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TRACO 2019 – Ovarian cancer and Immune checkpoints

November 29, 2019


OUR FIRST SPEAKER IS TINA ANNUNZIATA SHE DID HER MEDICAL DEGREE AND Ph.D. TRAINING AT GEORGETOWN UNIVERSITY, WHERE SHE ALSO DID HER RESIDENCY, THEN SHE CAME TO NCI AND WORKED WITH LOU STATED METABOLISM BRANCH ON NF KAPPA B SIGNALING IN MULTIPLE MYELOMA AND SUBSEQUENTLY SWITCHED TO OVARIAN CANCER AND SHE NOW HEADS THE CLINICAL OPERATIONS IN THE WOMEN MALIGNANCIES BRANCH AND SHE’S A MEMBER OF NUMEROUS SOCIETIES, ACR ASCO AND SHE’S ASSOCIATE EDITOR OF BMC CANCER. SHE WILL LECTURE ON OVARIAN CANCER AND GENOMICS ERA. TINA.>>THANK YOU VERY MUCH. THANK YOU FOR THE INVITATION TO TALK. I WILL TALK ABOUT THE OVARIAN CANCER AND IN THE SPECIFICALLY IN THE GENOMICS REALM AS TERRY MENTIONED. WHAT IS CANCER GENOMICS? GENOMICS AS YOU KNOW STUDY OF THE GENOME MEANING CHROMOSOMES, GENE EXPRESSION AND GLOBAL ANALYSIS MORE SO THAN INDIVIDUAL ENTITIES. THE GENOMICS ERA I WOULD SAY REALLY STARTED IN 1959 WHEN (INDISCERNIBLE) STUDIED CHROMOSOMES TO IDENTIFY RECURRENT ABNORMALITIES, SOMETHING CALLED THE PHILADELPHIA CHROMOSOME IN CHRONIC MYELOGENOUS LEUKEMIA. WHAT IS THAT? THEY LOOKED AT A BROAD PICTURE WHAT THE CHROMOSOMES WERE AND SAW PATIENTS WITH CML SEEM TO ALL HAVE E THIS CHROMOSOME HERE PHILADELPHIA CHROMOSOME IN PHILADELPHIA AT THE TIME. IT WASN’T UNTIL 1973 THAT JANET ROWLY DISCOVERED THIS WAS A FUSION BETWEEN CHROMOSOME 9 AND CHROMOSOME 22 THEN 1984 DISCOVERED THIS CHROMOSOME FUSION WAS AT THE BREAK POINT CLUSTER REGION WHICH FUSED THE ABLE GENE WHICH IS A TYROSINE KINASE TO THE BREAK POINT CLUSTER REGION AND THAT CAUSED CONSTITUTIVE ACTIVATION OF BCR ABLE KINASE TO DRIVE CANCER CELLS. IN 1996, MANY YEARS LATER, FROM THE 59, BRIAN DRUGGER DISCOVERED YOU COULD BLOCK THE ABLE KINASE USING THIS DRUG WE BECAME APPROVED FOR TREATMENT OF C MECHANICSS. SO THAT WAS REVOLUTIONARY BECAUSE IN CANCER TREATMENT THEY WERE TARGETING A SPECIFIC MUTATION THAT WAS — OR FUSION THAT WAS DISCOVERED BY GENOMICS APPROACH. WHAT IS FUNCTIONAL GENOMICS? THOSE DIDN’T DO A FUNCTIONAL EXPERIMENT UNTIL LATE IN 1959 THEY DID A OBSERVATIONAL EXPERIMENT. IT WAS FUNCTIONAL — TO LOOK FOR WHAT PART OF THE GENOME IS FUNCTIONING TO CAUSE AN EFFECT. WHAT CAN ACTUALLY TRANSFORM CELLS TO CANCER. THAT WOULD BE A FUNCTIONAL EXPERIMENT. SO HERE WE ARE LOOKING FOR A DRIVER ALTERATION, YOU HEARD THAT TERM BEFORE, WHAT IS DRIVING THE CANCER, MUTATION, A FUSION EVENT, ET CETERA. IN FUNCTIONAL GENOMICS THE FIRST MAJOR LOOK INTO CANCER WAS IN 1981 WITH THE DISCOVERY OF THE HER 2 NU ONCOGENE, THE REASON IT’S CALLED NU YOU MAY KNOW BECAUSE THEY USED NEURAL BLASTOMA THAT THEY PUT INTO MOUSE FIBROBLASTS AND SAW WHAT PART OF THE GENOME WOULD TRANSFORM THESE FIBROBLASTS INTO CANCER. THEN IN 1984, (INDISCERNIBLE) ET AL DISCOVERED NU WAS SIMILAR TO EGF RECEPTOR, SO THAT’S WHAT — WHEN IT CAME TO BE CALLED H — HER 2. THEN IN 1985, KOOSENS DISCOVERED HER 2 WAS PRESENT ON CHROMOSOME 17 AND THERE YOU CAN SEE THE AMPLIFICATIONS OF THE LOCUST ON THESE CHROMOSOME 17S. IN 1987 DR. SLAYMAN ET AL DISCOVERED HER 2 WAS PROBABLY THE MOST IN SOME BREAST CANCERS, HERE YOU CAN SEE THE AMPLIFY QUAILINGS ACROSS SOME OF THE BREAST CANCERS. THEN YOU KNOW HER 2 BECAME TARGETED USING HERCEPTIN WHICH IS A MONOCLONAL ANTIBODY THAT CAN TARGET THE SIGNALING OF THIS PROTEIN AND IS PIVOTAL TREATMENT IN THE THERAPY OF BREAST CANCER THAT OVEREXPRESS OR HAVE AMPLIFICATION OF HER 2. SO HOW CAN WE USE GENOMICS TO STUDY OVARIAN CANCER TO FIND OUT DO WE HAVE ANY DRIVERS OF OVARIAN — IN OVARIAN CANCER. LET’S BACK UP AND TALK ABOUT OVARIAN CANCER ITSELF. OVARIAN CANCER IS THE MOST LETHAL GYNECOLOGIC MALIGNANCY IN THE U.S., THAT LEADS TO 16,000 DEATHS PER YEAR. IT’S THE FIFTH MOST COMMON CAUSE OF CANCER DEATH IN WOMEN. THAT’S BECAUSE 70% OF CASES ARE DIAGNOSED WHEN PATIENT ADVANCE STAGE OF DISEASE AND LESS THAN 35% OF THESE PATIENTS WITH ADVANCE DISEASE WILL BE ALIVE AT FIVE YEARS. SO WHAT IS ADVANCED DISEASE? WE CONSIDER STAGE 3 AND STAGE 4 TO BE ADVANCE DISEASE AND HERE YOU CAN SEE MOST OF THE CASES ARE DIAGNOSED HERE IN THIS ADVANCE STAGE. AND SURVIVAL CERTAINLY STAGE 4 IS VERY POOR, FIVE YEAR SURVIVAL. IF YOU COULD IDENTIFY IT EARLY NOT FREQUENTLY IDENTIFIED EARLY BUT SURVIVAL WOULD BE VERY GOOD. WHAT IS TREATMENT FOR NEWLY DIAGNOSED OVARIAN CANCER? IT’S COMPLETE SURGICAL STAGING TO MAKE SURE YOU TREAT YOUR GOING FORWARD STAGE THE CORRECT STAGE. OPTIMAL CYTOREDUCKTIVE SURGERY FOLLOWED BY IN CONJUNCTION WITH CHEMOTHERAPY AND OF COURSE CLINICAL TRIALS AT ANY STAGE OF THIS. SO THE CHEMOTHERAPY IS VERY INTERESTING, IT’S ACTUALLY A COMBINATION OF MAT NUMBER AND TAX — PALACE TIN OR CARBO PLAN TIN OR CARBO PAXIL DOSE TACK SILL, THIS IS THE MAIN — DOECY TAXOL, THE MAIN STAY FOR DECADES. WE HAVE NOT IMPROVED UPON THAT EXCEPT IN RECENT YEARS. INTRAPERITONEAL, IT WILL INTERPERITONEAL, IF IT IS STAGE 3 WITH OPTIMAL REDUCTION. SO THIS IS THE BRIEF HISTORY OF WHERE WE WENT WITH — WHERE WE HAVE COME WITH CHEMOTHERAPY, IN THE 60s WE ONLY HAD AL COLLATING CHEMOTHERAPY AND NOBODY SURVIVED PAST FIVE YEARS. IN 1970s INTRODUCED THE PLATINUM, WE GOT 5% OF PATIENTS LIVING BEYOND FIVE YEARS. IN THE ’80s WE COMBINED THESE WITH THESE AND WE FOUND OKAY MAYBE 15% OF PATIENTS WERE NOW HAVING LONG TERM SURVIVAL. IN THE ’90s WE HAD INTRODUCTION OF THE TAXINI, PA CASH FLOW — PACLOTAXOL BEING THE FIRST ONE. 35% OF WOMEN LIVING LONG TERM WITH THIS DISEASE. WITH COME BY NATION CHEMOTHERAPY. — COMBINATION CHEMOTHERAPY. IN THE 2000 ERA ADVANCE IS TO DELIVER CHEMOTHERAPY INTO THE PERITONEAL CAVITY DIRECTLY. THAT — BUT THAT’S ONLY APPLICABLE TO A SMALLER SUBSET OF THE WOMEN. SO WHAT IS OVARIAN CANCER FROM A BIOLOGICAL STANDPOINT? MOST CANCERS ARE CIRRUS CANCER, 80%, AND THAT IS LOOKING LIKE THIS TOP PANEL. BUT YOU CAN SEE END MYAL CLEAR CELL IS ALSO MAKING UP THIS — ENDOMETRIAL CELL OVARIAN CANCER THEY LOOK VERY DIFFERENT SO THIS IS THE CLEAR CELL LOOKS VERY DIFFERENT FROM FROM THE CIRRUS WHICH LOOKS DO DIFFERENT FROM THE ENDOMETRIAL, ET CETERA. SO WHY ARE WE TREATING A DISEASE THAT LOOKS SO DIFFERENT, EVERYBODY GETTING THE SAME CHEMOTHERAPY THOUGH THERE MIGHT BE HAVING A DIFFERENT DISEASE. SO WE DON’T EVEN KNOW WHAT THE TISSUE OF ORIGIN IS, IT’S THOUGHT THE CIRRUS CANCER DON’T COME FROM THE OVARY, THEY START IN THE FALLOPIAN TUBE. ESPECIALLY IN PATIENTS WITH HEREDITARY OVARIAN CANCER. THEY MIGHT COME IN THE FALLOPIAN TUBE AND NOT FROM THE OVARY ITSELF. ENDOMETRIOSIS CAN BE A SOURCE SO EVEN FARTHER INTO THE UTERUS. THE CLEAR CELL CANCERS COME FROM THE ENDOMEET YUM, THAT PIECE SPREAD RETROGRADE TO THE OVARY AND PERITONEAL CAVITY WHICH IS ALSO NOT DIRECTLY FROM THE OVARY. THEN THE MUSINOS CANCER, WE DON’T KNOW IF THEY ARE FROM THE GLANDS OR CERVIX S FURTHER FROM THE OVARY OR INTESTINAL SORT. SO THERE’S A LOT IN THE AIR THAT WE NEED TO LEARN ABOUT FROM THE MOLECULAR STANDPOINT HOW THESE CANCERS ARE BIOLOGICALLY DIFFERENCE AND THEN WE CAN HOPEFULLY GET TO BETTER TARGETED CURES. SO OF COURSE WE HYPOTHESIZE THAT INCREASING UNDERSTANDING ABOUT THE BIOLOGICAL AND BIOCHEMICAL EVENTS UNDERLYING OVARIAN CANCER MIGHT CREATE NEW AVENUES FOR TREATMENT AND THE QUESTION IS, CAN WE USE GENOMICS TO FIGURE THIS OUT. VERY EARLY ON, ABOUT A DECADE AGO, IN CLEAR CELL CANCER, THERE WAS A VERY PROMINENT STUDY. JUST SO TO HIGHLIGHT CLEAR CELL CANCER ARE A RARE SUBSET OF OVARIAN CANCER, 5 TO 10%, WHEREAS THE HIGH GRADE CIRRUS CANCER MAKE UP 70%. CLEAR CELL CANCERS HAVE A WORST RESPONSE TO STANDARD CHEMOTHERAPY WITH CISPLATIN AND PA CASH PACLITAXEL AND
ASSOCIATED WITH ENDOMETRIOSIS IN 40% OF CASES. SO BACK IN 2010, TEN YEARS AGO THIS PAPER WAS PUBLISHED IN THE NEW ENGLAND JOURNAL LOOKING AT SEQUENCING GENOMIC SEQUENCING OF CLEAR CELL OVARIAN CANCER. SO THEY STARTED OUT BY SEQUENCING 18 CLEAR CELL CANCERNDS AND ONE CELL LINE IN THEIR DISCOVERY PHASE AND THEN THEY DID TARGETED EXOME SEQUENCING IN 210 ADDITIONAL SAMPLES AND THROUGH IN ENDOMEETOID AND CAM PAIRED THERE SO WHEN THEY DISCOVERED THAT VALIDATION PHASE THEY LOOK AT PROTEIN EXPRESSION OF THEIR TARGETS IN ANOTHER 455 SAMPLES. AND WHAT THEY FOUND WAS THAT THERE WAS ACTUALLY A RECURRING MUTATION OR A BUNCH OF MUTATIONS IN THE ARID 1A GENE. SO IF YOU LOOK AT THIS, THIS IS JUST SHOWING YOU THAT THESE MUTATIONS OCCUR THROUGHOUT THE LOCUST OF THE ARUD 1A AND THEY HAVE NON-SENSE, INSERTIONS THEY HAVE MISSENSE MUTATIONS, SO THIS KIND OF TELLS YOU IT’S PROBABLY NOT AN ONCOGENE BUT MAYBE A LOSS OF TUMOR SUPPRESSOR. BECAUSE IT WAS AN ONCOGENE YOU HAVE ONE ACTIVATING MUTATION. HERE WE HAVE MUTATIONS THROUGHOUT THE WHOLE LOCUST. SO WHAT IS ARID 1A N A MEMBER OF THE SPLICE NIP CHROMATIN REMODELING COMPLEX, IT’S FOUND MUTATE IN BREAST CANCER AND LUNG CANCER. IT’S ON CHROMOSOME ONE P 136 AND DELETE IN 6% OF CANCER OVERALL. SO AGAIN, ALL THESE THINGS SUGGEST THANK YOU SUPPRESSOR GENE WHERE IT’S DELETED OR LOSS OF FUNCTION. IN THIS PAPER THEY SHOWED LOSS OF PROTEIN IN THIS IS THE PROTEIN OF THE ARID 1A CALLED BAF 250 SO IN 73% OF CLEAR CELL CASES THERE HAVE LOSS OF THIS ARID 1A WHEN MUTATED THERE WAS LOSS OF MANY PROTEIN EXPRESSION SO ALONG TUMOR SUPPRESSOR. THERE WAS LOSS IN SOME CASES THAT TIN HAVE A MUTATION, WHETHER THIS IS EPIGENETIC SILENCING OF THE PROTEIN. AND CLEAR CELL ENDOMETRIED YOU CANCERS NOT AS BUT STILL SO THIS TELLS YOU NOW THAT WE ARE FINDING A NEW BIOLOGICAL DIFFERENCE BETWEEN CLEAR CELL CANCER AND HIGH GRADE CIRRUS CANCER. SO TO SUMMARIZE THE MUTATION WAS LOST AND/OR LOST IN OVER 40% CLEAR CELL CANCER, 30% ENDOMY TRIED BUT LESS THAN 1% CIRRUS. ICE ONGOING MECHANISM SO YOU CAN’T TARGET LIKE AN ONCOGENE BUT IT HAS PROBABLY TUMOR SUPPRESSING PROPERTIES BUT UP CLEAR THERAPEUTIC UTILITY. IT MIGHT HAVE A DIAGNOSTIC PURPOSE BUT THERE WAS — IT WAS FOUND BY SCREENING EXPERIMENT NOT A FUNCTIONAL EXPERIMENT. MUSINIS OVARIAN CANCER IS LESS COMMON SUBTYPE, MORE SO — LESS COMMON THAN THE CLEAR CELLS. MUSINOUS OVARIAN CANCER SO STANDARD CHEMOTHERAPY YOU YOU
HAVE A WORSE OVERALL SURVIVAL THAN THE OVERALL POPULATION OF OVARIAN CANCER. SO MUSINOUS CANCER ALSO TEND TO RESPOND POORLY TO STANDARD CHEMOTHERAPY. GENE EXPRESSION ANALYSIS, THIS IS AN OBSERVATIONAL EXPERIMENT AND NOT A FUNCTIONAL EXPERIMENT. SO THEY WERE LOOKING AT CLEAR CELL CANCERS, SORRY, CIRRUS CANCERS COMPARED TO MUCINOUS CANCER AND IN THE GENE EXPRESSION PROFILING MUCINOUS CANCERS CLUSTER TOGETHER SO THEY HAVE A DIFFERENT GENE EXPRESSION THAN CIRRUS CANCERS EITHER LOW GRADE POTENTIAL OR HIGH GRADE. SO BASED ON THIS WHICH WAS PUBLISHED IN 2006, IN THE COOPERATIVE GROUP WHERE WE DO CLINICAL TRIALS FOR OVARIAN CANCER, THE MUCINOUS SUBGROUP WAS TAKEN OUT OF THOSE CLINICAL TRIALS AND WE DO SEPARATE CLINICAL TRIALS WITH TARGETED TO MUCINOUS PATIENTS COMPARED TO CLINICAL TRIALS THAT INCLUDE CIRRUSSER OTHER HIGH GRADE SUBTYPES. SO THIS WAS A CLASSIFICATION THAT CAME OUT OF A GENOMICS APPROACH. IN MUCINOUS CANCERS WHAT ARE THE BUY LOGICAL MECHANISMS IN A SMALL SERIES IT WAS FOUND THAT KRAS MUTATIONS WERE COMMON IN MUCINOUS CANCERS. AND ALSO IN CIRRUS LOW GRADE CIRRUS CANCER. SO WE’RE LOOKING AT CIRRUS CANCERS HERE BUT WE HAVE NOW SUBSEQUENTLY DIVIDED CIRRUS CANCER INTO HIGH GRADE AND LOW GRADE BECAUSE THEY DO SEEM TO HAVE A DIFFERENT CELL OF ORIGIN, A DIFFERENT BIOLOGICAL MECHANISM AND DIFFERENT MUTATION PATTERNS. SO LOW GRADE ARE DISTINCT FROM HIGH GRADE CIRRUS CANCERS AND THEY HAVE LIKELY TO HAVE KRAS OR BRAF MUTATION. IT WAS FOUND IN 68% OF LOW GRADE SEROUS CANCER AND BORDERLINE TUMORS BUT NONE OF THE HIGH GRADE SEROUS CANCERS SO THESE ARE ACTUALLY COMING FROM A DIFFERENT SOURCE. LOW GRADE VERSUS HIGH GRADE. THIS IS JUST SHOWING YOU GRAPHICALLY WHAT I SAID, THE SEROUS BORDERLINE AND SEROUS CARCINOMAS HAVE A BRAF OR KRAS MUTATION, NOTHING IN HIGH GRADE SEROUS CANCERS AND NOTHING IN CLEAR CELL OR ENDOMETROID. SO WHAT IS THE RAS PATHWAY? YOU PROBABLY ARE FAMILIAR WITH RAS PATHWAY, IT CAN BE A DRIVER MUTATION. IF RAS IS MUTATED IT CAN SIGNAL THROUGH RAF ALSO MUTATED IN SEPARATE CANCERS SIGNALLY THROUGH MEK AND ERK TO STIMULATE GENE EXPRESSION CELL SURVIVAL AT PROLIFERATION. SO THERE WAS A CLINICAL TRIAL PERFORMED WITH A MEK INHIBITOR SO DOWNSTREAM OF RAS, THE THOUGHT WAS TO BLOCK MEK WITH THIS DRUG CALLED SELUMETNIB SO 52 PATIENTS WITH LOW GRADE SEROUS OVARIAN CANCER, 8 RESPONSES AND 34 PATIENTS HAD STABLE DISEASE WITHIN 34 MONTHS CONSIDERED SOMEWHAT A BENEFIT. BUT THE INTERESTING THING THAT THEY FOUND WAS THAT THE KRS OR BR AF MUTATION WAS NOT CORRELATED WITH RESPONSE. SO IN PATIENTS THEY HAD FIVE PATIENTS WHO RESPONDED, SEVEN PATIENTS RESPOND AND FIVE OF THE SEVEN DID NOT HAVE A BRAF MUTATION, TWO HAD BRAF OR RKAS MUTATION SO THE RESPONSE DIDN’T CORRELATE WITH PRESENT MUTATION AND THE PRESENCE OF THE MUTATION IN THESE PATIENTS DID NOT CORRELATE WITH RESPONSE. SO WHAT’S GOING ON HERE, WE THOUGHT WE HAD A MUTATIONAL PATHWAY THAT WE IDENTIFIED. WE ALL KNOW RAS SIGNALS THROUGH THE KRAS MUTATION CAN BE SIGNALING IN A TON OF PLACES AND WE CAN’T JUST BLOCK HERE TO OVERCOME THAT. SO THEY ARE BACK TO THE DRAWING BOARD WITH THE RAS MUTATION AND WE NEED BETTER DRUGS TO TARGET MORE UPSTREAM IS THE ANSWER. SO HIGH GRADE SEROUS CANCER IS THE MOST COMMON CAUSE CANCER, MOST COMMON HISTOLOGY OF OVARIAN CANCER AND SO THAT WAS WHAT WAS INCLUDED INITIALLY IN THE CANCER GENOME ATLAS. THE CANCER GENOME ATLAS LOOKED FOR OBVIOUSLY MOLECULAR ABNORMALITIES THAT WOULD AFFECT INFLUENCE PATHOPHYSIOLOGY, EFFECT OUTCOME AND CONSTITUTE THERAPEUTIC TARGETS. SO IN THIS INITIAL STUDY PUBLISHED IN 2011, 489 HIGH GRADE SEROUS CANCERS WERE ANALYZED FOR MESSENGER RNA, MICRORNA, DNA COPY NUMBER AND METHYLATION. THEN THEY DID A WHOLE EXOME SEQUENCENING A SUBSET OF THOSE. 360. PATIENTS HAD TO BE NEWLY DIAGNOSED SO NO PRIOR TREATMENT, HIGH GRADE SEROUS CANCER, HAD TO HAVE NO PRIOR TREATMENT AND THEY HAD TO HAVE A COMPANION NORMAL TISSUE SPECIMEN BUT THIS IS PRETTY INTERESTING SO THEY COULD HAVE A DECENT NORMAL TISSUE BUT THEY COULD ALSO JUST HAVE LYMPHOCYTES. SO THIS WILL ONLY REALLY HELP IN DNA ANALYSES AND NOT THE RNA ANALYSES. SO THIS WAS THE INITIAL FINDING, INTERESTINGLY YOU CAN SEE HERE IN GLIOBLASTOMA THIS IS COPY NUMBER ANALYSIS. RED IS SHOWN AMPLIFICATION AND DELETIONS ARE SHOWN IN BLUE. YOU CAN SEE IN GLEE BLASTOMA WHICH WAS ONE OF THE FIRST CANCERS THAT WAS INCLUDED IN THE CANCER GENOME ATLAS, THERE WAS DISTINCT AREAS OF AMPLIFICATION AND DELETION AND THE REST OF THE GENOME IS QUIET. IN HIGH GRADE SEROUS OVARIAN CANCER, THERE’S GENOMIC INSTABILITY WHICH IS ALL THROUGHOUT THE WHOLE GENOME. THERE IS RECURRENT THEMES BUT IT’S NOT JUST ONE TWO, IT’S EVERY CHROMOSOME HAS AMPLIFICATIONS AN DELETIONS. SO THEN THIS BECAME A HALLMARK OF OVARIAN CANCER, HIGH GRADE SEROUS OVARIAN CANCER IS GENOMIC INSTABILITY AND HOW WE CAN TARGET THAT AS A THERAPEUTIC. TO LOOK AT THE MUTATIONS IT WAS FOUND THERE WAS NOT A LOT OF RECURRING MUTATIONS. T P53 WAS A HALLMARK SO P53 WAS FOUND MUTATED IN ALMOST ALL CANCER WHERE IT WAS SEQUENCED. IT WAS SEQUENCED 316 AND 302 HAD A P53 MUTATION. THE NEXT MOST COMMON WERE THE BRCA MUTATIONS SO BRCA 1 AND 2 AND YOU MAY BE FAMILIAR WITH THESE AS CAUSES OF HEREDITARY BREAST CANCER, ALSO HEREDITARY BREAST AND OVARIAN CANCER SYNDROME IS WHAT THEY CALL IT. SO BRCA 1 AND 2. THEN BRCA 1 AND 2 ARE INVOLVED IN HOMOLOGOUS RECOMBINATION PATHWAY. SO THEY LOOKED AT OTHER GENES THAT MIGHT BE AFFECTED IN HOMOLOGOUS RECOMBINATION WHICH I’M GOING TO TALK ABOUT A LITTLE BIT LATER. BUT YOU CAN SEE HERE BRCA GENES WERE METHYLATED OR MUTATED. METHYLATION IS IN GREEN AND — METHYLATION IS IN PURPLE AND MUTATION IN GREEN. SO THEY COULD HAVE — SORRY GERM LINE MUTATION OR SOMATIC MUTATION AND THEN HERE THE METHYLATION. SO GERM LINE MUTATION IS THE PURPLE, SO MAT UK MUTATION IS GREEN AND METHYLATION IS IN THE BLUE GRAY. SO IF YOU LOOK AT THE BRCA PEOPLE WITH BRCA MUTATION CAN HAVE A BETTER RESPONSE TO STANDARD CHEMOTHERAPY THAN PEOPLE WITHOUT. SO THAT WAS INTERESTING PROGNOSTIC FINDING. THEY ALSO FOUND OTHER PATH — OTHER PROTEINS OR GENES IN THE HOMOLOGOUS RECOMBINATION REPAIR PATHWAY, THAT WERE SIMILARLY MUTATED. SO THEY WERE THINKING THIS WAS A PATHWAY THAT WAS AFFECTED IN MANY OVARIAN CANCERS. YOU CAN SEE THAT THIS IS — WAS FOUND IN ALMOST HALF OF THE OVARIAN CANCERS IN THIS DATA SET. THESE ARE SOME OF THE OTHER MAJOR PATHWAYS THAT WERE ALTERED, THE CELL CYCLE PROGRESSION PATHWAY AND THIS IS THE DNA REPAIR THAT WE ALREADY TALKED ABOUT. SO WHAT CAME — WHAT WAS THE NEXT STEPS AFTER CANCER GENOME ATLAS? WERE THERE NEW THERAPEUTIC APPROACHES? INTERESTINGLY 50% OF CASES HAD HOMOLOGOUS RECOMBINATION DEFECT, WE WILL TALK MORE ABOUT PARP INHIBITOR USED TO TARGET HOMOLOGOUS RECOMBINATION DEFICIENT CANCERS. THERE WERE OTHER COMMONLY DEREGULATED PATHWAYS LIKE THE RAS PI 3 KINASE PATHWAY, THE NOTCH PATHWAY, AND ALSO ABERRANT GENES OR NETWORKS THAT WERE TARGETABLE. SO THE IDEA IS THERE’S NOT ONE PARTICULAR DRIVER AS WE SAW EARLY IN THE TALK WITH I TALKED CML WITH THE ONE DRIVER THROUGH THE ABLE KINASE. THIS DOES NOT HAVE ONE DRIVER SO WE THINK WE NEED TO TARGET NETWORK PATHWAYS IN ORDER TO OVERCOME CHEMOTHERAPY RESISTANCE. SO PARP INHIBITORS. THIS IS PA HOT TOPIC IN OVARIAN CANCER. PARP INHIBITORS ARE RELEVANT IN PATIENTS WITH BRCA MUTATION. BRCA IS NOT DISCOVERED BY THE CANCER GENOME ATLAS. IT WAS DISCOVERED IN 1990 WHEN MARY CLAIRE KING AND HER GROUP FOUND RECURRING LOCUST ABNORMAL IN FAMILIES OF HEREDITARY BREAST CANCER, BREAST OR OVARIAN CANCER. THEN THE CANCER GENOME ATLAS SHOWED US BEYOND BRCA MUTATIONS THERE ARE OTHER WAYS OF ALTERING THE HOMOLOGOUS RECOMBINATION PATHWAY. AND THAT CAN BE GERM LINE MUTATION SOMATIC MUTATION METHYLATION OR OTHER MUTATIONS THAT AFFECT DNA REPAIR PATHWAY. BEYOND THIS PEOPLE COME UP WITH GENE EXPRESSION SIGNATURES AND RAD 51 CAME UP TO BE A STRONG PREDICTOR OF HOMOLOGOUS RECOMBINATION DEFICIENCY. YOU CAN SEE PATIENTS WITH RECOMBINANT HOMOLOGOUS RECOMBINATION INTACT HAS DEFICIENCY, THIS IS BREAST CANCER BUT THE SAME HOLDS TRUE IN OVARIAN CANCER. SO A LOT OF TRIALS PRESENTED THIS PAST WEEK AT THE ESMO MEETING IN EUROPE, WE ARE TRYING TO USE HOMOLOGOUS RECOMBINATION TESTS TO SEGREGATE PATIENTS WHETHER OR NOT THEY SHOULD GET PARP INHIBITORS. THAT’S EXPERIMENTAL BUT UP AND COMING. THIS IS JUST REPEAT IN A CELL LINE. SO I HAVE BEEN TALKING ABOUT HOMOLOGOUS RECOMBINATION OF PARP INHIBITION. SO MORE BACKGROUND ON THE PATHWAY WE ARE TARGETING HERE. DURING NORMAL CELL METABOLISM OR ENVIRONMENTAL EXPOSURES UV LIGHT YOU CAN GET SINGLE STRAND DNA BREAKS. SO THOSE SINGLE STRAND DNA BREAKS ARE MARKED BY THE ENZYME PARP WHICH STANDS FOR POLYADP RIBOSE POLYMERASE. SO THAT PUTS ON A STRING OF ADP RIBOSE TO MARK THAT SINGLE STRAND BREAK. IF YOU USE A PARP INHIBITOR, THAT DOES NOT GET IDENTIFIED SO YOU HAVE YOUR SINGLE STRAND BREAK THAT PERSISTS IN REPLICATING CELLS WHEN YOU HAVE THE GYRASE ENZYME, YOU HAVE TO NIK THE DNA TO UNTWIST IT IN ORDER TO GET REPLICATION GOING. THE MACHINERY IN THERE. THAT DOUBLE STRAND — SINGLE STRAND GETS CONVERT TO A DOUBLE STRAND BREAK. SO IN A NOER MALL CELL HOMOLOGOUS RECOMBINATION PATHWAY IS BEST TO REPAIR A DOUBLE STRAND BREAK. SO NORMAL CELLS WOULD BE FINE, THEY WOULD REPAIR BY HOMOLOGOUS RECOMBINATION AND SURVIVAL. IN A CANCER WITH A BRCA DEFICIENCY, THIS PATHWAY IS ALMOST KNOCKED OUT SO THAT CANCER THAT HAS NO BRCA CANNOT REPAIR THE DOUBLE STRAND BREAK AND IT BECOMES OVERWHELMED WITH DOUBLE STRAND BREAK AND WILL UNDERGO CELL DEATH. THIS WAS SHOWN EXPERIMENTALLY, HERE IS A PARP INHIBITOR, AN ORAL DRUG, IT IS — HAS SYNTHETIC LETHALITY IN CELL LINES AT LEAST WITH BRCA MUTATION. THIS IS EFFECTIVENESS, THIS IS DOSE ESCALATION OF THE LAP AND SURVIVAL OF THE CELL LINE IN CULTURE. HEAR IS WILD TYPE BRCA, HERE IS BRCA 2 MUTATION AND BRCA 1 MUTATION IN THE CELL LINES. YOU CAN SEE BRCA 1 AND 2 MUTATIONS ARE MORE SENSITIVE TO PARP INHIBITION THAN WILD TYPE BRCA. SO WE PERFORMED IN — BACK IN THE EARLY 2000 A PHASE 1 STUDY WINING ELAPRIB WITH CARBO PLATIN, A DRUG THAT CAN CAUSE SINGLE STRAND BREAKS. SO WE HAD ONE COHORT PATIENTS WITH BRCA MUTATION, WE HAD ANOTHER COHORT WITH TRIPLE NEGATIVE BREAST CANCER WHICH CAN HAVE NORMAL BRCA BUT MIGHT HAVE HOMOLOGOUS RECOMBINATION DEFECT, AND ANOTHER COHORT WITH HIGH GRADE SEROUS OVARIAN CANCER, NO BRCA MUTATION BUT MIGHT HAVE 50% MIGHT HAVE HIGH DEFICIENCY IN HOMOLOGOUS RECOMBINATION. SO WE PERFORMED ALL OF THESE — WE HAVE THESE COHORTS AND DID SEE INTERESTING ACTIVITY IN THE BRCA COHORT. THESE ARE TOES ESCALATION IN TRIPLE NEGATIVE BREAST CANCER. SO JUST SHOWING YOU BRCA MUTATION COHORT, WE HAD PATIENTS, ENROLLED 45 PATIENTS IN THE STUDY, WE DID — DOSE ESCALATION IN THE PHASE 1 WAS 30 PATIENTS AND THE EXPANSION WAS 15. SO YOU WILL SEE NEXT SLIDE SOME PATIENTS WITH LOWER THAN THE MAXIMUM DOSE. MAXIMUM DOSE IN THE EXPANSION COHORT WAS CARBO PLATIN WITH AUC 5 WHICH IS STANDARD DOSE ELAPRIB WAS GIVEN 400-MILLIGRAMS TWICE DAILY. SO THESE ARE THE DOSE LEVELS. WE HAVE PATIENTS ON MULTIPLE DOSE LEVELS BUT EVEN LOWER DOSE LEVELS WE HAD GOOD RESPONSES SO THIS GRAPH IS SHOWING YOU THE CHANGE IN TUMOR SIZE FROM BASELINE, SO 20% — 30% DECREASE CONSIDERED PARTIAL RESPONSE AND THEN OBVIOUSLY 100% IS COMPLETE RESPONSE. PROGRESSION IS MORE THAN 20% GROWTH SO WE HAD NO ONE PROGRESS IN THIS COHORT WHICH IS AMAZING. SO THESE HAD PREVIOUSLY MISSING PLATIN AWE LOAN AND THEY WERE RESISTANT TO PLATINUM. WE GAVE THEM PLATINUM PLUS PARP INHIBITOR AND NEARLY ALL HAD CLINICAL BENEFIT. SO THEY ALL HAD STABLE DISEASE OR RESPONSE. OF COURSE WE HAD THE MOST PATIENTS ON DOSE LEVEL 6 BECAUSE THAT WAS EXPANSION COHORT BUT EVEN PATIENTS LIKE I MENTION ON DOSE LEVEL 1, 2, 3 HAD RESPONSES. SO THIS IS A PRETTY AMAZING RESULT THAT WE CAN HAVE A THERAPY, PARP INHIBITOR THAT WAS TARGETED FOR B RCA SYNTHETICALLY LETHAL IN CELLS WITH HOMOLOGOUS RECOMBINATION DEFICIENCY. WE HAVE NO COMPLETE RESPONSE, THAT ONE DOWN PAR STILL HAD A LITTLE DISEASE LEFT. WE HAD 15 PARTIAL RESPONSES, 44% PATIENTS. WE HAD 13 PATIENTS WITH STABLE DISEASE GREATER THAN FOUR MONTHS. AND THEN WE HAD AN OVERALL CLINICAL BENEFIT OF 82%, THAT WAS VERY EXCITING. WELL TOLERATED IN COMBINATION WITH THE CARBO PLATIN, HIGHLY ACTIVE IN BRCA DEFICIENT CANCERS, GREATER ACTIVITY AT THE HIGHER DOSE. BUT THIS IS POSITIVE PROOF OF CONCEPT AS I SAID THAT THE ACTIVITY AND TOLERABILITY OF THIS COMBINATION REGIMEN AND GENETICALLY DEFINED SUBGROUP. SO WHERE CAN WE GO WITH NEW TARGETS? WE TOOK A FUNCTIONAL GENOMICS APPROACH. WE WERE LOOKING FOR ACTIONABLE MUTATIONS THERE IS A LOT OF TRIALS GOING ON WITH ACTIONABLE MUTATIONS SO HOW DO WE DEFINE THAT? PEOPLE ARE USING THESE COMMERCIALLY AVAILABLE TESTS, TO REPORT MUTATIONS THAT MIGHT BE POSSIBLE OR UNLIKELY TO BENEFIT. PEOPLE ARE ENROLLING IN CLINICAL
CLINICAL TRIALS, THE NCI IMPACT WILL PUT PATIENTS IN CATEGORIES OF THERAPIES, BASED ON MUTATIONAL ROAD OR MUTATIONAL PROFILE. BUT TYPICALLY IN THESE SETTINGS THERE’S NO FUNCTIONAL SO THEY OBSERVE MUTATION BUT DON’T GO BACK AND DO AN EXPERIMENT IN THE LAB TO SHOW THAT MUTATION IS RESPONSIBLE FOR THE SENSITIVITY TO A PARTICULAR DRUG. SO THIS WAS A REVIEW THAT WAS PUBLISHED IN 2015, THE WORD ACTIONABLE DEPENDS LARGE PART ON THE STRENGTH OF THE DATA LINKING THE TARGET TO THE TARGETED THERAPY. SO THIS BASKET TRIAL DESIGN TO WORK YOU HAVE TO HAVE TWO KEY CONDITIONS, THE TUMOR MUST DEPEND ON THE TARGET PATHWAY AND THAT THE TARGETED THERAPY THAT YOU ARE USING MUST RELIABLY INHIBIT THE TARGET. SO THESE PEOPLE CORRECTLY SAID ACHIEVING BOTH GOALS CAN BE A MATTER OF SOME COMPLEXITY. SO WE THOUGHT THAT FOR — TO DEFINE AN ACTIONABLE TARGET WE ACTUALLY NEEDED A FUNCTIONAL EXPERIMENT. SO ACTUAL HI WE DID FUNCTIONAL GENOMICS AS ONE APPROACH. THE FUNCTIONAL GENOMICS APPROACH THAT WE TOOK WAS BASED ON SH RNA LIBRARY PUBLISHED BY LOU STATED IN 2006 IN NATURE. HE CREATED AN SH RNA LIBRARY THAT HAS A BAR CODE SO THESE CAN BE PUT IN A POOL AND YOU CAN PULL OUT THE INDIVIDUAL PHONES OR IDENTIFY THE LOSS OF THE CLONES USING A BAR CODE. IN THIS PARTICULAR SETTING, HE ACTUALLY TARGETED 2500 HUMAN GENES, NOW UP TO I THINK 15,000. SO WE USE THE APPROACH WITH SH RNA LIBRARY, INFECT CANCER CELLS AND TURN ON SH RNA EXPRESSION USING INDUCIBLE CONSTRUCT OR YOU HAVE THE SH RNA OFF. YOU LOOK FOR THE SH RNA — LOOK FOR THE DROP-OUT OF THE BAR CODE IN THE SH RNA ON AND THAT BAR CODE WILL IDENTIFY WHICH GENES WERE IMPORTANT: SO WE DID THIS IN FOUR OVARIAN CANCER CELLS LINES, WE HAVE TWO SERIOUS CELL LINES AND TWO NON-SEROUS CELL LINES. WE FOUND SOME GENES COMMON TO SEROUS AND NON-SEROUS AND SOME COMMON IN SEROUS AND SOME NON-SEROUS. SO OVERALL IN THIS MOST COMMON GROUP, THERE WAS 63 SH RNAs THAT REPRESENTED 55 GENES, THIS IS IFFY BUT THESE WERE THE GENES MOST INTERESTING. SO WE HAVE FOLLOWED THESE UP IN SIX ADDITIONAL CELL LINES USING TWO DIFFERENT RNAi CONSTRUCTS IN ORDER TO SELECT THE DRUGGABLE TARGETS. WE ARE DOING FUNCTIONAL FOCUSED SCREENS IN SUBGROUPS OF OVARIAN CANCER AND WE HAVE COMBINATION MATRIX STUDIES ONGOING. ONE OF THE TOP TARGETS WAS THE GENE FOR CHECK 1. WE FOUND IT WAS OVEREXPRESSED IN NEARLY ALL OF OVARIAN CANCER. WHICH SUPPORTS THE FACT THAT WE FOUND AS ONE TOP GENE IN BOTH SEROUS AND NON-SEROUS CANCERS. SO IT’S GENERALLY AN IMPORTANT GENE IN OVARIAN CANCER BASED ON OVEREXPRESSION. SO WE PRIORITIZE THIS AS ONE OF OUR TOP TARGETS. WHAT IS CHECK? IT IS INVOLVED IN HOMOLOGOUS RECOMBINATION PATHWAY, ALSO INVOLVED IN GENERIC DNA CELL CYCLE CONTROL. SO WHAT HAPPENS IS WHEN DNA IS DAMAGED YOU HAVE THE DNA DAMAGE RESPONSE. THIS SINGLES THROUGH ATM TO ACTIVATE CHECK ONE OR TWO WHICH GOES IN HERE AND CAN BLOCK THE CELL CYCLE CHECK WAY. IF THIS IS AMPLIFIED YOU HAVE MORE BLOCKING SO YOU WOULD HAVE MORE TIME TO REPAIR GENOMICALLY UNSTABLE PHENOME THAT WE SAW OCCUR IN OVARIAN CANCER SO THAT’S WHY IT’S OVEREXPRESSED IS BECAUSE THERE’S THAT GENOMIC INSTABILITY. THE OTHER THING CELL MUTATED P53 HAVE LOST THIS OTHER CHECK POINT, THE G1S CHECK POINT SO HIGH GRADE SEROUS OVARIAN CANCER P53 IS KNOCKED OUT FOR THE MOST PART THEY RELY ON THIS G2M CHECK POINT TO REPAIR ANY DNA DAMAGE THAT’S GONE ON, OTHERWISE THEY CAN’T AND JUST GO THROUGH THE CELL CYCLE WITH THE MUTATED GENOME. THAT COULD LEAD TO THOSE CHROMOSOMAL ABNORMALITIES WE SAW BACK IN THE CANCER GENOME ATLAS. SO WE FOUND IN OUR CELL LINES, SCREENING THAT THE HYBRID SEROUS CANCERS WERE MORE SENSITIVE BY SEVERAL FOLD. TO THE CHECK INHIBITOR. THAN THE NON-SEROUS CANCERS. SO WE DO HAVE A CLINICAL TRIAL WE ARE STILL ENROLLING TO. AND THIS IS SHOWING PROMISING RESULTS SPECIFICALLY IN HIGH GRADE SEROUS CANCERS THE NON-BRCA COHORT. THIS IS VERY HELPFUL BECAUSE WE NOW HAVE THE PARP INHIBITORS FOR THE BRCA COHORT AND WE HAVE THIS CHECK INHIBITOR FOR THE NON-BRCA COHORT. THIS WAS FOUND BY JUNCTIONAL GENOMICS APPROACH AND NOT OBSERVATIONAL APPROACHMENT THIS IS A STUDY ONGOING BY DR. LEE, IS THIS E RECENTLY PUBLISHED THIS IN THE LANSETT ONCOLOGY IN FEBRUARY 2018. THIS IS HER CLINICAL TRIAL THAT FOUND THE HIGH GRADE SEROUS OVARIAN CANCER WITHOUT BRCA MUTATION, HAD HIGHER RESPONSE RATE THAN ONE WITH BRCA MUTATION. THIS IS VERY PROMISING, MOST OF THE PATIENTS ARE HAVING SOME BENEFIT, STABLE DISEASE AND SOME WITH RESPONSE. THESE PATIENTS ARE STILL ON STUDY AT THE TIME OF THIS PUBLICATION. GRAY BARS MEAN PALACE NUMBER RESISTANT, THESE PATIENTS NO LONGER RESPOND TO PLATINUM THERAPY, NO LONGER RESPOND O TO STANDARD CHEMOTHERAPY YET STILL HAVING DRAMATIC AND LONG LASTING RESPONSES TO THIS CHECK INHIBITOR. AGAIN, SHE SHOWED THAT PATIENTS, HOW LONG THEY STAYED ON STUDY. THESE ARE ONES WITH THE DOCUMENTED RESPONSE. AND BUT EVEN THOSE ONES WITHOUT RESPONSE STILL STAY ON WITH STABLE DISEASE FOR QUITE SOME TIME AND WE ARE OUT LONGER THAN THIS BECAUSE THIS WAS 2018. SO TO SUMMARIZE OVARIAN CANCER IS NOT JUST ONE DISEASE, OVARIAN HAS EPITHEMEIAL AND NON-EPITHELIAL COMPONENTS, WE DID NOT TALK ABOUT THE NON-EPITHELIAL TODAY. IN THE EPITHELIAL WE HAVE HIGH GRADE SEROUS MARKED BY P 53 MUTATION AND DEFECTS IN HOMOLOGOUS RECOMBINATION PATHWAY, THESE ARE POTENTIAL TARGETS FOR THERAPY. LOW GRADE SEROUS CANCERS ARE DIFFERENT BIOLOGY RELYING ON KRAS AND BRAF MUTATIONS, MUCINOUS OVARIAN CANCER ALSO HAVE DIFFERENT HER 2 IMPLICATIONS ANDS WE HAVE ANOTHER CLINICAL TRIAL I DIDN’T TALK ABOUT TODAY THAT WE ARE TARGETING A DIFFERENT ANTIGEN EXPRESSION IN MUCINOUS CANCER OF THE OVARIAN, OVARIAN AND MUCINOUS AND GI CANCERS SO THAT’S EXCITING. WE HAVE CLEAR CELL CANCERS WHICH ARE REPRESENTED BY THE ARID 1A ENDOMETROID AS WELCOMING FROM ENDOMETRIOSIS ARID 1A IS TARGETED BY ANGIOGENESIS PATHWAYS WHICH I DIDN’T TALK ABOUT HERE. SO TO SUMMARIZE WITH FUNCTIONAL GENOMIC WE STARTED IN FUNCTIONAL GENOMICS SCREEN WHERE WE TOOK FRAGMENTS AND THROUGH IT IN. WE DO A FUNCTIONAL GENOMICS SCREEN USING SH RNA KNOCK OUT TO SEE WHAT IS REQUIRED AND WHAT WILL KILL THE CELLS. IF WE PUT THAT ALL TOGETHER AND DO A FUNCTIONAL GENE IDENTIFY DRIVER PATHWAY TO A CLINICAL TRIAL, WE WILL HOPEFULLY HAVE MORE SUCCESS IN TREATING INDIVIDUAL CASES. SO WITH THAT I WILL TAKE ANY QUESTIONS. LET ME IDENTIFY HERE, THIS IS DR. LEE WHO I MENTIONED WHO IS STILL RUNNING THE TRIAL WITH THE CHECK INHIBITOR AND SHE WAS HEAVILY INVOLVED IN THE PARP INHIBITOR STUDIES I MENTIONED AS WELL AND OUR BRANCH CHIEF, HIS IS THE REST OF OUR TEAM. TRANSLATIONAL SCIENTISTS FOR THE FUNCTIONAL GENOMICS SCREENS ARE LISTED HERE AND MY COLLABORATORS IN OTHER BRANCHES. THANK YOU.>>PERHAPS YOU CAN COMMENT (INAUDIBLE)>>IV THERAPY IS STILL CONSIDERED THE BEST WAY SPECIFICALLY IN WOMEN WHO HAVE UP FRONT OPTIMAL DEBULKING OF STAGE 3. THAT’S THE ONLY PLACE IT’S BEEN PROVEN TO BE BENEFICIAL. OTHER STUDIES LOOKED LIKE EARLIER STAGE OR LATER STAGE HAVE NOT BEEN ABLE TO REPRODUCE THAT BENEFIT. THE IDEA WAS THAT THE INTERPERITONEAL CHEMOTHERAPY IS DIFFICULT TO ADMINISTER BECAUSE IT CAN LEAD TO TOXICITY. SO IF PEOPLE ARE NOT — IT’S NOT WIDELY ADOPTED EXCEPT IN THAT ONE SPECIFIC INSTANCE. WE ARE DOING AN INTERESTING CLINICAL TRIAL, DOING IP CELL THERAPY, I DIDN’T TALK ABOUT HERE. WHERE WE PUT IN CAR T-CELLS OR ACTIVATED MONOCYTES. SO THAT’S ANOTHER APPROACH THAT WE ARE TESTING. (OFF MIC)>>INTERESTING QUESTION, WE ARE NOT SURE WHY THE BRCA 1s DID NOT RESPOND. ONE OF THE THOUGHTS, THERE’S TWO MAJOR AREAS. SO ONE THOUGHT IS THAT THE WHEN BRCA MUTATED CANCERS BECOME RESISTANT TO PLATINUM, IT MEANS THEY HAVE RENEW AT A TIMED BRCA GENE TO HAVE FUNCTIONAL HOMOLOGOUS RECOMBINATION PATHWAY. SO THAT’S A POSSIBILITY. BRCA MUTATION HAS UNDERGONE A SECOND MUTATION THAT RESTORES THE READING FRAME. THEY HAVE FUNCTIONAL SO THEY’RE NO LONGER HAVING HOMOLOGOUS DEFICIENCY. THAT’S ONE THOUGHT. THE OTHER THOUGHT IS THERE IS OTHER DEFECTS IN THE CELL CYCLE PATHWAY IN THE CYCLINE E MUTATIONS IN THE NON-BRCA MUTATION CARRIERS. THAT MIGHT BE MORE GEARING TOWARDS THE CHECK PATHWAY. THAT’S NOT DRIVEN AT THE MOMENT. SO WHAT ABOUT COMBINING CHECK INHIBITOR WITH BRCA? WITH THE PARP INHIBITOR? WOULD BE AN INTERESTING APPROACH TO DO THAT IN THE FUTURE. (OFF MIC)>>YOU’RE WELCOME. [APPLAUSE] OUR NEXT LECTURER IS STEPHANIE GOFF FROM GEORGIA TECH. HER MEDICAL DEGREE UNIVERSITY OF SOUTH FLORIDA, RESIDENCY AT COLUMBIA UNIVERSITY AND SHE DID A SURGICAL ONCOLOGY FELLOWSHIP& COMBINED WITH DANA-FARBER CANCER INSTITUTE, BRIGHAM AND WOMEN’S HOSPITAL, MASSACHUSETTS GENERAL HOSPITAL. THEN SHE CAME TO NCI. SHE’S GOING TO LECTURE ON IMMUNE CHECK POINT BLOCKADE. STEPHANIE.>>THANK YOU. THIS HAS BEEN A FUN LECTURE TO GIVE OVER THE LAST FOUR YEARS, ONE OF THE SLIDE WE’LL GET TO AT THE END SHOWS THIS IS A FIELD THAT’S HE CAN PLEADED. IN FACT ALTHOUGH THE NOBEL AWARD WINNERS THIS YEAR WERE JUST NAMED FOR LAST YEAR RECEIVED THEIR NOBELS FOR THIS VERY TOPIC. SO LET’S JUMP IN TO A LITTLE BIT ABOUT WHAT I’M GOING TO TALK ABOUT. THE FIRST ARE THE BASICS OF IMMUNE THERAPY, THEN INDO A LITTLE BIT ABOUT THE MECHANISM OF ACTION OF CHECK POINT BLOCKADE WE’LL REVIEW THE CLINICAL EARLY EXPERIENCE AND IMMUNE RELATED ADVERSE EVENTS BECAUSE AS A CLINICIAN SCIENTIST, THESE DRUGS MADE US RETHINK ABOUT HOW WE TRACK DRUGS AND HOW WE DOSE ESCALATE AND CREATE NEW DRUGS WITH THE HELP OF THE FDA. THEN I’LL GO THROUGH THE DATA THAT WAS THE FIRST CLINICAL SUCCESS OF CHECK POINT BLOCKADE WHICH WAS IN MELANOMA. AND THOSE ARE THREE OF THE DRUGS WE WILL TALK ABOUT, THEY LOOK LIKE MOUTHFULS, BUT GET EASIER AS WE GO ALONG. IPILIMUMAB, YOU MAY HAVE SEEN THESE IN TELEVISION COMMERCIALS, URUGUAY OPTIVA. WE WILL TALK ABOUT CHECK POINT BLOCKADE IN CANCER OTHER THAN MELANOMA AND A QUICK DIAGRAM WHERE THIS MIGHT LEAD EXPERIMENTALLY. TO START WITH, ONCOLOGY COVERS ALL CANCER. AND TRADITIONALLY THERE’S THREE MAIN WAYS TO STUDY CANCER, ANYONE KNOW WHAT THE VERY FIRST WAY TO TREAT CANCER WAS? YOU HAD A CHOICE BETWEEN IMMUNOTHERAPY, CHEMOTHERAPY, RADIATION OR SURGERY, WHAT WAS THE FIRST ONE? WHAT DO YOU THINK WE FIGURED FIRST, HOW TO CUT THINGS, BURNS THINGS OR POISON THINGS? WE CUT THEM FIRST. THE FIRST MODE OF TREATING CANCER WAS AN OPERATION AND IT WAS BACK IN 3,000 BC. THERE’S AND I JIM SCROLL THAT SHOWS SOMEONE CUTTING A TUMOR OFF THE CHEST PROBABLY NOT DONE UP TO STANDARDS OF TODAY AND CERTAINLY WITHOUT PLASTIC SURGERY RECONSTRUCTION. NEXT FIGURED HOW TO BURN OR POISON THINGS. BURN. SO MARIE CURRY SOON AS SHE MY OUT WHAT RADIATION WAS TRIED TO APPLY IT TO CANCER. IT’S A DOUBLE EDGE SWORD. IN FACT RADIATION WHEN IT FIRST CAME OUT WAS USED AS A TOY. SHOEMAKERS, SHOE SALESMEN WOULD USE IT TO TRY TO MAKE SURE PEOPLE’S SHOES FIT CORRECTLY. THEY WOULD HAVE BOXES IN AND THE PERSON WOULD TRY ON THE SHOES AND PUT SHOE IN THE BOX AND THE SALESMAN WOULD LOOK DOWN TO SEE WHAT THE BONES WERE IN THE SHOES THAT WAS FINE UNTIL THE SHOE SALESMEN STARTED GETTING THYROID CANCER FROM RADIATION EXPOSURE. NO LONGER WE HAVE THAT BUT BECAUSE WE FIGURED OUT RADIATION IS SO POWERFUL WE START AD APPLYING IT TO TUMORS. IN THE 1940, WORK HAPPENED IN BOSTON THAN HERE TO THE NCI TO DEVELOP CHEMOTHERAPY. THAT STARTED WITH YOUNG CHILDREN WITH LEUKEMIA. THE MOST RECENT PILLAR WE HAVE ADDED IS IMMUNOTHERAPY, THE FIRST ONE GOT APPROVED IN 1992, LOW DOSE INTERLEUKIN 2 CELL CANCER. SO ONLY THE LAST THREE DECADES WE HAVE ACTUALLY CONTEMPLATED A THOUGHT THAT THE IMMUNE SYSTEM COULD PLAY A PART IN CANCER THERAPY. SO THERE’S THREE WAYS TO GET THE IMMUNE SYSTEM TO>>AFTER CANCER. OF YOU HAVE A LOT OF IMMUNE CELLS, FIRST TO STIMULATE ALL THE IMMUNE CELLS IN YOUR BODY, A NON-SPECIFIC STIMULATION OF IMMUNE REACTIONS. WE CAN DO THIS IN TWO WAYS, ONE IS TO GIVE A STIMULUS THAT TURNS ON ALL T-CELLS IN YOUR BODY, AND THE OTHER WAY IS TO TURN OFF ALL THE THINGS HOLDING BACK YOUR IMMUNE SYSTEM. AND THAT IS CHECK POINT BLOCKADE, WE’LL GET INTO IN DEPTH IN THIS LECTURE. BUT ANOTHER WAY TO THINK ABOUT THOSE CELLS THAT LIVE IN YOUR BODY AS JUST SORT OF ELEMENTARY SCHOOL CELLS, ANOTHER WAY SO TO TEACH THOSE CELLS HOW TO DO IT, WITH VACCINE SO THIS COULD BE LIKE HIGH SCHOOL VERSION OF T-CELLS. THEY HAVE BEEN TAUGHT WITH ACTIVE IMMUNIZATION, WITH EITHER PEP DID OR RNA OR WHOLE TUMOR, THEY HAVE BEEN TAUGHT HOW TO SEE THE CANCER WITH THE THOUGHT THEY COULD THEN GO OUT AND ATTACK IT. THIRD IS COLLEGE TYPE T-CELLS: TAKEN THEM OUT OF THE BODY, DONE SOMETHING TO THEM IN THE LAB, EDUCATED THEM AS BEST WE CAN AND GIVE THEM BACK. THAT’S ADOPTIVE IMMUNOTHERAPY, THAT’S MORE MY NICHE AREA WHAT I DO CLINICALLY BUT WHAT WE WILL TALK ABOUT TODAY IS CHECK POINT BLOCKADE. SO WHAT ARE SOME OF THE CELLS OF THE IMMUNE SYSTEM? THIS IS BASIC BIOLOGY STUFF. WE HAVE GOT TWO DIFFERENT IMMUNE SYSTEMS, ONE IS THE INNATE IMMUNE SYSTEM THAT ALLOWS US TO REACT RAPIDLY TO ANYBODY WHO HAS A BAD ALLERGY, WORRIED ABOUT ANAPHYLAXIS IS PART OF INNATE IMMUNITY. THE SECOND PART IS ANAPHYLAXIS IS ADAPTIVE IMMUNITY. WHAT WE THINK IS THE BEST WAY TO ATTACK CANCER IS PART OF THE ADAPTIVE IMMUNITY AND SPECIFICALLY T-CELLS. THAT’S WHAT THE CHECK POINT BLOCKADE PRIMARILY WORKS ON. SO HOW IS A T-CELL BORN? WE HAVE LOTS OF T-CELLS. ABOUT FOUR TIMES TEN TO THE 11th, THINK OF A THIMBLE FULL OF BLOOD HAS A MILLION T-CELLS IN EVERY THIMBLE FULL OF BLOOD AND WE HAVE A REPERTOIRE OF T-CELLS THAT CIRCULATE IN BOWER DIAND WHEN WE ARE YOUNG AN MOST OF US IN THIS ROOM HAVE A WORKING THYMUS, AT LEAST A REMNANT OF IT AND CELLS GO THROUGH THERE. IF A PROTEIN IS PRESENT IN OUR BODY AND CREATES A STRONG REACTION TO THE T-CELL, THE THYMUS WILL DESTROY IT BECAUSE YOU DON’T WANT CELLS ATTACKING YOUR BODY ALL THE TIME. THAT’S WHERE AUTOIMMUNE DISEASE COMES UP. IF A CELL GETS A VERY NON-SIGNAL AT ALL IT WILL ALSO GET KILLED SO CELLS IN THE MIDDLE THAT MAKE THEIR WAY OUT INTO THE WORLD TO PROTECT OUR BODY FROM THINGS WE DID FROM VIRUSES SPECIFICALLY. HOW DOES A T-CELL GET ACTIVATED? IT HAS A NUMBER OF SIGNALS, NOT JUST A ONE STEP PROCESS. AS YOU U MIGHT IMAGINE ANYTHING THAT’S IN THE BODY HAS MULTIPLE WAYS TO GET ACTIVATED IN MULTIPLE WAYS TO SLOW IT DOWN. SO WE HAVE TWO T-CELLS, A CD8 T-CELLS TRADITIONALLY KNOWN AS A CYTOTOXIC T-CELL OR KILLER T-CELL, WE HAVE A CD4 T-CELL, HELPER CELL. I’M SURE YOU HAVE KNOWN GOING THROUGH CAREER EVERYTHING IS NOT ADS SIMILAR MR. I MID AS IT IS WHEN IT WAS FIRST TAUGHT TO YOU SO CD8 AND CD4 HAVE WIDER ROLES THAN BEING KILLER BUT NOW WE’LL FOCUS ON THAT. WHAT HAPPENS ON THE CELL SURFACE IS THERE’S HISTOCOMPATIBILITY COMPLEX. MHC. THAT’S LIKE YOUR WHITE BLOOD CELL TYPE. IT DETERMINES WHAT YOUR BODY CAN SEE AND CAN’T SEE. BECAUSE AS THINGS ARE GETTING CHEWED UP WITHIN YOUR BODY, BY PROPERTY OWESOME BEING PLACED ON MHC PARTICLES ON THE GOLGI, BACK OUT TO THE SURFACE, IT’S THE SPECIFIC SHAPE OF THIS MHC THAT DETERMINES WHAT PIECE OF THE PEPTIDE ENDS UP ON THE SURFACE AND THAT COMBINATION OF THE SHAPE OF THE MHC AND THE PIECE OF PEPTIDE THAT’S IN THE MIDDLE THAT THE T-CELL CAN SEE. WE’LL GET INTO THIS A LITTLE BIT MORE LATER. BUT JUST TO KNOW FOR INSTANCE IF YOU ARE TARGETING THINGS, SAY YOU WANT TO TARGET AN ANTIGEN KNOWN TO BE ON CANCER LIKE KRAS OR TP 53, THEY MAY BE PRESENT IN 70% OF CANCER BUT BECAUSE MOST PATIENTS DON’T SHARE THE SAME MHC T-CELL TREATMENT THAT WORKS FOR ONE MAY NOT WORK FOR ANOTHER BECAUSE IT’S THE COMBINATION THAT’S IMPORTANT. A SECOND TYPE OF T-CELL CD4 REQUIRE AS DIFFERENT MHC OR CLASS 2. THESE ARE COMING THROUGH THEIR ENDOCYTOSE, SPLIT INTO PIECES, CLIP IS REQUIRED THEN THEY GET INTO GROOVE OF MHC AND AGAIN PRESENTED. WHAT’S IMPORTANT TO KNOW IS THAT IT REQUIRES THE COMBINATION OF THE SHAPE OF THE MHC AND PEPTIDE IN BETWEEN THAT CAN RECOGNIZE THE T-CELL. SO IT’S THAT SPECIFICITY THAT THIS ONE T-CELL OUT OF A HUP THOUSAND IN YOUR BODY SEES THIS PARTICULAR COMBINATION, IT WON’T BE OVERWHELMING BECAUSE IF YOU HAD TOO MANY OF THEM, DEDICATE TO ONE THING YOU WOULDN’T BE ABLE TO FIGHT IT BUT EVERYTHING YOU GET A VACCINATION FOR WHEN YOU WERE YOUNG OR EVERYTHING ALL THE VIRUSES YOU WERE EXPOSED TO AS YOU HAVE AGED YOU WILL HAVE A POPULATION OF T-CELLS FLOATING AROUND, ONE IN A HUNDRED THOUSAND, ONE IN 20 TO 50,000 THAT CAN SEE EACH PIECE OF THAT VIRUS. WE HOPE TO EXPLOIT IT FOR CANCER. THE FIRST IS THAT SPECIFICITY, THE T-CELL HAS TO SEE ITS TARGET IN CONTEXT OF MHC. IF THAT DOESN’T HAPPEN THE OTHER DOWNSTREAM STUFF DOESN’T MATTER. THE CD4, CD8 HAS TO ENGAGE FIRST. ONCE IT ENGAGES HOWEVER, HERE IS YOUR T-CELL. CD 3 IS MARKER FOR ALL T-CELLS WHETHER CD4 OR CD8. SO WHAT’S THE SIGNAL ONE IS ACTIVATED, ALL THE GRAY LINES START TO HAPPEN. THE R ACTIONS PATHWAY IS ACTIVATED, PI 3 KINASE IS ACTIVATED. PLC GAMMA PATHWAY GETS ACTIVATED. BUT THERE HAS TO BE A SECOND SIGNAL, THINK THE T-CELL COLLISION TOGETHER IT HA Z TO CLICK ON OR CLICK OFF. IF IT COLLISION ON THE BTLA PD 1 OR CT LA 4 THAT T-CELL WILL GET TURNED OFF. IF YOU SEE NEGATIVE REGULATORS OF THAT INTERACTION IN THE RED. IF IT COLLISION ON CD 28 OR I CLASS IT WILL GET ACTIVATED. THAT’S HOW YOU ACTIVATE ALL THESE PATHWAYS RATHER THAN BLOCKING THEM. AND THERE ARE DOWNSTREAM PATHWAYS AS WELL. SO IT’S NOT ONLY SPECIFICITY THAT SIGNAL 1, IT’S THE SIGNAL 2 THAT TURNS THAT CELL EITHER ON OR OFF SO IT DOESN’T MATTER IF IT SEES IT, IT HAS TO BE CLICKED ON OR OFF. TO MAKE THAT CELL WORK. WE CALL THESE THE CO-STIMULATORY MOLECULES. WHICH IS A MISNOMER BECAUSE THEY DON’T ALL STIMULATE, SOME REGULATE. BUT CO-STIMULATORY MOLECULES ARE SECOND SIGNAL ON A T-CELL. THE THIRD SIGNAL ONCE YOU GET ACTIVATION OF SPECIFIC T-CELL SIGNAL, THEN THE PRESENCE OF THE CYTOKINES THAT YOU ARE AROUND WILL TURN THOSE INTO DIFFERENT KINDS OF T-CELLS. HIS IS WHERE I SAID IT GETS MORE COMPLICATED THAN SAYING THEY ARE HELPER CELLS OR CYTOTOXIC CELLS. YOU CAN GET DIFFERENT HELPER CELLS, REGULATORY CELLS, THESE HAVE A DIFFERENT PATH DEPENDING ON CYTOKINES PRESENT. WHEN THE CELL IS CLICKED ON DEPENDING ON THE MILIEU IT’S SITTING IN WILL DETERMINE WHAT SORT OF CELL IT BECOMES. WHAT THE DRUGS DO, SIGNAL TO CHECK POINTS. THE REASON WE HAVE THEM IS SO OUR BODIES CAN PROMOTE SELF-TOLERANCE. SO THE INITIAL RESPONSE TO ANTIGEN WILL OCCUR IN SECONDARY LYMPH NODE ANTIGENS. THE SPLEEN, TONSILS, PATCHES ARE A SPECIALIZED AREA WITHIN THE GUT THAT HAVE LITTLE PATCHES OF INFLAMMATORY T-CELLS. MOW CO-IS A ASSOCIATED LYMPHOID TISSUE IN THE LUNGS. THEY LIMIT COLLATERAL DAMAGE, WHEN YOU GET A SPLINTER FIRST THING THAT HAPPENS IS THAT THE IMMUNE CELLS RUSH TO SO IT OF THAT SPLINTER AREA GETS RED, IF IT GETS INFECTED YOU WILL GET A LITTLE PUS. BUT THEN IN ORDER FOR THAT HOLE WHERE IT WENT IN FOR THAT TO START TO HEAL THE SPLINTER HAS TO COME OUT AND THEN ALL THAT INFLAMMATION THAT’S THERE HAS TO DIE DOWN. ONCE IT GETS RID OF WHATEVER BACTERIA MAY HAVE COME IN ON THE SPLINTER IT HAS TO GO AWAY IN ORDER TO LET THAT WOUND HEAL. ANY THAT HAVE SEEN SOMEONE WITH A CHRONIC WOUND KNOWS IT STAYS RED, IT STAYS INFLAMED BECAUSE IT CAN’T LIMIT THAT COLLATERAL DAMAGE. SO FOR CANCER IMMUNOTHERAPY TO WORK WE HAVE TO CREATE OPPORTUNITIES TO BREAK THE TOLERANCE. SO A LOT OF PROBLEM WITH CANCER IS THAT IN THE — THERE ARE LOTS OF PROBLEMS BUT ONE IS IT LOOKS LIKE YOU UP UNTIL A CERTAIN POINT, MADE OF YOUR OWN DNA T SAME CELLS IN YOUR BODY, IT DOESN’T LOOK FOREIGN, DOESN’T LOOK LIKE A VIRUS OR BACTERIA SO YOUR BODY WON’T ATTACK IT. SO WE HAVE TO FIGURE A WAY TO BREAK THAT TOLERANCE. CTLA 4 STAND FOR CYTOTOXIC T LYMPHOCYTE ANTIGEN FOUR. ON THE SURFACE OF T-CELLS. WHEN THIS T-CELL THAT IS NAIVE OR RESTING GETS THE FIRST SIGNAL SO, THE TCR HAS SEEN ITS PEPTIDE IN THE CONTEXT OF MHC, AND ACTIVATED BECAUSE THE CO-STIMULATORY MOLECULE IS CLICKED ON, THAT T-CELL STARTS TO PUT CTLA 4 ON THE SURFACE OF THE CELL. WHAT THAT DOES, THIS ODDLY SHAPED PIECE OVER HERE, IT WAS SORT OF THE SHAPED LIKE THIS. IT COMPETES FOR THAT SAME LIGAND. SO IT WILL BIND TO THE SAME LIGAND THAT TURNED IT ON AND TURN IT OFF, IT OUTCOMPETES AND BINDS MORE STRONGLY HERE THAN HERE. CTLA 4 IS TRAP TO THE SURFACE IN CORRELATION TO STRENGTH OF THE CD 28 STIMULATION AND IT COMPETES WITH HIGHER AFFINITY FOR THE CD8 6 WHICH IS A LIGAND FOR CD 28 AND HAS A DAMPENING EFFECT ON THE DOWNSTREAM PROCESSING. CTLA 4 IS CONSTITUTIVELY PRESENT ON SPECIAL CLASS OF CELLS CALLED T REGULATORY CELLS. T REGULATORY CELLS EXIST TO FIND T-CELLS AND TURN THEM OFF. THIS WAS DESCRIBED BY JIM ALLISON WHO WON THE NOBEL LAST YEAR. HIS CO-RECIPIENT WHOSE NAME I ALWAYS MESS UP, A JAPANESE SCIENTIST. PARDON ME. HE WAS DISCOVERING ARE AT THE SAME TIME PD 1 PROGRAM DEPTH RECEPTOR ONE WHICH WORKS IN A SIMILAR FASHION. THAT WHEN YOU GET A T-CELL HERE THAT’S BEEN TURNED ON IT HIT ITS CO-STIMULATORY RECEPTOR, IT GOES OUT TO TISSUE WHERE THE INFLAMMATION IS HAPPENING. THAT INFLAMMATION ON THAT TISSUE, WHERE THAT SPLITTER GOES IN, THAT TISSUE IS GOING TO START UPREGULATING PDL 1 OR 2, THE LIGAND FOR PD 1. BECAUSE THAT TISSUE STARTS TO EXPRESS IT, IT’S PUTTING OUT YOU HAVE DONE YOUR JOB, GO AWAY NOW SIGNAL TO THE T-CELL AND STARTS TO TURN THAT T-CELL OFF. SO PRIMED T-CELL IS HEADING TO THE PERIPHERAL TISSUE TO ENGAGE A TARGET AND ONCE ACTIVATED, IT BEGINS TO EXPRESS PD 1. THE INFLAMMATION PRESENT IN THE TISSUE PROMOTES UPREGULATION OF THE LIGANDS OF PD 1 AND THIS LIMITS COLLATERAL DAMAGE DURING CELL MEDIATED DESTRUCTION. SO IT’S WHY YOUR HAND DOESN’T START TO DESTROY ITSELF WHEN GETTING RID OF THE SPLINTER. THOSE CELLS GET THERE, DO THEIR JOB, THEN TURN OFF AGAIN. WHAT IS THE ROLE OF CD 1 CDL 1 IN CANCER? WHAT WORKS IN TWO DIFFERENT WAYS. THE FIRST WAY IS THAT THERE ARE SOME CANCER CELLS THAT THE WAY THEY BECOME KAREN CELLS IS THEY — CANCER CELLS IS THEY TURN ON THE PROCESSING THAT UPREGULATE PDL 1. SO THERE’S SOMETHING ABOUT WHAT MAKES THEM CANCER THAT ALSO MAKES THEM EXPRESS PDL 1 ON THE SURFACE. THIS IS TRUE OF HODGKIN’S LYMPHOMA, WILL OVEREXPRESS PDL 1. VARIOUS CANCERS TO CERTAIN DEGREE WILL EXPRESS PDL 1 ANYWHERE FROM ONE TO 40% ON THEIR SURFACE. SO WHEN THAT HAPPENS, GOING IN THE T-CELL — EVEN IF T-CELL SEE IT IS CANCER IT WILL GET SHUT OFF RIGHT AWAY. THEN THERE’S THE ADAPTIVE IMMUNE RESISTANCE WHERE A TUMOR CELLS IS SEEN BY T-CELL, BECAUSE IT STARTS TO INFLAME THE AREA AROUND IT, THAT INTERFERON GAMMA RELEASED BY THAT T-CELL TO DO THAT UPREGULATE THE STAT JACKS PATHWAY WHICH UPREGULATE PDL 1 WHICH STARTS TO TURN IT OFF, SO OUR BODY LIKE EVERY OTHER SYSTEM YOU YOU TALKING ABOUT SENSING OXYGEN, CARBON DIOXIDE IS THIS REGULATORY FEEDBACK LOOP. AND THIS IS JUST ONE FOR THE IMMUNE SYSTEM. SO CANCER CELLS INCREASE PDL 1 ON SURFACE AND SUCCESSFUL T-CELL TUMOR DESTRUCTION INCREASE PDL 1 IN RESPONSE TO INTERFERON GAMMA. SO WHEN WE STARTED THINKING ABOUT CAN WE BLOCK THESE AND SEE IF WE CAN GET A CANCER TUMOR RESPONSE, WHERE WOULD YOU START? WHERE WE STARTED I USE THE ROYAL WE, I WAS STILL IN RESIDENCY WERE TUMORS KNOWN TO RESPOND TO OTHER IMMUNOTHERAPY. SO MELANOMA THERE IS ESTIMATED 9,000 DEATHS PER YEAR IN THE UNITED STATES. WHEN SOMEONE DEVELOPS METASTATIC DISEASE, WHEN THAT MELANOMA SPREADS TO OTHER DISEASE SITES, THE LONGER THE LIVER, PATIENTS ONLY HAVE ABOUT A 20% FIVE YEAR SURVIVAL. HOWEVER, ENTERLIEU KICK 2, ONE OF THOSE NON-SPECIFIC STIMULATORS THAT TURN ON ALL THE T-CELLS IN THE BODY COULD CURE PEOPLE. SO THESE ARE PEOPLE WHO GOT THIS DRUG, WITH METASTATIC DISEASE EXPECT TO DIE SHORTLY, THEY ARE NOW ALIVE 10, 15, 20 YEARS LATER WITH NO EVIDENCE OF DISEASE. THAT RESPONSE RATE IS LOW. IT’S 4%. BUT IT’S A NUMBER. IT’S NOT ZERO. SO THAT WAS ONE OF THE FIRST PLACES THAT WE STARTED TO LOOK THE OTHER IS KIDNEY OR RENAL CELL CANCER, 15,000 DEATHS PER YEAR, ABYSMAL SURVIVAL RATE FOR PATIENTS WITH METASTATIC DISEASE AND INTERLEUKIN HAS SHOWN IT COULD CURE SYSTEM OF THESE PATIENTS. WE DON’T USE THE WORD CURE OFTEN. WE NEVER USE IT WITH CHEMOTHERAPY. IT’S ONLY BECAUSE WE HAD THE OPPORTUNITY TO WATCH THESE PEOPLE 15 TO 20 YEARS AND THEIR DISEASE IS NOT COME BACK THAT WE FEEL COMFORTABLE USING THAT WORD HERE. WE ACTUALLY STARTED THE FIRST TRIAL OF ANTI-CTLA 4 IPILIMUMAB IN CONJUNCTION WITH DR. ALLISON WHO HAD DONE THE WORK IN MICE. WE STARTED A PHASE 1 TRIAL USING A MONOCLONAL ANTIBODY, AND ENROLLED 14 PATIENTS. IT WAS A SMALL TRIAL, PHASE 1 TO DETERMINE SAFETY. BUT IN THAT SMALL TRIAL, WE HAD TWO COMPLETE RESPONDERS AND ONE PARTIAL RESPONSE. BUT THE WAY DRUGS NORMALLY WORK WHEN TESTING IN PHASE 1 IS YOU START LOW DOSE, AND IF YOU DON’T GET ANY SIDE EFFECT YOU TWO TO HIGHER DOSE. IF NONE OF THAT YOU GO TO NEXT HIGHER DOSE. BUT WHAT WE FOUND WAS THAT WE STARTED TO GET THESE TOXICITIES. DERMATITIS AND INFLAMMATION OF THE SKIN AND INFLAMMATION OF THE LIVER AND RARELY THIS INFLAMMATION OF PITUITARY GLAND CALLED HIGH POTSITIS. WHAT WE ARE SEEING IS TUMOR COULD GO AWAY, A NODULE IN THE LUNG OF PATIENT. THAT’S PRE-TREATMENT, SEE THE SOLID MASS. YOU CAN SEE HERE THAT MASS IS GONE. AT THE SAME TIME WHAT YOU CAN SEE HERE THIS IS THE SKIN AND YOU HAVE INFLUX OF CD8, THERE’S INFLUX OF CD8 CELLS THAT CAUSE A RASH OF THIS PATIENT, COLON, BIOPSIES OF THE COLON AND INFLUX OF CD8 CELLS COLITIS WHICH CAUSE SEVERE DIARRHEA. AND HERE IN THE LIVER SURROUNDED — COLON AGAIN, AND THIS IS LIVER SO WE ARE SEEING BAD SIDE EFFECTS AT THE SAME TIME WE ARE SEEING RESPONSES. SO THE FIRST THING WE DID BECAUSE WE WERE SEEING RESPONSES, BUT BECAUSE WE WERE SEEING TOXICITY, WE REDUCED THE DOSE. SO WE SAID WELL, THREE SEEMED TO BE TOO MUCH, WE ARE SEEING TOO MANY SIDE EFFECTS LET’S GO DOWN TO ONE SO WE DID THAT. BUT WHAT WE WERE FINDING IS PEOPLE WHO WERE GETTING RESPONSES FOR THE SAME ONE WERE GETTING THE SIDE EFFECTS SO THAT WAS DIFFERENT WITH CHEMOTHERAPY. CHEMOTHERAPY PEOPLE WOULD RANDOMLY GET SIDE EFFECTS AND IT HAD ABSOLUTELY NO CORRELATION WHETHER OR NOT THEY WERE GOING TO RESPOND TO THE CHEMOTHERAPY. AND TESTIFY SIGNATURES CAN’T. LOOK AT PEOPLE WHO HAD A GRADE TOXICITY THAT HE RECOLLECTS GRADED 1 TO 5, 5 BEING SO BAD THE PATIENT DIED AND ONE BEING MILD. SO THREE SORT OF IN THE MIDDLE. ANYBODY HA HAD A HIGHER THAN GRADE 3 ADVERSE EVENT HAD A 36% CHANCE OF RESPONDING. IN MELANOMA, IN KIDNEY CANCER IT WAS GREATER. NO PATIENT THAT DID NOT — USING A LOT OF DOUBLE NEGATIVES. IF YOU DID NOT HAVE SEVERE SIDE EFFECT YOU DID NOT GET A RESPONSE. SO IT WAS FELT INSTEAD OF LOWERING OUR DOSE, WE ARE GOING TO PUSH THE ENVELOPE AND INCREASE THE DOSE. WE KNEW WE WOULD GET MORE TOXICITY BUT THOUGHT WE WOULD GET MORE RESPONSE. SO WE DID A FORMAL PHASE 2 INTERPATIENT. A DOSE OF THREE, THEY TOLERATED OKAY WE GIVE THEM A DOSE OF FIVE NEXT TIME AND AGAIN THIEF THEM A DOSE OF NINE NEXT TIME. ALL WITHIN THE SAME PATIENT. WHAT WE FOUND WAS THAT THE CORRELATION HELD TRUE YOU HAD A GRADE 3, 4, IMMUNE RELATED ADVERSE EVENT, 14 OUT OF 50 PATIENTS RESPONDED FOR RESPONSE RATE OF 28%. EVEN IF YOU HAD A LOW GRADE IMMUNE RELATED ADVERSE EVENT 8 OF 36 RESPOND WIDE IS STILL 22%. BUT IF YOU HAD NO IMMUNE RELOAD VERSE EVENT, IT WAS UNLIKELY YOU WERE GOING TO RESPOND ONE OF OF 53 PATIENTS. THE MOST COMMON WAS INTERCOLITIS, IN THE BOWEL. WE COULD GIVE STEROIDS AND TOXICITIES WOULD GO AWAY BUT RESPONSE WOULD HOLD. SO WE FIGURED HOW TO MANAGE THE IMMUNE RELATED ADVERSE EVENTS AND GOING OUT HERE, CLOSE TO NINE YEARS THIS IS SOMETHING WE TAKE FOR GRANTED NOW IN 2019 BUT PRIOR TO 2011 YOU NEVER SAW A DRUGNA HAD THIS SHAPE, THE TAIL OF THE CURVE. LOOK AT CHEMOTHERAPY, EVEN THE BEST CHEMOTHERAPIES IF THEY PROLONG LIFE A LITTLE BIT THEY ALL DROP TO ZERO. EVERYONE DIES. BECAUSE CHEMOTHERAPY IS NOT CAPABLE OF TACKLING METASTATIC DISEASE SO WHILE WE ARE COMFORTABLE WITH GRAPHS THAT LINGER OUT TO THE SIDE HERE THAT HAVE A TAIL ON THE CURVE, 10, 20%, THE PATIENTS ARE ALIVE 9 YEARS AFTER TREATMENT SO THIS WAS USHERED IN THE NEW ERA OF IMMUNE THERAPY. IN MELANOMA THEY DEVELOPED TWO MEANS. FIRST, REMEMBER WE TALKED CD 28 AS POSITIVE STIMULATOR, CTLA 4 NEGATIVE REGULATOR AND PD 1 IS A NEGATIVE REGULATOR. MONOCLONAL ANTIBODIES THAT BLOCK PD 1 AND ANTI-CTLA 4. THOSE ARE THE NAMES I DISCUSSED WITH YOU A LITTLE BIT EARLIER. IF IN YOUR READING OF THE LITERATURE YOU SEE MAB AT THE END, THAT STANDS FOR MONOCLONAL ANTIBODY, THE MU MEANS IT’S URINIZED. THE LIZ MEANS MAUREENIZED AND THE COMPANIES PICK THE FIRST PART. DR. ALLISON WHO STARTED HIS CAREER AT SAN FRANCISCO SAID THAT HE REALLY, REALLY WANTED TO CALL THIS HIPPYLUMIMAB BUT THEY WOULDN’T LET HIM DO IT. AS ALL THINGS GO WHEN YOU START TO GET GOOD RESPONSES PEOPLE WANT TO MAKE SURE WELL, THAT’S THE NCI, THEY TREAT PEOPLE THAT COME, WE WANT TO MAKE SURE THIS IS APPLICABLE TO BIGGER GROUP OF PEOPLE SO THEY DID A HUGE NATIONWIDE STUDY PHASE 3 SO THEY RAP DOCUMENTIZED TO GET OR NOT GET IPILIMUMAB AND WHAT THEY FOUND WAS YOU GIVE OBJECTIVE RESPONSE RATE IN 7% INCLUDING SOME COMPLETE RESPONDERS, AND THIS DRUG IPILIMUMAB, NOW URUGUAY FOR METASTATIC MELANOMA IN MARCH OF 2011. THAT SURVIVAL DATA WAS UPDATED THREE YEAR OVERALL SURVIVAL, 20, 26%, TAIL OF THE CURVE WHICH WE TALKED ABOUT BEFORE. SO THE OTHER DRUG NOVULUMAB BLOCKED PD 1, THE PLOT WE ARE LOOKING HERE NOW IS A SPIDER PLOT. IT TAKES THE SUM OF THE MEASUREMENTS YOU WILL SEE FREQUENTLY IF YOU LOOK AT CLINICAL TRIALS. THE SUM OF ALL THE MEASURABLE LESIONS A PATIENT HAD AS THE BEGINNING AND TRACKS THEM OVER TIME SO STARTING POINT IS ZERO. THIS PATIENT PROGRESSED FIRST HAVE IT SIT, TUMORS GOT BIGGER SO SLOPE IS UPWARDS. PATIENTS WITH SLOPE GOES DOWNWARD, ANYTHING BELOW 30% THIS DASH LINE HERE IS CONSIDERED RESPONSE. SO YOU CAN SEE THEY DIDN’T KNOW IN WHAT CANCER THIS MIGHT WORK SO THEY TESTED IT IN A NUMBER OF MELANOMA LUNG CANCER KIDNEY CANCER PROSTATE CANCER AND COLOW RECTAL CANCER. MELANOMA HAT 20%, LUNG CANCER 18, RENAL 27, BUT PROSTATE AND COLORECTAL NO RESPONSE AT ALL. THEY ONLY HAD GRADE 3 TO 4 TOXICITY IN 6% SO THE TOXICITY RATE WAS BETTER THAN IPILIMUMAB AND THE RESPONSE RATE WAS ABOUT THE SAME. SO THEY DID A BIGGER TRIAL. THIS TIME THEY TOOK BECAUSE IPILIMUMAB WAS APPROVED PATIENTS HAD TO HAVE ALREADY GOTTEN IPILIMUMAB TO BE ON THIS TRIAL SO YOU ARE TALKING PATIENTS NOT ONLY WITH METASTATIC DISEASE BUT PATIENT WHOSE HAVE ALREADY TRIED IPILIMUMAB AND FAILED TO CONTROL THEIR DISEASE SO THEY ARE NOW PROBABLY OF THOSE 12 MONTHS WE THINK A PATIENT WITH METASTATIC DISEASE HAS, THEY HAVE SPENT 6 TRYING TO GET IPILIMUMAB. THIS PLOT IS CALLED A WATER FALL PLOT SO INSTEAD OF SHOWING THE WAY THIS ONE DOES SHOWING THINGS OVER TIME, IF YOU TAKE THE MAXIMUM DEFLECTION POINT ANY ONE OF THESE FOR EACH PATIENT YOU WOULD GET A WATER FALL PLOT SO FOR PATIENTS WHOSE DISEASE GOES AWAY THEY SIT HERE AT MINUS 100, AGAIN THIS DASH LINE IS SHOWING YOU THE 30% DECREASE, WHAT WE CONSIDER A RESPONSE. AND THEN ANYTHING THAT GOES UP IS THE PATIENT — MEANS THE PATIENTS PROGRESSED IN NEVOLUMAB VERSUS CHEMOTHERAPY OF CHOICE, RESPONSE RATE OF 32% WITH FOUR COMPLETE RESPONSES. ON THE BEST OF THIS IT WAS APPROVED FOR MELANOMA, REFRACTORY MELANOMA IN DECEMBER 2014. ANY VOL HAS BEEN WHY DO WE NEED TO MAKE PATIENTS GO THROUGH IPILIMUMAB IF EAT ET NOT BETTER. WHAT WAS HAPPENING IN THE BACKGROUND IS PEOPLE UNCOVERED BRAF MUTATIONS AND A DRUG THAT COULD TARGET BRAF MUTATION SO ANY PATIENT THAT HAD BRAF MUTATION NEEDED THAT OTHER DRUG SO THEY WERE NOT PART OF THIS TRIAL. SO THEY TESTED NIVOLUMAMB, THE MONOCLONAL ANTIBODY WE ARE TALKING ABOUT, DECARBAZINE DOES VERY LITTLE IN PATIENTS WITH MELANOMA, IT MAKES THEM GET SMALLER BUT FOR A SHORT PERIOD OF TIME. WHAT YOU CAN SEE IN THE SURVIVAL CURVE. SO NIVOLUMAB IS THE YELLOW LINE THAT FLATTENS OUT AND EVERIER CHEMOTHERAPY STUDIED IS ON ITS WAY DOWN TO ZERO. AND AGAIN, THIS IS ONLY 15 OAR 18 MONTHS, IF YOU WERE TO EXTEND OUT TO 36 MONTHS THIS HITS ZERO AT 16 MONTHS AND THIS IS STILL GOING AT 30%. SO OBJECTIVE RESPONSES. WITH SOME CRs. YOU CAN SEE THIS TAIL OF THE CURVE HERE. SO FIVE YEAR OVERALL SURVIVAL OF 34%. (INDISCERNIBLE) ALSO TARGETING PD 1 BUT BY A DIFFERENT COMPANY. ONE IS BASED ON IGG 2, SORRY ON IGG 1 AND OTHER IS ON IGG 4. BACKBONE. BUT AGAIN, THIS WAS FOR PATIENTS WHO REFRACTORIED IPILIMUMAB. THESE TWO COMPANIES WERE IN A BATTLE WHO WAS GOING TO GET FDA APPROVAL FIRST. FOR EACH DIFFERENT INDICATION. NIVOLUMAB ONE FOR ONE,, I’M SURE YOU SEE THEM ON TV, THEY BOTH SPEND ABOUT THE SAME AMOUNT ON THEIR AD BUYS. SO THEY DID A PHASE 1 DOSE COMPARISON, YOU CAN SEE TWO MILLIGRAMS, 10 MILLIGRAMS, DIFFERENCES IN THE DOSES. AGAIN YOU SEE THIS FLATTENING OF THE CURVE, THIS TAIL OF THE CURVE. WE GOT EXCITED ABOUT AND THEY GOT FDA APPROVAL IN SEPTEMBER 2014. AGAIN, THIS IS NOW RANDOMIZING VERSUS CHEMO. YOU CAN SEE THE TAIL OF THE CURVE COMING OUT. WE WANTED TO SEE FOR FIRST LINE THERAPY. SO AGAIN, IPILIMUMAB HAS BEEN COMPLETELY APPROVED, TIMBER LIZ HAS BEEN HAD NOT BEEN. THEY FOUND PIMBOLIZMAW 20% RESPONSE RATE, IPILIMUMAB 12%. ALL WITH IMPRESSIVE SURVIVAL CURVES BUCK SEE IPILIMUMAB LAGS BELOW THE OTHERS. IPILIMUMAB HAD HIGHER INCIDENCE OF SIDE EFFECTS. SO THESE ARE THE UPDATED SURVIVALS PUBLISHED IN 2016. YOU CAN SEE WE ARE OUT TWO YEARS, 60% SURVIVAL. SO AGAIN TO REMIND YOU MEDIAN SURVIVAL FOR PATIENTS WITH METASTATIC MELANOMA WAS 12 MONTHS, TEN YEARS AGO. THIS IS A CARTOON OF DIFFERENT CHECK POINTS THAT HAPPEN. AND THESE ARE THE TWO APPROVED ANTIBODIES. THEY DON’T OVERLAP SO THE QUESTION CAME UP CAN WE COMBINE THESE TWO TO GET A BETTER RESPONSE. SO THESE ARE PATIENTS THAT WERE PREVIOUSLY UNTREATED. IT WAS A PHASE 3 RANDOMIZE CONTROL ONE VERSUS THE OTHER VERSUS THE COMBINATION. 945 PATIENTS. WHICH IS A BIG TRIAL. CONSIDERING CAPTURING ALL PATIENTS WITH MELANOMA IN THE COUNTRY. NUMBER OF PATIENTS THAT GOT A RESPONSE 44% WITH NIVOLUMAB, 19% WITH IPILIMUMAB, CLOSE TO 60% WITH COMBINATION. THAT SOUNDS GREAT BUT THEN THE GRADE 4 ADVERSE EVENTS, 16% WITH NIVOLUMAB, 27% IPILIMUMAB BUT COMBO, HALF THE PATIENTS HAD SEVERE AUTOIMMUNE EFFECT. SO THESE ARE UPDATED RESULTS PRESENTED AT ASCO A FEW YEARS BACK BUT NOT PUBLISH TO THE BEST OF MY KNOWLEDGE BUT SHOWS MINIMUM FOLLOW-UP 18 MONTHS THE ORANGE IS COMBINATION THERAPY, THE BLUE IS THE SINGLE THERAPY WITH NIVOLUMAB AND GREEN IS IPILIMUMAB. AND FDA APPROVED COMBINATION IN JANUARY OF 2016. SO WE GOT THINKING WHY IS THIS WORKING IN MELANOMA? THIS CHART IS ONE IF YOU GET INTERESTED IN GENETICS OF CANCER YOU WILL SEW FREQUENTLY, IT MEASURES THE NUMBER OF MUTATIONS PRESENT IN CANCER BASED ON A PERCENTAGE OF THE TOTAL AMOUNT OF GENE EXOME IN THAT PATIENT. SO YOU CAN SEE IT HAS MEDIANS AT THE GRAY BARS BUT SHOWS YOU THE WIDE RANGE. MELANOMA HAS HIGHEST MEDIAN TUMOR MUTATION BURDEN. OF ALL THE CANCER. LUNG CANCER IS NEXT. BLADDER, SO FORTH. AND THE THOUGHT WAS IF YOUR BODY ONLY SEES THINGS THAT ARE DIFFERENT THEN EVENTUALLY THIS CANCER HAS CREATED ENOUGH DIFFERENCES THAT IT LOOKS DIFFERENT ENOUGH THAT THE IMMUNE SYSTEM IS GOING AFTER IT. LIELY HUE AT A TIMED TUMORS. WHAT THE OTHERS? NON-SMALL CELL LUNG CANCER IS HUGHLEY MUTATED, BLADDER CANCER, THE KIDNEY FILTERS EVERYTHING THE LIVER DOESN’T SO EVERY TOXIN AND POISON IS IN OUR BODY SITS IN OUR BLADDER FOR A WHILE SO IT MUTATES THINGS. THERE’S A SPECIFIC TUMOR CALLED MISMATCH REPAIR DEFICIENCY SO OVER THE COURSE OF BEENING A TUMOR IT LOST THE ABILITY TO FIX THE DNA EVERY TIME THAT IT REPLICATES. SO IF PATIENT HAS BASELINE THEY WILL DEVELOP A MULTI-CANCER SYNDROME, OR THE TUMOR ITSELF CAN DEVELOP A SOMATIC MUTATION. AND ONE OF THESE FOUR PROTEINS, THEY ARE STARTING TO IDENTIFY FEW MORE BUT THESE ARE THE FOUR MAIN ONES SO EVERY TIME THAT TUMOR REPLICATES, ITS DNA BREAKS APART AND IT’S SUPPOSED TO GET ZIPPED BACK WITH PERFECT COPY. WHEN THOSE PERFECT COPIES DON’T HAPPEN, THESE PROTEINS HELP PUT IT BACK TOGETHER. SO TUMOR MISSES THESE, THE IRREGULAR PLACES NEVER GET FIXED, THAT’S HOW YOU END UP WITH HIGHLY MUTATED TUMORS. NIVOLUMAB WAS TESTED IN NON-SMALL CELL LUNG CANCER WITH RESPONSE RATE OF 14 1/2%. AND IT WAS APPROVED FOR REFRACTORY SQUAMOUS NON-CELL NON-SMALL CELL LUNG CANCER BASED ON THESE DATA. NIVOLUMAB AS WELL, THESE TWO COMPANIES GOING BACK AND FORTH FOR THE SAME DRUGS. PIMBOLIZMAB AS WELL SO ALL THE DATA ARE IN YOUR HAND OUTS. WE DON’T NEED TO GO THROUGH IT ONE BY ONE. BUT THE OVERALL THOUGHT PROCESS IS THE SAME. GET A RESPONSE RATE OF 20%, IT TENDS TO BE DURABLE. THERE ARE SOME SIDE EFFECTS THAT CAN BE AMELIORATED BY STEROIDS. YOU GET THE PATIENT THROUGH THEY HAVE A LONG TERM GOOD LONG TERM OUTCOME. ANTI-PDL 1 IS BLOCKING THE OTHER SIDE OF THE PATHWAY AND IT WAS THIS DRUG CALLED OTIZALIZMAB IN BLADDER CANCER WHICH IS HIGHLY MUTATED. IN PATIENTS WITH UPREGULATION OF PDL 1 ON TUMORS HAD 40% RESPONSE RATE. AND IT WAS APPROVED FOR CANCER ON THE BEST OF THAT. THOUGH THIS IS SHORT, AT ONE YEAR YOU STILL GOT A 40% SURVIVAL RATE WHICH IS UNHEARD OF FOR PATIENTS WITH METASTATIC YOURTHELIAL CANCER. JUST ANOTHER EXAMPLE OF HOW IT’S WORKING. THEY ALL LOOK THE SAME, THE TAIL OF THE CURVE IS SHOWING UP EVERYWHERE. THIS GOT INTERESTING BECAUSE EVER DRUG YOU HEARD OF GETS APPROVED FOR ONE CANCER OR ANOTHER. SO PEMOTREXIB FOR MESOTHELIOMA OR COLON CANCER OR INTERLEUKIN TWO FOR MELANOMA, IT IS ASSOCIATED WITH A SPECIFIC CANCER. BUT WHAT WE FOUND WAS IN MISMATCH REPAIR DEFICIENT CANCER IT DIDN’T MATTER THE CANCER AS LONG AS THERE WAS DEFICIENCY OF PROTEINS. THEY DID THREE PARALLEL COHORTS, COLON CANCER THAT HAD THE ABILITY TO FIX ALL ITS MISMATCH REPARIS. SEW PROFICIENT. THEN COLON CANCER THAT LOST THE ABILITY TO FIX MISMATCH REPAIR, IT LOOKED AT OTHER TUMORS THAT LOST THEIR ABILITY TO FIX THEIR MISMATCHES. IT IS STRIKING THAT THERE’S ONLY ONE OUTLIER. ALMOST EVERY PATIENT THAT HAD A MISMATCH REPAIR DEFICIENT CANCER WHETHER COLORECTAL OR NON-COLORECTAL THESE ARE BLUE AND BLACK. ALMOST ALL PATIENTS SAW DECREASE IN TUMORS. WHEREAS THE CONVERSE WAS ALSO TRUE IF YOU HAD MISMATCH REPAIR PROFICIENT YOU PROGRESSED. THE DRUG DID VERY LITTLE FOR YOU. IT IS RARE THE SEE SOMETHING THAT CLEAN. WHEN THEY LOOK AT PATHOLOGY, YOU ARE LOOKING AT A MIX OF TUMOR AND NORMAL ADJACENT TO THE TUMOR. YOU CAN SEE PDL 1 IS HIGH ON ALL TUMOR CELLS. THERE’S A LITTLE BIT IN THE NORMAL TISSUE BUT YOU CAN SEE WHERE THE CD8 T-CELLS STARTED TO COME IN TO THE TISSUE. RIGHT AT THE INTERFACE. WHEREAS WHEN YOU HAVE GOT A CANCER THAT HAS MISMATCH REPAIR ABILITIES, IT DOESN’T HAVE MUTATIONS, VERY LITTLE PDL 1 IS UPREGULATED FEW CD8 CELLS RECRUIT TO TUMOR AND YOU CAN SEE HERE EACH BROWN DOT IS CD8 T-CELL, THERE AREN’T THAT MANY. SO THE IMMUNE SYSTEM ISN’T SEEN THAT CANCER THE SAY WAY. SO FOR THE FIRST TIME EVER IN MAY OF 2017, THE FDA APPROVED A DRUG NOT FOR SPECIFIC TUMOR TYPE. YOU CAN HAVE ANY TUMOR YOU CAN THINK OF, IF IT’S MISSING THESE PROTEINS, IT’S APPROVED TO GET THIS DRUG. IT’S THE FIRST TIME THAT HAPPENED. BACK AND FORTH BETWEEN THESE TWO DRUGS, NIVOLUMAB FOLLOWED SHORTLY AFTER, MACRO SATELLITE INSTABILITY IS ANOTHER MARKER OF HAVING A HIGH TUMOR MUTATION BURDEN. IT IS SOMETIMES CONSIDERED SYNONYMOUS WITH MISMATCH REPAIR, IT IS NOT. BUT THEY ARE CLOSELY LINKED. SO FDA APPROVAL IS GIVEN FOR THOSE AS WELL. YOU CAN SEE THIS WAS JULY AND THIS WAS MAY NECK AND NECK ON EVERY INDICATION BACK AND FORTH FOR. HIGHLY MUTATED TUMORS WORKS. MELANOMA, MISMATCH PRO DEFICIENCY. WHAT ABOUT OTHER TUMORS? KIDNEY CANCER, HODGKINS LYMPHOMARKS HEAD AND NECK SQUAMOUS CELL AND MERKLE CELL? THE KIDNEY CANCER AGAIN, YOU ARE GETTING THIS TAIL OF THE CURVE. BECAUSE OF THIS TAIL OF THE CURVE GOT APPROVED. IN NOVEMBER OF 2015. THESE ARE PATIENTS WITH HODGKINS LYMPHOMA SO CLASSIC LYMPHOMA, LOOK HOW MANY LINES DROP BELOW ZERO AND HOW MANY DROP BELOW 50%. SO SEVEN WENT INTO COMPLETE REMISSION OF REFRACTORY HODGKINS LYMPHOMA, THESE ARE PATIENTS THAT HAVE HAD STEM CELL TRANSPLANT AND HAD LYMPHOMA COME BACK. THE PATIENTS THAT WERE GIVEN RITUXIMAB AND HAD IT COME BACK. SO THESE ARE PATIENTS THAT TRADITIONALLY THERE’S NO FURTHER THERAPY FOR AND SEVEN IN COMPLETE REMISSION. AGAIN, PEMBRHLIZMAB KNOWED WITH WATER FALL PLOT THAT LOOKS SIMILAR. IN HEAD AND NECK CANCER AGAIN GETTING SIMILAR RESULTS, ALSO RECEIVED FDA APPROVAL. MIRACLE CELL CARCINOMA IS INTERESTING IS THAT IT’S CAUSE BY A VIRUS SO THE VIRUS GOES INTO A MURKLE CELL AND CREATES AN ABERRATION. SO BECAUSE VIRUS IS THERE T-CELLS GO THERE. THE T-CELLS ARE THERE BUT DON’T HAVE THE ABILITY TO WORK BECAUSE THEY GET TURNED OFF BY THE CHECK POINT BLOCKADE SO BY GIVING THESE DRUGS, YOU ALLOW T-CELLS TO GET TO WORK, 32 PATIENT OF THE PATIENTS IN THIS TRIAL RESPONDED AND EIGHT ARE IN COMPLETE REMISSION AND IT ALSO GOT APPROVAL. WHEN WE BLOCK THE PD 1 PDL 1 PATHWAY THERE’S A NUMBER OF RESPONSE RATES ALL THESE HAVE BEEN APPROVED BY THE FDA. SO WHAT ABOUT OTHER CANCER? BREAST CANCER, HERE ARE A FEW TRIALS PRESENTED OVER THE COURSE OF THE LAST FEW YEARS. WHILE IT’S NOT AS ROBUST AS SOME OF THE OTHER STUDIES IF YOU WERE TO LOOK AT PATIENTS THAT HAD HIGH LEVELS OF PDL 1 EXPRESSION WITH METASTATIC TRIPLE NEGATIVE BREAST CANCER YOU GET 44% RESPONSE RATE. THAT’S ONLY FOUR OUT OF NINE SO VERY SMALL NUMBER. BUT STILL, THE FACT THEY ARE NOT ZERO MEANS THERE’S SOME ROLE FOR THE IMMUNE SYSTEM IN THAT TRIAL. THE COMBINATION OF PD 1 ANTIBODY AND CHEMOTHERAPY WAS APPROVED IN METASTATIC BREAST CANCER ON THE BASIS OF THIS PAPER SHOWING THAT WHEN YOU LACK AT 379 PAGES WITH PDL 1 POSITIVE TUMORS, CHEMO PLUS ITILIZAMAB 63% WITH CHEMO AND PLACEBO 42% AND CHEMO SURVIVAL WAS 17% HIGHER WITH ADDITION OF THE MONOCLONAL ANTI-BODY. SO THAT WAS APPROVED THIS YEAR IN MARCH. THE FIRST APPROVAL OF THE CHECK POINT BLOCKADE FOR METASTATIC BREAST CANCER. WHEN I FIRST STARTED GIVING THE LECTURE THERE WERE THREE INDICATED APPROVAL BY FDA. THIS WAS THE FIRST YEAR I GAVE THIS LECTURE. YOU CAN SEE NOW AS THE YEARS HAVE GONE ON, THE NUMBER OF DIFFERENT CANCERS THAT RECEIVED APPROVAL FOR VARIOUS IMMUNE CHECK POINT BLOCKADES HAVE COME UP. THAT INCLUDES PEMBROLIZMAB. NIRVOLUMAB. ABELUMAB IS PDL 1 AND CYCLEMAB IS PDL 1, ESOPHAGEAL, BREAST, CUTANEOUS, SMALL CELL LUNG CANCER, PRIMARY MEDIASTINAL B CELL LYMPHOMA, CERVICAL, LIVER CANCER, STOMACH CANCER, ALL GETTING APPROVALS ACROSS THE WHAT’S INTERESTING FROM A TRIALIST STANDPOINT IS IF YOU WERE TO GO TO CLINICALTRIALS.GOV RIGHT NOW, TWO WEEKS AGO, THERE WERE 2,250 TRIALS TARGETING IT, AND THE BUBBLE PLOT HERE IS SHOWING YOU WHAT THEY ARE IN COMBINATION WITH. SO 339 OF 1700 ARE ANTI-PD 1 PDL 1 IN COMBINATION WITH CTLA 4, 283 TRIALS ARE IN COMBO WITH CHEMOTHERAPY, 114 IN COMBINATION WITH RADIOTHERAPY, 58 WITH COMBO AND RADIOTHERAPY AND SOME OF THESE ARE OTHER CHECK POINTS. SO THERE IS A WHOLE LIST OF COMBINATIONS THAT ARE COMING ALONG. SO THESE ARE THE CHECK POINTS. SO YOU HAVE A MACROPHAGE THAT SHOWS THINGS TO A T-CELL, YOU HAVE DENDRITIC THINGS THAT SHOW THINGS TO A T-CELL AND TUMOR THAT SHOWS THINGS TO T-CELL. ANYTHING THAT’S GOT A RED ARROW IS A CHECK POINT. SO WE ARE LEARNING HOW TO BLOCK THEM ONE BY ONE. I TRY TO FINISH UP EARLY TO LEAVE TIME FOR QUESTIONS. BUT I KNOW I JUST THROUGH A BUNCH OF DATA AT YOU. HIT ME. [APPLAUSE] (OFF MIC)>>SO A LOT OF IT WILL DEPEND ON EACH HISTOLOGY HAS ITS OWN THAT’S BEEN APPROVED. SO PATIENTS WITH MELANOMA IF YOU WANT TO GIVE COMBINATION, THEN IT’S ONLY APPROVED FOR IPI AND NIVOLUMAB TOGETHER. IF YOU HAVE A PATIENT WHO MAY BE — YOU HAVE A YOUNG HEALTHY PATIENT THAT TAKES ANYTHING YOU CAN THROW AT THEM, BEST CHANCE FOR RESPONSE RATE POSSIBLE YOU WILL GIVE THEM THE THING WITH HIGHEST RESPONSE RATE EVEN WITH HIGH SIDE EFFECT. IF YOU HAVE A PATIENT WHO IS A LITTLE WEAKER, WHO MAYBE HISTORY OF AUTOIMMUNE PROBLEMS LIKE IGG OR OTHER THINGS YOU DON’T WANT TO GIVE A DRUG THAT WILL FLAIR& IT UP SO YOU WILL PICK SOMETHING A LITTLE WEAKER SO IT ALL DEPENDS WHERE THE PATIENT IS IN THEIR PROFILE. IF SOMEONE IS COMING TO US FOR A TRIAL, THESE DEPEND ON CERTAIN MARKERS IN TUMORS. YOU HAVE TO GET MOLECULAR PROFILING.>>IT IS DIFFICULT TO MEASURE PROLIFERATION OF T-CELLS IN A SITE WHERE YOU WANT THEM. SO IT’S EASY TO MEASURE IN THE BLOOD. I CAN TELL YOU T-CELL LEVELS IN THE BLOOD DON’T CHANGE OVER GIVING ONE OF THESE DRUGS. BUT YOU CAN’T ALWAYS BIOPSY TUMOR SO EARLY STAGE WHEN WE WERE TRYING TO LEARN AS BEST WE COULD YOU COULDN’T BIOPSY TUMOR OFTEN. WHAT OTHERS NOT HERE THE NCI HAVE DONE, IS THAT YOU CAN LOOK THE REPERTOIRE OF THE T-CELL WILL CHANGE. SO THINGS WITH SOME WEARING ON THE TUMOR WILL INCREASE SO YOUR T-CELL POPULATION WHICH RIGHT NOW IS POLYCLONAL, IF YOU WERE TO MAP OUT YOUR T-CELL CELLS THEY WOULD ALMOST ALL BE DIFFERENT. ONCE YOU HAVE GIVEN A CHECK POINT DRUG YOU HAVE A BURST OF CERTAIN TCR CLONE TYPES THAT BECOME PREDOMINANT SO IT’S LIKE IF YOU WERE TO TAKE YOU NOW, IT WILL BE FLAT BUT IF YOU GET THE FLU BECAUSE YOU HAVEN’T GOT YOUR FLU SHOT YET YOU GET A SPIKE OF FLU VIRUS AND THAT AS YOUR FLU GOT BETTER IT GOES DOWN. PATIENTS GET SPIKE OF WHAT WE THINK ARE THE CANCER ASSOCIATED T-CELL CLONES, BUT THEY STAY UP OVER TIME WHILE GETTING THE DRUG. SO IT’S DIFFICULT TO QUANTITATE BUT QUALITATIVELY WE KNOW YOU SEE LITTLE CHANGES LIKE THAT. (OFF MIC)>>PEOPLE ARE TRYING TO DO THAT WITH COMBINATIONS — THE CONCEPT IS IF YOU GIVE A LITTLE CHEMOTHERAPY, IT WILL KILL THE TUMOR. WE OFTEN KNOW THAT CHEMOTHERAPY ISN’T EFFECTIVE AT KILLING ALL THE TUMOR BUT IF IT KILLS IT A LITTLE BIT IT MAY RELEASE ANTIGENS WHICH PRIME T-CELLS SO GIVING CHEMOTHERAPY OR RADIATION TO A TUMOR GIVES YOU A BURST LIKE A VACCINE, SO IF YOU DO THAT AT THE SAME TIME YOU ARE GIVING CHECK POINT DRUGS IT SHOULD, SHOULD MAKE IT SUCH T-CELLS GO TO SITE OF TUMOR MORE EASILY. THAT’S ALL THEORY THAT’S BEING TESTED RIGHT NOW. DRUGS LIKE THIS WILL NEVER BE COMPLETELY 100% TUMOR SPECIFIC BECAUSE THEY GO AFTER ALL THE T-CELLS IN THE BODY. THE SIDE EFFECTS YOU SEE ARE EVIDENCE OF THAT. IT IS COMMON FOR WOMEN TO GET A CONDITION WHERE IS IMMUNE SYSTEM ATTACK IT IS THYROID. YOU CAN SEE THYROIDITIS IN THIS WAS PATIENT VERSUS T-CELLS FLOATING AROUND THAT KNOW HOW TO SEE THYROID BUT KEPT IN CHECK BY THESE CHECK POINTS. SO ENWHETHER WE GIVE THE DRUG TO HELP WITH CANCER, WE INADVERTENTLY RELEASE BREAKS ON ONES THAT KNOW HOW TO SEE THE THYROID. SO BECAUSE PEOPLE ARE NOT MICE WE WILL N GET A PERFECT TUMOR SPECIFIC MODEL WITH THESE PARTICULAR ANTIBODIES. USING SORT OF WHAT I TALKED ABOUT AT THE BEGINNING WITH THE CELLS, THE COLLEGE CELLS TAKEN OUT IN THE LAB, YOU CAN GET VERY SPECIFIC WITH THOSE. BUT THAT IS HIGHLY PERSONALIZED VERY EXPENSIVE COMPLICATED THING TO DO. THESE DRUGS YOU GET INFUSION EVERY TWO OR THREE WEEKS RELATIVELY SIMPLE THINGS TO DO. EASIER FOR PATIENTS. THERE IS A GROUP HERE LED BY DR. GULLEY OVER IN NCI THAT IS LOOKING AT A PDL 1/TGF BETA TRAP MOLECULE. SO IT GOES TO THE SITE AND SUPPOSEDLY WILL ONLY GO TO A SITE WITH HIGH LEVEL TGF BETA. THAT MIGHT MAKE IT MORE SITE SPECIFIC. THOSE ARE STILL STUDIES IN TRIALS RIGHT NOW. QUESTION IN THE BACK? (OFF MIC)>>THERE’S ALWAYS A QUESTION WHETHER YOU’RE GOING TO GET FRACTURESIDE BECAUSE PART OF THE WHAT THE T-CELLS AXIS DOES IS UPREGULATE PD 1. WITHIN THE T-CELL ITSELF. SO IF YOU GET HIGH ENOUGH CONCENTRATIONS OF IT YOU CAN HAVE T-CELLS KILLING EACH OTHER. WE FEEL THE DOSES IN CLINICAL TRIALS NOW DON’T DO THAT. YOU CAN PUSH THE ENVELOPE IN MURINE STUDIES BECAUSE YOU CAN TREAT WITH HIGHER LEVELS SO YOU CAN PUSH WHERE YOU SEE THAT PHENOMENON BUT WE HAVEN’T SEEN NOT THAT I WOULD SAY EVERYBODY LOOK AS CAREFULLY AS THEY SHOULD BUT YOU DON’T OFTEN SEE KILLING OF OTHER T-CELLS IN HUMAN STUDIES.>>MY BOSS, DR. ROSEBERG IS AT A LOT OF CANCER MEETINGS. SO WHEN — AND WE HAVE BEEN KNOWN AS A PLACE THAT CAN PUSH THE ENVELOPE. HE DEVELOPED IL 2 SO IT WAS — HE DIDN’T DISCOVER I BUT HELPED DEVELOP IT CLINICALLY. SO HE FEELS STRONGLY OUR ROLE AS THE NCI IS TO TAKE PROMISING THINGS IF THERE ARE INVESTIGATORS WHO DON’T HAVE THE RESOURCES TO GET A TRIAL STARTED QUICKLY. SO DR. ALLISON RECOGNIZED THAT WE HAD THE OPPORTUNITY TO DO SOMETHING QUICKLY. HE WAS WORKING ON HIS OWN STUDY. HE WAS PURELY A LAB GUY. HE DIDN’T HAVE ANY CLINICAL EXPERIENCE AT ALL AND DIDN’T HAVE A GREAT — HE WAS WORKING ON BASIC T-CELL IMMUNOLOGY SO HE WAS NEVER REALLY EVEN PART OF A CLINICAL CANCER GROUP. AN ONCE HE DECIDED MAYBE THIS COULD WORK IN CANCER MODELS HE WORKED WITH SOME FOLKS THAT NEW DR. ROSENBERG AND THAT’S HOW THAT WORKED ITSELF OUT. (OFF MIC)>>PATIENT WITH METASTATIC BREAST CANCER? THAT WAS MY PATIENT. (OFF MIC)>>I KNOW JUDY VERY WELL. SHE HAS APPEARED ON NEWSPAPERS AND STUFF SO I’M NOT DIVILLE,ING ANY HIPAA RELATED INFORMATION. SHE IS NOW FOUR YEARS OUT STILL DISEASE FREE. SO WHEN I FIRST MET HER SHE HAD úREACHED A POINT IN HER METASTATIC CANCER WHERE SHE WAS IN SEVERE PAIN. ALMOST DROWSY FROM THE POINT OF ALL THE NARCOTICS SHE WAS TAKING I DID OPERATION TOOK OUT TUMOR ON HER BREAST AND WE STUDYED THAT IN THE LAB, TOOK US FOUR MONTHS TO FIND THE RIGHT CELLS THAT WE WANTED TO GIVE HER. WE GAVE THOSE CELLS BACK TO HER IN DECEMBER OF 2015 AND I SAW HER LAST MONTH AND SHE’S DOING GREAT. SO SHE PART OF NOT ONLY THE PAIN BUT SHE DEVELOPED SUCH A LARGE TUMOR MASS IN HER LEFT AXILLA AND BRACHIAL PLEXIS THAT SHE COULDN’T MOVE HER LEFT AMPLE, SHE WAS AN ACTIVE KAYAKER AND HIKER SO THIS WAS AFFECTING HER LIFE. SHE CIRCUMVENTED THE WORLD IN A KAYAK LAST YEAR. SO ONE DAY IT WILL BE MORE MAINSTREAM, AND WE’LL GET IN TRACO. IT’S NOT MAINSTREAM ENOUGH YET TO BE PART OF THE CURRICULUM. (OFF MIC) SHE HAD OR MOPE RECEPTOR POSITIVE EPI– HORMONE RECEPTOR POSITIVE WHEN SHE WAS DIAGNOSED IN 2003, WHEN WE RESECONDED IN THERAPY IT LOST HORMONE RECEPTOR POSITIVITY. SO THAT PARTICULAR WAS TRIPLE NEGATIVE. BUT BECAUSE WE DIDN’T BIOPSY EVERYTHING IN HER BODY WE HAD TO PRESUME SOME HAD RECEPTOR HORMONE POSITIVE TUMORS THERE. SHE’S LUCKY SHE HAD THE FOUR MONTHS. THAT’S WHY CELL THERAPY IS STILL VERY MUCH A THING OF THE FUTURE. WE USE IT RIGHT NOW AS A TOOL TO LEARN AS MUCH AS WE CAN ABOUT THE IMMUNE SYSTEM IN HUMANS. BUT IT’S NOT FOR EVERYBODY FOR THAT REASON. IT’S WHAT I HAVE SPENT THE LAST FIVE YEARS DOING, HOPEFULLY SPEND THE NEXT 25 YEARS DOING. [APPLAUSE]

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