MULTIINSTITUTIONAL
TRIAL TO GET PREPARED AND ONCE
THAT HAPPENED WE KIND OF LET IT
GO AND LET THEM DO THE TRIAL,
LET PHARMACY DO THE TRIAL.
WHEN WE FOLLOWED UP OUR
PATIENTS, RECENTLY, WE HAD AN
OVERALL RESPONSE RATE OF 13-20%.
AND A 5 YEAR SURVIVAL OF CLOSE
TO 23%.
AND MORE IMPORTANTLY WE
DEVELOPED ALEGORITHMSES THAT
WENT OUT INTO THE WORLD.
SO WHAT ARE ANY OF YOU FAMILIAR
WITH SURVIVAL CURVES?
HAVE YOU HAD ENOUGH CLINICAL
LECT OURS AT THIS POINT.
SO THIS TELLS YOU AT BEGINNING
OF THE TRIAL ALL PATIENTS WERE
ALIVE.
AT 12 MONTHS, 1 YEAR, ABOUT HALF
THE PATIENTS WERE ALIVE,
DEPENDING ON WHAT TRIAL THEY
WERE ON, NOW TAKEN–THEY WE'RE
OUT HERE, WHAT YOU HAVE TO KEEP
IN MIND THOUGH, WE'RE AT 7 YEARS
AND THERE'S STILL PATIENTS
ALIVE.
THESE ARE PATIENTS WITH WIDE
SPREAD METASTATIC DISEASE THAT
HAD 1 OR MORE OTHER TREATMENT
BEFORE THEY GOT TO US.
SO THEY ALREADY USED UP THAT
ONCE HAVE YOU METASTATIC
DISEASE, HAVE YOU THIS LONG TO
LIVE.
THEY GOT THAT, AND WE'VE GOT
THEM NOW LIVING 7, 8, 9, 10
YEARS.
SO THAT WENT OUT INTO TRIAL AND
IT HAD A BIG NATIONAL TRIAL,
PUBLISHED IN THE NEW ENGLAND
JOURNAL AND 11% RESPONSE RATE.
COMPLETE RESPONSES IN 3 PATIENTS
AND YOU CAN SEE THE SURVIVAL
CURVE HERE AGAIN, THEY DIDN'T
HAVE AS RUNNING TO FOLLOW UP BUT
AT 4 YEARS THEY HAVE 10-20% OF
PATIENTS ALIVE AND SO THIS WAS
APPROVED FOR METASTATIC
MELANOMA, THE CHECK POINT
MODULATOR EVER TO BE APPROVED
FOR ANYTHING IN MARCH OF 2011.
NIVOLUMACK, WAS A PHASE 1 DOSE
ESCALATION AND IN ADDITION TO
THE TUMORS THAT WE KNEW COULD
RESPOND, MELANOMA AND KIDNEY
CANCER THIS WAS A TRIAL AT JOHNS
HOPKINS AND THEY–A NUMBER OF
DIFFERENT TREATMENTS, MEL AN OHM
ANONSMALL LUNG CANCER, RENAL
CELL CANCER, CASTRATION
RESISTANT PROSTATE CANCER AND
COLORECTAL CANCER.
THIS IS CALLED A SPIDER PLOT AND
THIS IS FOR EACH AND EVERY
PATIENTOT TRIAL, IT MARKS THE
LENGTH OF THE SUM OF ALL THEIR
TUMORS THAT WERE MEASURING.
AND IT DOES IT AS A PERCENTAGE
SO AT BASELINE THERE'S BEEN NO
CHANGE.
IN PATIENT WHO IS GO NEGATIVE,
THAT MEANS THE TUMOR HAS SHRUNK
DURING THE COURSE OF TREATMENT
AND THE PATIENT WHO IS GO
POSITIVE MEANS THE TUMOR GOES UP
AND WHAT THEY'RE ATTEMPTING TO
SHOW WITH THIS FIRE BLOT IS THAT
TUMORS DON'T GO COMPLETELY AWAY,
THEY STAY AWAY FOR A WHILE.
NOW KEEP IN MIND THIS, IS IN
WEEKS AND SO THIS IS ONLY ABOUT
ABOUT 10 YEARS HERE THIS, IS A
PATIENT WITH SMALL LUNG CANCER.
SOMETHING WE FOUND OUT IS WHEN
THEY RUSH IN, THEY ACTUALLY MAKE
THE CANCER SWELL A BIT.
SO IF THIS WERE A NORMAL CHEMO
THERAPY WHEN WE WENT FROM THIS
X-RAY TO THIS EXRAY ON A NORMAL
CHEMO THERAPY WOOLED HAVE SAID
THAT PATIENT PROGRESSED, TIME TO
TWITCH THERAPIES BECAUSE WE KNEW
THIS MIGHT HAPPEN WE WAITED WE
WAITED AND NOW THESE ARE GONE.
SO THE PSEUDOPROGRESSION HAPPENS
AS THE IMMUNE CELLS INTRUCKS
INTO THE TUMOR AND MAKE THE
TUMOR GO AWAY.
THIS WAS FOLLOWED UP WITH A
BIGGER PHASE 3 RANDOMIZED
CONTROL TRIAL WHERE THEY
TESTED–THESE ARE ALL PATIENTS
BECAUSE NIVOLUMAB WAS AN
APPROVED DRUG, AND IT HAD TO
ALREADY FAILED THE CONTROL
DISEASE.
SO THESE ARE PATIENT HIGHLY
REFRACTORY TO TREATMENT.
THEY GOT EITHER NIVOLUMAB,
VERSES CHEMOTHERAPY OF CHOICE.
THIS IS CALLED A WATER FALL
PLOT, VERY SIMILAR TO A SPIDER
PLOT, EXCEPT SHOWING THE COURSE
OF THE ENTIRE TREATMENT, IT JUST
SHOWS MAXIMUM RESPONSE.
SO ANY PATIENT HERE THAT GOES
DOWN TO 100, THOSE ARE COMPLETE
RESPONDERS.
ANY PATIENT THAT GETS BELOW THIS
DOTTED LINE THAT'S A PATE
RESPONSE.
PARTIAL RESPONSE IS A 30%
DECREASE IN THE SUM OF THE
LONGEST DISCIPLINARY AMTEROF THE
TUMOR AND THEN PEOPLE ARE
DECLARED PROGRESSIVE DISEASE IF
THEY GO BOARD 20%.
OT BASIS OF THIS, NIVOLUMAB WAS
APPROVED FOR REFRACTORY MELANOMA
IN DECEMBER OF 2014.
JUST LAST YEAR.
THEY THEN SAID, WELL WE USE
TODAY IN PATIENTS WHO USED
NIVOLUMAB, SO THESE ARE PATIENTS
WHO HADN'T GOTTEN TREATMENT YET
FOR METASTATIC DISEASE, THE
REASON THEY HAD TO HAVE
WILD-TYPE BRAF, HAD BEEN
APPROVED FOR MELANOMA BECAUSE IT
WORKS ON BRAF MUTATED TUMORS.
IN THIS TRIAL, THE PATIENTS GOT
THE NIVOLUMAB OR DACARBAZINE.
SO YOU SEE THE YELLOW CURVE ARE
THE PATIENTS THAT GOT NIVOLUMAB,
AND THE BLUE CURVE IS THE
PATIENTS THAT GOT CHEMO THERAPY.
IT'S A WIDE SPLIT, UNEXPECTED WE
WOULD SEE THIS KIND OF SURVIVAL
BENEFIT AND AT 1 YEAR ALMOST 60%
OF THE PATIENTS WERE ALIVE
VERSES 20% IN THIS ARM.
WHAT'S INTERESTING THOUGH IS
THAT THIS BOTTOM GRAPH WHICH IS
ACTUALLY PROGRESSION SHOWS THAT
EVEN IF YOU PROGRESS BECAUSE
THIS CURVE CUMS DOWN A LOT
QUICKER THAN THIS 1 DOES, HAVE
YOU A SURVIVAL ADVANTAGE BECAUSE
IT'S DONE SOMETHING TO KEEP YOUR
TUMORS UNDER CONTROL.
IT HASN'T MATE THEM GO AWAY
COMPLETEEE BUT IT'S KEEPING
THINGS YOU SHOULD CONTROL.
PEMBROLIZUMAB WAS JUST A
DIFFERENT COMPANY WITH CONTROL,
AND IT WAS TEST INDEED PATIENTS
TO BEBIN WITH, THIS WAS A PHASE
1 DOSE COMPARISON.
YOU KNOW PHASE 1, PHASE 2, PHASE
3 FF THEY DISCUSS THAT.
SO PHASE 1 IS LOOKING FOR
SAFETY, PHASE 2 IS IS LOOKING
FOR EFFICACY AND PHASE 3 IS TO
SHOW THAT IT'S CURRENTLY BET
THEY'RE AN WHAT'S AVAILAE.
SO THIS IS THE SAME DRUG AT 2
DIFFERENT LEVELS AND IT SHOWS
APPROVAL BETWEEN THE 2 BUT
MOTIER IMPORTANTLY DID SHOWS 50%
PATIENTS ALIVE AT A YEAR SO
THAT'S PRETTY GOOD.
SO THEY SAID YOU KNOW WHAT IN
THIS LOOKS GOOD, KEEP GOING.
DO A BIGGER TRIAL.
WE'RE GOING TO GO AHEAD AND
APPROVE YOU FOR REFRACTORY
MELANOMA.
SO THEY DID THE BIGGER TRIAL.
AGAIN DOSE COMPARISON BUT ALSO
VERSUS CHEMO.
BUT THE CURVES AREN'T AS
IMPRESSIVE AS THEY WERE IN THE
BEGINNING BUT STILL BETTER THAN
CHEMO THERAPY.
SO THEN THEY TRY IT AGAIN MUCH
LIKE THE OTHER 1, WELL, WHAT
HAPPEN FIST THEY GIVE IT FIRST.
SO THEY TESTED PEMBROLIZAB,
VERSES THE ANTICDLA 4, AT 2
DIFFERENT DOSING SCHEDULES AND
YOU CAN SEE THERE'S A DIFFERENCE
IN THE RESPONSE RATE.
IN A LARGE NUMBER OF PATIENTS
AGAIN THE SURVIVAL CURVE YOU CAN
SEE HERE, AGAIN THOUGH, YOU SAW
IMMUNE RELATED ADVERSE EVENTS
AND IT WAS HIGHER IN THE
PEMBROLIZUMABAISE ARM.
SO TO APPROVE ANTIBODIES
INTERFERE IN 2 DIFFERENT WAYS SO
ANTICTLA 4 BLOCKS THIS
INTERACTION, WE HAVE TUMOR ON
THE SIDE, T-CELL ON THIS SIDE.
ANTIT-CELL WORKS HERE AND IT
WORKS HERE AND HERE.
WHY DON'T WE USE THEM TOGETHER,
SO 2 DIFFERENT MECHANISMS.
SO THEY DID THAT.
SO PREVIOUSLY UNTREATED PATIENTS
WHICH IS NOW PHASE 3 RANDOMIZED
CONTROL TRIAL 1 VERSES THE
OTHER, VERS THE COMBINATION,
WHAT THEY DID DO FOR THE PRIAL,
HOWEVER AND YOU HAD TO HAVE PDL
1OT SURFACE OF THE TUMOR SO
THAT'S SELECTING FOR A SLATELY
BTER RESPONSE RATE THAN YOU
MIGHT EXPECT.
IT MIGHT BE HARD TO SEE THIS BUT
THE RESPONSE RATE IN THE VOLUME
ALONE WAS 44%, THE RESPONSE RATE
WITH IPILMAZAB,–HOWEVER THE
ADVERSE EVENTS WENT WAY UP IN
THE CONFRIRMATION SO YOU WENT
FROM 16, 20, WHICH IS TOLERABLE
TO OVER HALF THE PATIENTS IN THE
COMBINATION ARM GETTING A
SERIOUS SIDE EFFECT.
THIS IS JUST LOOKING AT THOSE
PATIENTS IN A DIFFERENT TRIAL
WHO WERE DEFINED AS PDL 1
POSITIVE, YOU CAN SEE THOSE
PATIENTS SEEM TO HAVE A SLIGHTLY
HIGHER RESPONSE RATE, BUT IT'S
NOT A PERFECT BIOMARKER, SO EVEN
THOSE PATIENTS THAT ARE PDL
NEGATIVE ENJOE A HIGH RESPONSE
RATE.
SO WHY MELANOMA, THIS IS
SOMETHING WE'VE BEEN TRYING TO
FIGURE OUT FOR A WHILE.
IF YOU LOOK AT SUFFER FROM STUFF
COMING OUT OF THE CCGA, YOU CAN
SEE MELANOMA HAS A HIGH LEVEL OF
NONSINON MOUSE MUTATIONS SO
THAT'S WHEN YOU LOOK AT THE
TUMOR GNA, TUMOR DNA AND YOU
LOOK AT NORMAL DNA, AND YOU
COMPARE THE 2 LOOKING FOR A
CHANGE IN THE DNA THAT LEADS TO
A CHANGE IN THE PROTEIN THAT'S
CODED SO NONSINON MOUSE MUTATION
THIS, IS NOT A LOGARITHMIC SCALE
AND I TELL YOU FROM THE WORK
WE'VE DONE ACROSS THE STREET, WE
GET 800-900 PATIENTS PERMELANOMA
THAT RESILIENCE SECTIONAL
ANALYSIS.
SO QUEY FIGURED BECAUSE WE'RE
BREAKING CELL TOLERANCE OUR
IMMUNE SYSTEMS KNOW HOW TO FIND
THESE MUTATIONS, THEY COME UP IN
THE PATIENT'S TUMOR, MAYBE
THAT'S RESPONSE TO THE T-CELL
MUTATIONS?
MAYBE THAT'S WHAT'S DOING?
SO WHAT ARE HIGHLY MUTATED
TUMORS, SO CAN WE TEST THOSE IN
THE ENVIRONMENT?
SO NONSMALL LUNG CANCER, CAN YOU
SEE HERE WE'RE NO LONGER TALKING
ABOUT RARE DISEASES, 160,000
DEATHS A YEAR FROM NONSMALL CELL
LUNG CANCER.
WORST PROGNOSIS FOR PATIENTS
WITH WIDE SPREAD DISEASE, ONLY
2% ALIVE AT 5 YEAR SURVIVAL AND
A HIGH CORRELATION BETWEEN
SMOKING IS A NUMBER OF
MUTATIONS.
ANOTHER GROUP OF TUMORS THAT
MIGHT BE WORTH WHILE LOOKING AT,
TUMORS WITH MISMATCHED REPAIR
DEFICIENCY SO THESE ARE TUMORS
THAT EITHER HAVE A GERM LINE
MUTATION IN 1 OF THESE 4 GENES,
PLUS OR MINE US A COUPLE OTHERS,
THAT MAKE IT IMPOSSIBLE FOR THEM
TO REPAIR THEIR MISMATCH DURING
THE COMBINATION, THERE'S AN
ADDITIONAL GROUP OF PATIENTS
THAT DEVELOP THIS
SPORODORSICALLY, AND IT'S A
FAMILIAL SYNDROME THAT PASSES
DOWN.
AND A THIRD TYPE OF BLADDER
CANCER, ONLY ABOUT 16,000 DEATH
PER YEAR BUT IT'S HIGHLY LETHAL
ONCE IT'S METASTATIC.
BLADDER CANCER BECAUSE EVERY
NOXIOUS THING WE EAT OR DRINK
GETS FILTERED THROUGH OUR KIDNEY
AND ENDS UP IN OUR BLADDER SO
THAT'S POTENTIAL CAUSING
MUTATION SPECIALIZATION OF
SPECIFIC ENDOTHELIAL WE DECIDED
TO START TESTING TEASE DRUGS IN
THE DISEASES, SO FOR NONSMALL
LUNG CANCER THIS, IS NIVOLUMACK,
THIS IS THROUGH 2 OTHER
TREATMENTS THIS, IS THIRD LINE
SALVAGE KIND OF CHEMO THERAPY.
THEY TREEDED 117 PATIENTS AND
WERE ABLE TO GET YOU KNOW A
DESCENT 14-15% RESPONSE RATE AND
WE CAN SEE THE WATER FALL PLOT
HERE SUBSTANTIAL SHRINKAGES AND
THE PATIENTS IN THE BLUE ARE ALL
ALIVE.
THEY DID A ABDOMEN ORDER OF
MICRONSIZED CONTROL TRIAL WITH
THE SAME ANTIBODY AND IT'S NOT
AS IMPRESSIVE AS THE OTHER 1 BUT
THE CURVE DEFINITELY SPLIT HERE
AT 1 YEAR, HAVE YOU A 42%
SURVIVAL VERSES 25% SURVIVAL.
THIS WAS APPROVED FOR REFRACTORY
NONSMALL CELL LUNG CANCER IN
MARCH OF THIS YEAR.
PEMBROLIVUMAB, 495 PATIENTS
SOUTH AMERICA OF THESE PATIENTS
HAD NEVER RECEIVED PATIENTS
BEFORE.
THE PATIENTS THAT WERE SMOKERS
AS YOU MIGHT IMAGINE AT MUTATION
RATE HIS A HIGHER RESPONSE RATE,
22%.
THOSE THAT NEVER SMOKED OR AT
LEAST REPORTEDLY NEVER SMOKED
HAD A 10% RESPONSE RATE.
–STOPPING THE CHECK POINT
BLOCKADE O THESE 3 PARALLEL
COHORTS, THESE 2 ARE COLORECTAL
CANCERS, THOSE IN AA PATIENT
WHOSE MISMATCH REPAIR GENES ARE
PROFICIENT, THOSE WHO ARE
DE-FICIENT WHETHER IT'S GERM
LINE OR INHERITED AND THOSE
OTHER CANCERS OVARIAN AND SO
FOCUS ON THE COLORS FOR A
SECOND, PROFICIENT IS IN THE
RED, DEFICIENT IS IN THE BLUE
AND BLACK.
CAN YOU SEE ALMOST ALL THE
PATIENTS WITH THE PROFICIENT
ACCIDENT DON'T RESPOND TO CHECK
POINT BLOCKADE.
THEY DON'T HAVE THE SAME NUR
OF MUTATIONS.
WHEREAS ALL THOSE THIS THE BLUE
AND THE BLACK SEEM TO BE
EXPERIENCING A DECREASE IN THEIR
TUMORS.
AGAIN, MORE FUEL TO THE
HYPOTHESIS, THIS WAS ALL BASED
ON ANTIGEN, BUT AGAIN WE'RE
BUILDING A LOT OF CIRCUMSTANTIAL
EVIDENCE, AND NO 1'S BEEN ABLE
TO ELUCIDATE THE MECHANISM AND
WHY THIS HAPPENED.
INTERESTINGLY THOUGH WHEN YOU
LOOK AT WHERE THE TUMOR AND THE
STROMA INTERFACE SO THIS IS
TRADITIONAL STAINING OF A
COLORECTAL CANCER AND TUMOR IS
ON THE TOP LEFT–MY LEFT, NORMAL
TISSUE IN THE BOTTOM CORNER,
THIS IS STAINING YOU CAN SEE THE
TUMOREROUS GLANDS, THESE ARE
ORDERED OUT OF CONTROL AND THIS
IS NICE, NORMAL SMOOTH THIS, IS
SUSTAINING FOR PDL 1.
AND ALMOST ALL THE REACKIVITY IS
RIGHT ON THE EDGE OF WHERE THE
TUMOR HITS THE NORMAL.
THIS STAINING CD8, AGAIN, ALLOT
EDGE OF WHERE THE TUMOR HITS THE
NORMAL.
CAN YOU SEE HERE IN–MISMATCHED
PROFICIENT COLORECTAL CANCER,
ALMOST NO PDL EXPRESSION AT ALL.
WHAT WE DO EYE LOT AND TAKE OUT
THESE TUMORS AND WE LOOK FOR THE
LYMPHOCYTES THAT GROW IN THEM.
YOU CAN SEE THE MISMATCHED
SUFFICIENT COLORECTAL CANCER WHO
IS WOULD HAVE MORE MUTATIONS,
HAVE'S ATTRACTED MORE
LYMPHOCYTES WHERE THE 1S THAT
ARE PROEFFICIENT DON'T HAVE ANY
PATIENTS, DON'T ATTRACT THE
LYMPHOCYTES HAVE A SMALLER
VOLUME.
SO BLADDER CANCER, AGAIN,–VERY
SMALL NUMBERS ONLY 29 PATIENTS,
BUT AT 12 MONTHS, 40% ALIVE.
FAIRLY REMARKABLE.
THIS IS NOT FULLY MATURE DATA
THIS, IS PRESENT INDEED ABSTRACT
FROM ASCO.
TREMELIMUMAB IS ANOTHER FORM,
AND IT FAILED ITS CLINICAL
TRIAL.
IT DID NOT GET APPROVED FOR
MELANOMA, IT DID NOT GET
PUBLISHED, ALTHOUGH YOU WON'T
FIND IT FROM THE A LOT, FROM THE
SURVIVAL DAMAGE.
ON A NEW FRONT WE'RE STARTING TO
LOOK AT BREAST CANCER ISSUES
PREVIOUSLY THOUGHT NOT TO
RESPOND TO IMMUNOTHERAPY.
BUT TRIPLE NEGATIVE BREAST
CANCER HAS A FAIRLY HIGH AMOUNT
OF PDL-1.
59 OF THE SAMPLELE STUDIED IN
THIS PARTICULAR TEST HAD PDL 1,
THEY TREATED THESE PATIENTS,
THEY HAD A RESPONSE RATE OF
ABOUT 18%.
THERE'S A LOT OF CONTROVERSY
THOUGH ON HOW FREQUENTLY YOU
SHOULD EXPECT TO FIND PDL
POSITIVE 1 TUMORS IN BREAST
CANCER BECAUSE ANOTHER GROUP
COMING OUT OF M. D. ANDERSON AND
THEY'RE ONLY ABOUT 20% OF TRIPLE
NEGATIVE BREAST CANCERS.
BUT YOU'LL SEE THIS REPEATED
OVER AND OVER AGAIN AND ABOUT
DIFFERENT HISTOLOGY SOMEONE
BETWEEN 15 AND 20% OF PATIENTS
WILL RESPONSE TO THERAPY WHICH
IS REMARKABLE.
GASTRIC CANCER AGAIN A DIFFICULT
DISEASE TO TREAT, ALMOST
UNIFORMLY FATAL.
AGAIN 40% OF THEM WERE POSITIVE
FOR PDL 1.
THEY HAD A RESPONSE RATE EVER
ABOUT 20%.
AND AGAIN, 25%, 20%.
NO INTERESTINGLY AGAIN WITH THE
THEORY THAT MUTATIONS THAT CAUSE
THIS, IF YOU HAVE HPV AS THE
DOMINANT DRIVE FOR WHY YOU HAVE
THE SQUAMOUS CELL CANCER YOU
DON'T NEED A LOT OF CANCERS TO
DO AND IF YOU DON'T HAVE HPV,
CAN YOU SEE THE RESPONSE RATE IS
HIGHER IN THE PATIENTS THAT ARE
HPV NEGATIVE THAN HPV POSITIVE
AND AGAIN CIRCUMSTANTIAL, BUT
MORE EVIDENCE TO PUT ON THE SIDE
THAT MUTATIONS ARE WHAT WE'RE
REACTING TO.
SETHIS IS THE PIPELINE FOR CHECK
POINTS.
THESE ARE ALL–WELL, NOT ALL,
ALL THE 1S WE KNOW OF
INTERACTING BETWEEN A T-CELL AND
AN ANTIGEN PRESENTING CELL OR A
TUMOR, HERE'S OUR MAIN SIGNAL 1,
PC R.
WITH AN MHC CLASS 1 OR 2.
, ALL THESE HAVE YET TO BE
INVESTIGATED.
TC LA IS HERE, IT'S HERE,
INTERESTINGLY, TDL1 HAS ANOTHER
RECEPTOR THAT WE HAVEN'T
IDENTIFIED YET.
CD80 WHICH NORMALLY ACTS AS A
KORESCEPTER FOR CD8, ACTUALLY
ACTS AS A LIGAND, SO THERE ARE
DRUGS COMING OUT OF THE
PIPELINE, TRY TO BREAK EACH AND
EVERY 1 OF THESE INTERACTIONS.
SO ANTIPDL1 WE BLOCK TODAY ON 1
SIDE AND WHAT HAPPEN FIST WE
BLOCK IT ON THE OTHER.
AGAIN ABOUT 40%.
THEY GOT A RESPONSE RATE OF 36%.
BLADDER CANCER, AGAIN THE WATER
FALL PLOT WE DISCUSSED BEFORE,
THE PATIENTS IN GREEN HAVE HIGH
LEVELS OF PDL-ON THEIR SURFACE
AND THEY'RE SHOWING THE BEST
RESPONSES.
SO THESE ARE THE DRUGS CURRENTLY
BLOCKING THE PDL, PDL1 PATHWAY,
AND MELANOMA 32%.
NONSMALL LUNG CANCER 17 TO 30%
NONE OF THESE HAVE BEEN APPROVED
CURRENTLY.
FDA APPROVED, THIS 1 WILL BE
DECIDED IN A FEW WEEKS.
THE CURRENT STATE OF WHERE WE
ARE WITH CHECK POINT BLOCKADE IN
THE CLINIC.
SO, AGAIN, CHECK POINT
MOTTULATION, THESE ARE OUR
TARGETS AND THIS IS WHERE THE
NEXT GENERATION OF IMMUNO
ONCOLOGISTS WILL BE WORKING.
THERE'S A WHOLE THE INFORMATION
I JUST THROUGH AT YOU.
BUT I'D BE HAPPY TO TAKE ANY
QUESTIONS.
>> [INDISCERNIBLE]
>> SO OUR THEORY AT THE CURRENT
TIME IS THAT WHEN IN THE COURSE
OF YOUR LIFE, YOU HAVE
ENCOUNTERED THIS ANTIGEN IN THE
PAST, IT IS LIKELY JUST BEEN
SHUT OFF, SO IT'S BECOME ANERGIC
AND THAT'S THROUGH NEGATIVE
SELECTION IN THE THYMUS, THROUGH
A NUMBER OF MECHANISMS.
BUT IT'S STILL OUT THERE, IT'S
FLOATING AROUND.
IF YOU LOOK AT THE GENES THAT
HELP DEVELOP THE TCR, THERE'S A
JOINING REGION AND CD-3 REGION
AND TCR ALPHA AND BETA AND
WITHIN THOSE YOU HAVE MULTIPLE
DIFFERENT WAYS, YOU COULD
LITERALLY WITH THE CONTENT OF
WORN PERSON'S DNA, MAKEOT ORDER
OF 10 TO THE 11th DIFFERENT
CCRs.
AND SO, WE HAVE THE CAPABILITY
OF CREATING ALL THOSE CCRs IF
THEY DON'T ENCOUNTER AN ANTIGEN,
THAT CELL DIES.
SO THAT T-CELL CREATES A CCR,
NEVER ENCOUNTERS ANTIGEN, IT
DIES.
THE DNA GETS READ EYE DIFFERENT
WAY TDOESN'T ENCOUNTER ANTIGEN,
IT DIES.
AND THEY KEEP CREATING CELLS
UNTIL NAY FIND 1 THEY CAN ENGAGE
WITH AND IT GETS ACTIVATED OR
BECOMES ANERGIC.
IT'S STOPS THAT INITIAL ANERGIC
REACTION SO IT MAY LEAD
SOMETHING TO APOPITOSE THAT
SHOULDN'T HAVE WHERE CDL 1 GETS
SHOT DOWN AT THE SECOND STEP,
DOES THAT MAKE SENSE.
>> OKAY.
>> RIGHT.
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> [INAUDIBLE QUESTION FROM
>> RIGHT.
>> [
AUDIENCE ]
INAUDIBLE QUESTION FROM
AUDIENCE ]
>> IT IS BEING REGENERATE SO
ANYTIME A LYMPHOCYTE CAN
REGENERATE AND MAKE PC R IT
WALKS.
SO IT DOESN'T SEEM LIKE IT WOULD
CONNECT MORE FREQUENTLY THAN IT
DOES BUT THE WAY EPIGENETIC
MODULATION GETS IN 1 FAMILY AND
1 CERTAIN SPOT, IT ALL DEPENDS
ON WHAT YOUR MHC IS AS TO WHAT
YOU CAN RECOGNIZE IN THE POCKET
OF AN MHC MOLECULE AND SO
THERE'S ACCORD NATION BETWEEN
WHAT CCR ALPHA AND BETA GENES
GET TURNED ON DEPENDING ON WHAT
H, LA YOU HAVE, BECAUSE IF YOU
HAVE HLAAC1, YOU WON'T MAKE PC R
THAT DON'T RECOGNIZE HLAAC1, SO
WE DON'T FULLY UNDERSTAND ALL
THE MECHANISMS BUT THERE'S
ENOUGH THERE TO CROSS TALK.
>> [INAUDIBLE QUESTION FROM
ANY OTHER QUESTIONS?
>> [
AUDIENCE ]
INAUDIBLE QUESTION FROM
AUDIENCE ]
SO A LOT OF THAT WORK HAS BEEN
PUSHED FORWARD BY TOM'S GROUP IN
CHICAGO DRYING TO CREATE A TUMOR
THAT AS A MORE INFLAMED LOOK.
SO THEY JOKE ABOUT TRYING TO
MAKE ALL THE TUMORS LOOK LIKE
MELANOMA SO WHAT CAN DO YOU TO
LEAD TO AND INCREASE AND
INFILTRATE THE TUMOR BECAUSE IF
DID YOU THAT, YOU CAN USE THE
IMMUNE MODULATING THINGS AGAIN
IT.
AND THERE'S JOHN HOPKINS WHERE A
CREATE A MORE INFLAMMED
PHENOTYPE AND IF THEY CAN DO
THAT, THEY WANT TO TRY TO USE
THE IMMUNE MOTE MODULATORS
AGAINST BY CREATING AN INFLAMED
TUMOR THEN THEY CAN TURN DOWN
INFLAMMATION AND KILL THE TUMOR
AT THE SAME TIME.
SO CONVERTING A INFLAMMED TUMOR
TO A INFLAME 1.
>> THIS BIOPSY WAS DONE WITH
PEMEBERLMAB, THIS WAS DONE PRIOR
TO APR, I THINK.
IN THEIR SUPPLEMENTAL FIGURURES
YOU CAN SEE PDL 1 UPREGULATIONED
AND THIS IS A PREE TREATMENT
BIOPSY.
[
APPLAUSE ]

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