IT IS MY PLEASURE TO INTRODUCE DR. DINA SINGER, DEPUTY DIRECTOR OF NATIONAL CANCER INSTITUTE, INTRODUCING OUR FIRST KEYNOTE. >> GOOD MORNING. I'M PLEASED TO WELCOME YOU TO THE NIH CONFERENCE ON CANCER, AUTOIMMUNITY AND IMMUNOOGY, WHICH REALLY REPRESENTS THE INTERSECTION OF THREE OF THE NIH INSTITUTES' INTERESTS, THE NCI, NIAMS AND NIAID. IT'S BEEN LONG RECOGNIZED THAT CANCER AND AUTOIMMUNITY ARE OPPOSITE SIDES OF A DISEASE COIN. BOTH ABERRATIONS IN A NORMAL IMMUNE RESPONSE BUT UNTIL RECENTLY THERE WERE FEW STUDIES THAT LOOKED AT THE RELATIONSHIP BETWEEN CANCER AND AUTOIMMUNITY. WITH THE ADVENT OF IMMUNOTHERAPY AND ADVERSE EVENTS, UNDERSTANDING THIS AT A MOLECULAR AND CELLULAR LEVEL HAS WILL BE A HIGH PRIORITY FOR ALL THREE OF THOSE INSTITUTES AND ACROSS MULTIPLE FIELDS OF RESEARCH. THE GOAL OF THIS MEETING, CLEAR FROM THE AGENDA, TO EXPLORE BASIC AND CLINICAL CONSEQUENCES OF THERAPEUTIC PERTURBATIONS IN THE IMMUNE SYSTEM. WE HOPE OVER THE NEXT TWO DAYS, AS WE HEAR TALKS FROM LEADERS IN THE AREAS OF CANCER AND AUTOIMMUNITY THEMES WILL EMERGE TO GUIDE OUR FUTURE RESEARCH. BEFORE I INTRODUCE OUR KEYNOTE SPEAKER, I'VE BEEN ASKED TO TAKE A MOMENT TO REMEMBER A GREAT COLLEAGUE AND A DEAR FRIEND. IT'S MOST FITTING THAT WE REMEMBER STEVE KATZ AT THIS MEETING. THE INTERSECTION OF CANCER, AUTOIMMUNITY AND IMMUNOLOGY, THE FOCUS OF THIS MEETING, WAS ALSO THE INTERSECTION OF STEVE'S SCIENTIFIC PASSIONS. STEVE WAS A PHYSICIAN-SCIENTIST, WHO COMBINED HIS CURIOSITY ABOUT FUNDAMENTAL BIOLOGY WITH A DEEP COMMITMENT TO HIS PATIENTS. STEVE SPENT HIS CAREER AT THE NIH, FIRST AT NCI, AS CHIEF OF THE DERMATOLOGY BRANCH, FOR MANY YEARS AS DIRECTOR OF NIAMS. THESE TITLES DON'T BEGIN TO DESCRIBE THE IMPACT STEVE HAD ACROSS THE NIH. SCIENTIFICICALLY, CLINICALLY, AND PERSONALLY. AS ONE OF HIS DERMATOLOGY TRAINEES ONCE SAID TO ME, STEVE IS A ROCK STAR. AND THAT WAS TRUE IN MANY WAYS. THROUGHOUT MY CAREER, STEVE WAS A MENTOR, AND A FRIEND. THE PERSON I TURNED TO WHEN I NEEDED PROFESSIONAL AND OFTEN PERSONAL GUIDANCE, ALWAYS MADE HIMSELF AVAILABLE WHEN I CALLED AND GAVE ME THE BEST ADVICE HE COULD. THE REMARKABLE THING ABOUT STEVE, HE PLAYED THAT ROLE FOR SO MANY PEOPLE AT NIH, FOR INSTITUTE DIRECTORS, P.I.s, TENURE TRACK INVESTIGATORS, AND IMPORTANTLY FOR HIS PATIENTS. HIS COMPASSION AND CONSIDERATION FOR OTHERS IS TRULY BOUNDLESS, AND LEASE DEEPLY MISSED. STEVE WOULD HAVE VERY MUCH ENJOYED THIS MEETING WHICH REFLECTS BOTH HIS SCIENTIFIC INTERESTS AND APPROACH TO RESEARCH, COMBINING SCIENTIFIC DISCOVERY AND CLINICAL MEDICINE FOR BENEFITS OF THE PATIENTS. I HOPE YOU DERIVE AS MUCH FROM THIS MEETING AS STEVE WOULD HAVE. IT'S MY FURTHER PLEASURE TO INTRODUCE ARLENE SHARPE, OUR FIRST KEYNOTE SPEAKER, WELL KNOWN TO MANY OF US FOR HER PIONEERING WORK IN T CELL CO-STIMULATION, LANDMARK STUDIES OF THE INHIBITORY PATHWAYS OF CTLA-4 AND PD-1 LAY THE GROUND WORK FOR THE CHECKPOINT BLOCKADE IMMUNOTHERAPY THAT IS NOW BEING SO EXTENSIVELY USED. ARLENE IS CHAIR OF THE DEPARTMENT OF IMMUNOLOGY AND PROFESSOR AT HARVARD WHERE SHE PURSUES HER RESEARCH PROGRAM. THE TITLE OF HER TALK FOR THIS MEETING IS "T CELL CO-STIMULATION IN AUTOIMMUNE DISEASES AND CANCER." PLEASE JOIN ME IN WELCOMING ARLENE TO THE PODIUM. >> THANK YOU FOUR THE INTRODUCTION. I'M HONORED TO BE HERE AND LOOK FORWARD TO AN EXCITING MEETING. IN MY TALK THIS MORNING IT'S GOING TO BE PART HISTORY ABOUT HOW WE GOT TO WHERE WE ARE, HISTORY OF T CELL CO-STIMULATION AND TOWARD THE END I'LL SHARE SOME OF THE RECENT WORK FROM MY LABORATORY. WE'RE BEGINNING TO APPRECIATE THE TUMOR MICROENVIRONMENT HAS MANY LAYERS OF IMMUNOSUPPRESSION. TUMORS EVOLVED TO EVADE IMMUNE ATTACK. WE KNOW THE IMMUNE SYSTEM AND TUMORS REALLY HAVE A DELICATE INTERPLAY THE IMMUNE SYSTEM IS ABLE TO ERADICATE MANY EARLY TUMORS BUT THEY DEVELOP STRATEGIES, INVADE THE IMMUNE SYSTEM. WE'RE BEGINNING TO APPRECIATATE THAT MANY INHIBITOR PATHWAYS ARE KEY IMMUNOREGULATORY PATHWAYS, SO TUMOR IMMUNITY IS LIMITED BY PHYSIOIMMUNOREGULATORY MECHANISMS. I'M GOING TO FOCUS ON PD-1 AND CTLA-4, BUT ALL OF THIS WORK HAS ITS HISTORY IN THE MODEL FOR T-CELL ACTIVATION, DEVELOPED IN THE LATE 1980s TO EXPLAIN HOW IT IS THE IMMUNE SYSTEM COULD RESPOND TO A FOREIGN THREAT BUT NOT RESPOND TO SELF. ACCORDING TO THIS MODEL, FOR T CELLS TO BECOME ACTIVATED THEY NEED TO RECEIVE TWO SIGNALS, FIRST CONFERRING SPECIFICITY, ANTIGEN PRESENTING CELL THROUGH MHC MOLECULES. FOR COMPLETE ACTIVATION ACCORDING TO THIS MODEL A SECOND SIGNAL OR CO-SIGNAL IS ALSO NEEDED. IF IT ONLY RECEIVED 1, IT COULD ENTER INTO A DIFFERENT FATE AND COULD BECOME HYPO RESPONSIVE TO FUTURE ENCOUNTERS WITH ANTIGEN. AND SO THIS SECOND SIGNAL HAD A PIVOTAL ROLE IN OUTCOME, WHETHER T CELLS WOULD BECOME ACTIVATED OR RENDERED HYPORESPONSIVE. SO THE FUNDAMENTAL IMPORTANCE OF CO-STIMULATION LED TO MUCH WORK IN THIS AREA BUT THERE WAS INTENSE THERAPEUTIC INTEREST IN CO-STIMULATORY PATHWAYS, HOPED THIS KNOWLEDGE WOULD HAVE THERAPEUTIC BENEFIT, USING THIS KNOWLEDGE TO INDUCE TOLERANCE TO TREAT TRANSPLANT REJECTION AND AUTOIMMUNE DISEASES ON THE ONE HAND, AND ON THE OTHER TO USE THIS KNOWLEDGE TO STIMULATE VACCINES AND OTHER TYPES OF THERAPIESES FOR INFECTIOUS DISEASES AND ALSO STIMULATE ANTI-TUMOR IMMUNITY. THE FUNDAMENTAL AND THERAPEUTIC IMPORTANCE OF CO-STIMULATION HAS LED TO GREAT WORK IN THIS FIELD. SO THE TWO SIGNAL MODEL HAS EVOLVED SO WHEN WE THINK ABOUT CO-STIMULATION TODAY, WE APPRECIATE THAT THERE ARE BOTH POSITIVE SECOND SIGNALS THAT WORK IN CONCERT WITH THE T-CELL RECEPTOR TO PROMOTE T-CELL RESPONSES, AND IN ADDITION THERE ARE NEGATIVE SECOND SIGNALS THAT ATTENUATE SIGNALS THROUGH THE T-CELL RECEPTOR. WE ALSO HAVE LEARNED MANY OF THESE INHIBITOR SECOND SIGNALS HAVE KEY ROLES IN MEDIATING T CELL TOLERANCE. IN ADDITION, WHILE THE TWO SIGNAL MODEL WAS PROPOSED TO EXPLAIN HOW NAIVE CELLS WOULD BECOME ACTIVATED, WE NOW APPRECIATE THAT THESE T CELL CO-STIMULATORY SIGNALS DO FAR MORE THAN REGULATE NAIVE T CELLS. THEY CAN CONTROL EFFECTOR, MEMORY T CELLS AND REGULATORY T CELLS. AND SO, WE NOW HAVE A VARIETY OF T CELL CO-STIMULATORY PATHWAYS THAT CAN DELIVER POSITIVE OR NEGATIVE SECOND SIGNALS, AND ONE OF THE CHALLENGES IN THIS FIELD IS TO UNDERSTAND THEIR UNIQUE AND OVERLAPPING FUNCTIONS. SO I'D LIKE TO START WITH CTLA-4 WHICH IS REALLY THE BEGINNING OF CHECKPOINT BLOCKADE. CTLA-4 WAS THE FIRST CO-INHIBITORY RECEPTOR DISCOVERED AND TRANSLATED TO THERAPY. AND AT THE BEGINNING THERE WAS A DEBATE, IT WAS UNCLEAR WHETHER CTLA-4 WHICH IS A COUSIN OF CD 28, THE KEY CO-STIMULATORY MOLECULE FOR NAIVE T CELLS, WHETHER IT HAD A STIMULATORY OR INHIBITOR ROLE. WORK SUGGESTED A STIMULATORY ROLE, WORK FROM ALLISON'S LAB, AND OTHER LABS SUGGESTED AN INHIBITORY ROLE. WORK FROM MY LAB AND ANOTHER CONVINCED THE FIELD OF THE CRITICAL INHIBITOR ROLE OF CTLA-4, RELATED TO PHENOTYPE OF THE CTLA-4 KNOCKOUT, WHICH IS SHOWN ON THIS SLIDE. I'M BIASED BUT I THINK THIS IS ONE OF THE MOST DRAMATIC PHENOTYPES OF AN IMMUNE KNOCKOUT MOUSE. THESE MICE DIE BY THREE TO FOUR WEEKS OF AGE, THEY DEVELOP MASSIVE SPLENOMEGALY AND ADENOPATHY, SPONTANEOUS T-CELL ACTIVATION, THIS IS THE HEART FROM ONE OF THESE ANIMALS. THESE ANIMALS DEVELOP A GIANT CELL MYOCARDITIS AND DEVELOP INFLAMMATION AND OTHER ORGANS, THIS WAS THE PANCREAS, THE ISLETS HAVE BEEN DESTROYED, AND SOME OF THE EXOCRINE IS DESTROYED, TISSUE DE DESTRUCTION. CTLA-4 HAS A CRITICAL ROLE IN DOWNREGULATING T-CELL ACTIVATION AND SECOND SIGNALS COULD BE INHIBITORY AS WELL AS STIMULATORY. AND THIS PHENOTYPE LOOKED FOR ALL THE WORLD LIKE AN AUTOIMMUNE DISEASE, AND LED US AND OTHERS TO ASK WHETHER CTLA-4 HAD A ROLE IN REGULATING INTOLERANCE AND IMMUNITY. WORK SHOWED IT IS A KEY MEDIATOR OF T CELL TOLERANCE, CTLA-4 CELLS REGULATORY T CELLS AS WELL AS SELF REACTIVE EFFECTOR CELLS, WORK THROUGH MAKING A CONDITIONAL CTLA-4 KNOCKOUT SHOWED CTLA-4 IS A KEY MEDIATOR OF REGULATORY T CELL FUNCTION WITHOUT CTLA-4 THESE REGULATORY T CELLS DON'T WORK WELL. IN ADDITION, FROM THE EARLY DAYS OF GWAS THERE WERE POLYMORPHISMS DESCRIBED IN CTLA-4, SOME OF THE WORK OF JOHN TODD AND LINDA WICKER IDENTIFYING POLYMORPHISMS ASSOCIATED WITH HUMAN AUTOIMMUNE DISEASES INCLUDING TYPE 1 DIABETES AND FAMILIAL GRAVES' DISEASE. MORE RECENTLY, IN ADDITION, THERE HAVE BEEN OTHER DISEASES ASSOCIATED WITH CTLA-4 MUTATIONS. ONE OF THESE CHAI, CTLA-4 HAPLOINEFFICIENCY WITH AUTOIMMUNE INFILTRATION IS A DISEASE WHERE THERE ARE MUTATIONS IN THE CTLA-4 GENE PRIMARILY IN AXON 1, THE LEADER -- ENCODES LEADER PEPTIDE, LESS CTLA-4 EXPRESSION, THESE INDIVIDUALS DEVELOP AUTOIMMUNE CYTOPENIAS AS WELL AS GASTROINTESTINAL AND LUNG AND BRAIN MANIFESTATIONS. THE OTHER DISEASE INVOLVES DEFICIENCIY IN LRBA, LIPOPOLYSACCHARIDE RESPONSIVE VESICLE TRAFFICKING GENE, CONTROLLING TRAFFICKING OF VESICLES. CTLA-4 HAS A CYTOPLASMIC LOCATION AND UPON T-CELL ACTIVATION IT IS SHUTED TO THE SURFACE FOR EXPRESSION, LRBA CONTROLS SHUTTLING TO THE SURFACE, AND WITHOUT IT GOES TO LYSOSOMES FOR DEGRADATION. THIS IS AN INDIRECT EFFECT, WE CAN HAVE DEFICIENCIES IN CTLA-4 GENETICALLY OR BECAUSE CTLA-4 CAN'T TRAFFIC TO THE CELL SURFACE. IN THIS DISEASE THE PATIENTS DEVELOP AUTOANTIBODIES, T REG DEFECTS, AUTOIMMUNE INFILTRATION AND ENTEROPATHY. SO, AS YOU KNOW, ELEGANT WORK FROM JIM ALLISON'S LAB FIRST IN MOUSE MODELS SHOWED BLOCKADE OF CTLA-4 CAN PROMOTE ANTI-TUMOR IMMUNITY, AND THROUGH JIM'S CHAMPION OF THIS APPROACH THIS LED TO THE FDA APPROVAL OF IPILUMINAB ANTI- CTLA-4 FOR MELANOMA IN 2011. THE BLOCKADE IS DEPICTED IN THIS SLIDE, CTLA-4 IS THE HIGH AFINNEY RECEPTOR FOR CD80 AND CD8 6, ANTI-CTLA-4 ANTIBODIES BLOCK CTLA-4 INTERACTION WITH B 7 MOLECULES SO THERE'S AN UNOPPOSED STIMULATION THROUGH CD28, WHICH CAN PROMOTE ANTI-TUMOR IMMUNITY. I'D LIKE TO TURN TO PD-1, WHICH BROADENS THE BENEFIT OF CHECKPOINT BLOCKADE. THE PD-1 RECEPTOR IS UPREGULATED ON T CELLS UPON THEIR ACTIVATION, AND WHEN PD-1 IS ENGAGED BY EITHER OF ITS LIGANDS, PD-L1 PD-L 2 IT BECOMES PHOSPHORYLATED LEADING TO TYROSINE PHOSPHATASE, LEADING TO DEPHOSPHORYLATION OF KINASES DOWNSTREAM OF THE T-CELL RECEPTOR OR CD28. AS A RESULT, THERE'S REDUCED T-CELL RECEPTOR IN CD28 SIGNALING, AND REDUCED EFFECTOR FUNCTIONS, REDUCED CYTOKINE PRODUCTION, AS WELL AS REDUCED COTOLYSIS. ONE INTRIGUING FEATURE OF THIS PATHWAY IS THE EXPRESSION PATTERNS OF THE LIGANDS WHICH ARE SHOWN ON THIS SLIDE, THIS IS ONE OF THE THINGS THAT REALLY HAS INTRIGUED US FROM IDENTIFICATION OF PD-L1 AND PD-L2 IS BINDING PARTNERS FOR PD-1, WORK THAT MY LAB DID IN COLLABORATION WITH GORDON FREEMAN'S LAB AT THE DANA-FARBER CANCER INSTITUTE, GORDON WORKING WITH HONJO LAB DEFINING PD-1/PD-L1 INTERACTIONS. WHEN WE COMPARE EXPRESSION OF PD-L1 AND PD-L2, PD-L1 IS BROADER, EXPRESSED ON VASCULAR ENDOTHELIUM, EPITHELIA, CELLS IN THE LIVER, CELLS IN THE ISLETS, AS WELL AS TROPHOBLASTS IN PLACENTA AND IN THE EYE. THIS EXPRESSION PATTERN SUGGESTED TO US PD-L1 WOULD HAVE THE POTENTIAL TO CONTROL T-CELL RESPONSES LOCALLY WITHIN TISSUES. PD-L2 IN CONTRAST IS MORE RESTRICTED IN ITS EXPRESSION, AND INITIALLY IT WAS REFERRED TO AS B 7DC INDICATING INITIAL EXPRESSION WAS APPRECIATED IN DENDRITIC CELLS AND MACROPHAGES AS TOOLS TO ELUCIDATE AND DESCRIBED PD-L2 HAVE BECOME BETTER WE APPRECIATE IT CAN BE EXPRESSED ON DENDRITIC CELLS, MACROPHAGES, B CELLS AS WELL AS CERTAIN TYPES OF T CELLS. IN ADDITION PD-L2 IS VERY IMPORTANT IN THE LUNG MICROENVIRONMENT, CAN BE EXPRESSED ON AIRWAY EPITHELIA. INTERFERENCE ARE IMPOTENT STIMULI FOR UPREGULATION PD-L1 EXPRESSION AND CAN UPREGULATE PD-L2, WHEREAS IL-4 AND GMCFS ARE THE MOST POTENT STIMULI. ONCE YOU GET INFLAMMATION, THIS PATHWAY BECOMES UPREGULATED TO TUNE DOWN T-CELL RESPONSES. PD-L1 AND PD-L2 SHARE PD-1 AS A BINDING PARTNER, EACH OF THE LIGANDS HAS A SECOND UNIQUE BINDING PARTNER, WORK WITH GORDON FREEMAN'S LAB SHOWED PD-L1, B 71 INTERACTIONS OCCUR AND THIS IS ALSO AN INHIBITOR INTERACTION. IN ADDITION WORKING TOGETHER WITH GORDON'S LAB WE IDENTIFIED PD-L2 INTERACTION WITH REPULSIVE GUIDANCE MOLECULE B AS SECOND BINDING PARTNER, IMPORTANT ROLES IN THE LUNG MICRO ENVIRONMENT, INTERACTION IS IMPORTANT FOR RESPIRATORY TOLERANCE. WHEN WE THINK ABOUT THE PD-1 PATHWAY IT'S A PARADIGM FOR CONTROLLING IMMUNE RESPONSES. I THINK P SHOULD STAND FOR PROTECT BECAUSE THIS PATHWAY IN TERMS OF PHYSIOLOGIC FUNCTION IS REALLY DESIGNED TO PROTECT THE HOST, HAS AN IMPORTANT ROLE IN COUNTER BALANCING POSITIVE SIGNALS THROUGH T-CELL RECEPTOR AND CO-STIMULATORY RECEPTOR, IMPORTANT ROLE IN TOLERANCE AND PARTICULARLY IN MAINTENANCE OF TOLERANCE AND CONTROLLING INITIAL ACTIVATION OF SELF REACTIVE CELLS. THIS PATHWAY IS A CRITICAL ROLE IN PROTECTING TISSUES FROM DAMAGE BY IMMUNE RESPONSES, HAS AN IMPORTANT ROLE IN CONTROLLING RESOLUTION OF INFLAMMATION, IN TISSUES, AND CAN ALSO SHARE TARGET ORGANS FROM AUTOIMMUNE ATTACK AND HAS A KEY ROLE IN HOMEOSTASIS. MY LAB AND OTHERS HAVE SHOWN IT REGULATES TOLERANCE AT CHECKPOINT, HAS IMPORTANT ROLE IN LIMITING INITIAL ACTIVATION OF SELF REACTIVE T CELLS BUT IMPORTANTLY CAN CONTRO POTENTIALLY PATHOGNIC SELF REACTIVE CD4 AND CD8 CELLS, AND WORK FROM MY LAB SHOWED PD-L1 ON NON-HEMATOPOIETIC CELLS CONTROLS THOSE RESPONSES IN THOSE CELLS LOCALLY. PD-L1 IS EXPRESSED ON THE VASCULATURE AND MAY HAVE THE POTENTIAL TO LIMIT EXTRAVASATION, ON TARGET ORGANS CAN PROTECT FROM AUTOIMMUNE DESTRUCTION. PD-L1 IS A MEDIATOR OF T CELL EXHAUSTION, THE SMARTEST IMMUNOLOGISTS HAVE EXPLOITED TO AVOID ERADICATION, IN CHRONIC INFECTION AND CANCER. IN THE SETTING OF CANCER, WE ARE BEGINNING TO APPRECIATE THAT TUMOR INFILTRATING CELLS BEHAVE LIKE THESE EXHAUSTED DYSFUNCTIONAL CELLS THAT HAVE BEEN DESCRIBED IN CHRONIC VIRAL INFECTION. BUT WHAT'S SPECIAL ABOUT CANCER IS THAT THE LIGANDS THEMSELVES CAN BE EXPRESSED ON TUMORS AS WELL. PD-L1 CAN BE EXPRESSED ON THE SURFACE OF ABOUT 30% OF SOLID TUMORS AS WELL AS CERTAIN HEMATOLOGIC MALIGNANCY, AND WORK HAS SHOWN PD-L1 ON THE TUMORS CAN INHIBIT ANTI-TUMOR IMMUNITY. THIS IS IMMUNOHISTOCHEMISTRY IN COLLABORATION WITH SOME OF MY COLLEAGUES AT THE DANA-FARBER CANCER INSTITUTE, AND BRIGHAM AND WOMEN'S HOSPITAL, GORDON FREEMAN, SCOTT, IS SABINAA AND DAVID, PD-L1 ON KIDNEY CANCERS AND NON-SMALL CELL LUNG CANCER. IN THE SETTING OF TUMOR THEN WE KNOW PD-1 IS HIGHLY EXPRESSED ON TUMOR CELLS AND THESE ARE DYSFUNCTIONAL, AND THAT PD-L1 CAN BE EXPRESSED ON THE TUMOR CELLS, HEMATOPOIETIC CELLS, AS WELL AS STROMAL CELLS AND OTHER NON-HEMATOPOIETIC CELLS IN A HUMAN MICROENVIRONMENT. AND THE ANTIBODY DRUG TARGETING PD-1 OR PD-L1 BLOCKS THIS INTERACTION AND AS A RESULT UNLEASHES A POTENT ANTI-TUMOR T-CELL RESPONSE, LEADING TO INCREASED KILLING OF TUMOR CELLS, AND INCREASED CYTOKINE PRODUCTION. AS YOU ALL KNOW, THIS HAS BEEN TRANSLATED TO THERAPY, BLOCKING THIS PATHWAY TO UNLEASH POTENT ANTI-TUMOR IMMUNITY, THERE ARE NOW SIX DRUGS THAT HAVE BEEN APPROVED BY THE FDA, THREE ANTI-PD-1 DRUGS, THREE ANTI-PD-L1 DRUGS. AND MANY MORE IN DEVELOPMENT AS WELL AS MANY BY SPECIFICS. THERE HAVE BEEN FDA APPROVAL OF ANTI-PD-1, PD-L1 INHIBITORS FOR 14 TYPES OF TUMORS. AND THESE ARE DEPICTED ON THIS SLIDE. AND THERE'S A RANGE OF RESPONSE RATES THAT YOU CAN SEE HERE, RANGING FROM ABOUT 15 TO 20%, TO 87% RESPONSE RATES. THE HIGH RESPONSE RATE HERE IS DUE TO WORK FROM MARGARET SHIP'S LAB, SHOWING PD-L1 AND PD-L2 ARE AMPLIFIED WITH HODGKIN'S'S DISEASE WITH JAK-2, 87% RESPONSE RATE, HOW TO DEFINE WHO WILL RESPOND AND THAT WILL BE THE SUBJECT OF SOME OF THE OTHER TALKS DURING OUR MEETING TODAY. BUT THERE ARE MORE CANCER IMMUNOTHERAPY TARGETS THAN PD-1. AND I HAVE MANY VERSIONS OF THIS SLIDE SO DON'T TRY TO READ THESE AT THIS POINT. I WANT TO MAKE THE POINT THAT THERE ARE NOW MANY INHIBITOR PATHWAYS, AND T CELLS AND TUMORS CAN EXPRESS MANY OF THESE PATHWAYS. INTERESTINGLY, MANY OF THESE PATHWAYS ARE CRITICAL REGULATORS OF THE BALANCE BETWEEN T-CELL ACTIVATION AND TOLERANCE, SIMILAR TO CTLA-4 AND PD-1, TARGETS FOR IMMUNOTHERAPY. IN ADDITION, THERE'S TIM-3, LAG-3, VISTA AND OTHERS MOVING TO THE CLINIC. HOWEVER, IT'S A DOUBLE-EDGED SWORD. TO ILLUSTRATE I'LL SHOW WORK WITH PD-1 LAG-3 DOUBLE KNOCKOUT MICE, WHEN THE MICE WERE MADE UNLIKE THE SINGLE KNOCKOUTS THESE ANIMALS SPONTANEOUSLY DEVELOPED AUTOIMMUNE DISEASE OVER FOUR TO NINE WEEKS OF AGE. AND THESE ANIMALS DEVELOP LYMPH ADENOPATHY AND TISSUE INFILTRATES SUCH AS MYOCARDITIS AND PANCREATITIS. WE NOW KNOW ALSO FROM ELEGANT WORK FROM JOHN WARY'S LAB THAT T CELLS CAN CO-EXPRESS MULTIPLE INHIBITOR RECEPTORS, THIS WORK INITIALLY CAME FROM ELEGANT STUDIES IN THE LCMV MODEL WHERE DURING A RESOLVED ACUTE INFECTION, THE T CELLS EXPRESSED ZERO TO 1 INHIBITOR RECEPTOR, IN CONTRAST DURING CHRONIC LCMV THEY EXPRESS TWO, THREE, FOUR RECEPTORS. IF YOU PLOT THE TOTAL NUMBER OF INHIBITOR RECEPTOS EXPRESSED ON T CELLS AGAINST THE DEGREE OF T CELL DYSFUNCTION HERE LOOKING AT POLY FUNCTIONALITY, CO-PRODUCER OF PD-1, SORRY, OF INTERFERON AND TNF ALPHA, WHAT YOU SEE IS THE MORE INHIBITOR RECEPTORS EXPRESSED, THE LESS FUNCTIONALITY. THIS HAS LED MANY IN THE FIELD TO ASK IF YOU BLOCK MORE THAN ONE RECEPTOR, CAN YOU HAVE ADDED BENEFIT? AND SO WORK HAS SHOWN THAT CO-BLOCKADE OF PD-1 AND ANOTHER RECEPTOR IN TUMOR MODELS CAN ENABLE BETTER RESCUE OF DYSFUNCTIONAL CELLS THAN BLOCKADE OF THE SINGLE INHIBITOR PATHWAY BUT IT'S ONLY PD-1 BLOCKADE ALONE THAT CAN HAVE SUBSTANTIAL EFFECTS. AND SO REALLY THE FUTURE IS IN COMBINATION THERAPY TO TRY TO INCREASE THE BENEFIT, AND THIS SLIDE SUMMARIZES SOME OF THE APPROACHES THAT ARE UNDERWAY. ONE IS TO BLOCK PD-1 PD-1 WITH ANOTHER INHIBITOR RECEPTORS, PD-1 AND CTLA-4 APPROVED FOR RENAL CELL CARCINOMA. LAG3, TIGIT, TIM-2, VISTA AND CD47 ARE IN CLINICAL TRIALS. AND ALONE AS WELL AS IN COMBINATION WITH PD-1. ANOTHER STRATEGY IS TO BLOCK PD-1 AND STIMULATE THE IMMUNE SYSTEM GIVING AGONISTIC ANTI-OX40, ANOTHER TO GIVE A KINASE INHIBITOR OR BRAF MEK INHIBITOR, CISPLATIN OR PARP INHIBITOR. INHIBITORS AND CHEMOTHERAPIES CAN HAVE EFFECTS ON IMMUNE CELLS, AND SOMETIMES SELECTIVE EFFECTS. IN ORDER TO HAVE RATIONAL COMBINATIONS WE NEED TO UNDERSTAND THESE. GOING BACK TO PD-1 BLOCKADE WITH THESE INHIBITORY RECEPTORS WE KNOW FROM ANIMAL MODELS YOU CAN BLOCK PD-1 IN ANY OF THESE RECEPTORS AND HAVE MORE BENEFIT THAN BLOCKING EITHER PATHWAY ALONE, BUT WE DON'T KNOW WHETHER THE SAME CELL TYPES OR THE SAME MOLECULAR CIRCUITS ARE BEING AFFECTED. SO WE REALLY NEED TO HAVE MUCH MORE ANALYSIS AND BASIC SCIENCE UNDERSTANDING IN ORDER TO UNDERSTAND HOW TO TARGET THESE PATHWAYS MOST RATIONALLY. OTHER APPROACHES INCLUDING PD-1 BLOCKADE AND ANGIOGENESIS BLOCKADE GIVING PD-1 BLOCKADE RADIATION AND EPIGENETIC REGULATORS. YOU KNOW THERE ARE SOME TUMORS WHERE WE HAVE HOT ENVIRONMENT, OTHERS WHERE THERE ARE COLD TUMORS, OR WE HAVE IMMUNE EXCLUDED TUMORS. SO OTHER TYPES OF APPROACHES ARE NEEDED TO STIMULATE IMMUNE RESPONSE SO OTHER APPROACHES UNDERWAY TO BLOCK PD-1 AND DELIVER A CANCER VACCINE, ONCOLYTIC VIRUS OR ENGINEERED T CELLS. PD-1 IS IS A BUILDING BLOCK FOR THESE COMBINATIONS, SO WE NEED TO UNDERSTAND THE PATHWAY DEEPLY. IN THE LAST FEW MINUTES I'LL SHARE RECENT WORK FROM MY LAB IN TERMS OF UNDERSTANDING THE PD-1 PATHWAY, IN TWO AREAS. FIRST, UNDERSTANDING PD-1 AND DEVELOPMENT OF T CELL MEMORY. UNDERSTANDING THE ROLE OF PD-1 IN REGULATING T CELL MEMORY IS IMPORTANT FOR SEVERAL PERSPECTIVES. FIRST, DURABILITY IS A KEY GOAL OF CANCER IMMUNOTHERAPY, AND SECONDLY MANY PATIENTS WHO ARE GETTING PD-1 BLOCKADE MAY DEVELOP AN INFECTION DURING THE COURSE OF THE THERAPY. SO WE NEED TO UNDERSTAND HOW PD-1 CONTROLS T CELL MEMORY. TO APPROACH THIS QUESTION, WE DID EXPERIMENTS SHOWN IN THIS SLIDE. WHAT WE DID IS WE INFECTED MICE WITH INFLUENZA, A PRIMARY INFECTION, WITH X31 FLU AND SECONDORY WITH PR 8-GP33 VIRUS, WITH DISTINCT NEUROAMINITIES. WE WOULD INFECT WITH ONE STRAIN, ANALYZE VIRUS-SPECIFIC CD8 T CELLS AND VIRAL LOAD DURING THE PRIMARY AND SECONDARY INFECTION. I ONLY AM GOING TO SHOW ONE EXPERIMENT, WHICH IS A CO-TRANSFER EXPERIMENT WHERE WE'VE TRANSFERRED A 50-50 MIX OF WILDTYPE AND PD-1 KNOCKOUT TCR TRANSGENIC CELLS INTO WILDTYPE MICE INFECTED WITH A STRAIN OF FLU, THEN ANALYZED PRIMARY AND RECALL RESPONSES. THIS EXPERIMENTAL DESIGN WE'RE COMPARING WILD TYPE AND KNOCKOUT IN THE SAME MOUSE, SAME ANTIGEN LOAD AND VIRAL CLUES. WHEN WE RECHALLENGE AFTER DAY 35 WE SEE THE WILDTYPE CELLS CAN EXPAND 16-FOLD IN A RECALL RESPONSE. IN CONTRAST PD-1 DEFICIENT CELLS EXPAND 1.8 FOLD, ALMOST 10-FOLD LESS IN TERMS OF RECALL RESPONSE, INDICATING THAT IN THE ABSENCE OF PD-1 DURING PRIMING THERE'S IMPAIRED MEMORY, IMPAIRED RECALL CAPACITY. SO THESE STUDIES INDICATE LOSS OF PD-1 BEFORE PRIMING OF NAIVE CELLS AND MEMORY. STUDIES I DON'T HAVE TIME TO SHOW YOU TODAY WE FOUND LACK OF PD-1 IN PRIMING LEADS TO OVERACTIVATION OF T CELLS, THERE'S EXCESSIVE PROLIFERATION COUPLED WITH CELL DEATH, WE GET SHORT-LIVED MEMORY CELLS AS OPPOSED TO LONG-LIVED MEMORY CELLS, THAT THERE'S A CELL-INTRINSIC ROLE FOR PD-1 SIGNALS, LIMITING EFFECTOR EXPANSION THAT PROMOTES MEMORY AND THINK PD-1 IS CRITICAL INTEGRATOR OF EARLY CD8 T-CELL ACTIVATION SIGNALINGS OPERATING BY PROMOTING CYCLING TO PROMOTE OPTIMAL MEMORY. PD-1 IS IMPORTANT IN PRESERVING PROGENITOR POOL. STUDIES HAVE IMPLICATION SEQUENCING IN COMBINATION MAY BE IMPORTANT, PRIMING AND VACCINATING BEFORE PD-1 BLOCKADE MAY BE IMPORTANT FOR ACHIEVING DURABLE MEMORY, AND I HAVE WONDERFUL COLLABORATIONS WITH SULLIVAN AT MGH TO LOOK IN THE CONTEXT OF TARGETED THERAPY AND KATHY WU AT DANA-FARBER. SUGGESTING DELETING PD-1 AND CONVENTIONAL OR CAR T CELLS MAY IMPAIR MEMORY DEVELOPMENT. SO THE CHOICE OF CELLS FOR ENGINEERING IS IMPORTANT AS WELL. I'D LIKE TO IN THE LAST FEW MINUTES TELL YOU ABOUT SOME OF OUR WORK ON THE FUNCTION OF PD-1 ON REGULATORY T CELLS. PD-1 HAS AN IMPORTANT ROLE IN REGULATING T CELL TOLERANCE THE ROLE OF PD-L1 IN REGULATING IS LESS WELL UNDERSTOOD. PD-1 IS EXPRESSED ON VARIETY OF T CELLS, NAIVE CELLS REGULATORY, FOLLICULAR, HELPER AND T REG CELLS. TO ANSWER THIS QUESTION WE'VE MADE CONDITIONAL KNOCKOUT MICE AND CROSSED THEM WITH FOXP3 CRE MICE, INDUCIBLE CRE, TO DELETE PD-1 ON T REGS. I'LL JUST SHOW A FEW PIECES OF DATA HERE. WHAT WE DID WAS TO DELETE PD-1 ON T REGS BEFORE INDUCTION OF EAE, AND WHAT YOU CAN SEE HERE IS THAT WHEN PD-1 IS DELETED, WE SEE THAT THERE IS COMPARED TO THE CONTROLS A DELAY IN ONSET OF DISEASE, AND A DELAY IN SEVERITY, SO DELETION OF PD-1 ON T REGS ONLY WILL AMELIORATE EAE. TO LOOK AT THIS IN MORE DEPTH WE DID TRANSCRIPTIONAL PROFILING OF THE T REGS FROM THE CNS OF THESE ANIMALS AND FOUND THAT THE T REGS HAVE REDUCED PI3 KINASE AKT SIGNALING. THERE'S A LITERATURE SHOWING INCREASED ACTIVITY OF THE PI3 KINASE AKT PATHWAY CAN RESULT IN EXPRESSIVE FUNCTION. OTHER STUDIES SHOWED THE PI3 KINASE AKT PATHWAY REGULATES GLYCOLYSIS AND MITOCHONDRIAL FUNCTION AND DECREASED GLYCOLYSIS AND INCREASED MITOCHONDRIAL FUNCTIONS HAVE BEEN ASSOCIATED WITH INCREASED T REG EXPRESSIVE CAPACITY. SIMILARLY WHAT WE FOUND IS THAT THE PD-1 DEFICIENT T REGS HAVE REDUCED GLYCOLYSIS, INCREASED MITOCHONDRIAL FUNCTIONS ASSOCIATED WITH THEIR ENHANCED EXPRESSIVE ACTIVITY. THOSE STUDIES INDICATE THAT PD-1 IS AN EQUAL OPPORTUNITY INHIBITOR. PD-1 RESTRAINS T EFFECTOR ACTIVITIES AS WELL AS T REG ACTIVITIES. PD-1 AND T REGS CAN LIMIT THEIR ACTIVATION AND EXPRESSIVE CAPACITY, AND INDUCIBLE DELETION OF PD-1 AND T REGS A AMELIORATES EAE AND OTHER STUDIES IN A TYPE 1 DIABETES MODEL. THE EFFECTS WE SEE IN T REG-SPECIFIC PD-1 DEFICIENCY CONTRAST WITH GLOBAL DEFICIENCY, IF WE INDUCE EAE WE SEE MORE. IMPORTANTLY, DETERMINING HOW THIS IS INTEGRATE THE. PD-1 IMMUNOTHERAPY WILL INHIBIT SIGNALS IN ALL CELL TYPES AND INTEGRATED OUTCOME IS ENHANCED ANTI-TUMOR IMMUNITY. STUDIES MIGHT SUGGEST DEVELOPMENT OF AGENTS THAT TARGET PD-1 ON EFFECTOR CELLS MIGHT BE EVEN MORE EFFECTIVE. THESE STUDIES MAY EXPLAIN WHY IT IS CTLA-4 IMMUNOTHERAPY MAY SYNERGIZE WELL WITH PD-1 BLOCKADE FOR CANCER BECAUSE PD-1 CELLS ARE MORE SUPPRESSIVE, CTLA-4 CAN ATTENUATE FUNCTION OF THE T REGS AND SOMEHOW REDUCES T REG FUNCTION. SO THESE T CELL CO-STIMULATORY AND CO-INHIBITOR PATHWAYS REGULATE THIS BALANCE BETWEEN T-CELL ACTIVATION AND TOLERANCE, AND DURING THE COURSE OF THIS MEETING WE'RE GOING TO BE DISCUSSING MANY QUESTIONS RELATED TO IMMUNE-RELATED ADVERSE EVENTS, THAT ARE SEEN WITH PD-1 AND CTLA-4 THERAPIES. WE NEED TO UNDERSTAND AND I'VE LISTED SOME QUESTIONS HERE, CAN KNOWN RISK FACTORS PRODUCE THE RISK OF THESE IMMUNE-RELATED ADVERSE EVENTS? WHAT CAN WE LEARN ABOUT AUTOIMMUNITY FROM THESE ADVERSE EVENTS? AND WHAT CAN WE LEARN FROM THESE ADVERSE EVENTS FROM AUTOIMMUNITY AND IMPORTANTLY LEARN MORE ABOUT NORMAL IMMUNE HOMEOSTASIS FROM BOTH THE AUTOIMMUNITY AND ADVERSE EVENTS. IT'S VERY RARE TO HAVE A SITUATION WHERE ONE KNOWS THE START TIME OF A THERAPY, AND THEN CAN STUDY PATIENTS BEFORE AND AFTER THE INTERVENTION, SO THERE'S GREAT POTENTIAL HERE TO UNDERSTAND THE PATHOGENESIS OF THESE ADVERSE EVENTS, AND AUTOMEAN DISEASE. WE'LL LEARN BY BRINGING PEOPLE TOGETHER, AS THIS MEETING IS TODAY, TO UNDERSTAND MECHANISMS INVOLVED. SO, I LEAVE YOU WITH A FEW CRITICAL QUESTIONS, HOW DO WE IDENTIFY KEY QUESTIONS IN THE FIELD AT THIS TIME? HOW DO WE IDENTIFY WHO RESPONSE TO CHECK POINT BLOCKADE? WHAT ARE MECHANISMS OF FAILURE TO RESPOND? AND MECHANISMS OF RESISTANCE THAT DEVELOP? HOW DO WE IDENTIFY WHO IS AT RISK FOR ADVERSE EVENTS, WE NEED TO UNDERSTAND ALL THIS INFORMATION IN ORDER TO RATIONALLY DEVELOP COMBINATION THERAPIES TO INCREASE BENEFIT THAT'S DURABLE WITH BEST SAFETY. AND SO TO SUMMARIZE THEN, THE SUCCESS OF CHECKPOINT BLOCKADE HAS LED TO A PARADIGM. THE FUTURE IS IN COMBINATION THERAPY THAT'S NEEDED TO SPEND BENEFIT OF IMMUNOTHERAPY. BUT IN ORDER TO DO THIS, WE NEED A BETTER UNDERSTANDING OF MECHANISMS THAT CONTROL ANTI-TUMOR IMMUNITY. UNDERSTANDING DEEPLY THE TUMOR MICROENVIRONMENT, FACTORS OF AGE, GENDER, OBESITY, DIET, MICROBIOME THAT CONTROL THESE TYPES OF RESPONSES AND INTEGRATE THE BASIC BIOLOGY INTO THE NEXT GENERATION OF THERAPIES AND ALSO DETAIL THE EVALUATION OF PATIENTS IS CRITICAL TO UNDERSTANDING MECHANISMS OF RESPONSE RESISTANCE AND ADVERSE EVENTS, IN ORDER TO INCREASE THE BENEFIT AND MITIGATE RISKS. BEFORE CLOSING I WOULD LIKE TO ACKNOWLEDGE PEOPLE IN MY LAB, THE WORK THAT I MENTIONED ON THE MEMORY T CELLS LED BY KRISTIN, AND ON REGULATORY T CELLS BY KATHERINE AND PETER, NOW CARRIED ON. I'D LIKE TO ACKNOWLEDGE COLLABORATIONS WITH FREEMAN'S LAB AT THE DANA-FARBER, MARSHA HAIGIS, JOHN WHERRY, JOHN JOHN DOENCH, RAFI AHMED, VIJAY KUCHROOO AND DARIO VIGNALI. I'M HAPPY TO ANSWER QUESTIONS IF THERE'S TIME. >> THE NEXT TALK, MY QUESTION IS RELATED TO THE T REG SPECIFIC PD-1 DELETION. IN YOUR MODEL DID YOU SEE THE MIGRATION OF EFFECT OF AUTOREG T CELLS IN THE BRAIN AFFECTED BY THE DELETION OF THE PD-1 T REG AND ALSO REGULAR T CELLS CAN PROMOTE MYELINATION, DO YOU THINK THE DELETION OF THE PD-1 T REG AFFECT THE RELAPSE OR DIFFERENT MODEL? >> SO WHAT WE SEE FROM OUR STUDIES WE SEE THERE'S AN INCREASED NUMBER OF T REGS THAT ARE IN THE CNS MICROENVIRONMENT, ALL OF OUR STUDIES WITH INDUCIBLE KNOCKOUTS THIS FOR BEFORE DELETION, STUDIES ONGOING TO LOOK AT WHAT LATER IN THE COURSE BUT I CAN'T TELL YOU THE RESULT AS YET. >> ARLENE, THAT WAS YOUR USUAL FANTASTIC TALK. TWO QUESTIONS, VERY SORT OF CLINICAL. THE USE OF ANTI-PD-L1 ANTIBODIES WHICH DON'T AFFECT PD-L1 AND AFFECT OF ANTI-PD-1 ANTIBODIES, AND HOW WOULD YOU COMPARE THEM? AND THE OTHER IS WHY DO MICE HAVE SUCH A POTENT EFFECT RELATED TO CTLA-4, INCLUDING EFFECT IN ANIMAL TUMOR MODELS BUT PD-1 APPEARS WEAKER? IN HUMANS, THERAPY IS VERY DIFFERENT. >> FIRST RELATES TO PD-L1 VERSUS PD-1, PD-L2 AS WELL. A LOT IS CONTEXT AND MICROENVIRONMENT DEPENDENT, IN SOME SETTING PD-L1 AND PD-L2 CAN HAVE OVERLAPPING FUNCTIONS, ON DENDRITIC CELLS AND CERTAIN TISSUE MICROENVIRONMENTS BUT OTHER SETTINGS WHERE PD-L1 IS EXPRESSED, PD-L2 IS NOT EXPRESSED. THERE ARE KNOW HARD AND FAST RULES. WHEN ONE BLOCKS PD-1 YOU LEAVE THE B 7 PATHWAY, ONE BLOCKS PD-L1, YOU LEAVE THE PD-L2 PATHWAY IMPACT, WHICH COULD HAVE SOME PROTECTIVE BENEFITS. REGARDING MICE VERSUS HUMANS, THAT'S A MORE DIFFICULT QUESTION, IT DEPENDS ON STRAIN BACKGROUND THAT WE CAN SEE AND DEPENDS ON TUMOR MODELS, BECAUSE WE CAN SEE EFFECTS, FOR EXAMPLE, HIGHLY IMMUNOGENIC TUMOR AND C 38 GETTING RESOLVED IN MICE THAT LACK PD-1 OR PD-L1 USING BLOCKERS BUT OTHER MODELS WITH FEWER MUTATIONS, YOU SEE LESSER EFFECTS. >> THANKS FOR YOUR WONDERFUL TALK. MY QUESTION RELATES TO AUTOIMMUNITY IN HUMANS. AND DATA SUGGEST THAT T CELLS THAT ARE EXTRACTED FROM PATIENTS WITH AUTOIMMUNE DISEASE HAVE HIGH LEVELS PD-L1. DO YOU P D-L1 -- PD-1, I'VE BEEN STUDYING THIS IN RHEUMATOID ARTHRITIS. >> YOU RAIS A VERY IMPORTANT POINT. PD-1 EXPRESS ALONE YOU CANNOT TELL WHETHER THE CELLS HAVE BECOME RECENTLY ACTIVATED OR WHETHER THESE CELLS ARE DYSFUNCTIONAL. YOU NIGHT TO DO FAR MORE, YOU NEED TO PROBE THE FUNCTION. I THINK WE'RE GOING TO HAVE A TALK BY DAVID HAFLER TWO WILL ANSWER YOUR QUESTION ABOUT HUMAN T REGS. >> MY QUESTION IS SIMILAR TO HER QUESTION. WONDERFUL TALK, BY THE WAY. ALSO I'M GOING TO TALK ABOUT HOW WE NEED TO START SEQUENCING THESE DRUGS, I AGREE WITH YOU. BUT IS THERE A WAY WE CAN DETERMINE WHEN THESE INITIAL T CELLS THAT ARE PRIMED, WHEN THE PD-1 IS TELLING US THEY ARE GETTING ACTIVE ACTIVATED BEING TURNED OFF, LAG3, TIM 3, OTHER SURFACE MARKERS. >> WE CAN BEGIN TO LOOK AT CERTAIN TRANSCRIPTION ALSIGNATURES. WE KNOW EXHAUSTED T CELLS, THERE ARE SUBSETS, MORE PRO PROGENITOR, THESE CELLS EXPRESS CXCR 5, THE MORE TERMINALLY EXHAUSTED EXPRESS HIGHER LEVELS OF PD-1 AND TIM-3, THE MORE CYTOTOXIC, SO THERE ARE OTHER, MAKERS BUT THE SIGNATURES NEED TO BE REFINED. >> PARIS, FRANCE. THANK YOU FOR THE WONDERFUL TALK. YOU SHOWED PD-1 WAS MANDATORY FOR PRIMING. THE CONSEQUENCE IN CLINICS SHOULD BE INCREASED RISK OF INFECTION AND IMPAIRED VACCINATION RESPONSE, IS THIS WHAT IS OBSERVED IN CLINICAL TRIALS? >> I THINK THERE ARE MAYBE DIFFERENT FUNCTIONS, ONCE YOU HAVE AN EFFECTOR CELLS OR EFFECTOR MEMORY CELL. THIS IS DURING PRIMING THAT YOU SEE THAT THERE CAN BE SUCH A PROFOUND EFFECT ON MEMORY SO FURTHER STUDIES NEED TO BE DONE DURING THE COURSE OF DEVELOPMENT AFTER YOU HAVE MEMORY CELLS THAT HAVE ALREADY BEEN FORMED THAT HAVE BEEN STUDIES SHOWING THEY CAN EXPAND SO IT'S DURING PRIMING THAT IS KEY. AND SO I THINK FURTHER STUDIES NEED TO BE DONE IN THE CLINIC TO ANSWER JUST THAT QUESTION. OKAY. WELL, THANK YOU AGAIN. [APPLAUSE] >> THANK YOU SO MUCH. NOW JUST TO TRANSITION TO ONE OF THE MORE SPECIFIC SETS OF TOXICITIES WITH USE OF THESE AGENTS, IT'S MY PLEASURE TO INTRODUCE DR. MICHAEL DUGAN FROM MASSACHUSETTS GENERAL HOSPITAL FOR THE GOSS TROUGH INTESTINAL TOXICITIES SESSION. >> GOOD MORNING. WE HAVE THREE SPEAKERS, DR. EREZ BAROUCH FROM ISRAEL AND DR. ROBERT BRESALIER FROM M.D. ANDERSON. I'M GOING TO TALK TODAY ABOUT CHECKPOINT BLOCKADE TOXICITIES IN THE GASTROINTESTINAL TRACT, FOCUSING ON THE SMALL INTESTINES AND COLON. THESE ARE MY DISCLOSURES. SO, ECHOING WHAT DR. SHARPE JUST SAID, IMMUNE RELATED ADVERSE EVENTS ARE MORE THAN SIDE EFFECTS, THEY ARE A WINDOW INTO IMMUNE REGULATION IN HUMANS. WE CAN LEARN BIOLOGY FROM SIDE EFFECTS, THE PHENOTYPE OF RECEPTOR KNOCKOUT OR BLOCKADE IN HUMANS IS IMMUNE RELATED ADVERSE EVENT AND WE CAN LEARN ABOUT THE EARLY STAGES BECAUSE WE HAVE AN ELEGANT SYSTEM, SOMETHING WE HAVEN'T HAD AN OPPORTUNITY TO LOOK AT BEFORE WHERE WE KNOW A SPECIFIC IMMUNE INTERVENTION, EXACTLY WHEN IT STARTED, AND WE HAVE THE OPPORTUNITY AT LEAST IN THEORY TO TRACK IMMUNE RESPONSES THAT RESULT FROM BEFORE THEY START TO AFTER THE IMMUNE INTERVENTION HAS BEGUN AND THEN ONCE SYMPTOMS OF AUTOIMMUNE DISEASE ACTUALLY SURFACE. THE INTRINSIC BIOLOGY IS INTERESTING BUT WE HAVE A CLINICAL PROBLEM TO SOLVE, HOW DO WE TREAT PATIENTS WHO DEVELOP THESE IMMUNE-RELATED ADVERSE EVENTS. WHEN WE'RE THINKING ABOUT TREATING WE HAVE TO THINK ABOUT FIRST REDUCING MORBIDITY AND MORTALITY FROM TH ADVERSE EVENT, PRESERVING ANTI-TUMOR IMMUNITY BECAUSE THESE PEOPLE HAVE A TERMINAL DISEASE IF UNTREATED. HIS GOING TO NEED NEW THERAPEUTICS, DRUGS THAT ARE BEYOND JUST SYSTEMIC STEROIDS, AS WELL AS DRUGS WE CAN GIVE CONCURRENTLY WITH IMMUNOTHERAPY SO PATIENTS DON'T HAVE TO STOP LIFE-PRESERVING TREATMENT AND WAYS OF IDENTIFYING PEOPLE AT HIGH RISK FOR DEVELOPING EVENTS AND PROPHYLAXING OR FINDING A WAY OF REDUCING RISK AHEAD OF TIME. THIS CAN BECOME IMPORTANT AS WE START USING MORE COMBINATION THERAPIES, WHICH ARE LIKELY TO HAVE MORE DIVERSE SIDE EFFECTS BUT ALSO MORE SEVERE ONES. SO, I MENTIONED AVOIDING STEROIDS, AND DO WE HAVE EVIDENCE THAT STEROIDS ARE ACTUALLY A PROBLEM IN TREATMENT OF IMMUNE-RELATED ADVERSE EVENTS? THE ANSWER IS WE DON'T KNOW. WE HAVE GOOD RETROSPECTIVE DATA FROM SLOAN-KETTERING. OVERALL BOTH GROUPS ARE ABLE TO RESPOND TO IMMUNOTHERAPY. ONES WITH STEROIDS SEEM TO DO A TEENY BIT BETTER. PATIENTS LARGELY ONLY RECEIVE STEROIDS IF THEY HAVE IMMUNE RELATED ADVERSE EVENT. ANYONE TWO HAD A SEVERE IMMUNE RELATED ADVERSE EVENT WAS LIKELY TO GET STEROIDS. SO WE DON'T REALLY KNOW IF THE RESPONSE COULD HAVE BEEN BETTER, IF WE HAD USED SOMETHING OTHER THAN STEROIDS WHICH IS TO SAY WHAT IF THERE'S A CORRELATION BETWEEN AN IMMUNE RELATED ADVERSE EVENT AND RESPONSE TO THERAPY, MAYBE THAT YELLOW LINE WAS SUPPOSED TO BE OR COULD HAVE BEEN UP HERE WHERE THE RED LINE IS, WE BROUGHT IT DOWN USING STEROIDS. SO IS THERE ANY EVIDENCE TO SUPPORT THIS? ONLY RETROSPECTIVE DATA. ONE OF MY COLLEAGUES AT MASS GENERAL, ENDOCRINOLOGIST, LOOKED AT UNIFORM POPULATION OF PATIENTS, METASTATIC MELANOMA TREATED WITH IPILUMINAB, DEVELOPED HYPOPHYSITIS. THERE WITH TWO TREATMENT PARADIGMS FOR HYPOPHYSITIS, ONE WAS LOW DOSE STEROIDS TO REPLACE ADRENOCORTICAL ACCESS, THE OTHER WAS HIGH DOSE TREATMENT PLAN WITH GOAL OF TRYING TO RESERVE PITUITARY FUNCTION, SHOWING PITUITARY OUTCOMES ARE SIMILAR BETWEEN THE TWO APPROACHES. WHAT'S STRIKING IS BOTH IN TERMS OF OVERALL SURVIVAL AND TIME TO TREATMENT FAILURE THERE'S A BIG DIFFERENCE. PEOPLE WHO GOT HIGH DOSE STEROIDS DID ABOUT AS WELL AS YOU WOULD EXPECT SOMEONE WHO RECEIVED IPILUMINAB TO DO. SO BETWEEN 15 TO 20% LONG-TERM SURVIVAL, PRETTY GOOD. WHAT WAS STRIKING IS LOW DOSE STEROID GROUP DID BETTER THAN EXPECTED FOR PATIENT TREATED WITH IPILUMINAB SUGGESTING MECHANISTIC CORRELATION BETWEEN THE ADVERSE EVENT AND ANTI-TUMOR RESPONSE, AND STEROIDS CAN BLUNT THAT. THERE'S RECENT DATA PATIENTS WITH LUNG CANCER TREATED WITH PD-1 OR PD-L1 INHIBITORS DON'T DO AS WELL, SUGGESTING WHEN IMMUNOTHERAPY STARTS THERE'S A REASON TO BE OFF STEROIDS. THE POINT OF MY TALK, THE GUT, THE GUT IS ARGUABLY THE MOST IMMUNOLOGICALLY COMPLICATED BARRIER IN THE BODY, ABLE TO TOLERATE DIETARY PROTEINS AND MICRO BACTERIA, AS WE INHIBIT PATHWAYS WE GET GUT TOXICITIES. THIS IS A TABLE LOOKING AT COMMON TOXICITIES FROM CHECK POINT BLOCKADE AND YOU CAN SEE THERE ARE A LOT OF G.I. SYMPTOMS, ALSO DIAGNOSES, ENTEROCOLITIS, PANCREATITIS, RARE TOXICITIES, GASTRITIS, CELIAC DISEASE, AND JUST TO EMPHASIZE ALTHOUGH BOTH LEAD TO TOXICITIES THEY ARE MORE COMMON WHEN CTLA-4 IS INHIBITED. THERE ARE DISEASES IN THE GUT INFLAMMATORY THAT WE DON'T SEE PARTICULARLY THE ALLERGIC DISEASES OF THE GUT. IgE MEDIATED FOOD ALLERGIES, EOSINIC DISEASE DON'T APAIR TO FLARE OR EMERGE IN PATIENTS TREATED WITH CURRENT CHECKPOINT BLOCKING STRATEGIES, WHICH REALLY SUGGESTS CTLA-4 AND PD-1 AND PD-L1 ARE NOT CRITICAL REGULATORS, NOT EVERYBODY DEVELOPS THESE DISEASES, AS WE EXPAND THE ARMAMENTARIUM IT'S LIKELY WE'LL START FIGURING OUT WHAT WHICH PATHWAYS DO CONTROL THESE DISEASES. SOMETHING TO WATCH OUT FOR. SO ENTEROCOLITIS IS THE MOST COMMON INFLAMMATORY TOXICITY IN THE GUT FROM CHECKPOINT BLOCKADE, HAS RANGE OF SEVERITIES, CAN BE SEVERE, LIFE-THREATENING, OFTEN INDOLENT, RESPONSE FOR TREATMENT-RELATED DIARRHEA AND CAN BE ISOLATED TO THE COLON BUT CAN INVOLVE THE ENTIRE G.I. TRACT FROM THE STOMACH THROUGH TO THE RECTUM. THE SYMPTOMS ARE USUALLY WATERY DIARRHEA, PATIENTS CAN HAVE PAIN AND CRAMPING, URGENCY IS COMMON, BLEEDING FAIRLY RARE AND IS USUALLY FROM SOMETHING ELSE, NOT FROM MUCOSAL DISRUPTION. AND CAN BE ACCOMPANIED BY NAUSEA AND VOMITING PROBABLY BECAUSE OF THE HIGH PREVALENCE OF INVOLVEMENT OF UPPER G.I. TRACT. WHEN THE DISEASE IS LOCALIZED TO THE COLON IT'S PAN-COLITIS, WE CAN LOOK AT THE LEFT SIDE OF THE COLON AND GET A DIAGNOSIS, BUT NOT EVERYONE HAS COLONIC DISEASE. LOOKING THROUGH OUR MGH RECORDS, THOSE ARE PATIENTS REFERRED TO GASTROENTEROLOGY FOR SUSPECTED COLITIS FROM CHECKPOINT BLOCKADE, AND WE FOUND FIRST THAT MOST OF THEM DID IN FACT HAVE MUCOSAL INFLAMMATION, BUT NOT ALL. IF YOU LOOK AT THOSE WHO DID, THE MAJORITY OF THEM HAD EITHER COLITIS OR ENTEROCOLITIS, SO DISEASE INVOLVING THE COLON BUT SIGNIFICANT FRACTION ACTUALLY HAD ISOLATED DISEASE IN THE UPPER G.I. TRACT. WHICH WE WOULD ONLY FIND ACTUALLY BY LOOKING AT THE UPPER G.I. TRACT TO SOMETHING LIKE UPPER ENDOSCOPY. MICROSCOPICALLY THIS IS A LYMPHOCYTIC COLITIS WITH SOME NEUTROPHILIC COMPONENT. T CELLS WE THINK ARE KEY DRIVERS BUT WE DON'T KNOW WHAT TARGETS ARE, DON'T KNOW ENOUGH ABOUT THE FUNCTION OF THESE T CELLS YET. EPITHELIAL APOPTOSIS, SUGGESTING ACCUSE RATHER THAN CHRONIC PROCESS. RIGHT NOW WE DON'T HAVE A COMPLETE PICTURE OF ALL OF THE IMMUNE CELLS INVOLVED, WHAT THEIR FUNCTIONS ARE, THAT'S AN IMPORTANT AREA FOR FURTHER RESEARCH, TO UNDERSTAND WHAT'S DRIVING THIS COLITIS. WE KNOW THAT BOTH CAN CAUSE COLITIS BUT CLINICAL SYMPTOMS ARE ONLY PARTIALLY OVERLAPPING. CTLA-4 IS MORE RECENTLY SEVERE, TENDS TO HAVE RAPID ONSET, DOSE DEPENDENT, THE MORE IPILUMINAB YOU GIVE THE MORE LIKELY TO HAPPEN AND MORE SEEN. AND RAPIDLY RESOLVES WITH APPROPRIATE TREATMENT. PD-1 COLITIS IS MORE VARIABLE, MORE LIKELY TO COME AT LATER TIMES IN TREATMENT COURSE, MORE LIKELY MICROSCOPIC INFLAMMATION, INDOLENT COURSE, NOT CLEARLY DOSE DEPENDENT AT LEAST TO ME AT THIS POINT AND OFTEN IS SLOWER TO RESPOND EVEN WITH APPROPRIATE THERAPY. THERE ARE A LOT OF SIMILARITIES BETWEEN CHECKPOINT COLITIS AND INFLAMMATORY BOWEL DISEASE, NOT COMPLETELY OVERLAPPING SYNDROMES EITHER. I'M SHOWING YOU A TYPICAL DEEP ULCER CROHN DISEASE, TYPICAL CHECKPOINT COLITIS. PAN COLITIS IS THE COMMON PRESENTATION FOR CHECK POINT BLOCKADE, DEEP ULCERS AND STRICTURES ARE RARE IN CHECKPOINT COLITIS, COMMON IN CROHN'S. AND THIS ENTERITIS CAN INVOLVE THE ENTIRE SMALL BOWEL AND MUCOSA, THIS NEVER OCCURS IN UC, RARE FOR CROHN'SS, TENDS TO BE MONO PHASIC. PER PERTURBATION HAS NOT LED TO IMMUNITY, IBB IS RELAPSING REMITTING DISEASE. SO THE ROLE IN SPONTANEOUS INFLAMMATORY BOWEL DISEASE, WE DON'T KNOW THE ANSWER. ONE WAY TO LOOK IS SEE WHAT HAPPENS TO PATIENTS WHO HAVE INFLAMMATORY BOWEL DISEASE WHO RECEIVE CHECKPOINT BLOCKADE. SO THIS IS SMALL RETROSPECTIVE ANALYSIS OF THE PATIENTS WE'VE TREATED AT MGH, MOST HAVE MEDICAL MELANOMA OR LUNG CANCER, AND WHAT WE FOUND IS THEY HAVE FAIRLY HIGH PERCENTAGE OF G.I.-RELATED ADVERSE EVENTS, FLARES OF UNDERLYING DISEASE OR WHAT LOOKS LIKE CHECKPOINT COLITIS, IT'S HARD TO DISTINGUISH, BUT THIS IS HIGHER THAN WE EXPECT FROM CHECKPOINT BLOCKADE ALONE. ANOTHER WAY TO LOOK IS ALL OF THE MELANOMA PATIENTS TREATED WITH CHECKPOINT BLOCKADE AT THE SAME TIME, AT MGH, SO WE HAD 16.8% CHANCE OF G.I.-RELATED PATIENTS WITH MELANOMA AND UNDERLYING IBD FLARED SUGGESTING THESE IMMUNE CHECK POINTS DO HAVE SOME ROLE IN MAINTAINING REMISSION IN INFLAMMATORY BOWEL DISEASE. JUST SO WE DON'T GET THE WRONG IDEA THESE PATIENTS STILL BENEFITED FROM CHECK POINT BLOCKADE, ABSOLUTELY BENEFITED. WE HAD TWO PERFORATIONS IN THIS COHORT AND BOTH OF THOSE PATIENTS ARE STILL ALIVE, ONE WITH COMPLETE RESPONSE. SO THEY UNDERWENT SURGERY, IT'S A BAD THING BUT WE HAD A POTENTIALLY LETHAL TUMOR THAT WAS CURED. SO I THINK FIVE OF THE PATIENTS IN THIS COHORT ARE STILL ALIVE SEVERAL YEARS AFTER TREATMENT. AGAIN, TWO COMPLETE RESPONSES, NO ONE DIED FROM THE G.I. TOXICITY. IN TERMS OF TREATMENT FOR CHECKPOINT COLITIS, CORTICOSTEROIDS ARE THE STANDARD OF CARE, 2/3 OF PATIENTS RESPOND. WE HAVE NO RIGOROUS PROSPECTIVE STUDIES TO SHOW EFFICACY OR APPROPRIATE DOSE. ANECDOTALLY OUTPATIENTS TEND TO DO WELL WITH 40 TO 60 MILLIGRAMS OF PREDNISONE. WE USE MUCOSAL SEVERITY TO DETERMINE WHEN TO TAKE THEM OFF. A THIRD TEND TO DO WELL WITH ANTI-TNF ALPHA, A KEY MEDIATOR. WE HAVE SIMILAR USE RATE FOR IPILUMINAB AND PD-1 COLITIS SUGGESTING THEY BOTH HAVE ABOUT THE SAME REFRACTORY NATURE. ANECDOTALLY WE TEND TO USE MORE ANTI-TNF ALPHA, HARDER TO TREAT. THIS SUGGESTING TRAFFICKING OF NEW T CELLS PLAYS A ROLE IN MAINTAIN THE INFLAMMATION OF THE COLON. INFLIXIMAB LOOKS SAFE, PATIENTS DO ABOUT AS WELL, IF ANYTHING INFLIXIMAB DID A BIT BETTER. CAN WE DETERMINE WHO IS GOING TO NEED IT AHEAD OF TIME? IN BOTH SERIES, COLONIC ULCERATION WAS A PREDICTOR. WE USED ENDOSCOPIC SCORE TO GRADE, HOW MUCH INFLAMMATION IS IN THE COLON, 0-3, A PREDICTOR OF WHETHER OR NOT PATIENTS ARE GOING TO NEED INFLIXIMAB. ULCERS ARE THE STRONGEST PREDICTOR IN OUR SERIES AS WELL. THERE'S NO ASSOCIATION WITH RECTAL BLEEDING. WE FOUND A TREND TOWARD INCREASED NEEDED INFLIXIMAB IN PATIENTS WITH ENTERITIS AND NO ASSOCIATION WITH PATHWAY BEING INHIBITED. WHAT IF PATIENTS DON'T RESPOND? WE DON'T HAVE A LOT OF DATA TO SUPPORT ANYTHING BEYOND THAT. WE'VE RARELY ENCOUNTERED THIS SO I DON'T HAVE ANECDOTAL EXPERIENCE. MOSTLY WHAT WE SEE ARE INFECTIONS AND SO I ALWAYS RESCOPE THESE PATIENTS AND LOOK CAREFULLY FOR INFECTION, OTHER OPTIONS, BLOCKADE OF P 40, THE JAK INHIBITORS ARE LIKELY TO REVERSE, I RECOMMEND AS LAST RESORT WHEN YOU HAVE A PATIENT WHO MIGHT DIE FROM COLITIS AND WE'LL HEAR ABOUT FECAL TRANSPLANTS LATER ON SO I WON'T GO INTO THAT. CORTICOSTEROIDS MIGHT LIMIT TREATMENT, WE DON'T HAVE A CLEAR ANSWER ON THAT YET. ENDOSCOPY CAN BE USED FOR RISK STRATIFICATION IN ULCER DISEASE AND IDENTIFYING PATIENTS WHO DON'T NEED STEROIDS. CTLA-4 AND PD-1 COLITIS ARE NOT COMPLETELY OVERLAPPING, SOME THINGS IN COMMON. CHECKPOINT BLOCKADE CAN FLARE IBD, WHAT THE ROLE IS, WE'LL HAVE TO STUDY. PREFERABLY IN PROSPECTIVE TRIALS. TNF ALPHA APPEARS TO BE A MEDIATEDDOR. WHAT'S THE OPTAL WAY TO TREAT COLITIS, WHILE BENEFITING OR PRESERVING ANTI-TUMOR RESPONSE, WE TO HAVE ADDRESS IN RANDOMIZED CLINICAL TRIALS, HOW TO THEY DIFFER MECHANISTICALLY IN HOW THEY CONTROL COLITIS AND WHAT DOES THAT TEACH US ABOUT GUT HOMEOSTASIS, CAN WE USE DETAILED UNDERSTANDING TO IDENTIFY TREATMENT TARGETED GETS AND CAN IT PROVIDE INSIGHT INTO EARLY EVENTS IN IBD. I WILL THANK YOU FOR YOUR ATTENTION. THANK THE MANY PEOPLE AT MULTIPLE INSTITUTES ACROSS BOSTON. I'LL BE HAPPY TO TAKE QUESTIONS ONCE WE HAVE THE GROUP COME BACK UP HERE FOR THE FINAL MODERATED SESSION. THANK YOU. [APPLAUSE] I WOULD LIKE TO FORMALLY WELCOME DR. EREZ BARUCH WHO WILL TALK ABOUT AN INTERESTING CAUSE OF DIARRHEA IN PATIENTS ON CHECKPOINT BLOCKADES, SOMETHING MOST OF US DID NOT APPRECIATE WOULD HAPPEN UNTIL HE STARTED LOOKING INTO IT. THANK YOU FOR THE PRIVILEGE OF BEING HERE THIS MORNING. THANKS FOR EVERYBODY THAT HELPED ME PASS THE SECURITY. IT WAS THE FULL MONDAY MORNING EXPERIENCE TODAY. OKAY. SO FOLLOWING THIS GREAT PRESENTATION BY MIKE ABOUT COLITIS, A COMMON G.I. TOXICITY, I WOULD LIKE TO TALK ABOUT ANOTHER UNDERREPORTED G.I. TOXICITY. IMMUNOTHERAPY INDUCED DIARRHEA IS DEFINED AS FREQUENCY OF BOWEL MOVEMENT, DISTINGUISHING WITH COLITIS AS A POSSIBLE CAUSE FOR THIS SYMPTOM. HOWEVER, WHEN WE LOOK AT THE GUIDELINES, THESE ARE TWO EXAMPLES OF THE GUIDELINES IN ISRAEL, THEY ARE UP TO DATE. IF THEY ARE ROOTING OUT INFECTION CAUSE, THIS IS COMMON IN THE CLINIC. SO MICHAEL REVIEWED IMMUNOTHERAPY INDUCED COLITIS. I WILL BRIEFLY COMMENT THE DIAGNOSIS IS BASED ON CLINICAL JUDGMENT. MANY PATIENTS WITH GRADE 2 OR GREATER WILL BE TREATED WITH CORTICOSTEROIDS AND INFUSION STOPPED AFTER A BASIC WORKUP. CESSATION WILL NOT BENEFIT THE PATIENT WE SHOULD ASK ARE THERE ANY OTHER POSSIBLE CAUSES FOR THIS IMMUNOTHERAPY INDUCED DIARRHEA. LAST-YEAR A PATIENT MADE US RECONSIDER THIS. 37 YEARS OLD, NO PRIOR MEDICAL HISTORY OTHER THAN MELANOMA, ANTI-PD-1 THERAPY IN ADJUVANT SETTING WITHOUT ADVERSE EVENTS UNTIL THE NINTH MONTH OF TREATMENT WHEN HE PRESENTED TO THE CLINIC WITH GRADE 3 DIARRHEA, APPROXIMATELY 10 PER DAY. AFTER INFECTION WAS RULED OUT, DIAGNOSED WITH ANTI-PD-1 INDUCED COLITIS, STEROIDS, NO CLINICAL IMPROVEMENT AFTER ANTI-PD-1 INFUSE WAS STOPPED WHILE CORTICOSTEROIDS ARE CONTINUED. HE HAD MULTIPLE CONSULTATION, IN ISRAEL AND ABROAD, AND UNDERWENT A YEAR LONG WORKUP WHICH MAINLY WAS AIMED FOR COLITIS, THIS INCLUDED MULTIPLE COLONOSCOPIES, REPEATED IMAGING, VIDEO CAPSULES, BIOPSIES, EVEN NERVE CONDUCTION TEST TO THE SPHINCTER, EACH TEST NORMAL, PATIENTS CONTINUED TO HAVE TEN DIARRHEAS PER DAY, NEGATIVE EFFECT MENTALLY ON THE PATIENT. WE NEED TO REMEMBER THIS WAS AN OTHERWISE HEALTHY PATIENTS, STAGE 3, NO EVIDENCE OF DISEASE, ADJUVANT SETTING. EVENTUALLY GOT LUCK, NEW FAMILY PHYSICIAN REVIEWED THE CASE AND NOTICED DIARRHEA HAD SYMPTOMS OF DIARRHEA CAUSED BY INABILITY TO INGEST FAT. A STRANGE OBSERVATION IN IMAGING DONE AS PART OF ROUTINE MELANOMA ASSESSMENT. THE VOLUME OF PANCREAS SHRANK 70%. COMBINED FINDINGS SUPPORTED POSSIBLE DIAGNOSIS ESTABLISHED BY LOW FECAL, THE GOLD STANDARD. ALL SYMPTOMS RESOLVED WITHIN A FEW DAYS FOLLOWING OVER THE COUNTER SUPPLEMENTARY PANCREATIC ENZYMES. THIS INTERESTING CASE, SEVERAL QUESTIONS. WAS THIS STRANGE COINCIDENCE OR UNREPORTED TOXICITY, ONLY MELANOMA OR ANTI-PD-1? MOST IMPORTANTLY HOW CAN WE DISTINGUISH THIS POTENTIALLY NEW AND POST LIKELY RARE TOXICITY FROM IMMUNE THERAPY INDUCED DIARRHEA, COLITIS. WE DESIGNED A CASE CONTROL STUDY, INCLUDING PATIENTS WITH DIFFERENT CANCERS, MELANOMA, NON-SMALL CELL, HEAD AND NECK SQUAMOUS. WE SAW PATIENTS WITH EVIDENCE OF PANCREATIC ATROPHY. IN ORDER TO DETERMINE IT WAS A RARE TOXICITY AND NOT INDUCED BY AGE, GENDER OR ADVANCED DISEASE AND HISTORY OF MULTIPLE LINES OF TREATMENT, WE MATCHED WITH CONTROL PATIENTS, IN ADDITION TO SUPPORT, WE COMPARED TO COLITIS CONTROL, PATIENTS WITH DOCUMENTED IMMUNOTHERAPY INDUCED COLITIS. EVERY PATIENT WAS CONSIDERED AS A CASE, ATROPHY PATIENT, QUALITATIVE NOT QUANTITATIVE. THE PURPOSE OF STATISTICAL ANALYSIS COLLECTED QUANTITATIVE DATA BY MEASURING PANCREATIC VOLUME. WE REPEATED IN A BLINDED FASHION TO ASSESS POTENTIAL BIASES. WE ALSO ADDRESSED TWO ADDITIONAL BIAS, FIRST PANCREATIC VOLUME IN DIFFERENT PATIENTS, AVOID FOLLOW-UP TIME BIAS, STANDARDIZED WITH FOLLOW-UP TIME. TO OVERCOME BOTH CONCERNS WE CREATED NEW PARAMETR, THE PROPORTION OF CHANGE IN PANCREATIC VOLUME DIVIDED BY NUMBER OF MONTHS OF FOLLOW-UP. THIS PARAMETER WAS USED IN STATISTICAL ANALYSIS. I WILL PRESENT HIGHLIGHTS OF THE STUDY AND FINDINGS IN THE RECENT PUBLICATION IN CANCER IMMUNOLOGY RESEARCH. SO OUT OF POTENTIAL POPULATION OF 617 PATIENTS, 403 HAD TREATMENT AND FOLLOW-UP CT SCANS. PANCREATIC ATROPHY IN 31, TWO WITH COMBINATION THERAPY, AND 25 ANTI-PD-1 PATIENTS. WE MATCHED 25 OF THE ATROPHY CASES TO 41 CONTROLS AND SECOND GROUP IMMUNOTHERAPY INDUCED COLITIS INCLUDED 22 PATIENTS. ATROPHY WAS PROFOUND, 43%, INTERESTINGLY THE ATROPHY WAS NO PATIENT DEMONSTRATED ANY SIGNS. UNFORTUNATELY WE WERE UNABLE TO CORRELATE FINDINGS, THIS TEST WAS NOT PERFORMED IN OUR CLINIC, WE DIDN'T HAVE RECOMMENDATION FOR ALL OF THE PATIENTS. NEXT WE COMPARED ATROPHY RATES BETWEEN CASES AND CONTROL. DESPITE THE PANCREATIC VOLUME, ATROPHY RATES WERE HIGHER IN THE CASE GROUP IN COMPARISON TO MATCHED CONTROL, SUPPORTING THAT PANCREATIC ATROPHY IS NOT ABLE OR DISEASE RELATED. NO ATROPHY PATIENT PRESENTED WITH TYPE 1 DIABETES, THE TYPE 2 OF ONE IS HARDER TO CONTROL. WE BELIEVE SOME MIGHT DEVELOP TYPE 1 DIABETES IN THE YEARS TO COME. SIGNS OF PANCREATITIS, INCREASED SIZE, ONE OF THESE THREE PATIENTS PANCREATITIS. FOUR PATIENTS COMPOSING 1% AND 13% OF AT ATROPHY GROUP DEVELOPED STEATORRHEA. NEXT MOVE WAS TO SEEK DIFFERENCES BETWEEN PATIENTS WITH STEATORRHEA AND COLITIS. PATIENTS INCLUDED IN COLITIS GROUP WITHOUT EVIDENCE OF PANCREATIC ATROPHY. ENDOSCOPIES WERE NOT PERFORMED TO ALL THE PATIENTS. SIMILAR FOLLOW-UP TIME. MEDICAL HISTORY, JUST LIKE THE TEXT BOOK. MOST WILL NOT PRESENT WITH ANY PAIN, JUST DIARRHEA AFTER INGESTION OF FOOD. ONE PATIENT APPROXIMATE PANCREATITIS, WITH CLASSIC PANCREATITIS SYMPTOMS, NAUSEA, VOMITING, EPIGASTRIC PAIN RADIATING TO THE BACK. EPI PRESENTED LATE IN TREATMENT, COLITIS PRESENTED EARLY IN ACCORDANCE WITH LITERATURE AT THE MEDIAN OF TWO MONTHS. MOST IMPORTANTLY, EPI AND STEATORRHEA CASES WERE RESISTANT, ALL, TO CORTICOSTEROIDS, COMPLETELY RESOLVED IN DAYS OF INGESTION OF PANCREATIC ENZYMES. THE ASSOCIATION BETWEEN THE SEVERITY OF ATROPHY AND PROGNOSIS, WITHIN THE ATROPHY GROUP HIGHER ATROPHY RATES WERE ASSOCIATED WITH SHORTER SURVIVAL, ATROPHY PATIENTS AS A GROUP SHOWED SURVIVAL IN COMPARISON TO CONTROLS, CONSISTENT WITH REPORT DUE TO USE OF INHIBITORS, MECHANISM IS UNCLEAR. CLINICAL DESCRIPTION, CONSISTENT WITH PREVIOUS CASE REPORT PUBLICATION, ANTI-PD-1 INDUCED ATROPHY, RESULTING IN STEATORRHEA. TWO PREVIOUS CASES DESCRIBING PANCREATIC ATROPHY, BOTH OF THE PUBLICATIONS ASSESS ATROPHY. THE MECHANISM BEHIND ATROPHY IS UNKNOWN, WE'RE NOT SURE IF THERE'S ONLY ONE MECHANISM. SOME MAY DEVELOP MOSTLY ASYMPTOMATIC PANCREATITIS, RESULTING IN ATROPHY, ACUTE IS ALREADY ESTABLISHED TOXICITY. ANOTHER WAS SUGGESTED DUE TO ANTI-VASCULAR EFFECT OF DRUGS BUT ANTI-PD-1 MAY HAVE IMPACT, SOME CELLS EXPRESS PD-1. IN ADDITION THIS MECHANISM MAY EXPLAIN LACK OF EFFECTIVENESS FOR -- LACK OF EVIDENCE FOR PANCREATITIS IN SOME OF THE PATIENTS. WE DEFINE NOT BASED ON VOLUME MEASUREMENTS. WE CHOSE THIS SINCE VOLUME MEASUREMENT REQUIRED DESIGNATED SOFTWARE AND THEY WERE TIME CONSUMING, SMALL CHANCE THE PROCESS WOULD BECOME PART OF CARE WE CHOSE TO MAKE IT MORE PRACTICAL. SECOND, WE DIDN'T HAVE ANY DOUBT REGARDING POSITIVE EVENTS, SOME DEVELOPED STEATORRHEA WITH NORMAL, WE CAN SAY THE TESTS ( INDISCERNIBLE). IN SUMMARY, DEVELOPING IN 8% OF PATIENTS, HIGHER INCIDENCE AMONG ANTI-CTLA-4, PAY RESULT IN EXOCRINE PANCREATIC INSUFFICIENCY. EPI IS INFREQUENT TOXICITY, 1% OF PATIENTS, A LITTLE BIT LESS, WHICH IS PRESENTED LATE INTO THE TREATMENT, EASILY DIAGNOSED WITH FECAL ELASTASE-1 TEST, ATROPHY IS REVERSIBLE. I WANT TO FINISH WITH THE LAST MORE GENERAL SLIDE TALKING ABOUT NON-COLITIS DIARRHEA. COLITIS IS THE MOST COMMON CAUSE, DRUGS CAN AFFECT ANY ORGAN IN THE BODY. WE NEED TO SUSPECT NON-COLITIS DIARRHEA WHEN SYMPTOMS DEVELOP MANY MONTHS AFTER THERAPY, NOT COLITIS CLASSIC, RELATED TO FOOD, NOT ACCOMPANIED BY ABDOMINAL PAIN. WE NEED TO CHOOSE SPECIFIC LAB TESTS, NON-COLITIS WORKUP CAN SAFE ENDOSCOPIES. I WOULD LIKE TO THANK THESE PEOPLE, AND THANK YOU ALL FOR LISTENING. [APPLAUSE] >> CLOSING THIS SESSION WE'LL HAVE DR. ROBERT BRESALIER FROM MD ANDERSON. >> THANK YOU. A PLEASURE TO BE HERE. SO LAST WEEK I WAS SPEAKING TO A STUDENT, HE ASKED WHAT'S THE DEFINITION OF A SCIENTIST? I SAID, WELL, MAYBE SOMEBODY WHO MAKES STRUCTURE OUT OF CHAOS. I THINK WHEN YOU LOOK AT THE LITERATURE, ONE WHAT I WANT TO IMPART TODAY IF NOTHING ELSE WE NEED TO SEEK THE RIGOR IN THE FIRST TALK WITH CLINICAL ASPECTS OF THE DOWNSTREAM EFFECTS OF INHIBITORS, SO I'M GOING TALK AS MUCH ABOUT WHERE WE NEED TO GO, WHAT WE DON'T KNOW AS WHAT WE DO KNOW, ALSO COMMON THEMES. I HAVE NO DISCLOSURES. THERE ARE MANY MORE ERUDITE SPEAKERS TO TALK ABOUT IMMUNOTHERAPY BUT WITH CANCER, TARGETING SINGLE MUTATIONS WITH TARGETED INHIBITORS ALMOST ALWAYS LEADS TO LEE LAPSE, IMMUNOTHERAPY HAS SPECIFICITY. I MADE THIS SLIDE FOR ANOTHER TALK, THE POINT ABOUT THIS SLIDE, I LIKE WHEN HE USED THE TERM THAT T CELLS ARE THE SOLDIERS OF THE IMMUNE SYSTEM, AND WE'RE HEARD ABOUT MECHANISMS IN THE FIRST TALK. AND THE GOALS OF THERAPY, AND HOW THESE DRUGS MAY WORK BUT ALSO HOW THEY MAY LEAD TO SIDE EFFECTS. AND THE GENERAL ASSUMPTION IS WE'RE DEALING WITH AUTOIMMUNE DISEASE, THAT'S A REASONABLE ASSUMPTION, BUT I THINK AS WE HEARD FROM MICHAEL SOME OF THESE DOWNSTREAM EFFECTS HAVE THE CHARACTERISTICS OF END ORGAN AUTOIMMUNE DISEASE BUT NOT ALL AND THERE ARE DIFFERENCES. THE OTHER THING IS IMMUNE RESPONSE IS DYNAMIC AND CHANGES RAPIDLY. SO THERE ARE A LOT OF INHIBITORS, BOTH FDA APPROVED AND IN DEVELOPMENT, WE HEARD ABOUT THESE IN TERMS OF CLASSES, CTLA-4, PD-1, PD-L1. ONE THING WE NEED TO TEASE OUT IS WHEN WE TALK ABOUT SIDE EFFECTS, ARE THERE DIFFERENCES, WHAT ARE THE MECHANISMS OF THESE DIFFERENCES. WHEN WE COMPARE THESE AS GROUPS, THERE ARE DIFFERENCES. ANTI-CTLA-4 SEEMS TO BE HARD WIRED, ANTI-PD-1 THERE'S INDUCED RESISTANCE. WHEN WE TALK ABOUT TOXICITY, AS WE HEARD FROM MICHAEL, ADVERSE EVENTS ARE RELATIVELY FREQUENT, UP TO 75% OF INDIVIDUALS RECEIVING ANTI-CTLA-4 THERAPY ARE SOME SORT OF ADVERSE EVENT. LOOKING AT DENOMINATOR, LESS FREQUENT WITH ANTI-PD-1 THERAPY, BUT BECAUSE THESE DRUGS ARE BEING USED SO FREQUENTLY NOW FOR SO MANY INDICATIONS, THERE'S A GREAT INCREASE IN THE NUMBER OF REPORTED ADVERSE EVENTS. SO IMMUNE RELATED ADVERSE EVENTS CAN OCCUR AT ANY END ORGAN, GENERALLY MANY OF THESE ARE MILD AND WE CAN DEAL WITH THEM SYMPTOMATICALLY BUT THERE ARE THOSE WITH LATER STAGE DISEASE. HOW DO WE GRADE DISEASE ? MOST LITERATURE AND GUIDELINES RELY ON COMMON TOXICITY ELEMENTS WHICH DEAL WITH SYMPTOMS AND DON'T INCORPORATE THINGS LIKE COLONOSCOPY, HISTOLOGICAL FINDINGS, THIS COMES INTO PLAY WITH LIVER AS WELL. AND WE'RE GOING TO NEED BETTER GRADING SYSTEMS TO REALLY UNDERSTAND WHAT THE LEVEL OF TOXICITY IN AN INDIVIDUAL PATIENTS, CAN WE PREDICT TOXICITY, WHAT'S THE BEST PATHWAY TO TREATING THE PATIENT. LESS, SKIN IS COMMON, G.I. IS COMMON. WITH GROWING NUMBER OF PATIENTS, WE SEE IT FREQUENTLY. THIS IS 'EM EMPHASIZED BY THIS SLIDE. THESE ARE TIME TRENDS OF SPONTANEOUS REPORTS TO THE FDA FOR COLLECTED TOXICITY FROM CHECKPOINT INHIBITORS. ALTHOUGH OVERALL TOXICITY, THE TOP LINE, THESE PHYSICIANS ARE URGED TO REPORT SIDE EFFECTS OF DRUGS TO THE FDA, YOU CAN SEE THE NUMBER OF SIDE EFFECTS REPORTED HAS INCREASED EXPONENTIALLY. ANOTHER THING TO REMEMBER, WE'RE USED TO LOOKING AT ACUTE TOXICITY OF DRUGS, WHERE WE GIVE A DRUG, SEE A SHORT PEAK RELATIVELY EARLY ON, BUT THE SIDE EFFECTS FROM THE DRUGS MAY BE DELAYED AND PROLONGED, SOMETHING WE NEED TO KEEP IN MIND AS WELL. AND NOW WE HEARD ABOUT MECHANISMS, AND THE ASSUMPTION IS WITH THESE DRUGS, WE'RE DEALING WITH AUTOIMMUNE DISEASE, YOU CAN SEE THAT AS I'LL SHOW YOU LATER THAT WHEN REPORTS GET MADE TO THE FDA WITH GENERAL CATEGORIZATION BY CLINICIANS THEY ARE ALMOST ALWAYS CALLED AUTOIMMUNE HEPATITIS OR COLITIS BUT THERE ARE MANY POTENTIAL MECHANISMS, AND I SUBMIT WHILE OFTEN ASSUMPTION IS IT'S AN ISSUE OF RECOGNIZING ANTIGENS PRESENT ON TUMORS AS SELF, THIS MIGHT NOT BE THE ONLY MECHANISM, THIS IS FROM LAST YEAR NEW NEW ENGLAND JOURNAL, INCLUDING INCREASED LEVELS OF EXISTING ANTIBODIES, INFLAMMATORY CYTOKINES, AND OTHER MECHANISMS. ARE THESE REALLY THE SAME AS AUTOIMMUNE DISEASES? I'LL TALK ABOUT AUTOIMMUNE HEPATITIS. WELL, MAYBE. BUT WE TREAT -- WE CERTAINLY TREAT THESE AS IF THEY WERE AUTOIMMUNE CLINICAL ENTITIES, BUT THERE ARE DIFFERENCES AND THERE'S MUCH TO LEARN REGARDING MECHANISMS, I WANT TO EMPHASIZE THAT. THE OTHER POINT THAT'S IMPORTANT, IT'S BEEN ALLUDED TO BY OTHE SPEAKERS, MANY TUMORS DO EXPRESS SOME MARKERS ON THE CELL SURFACE, AND THESE ARE IN MICROENVIRONMENT WHERE THEY ARE SUSCEPTIBLE TO IMMUNE CHECKPOINT INHIBITORS, SOME TUMORS JIM ALLISON LIKES TO CALL COLD TUMORS WHICH DON'T. HERE YOU WITH POTENTIALLY INDUCE A MICROENVIRONMENT IN A SITUATION AMENABLE TO IMMUNE CHECKPOINT BLOCKADE TREATMENT, WITH OTHER COMBINATION THERAPIES WITH AGENTS THAT CREATE IMMUNOGENIC TUMOR MICROENVIRONMENTS, AND THEN WILL BE SUSCEPTIBLE. I THINK WITH INCREASED TOXICITY, SOMETHING WE'RE GOING TO SEE MORE AND MORE AS WE PROCEED WITH COMBINATION THERAPIES. THIS IS ONE DEFINITION OF FLYING BY THE SEAT OF YOUR PANTS, WORK WITHOUT FORMAL GUIDELINES OR EXPERIENCE. UNTIL RECENTLY WE'VE WORKED WITHOUT FORMAL GUIDELINES, EVEN THE GUIDELINES WE HAVE ARE BASED ON ANECDOTES, SMALL CASE SERIES, BUT ONE OF MY FAVORITE FOOTBALL COACHES SAID FLYING BY THE SEAT OF YOUR PANTS PRECEDES CRASHING BY THE SEAT OF YOUR PANTS AND WE NEED TO DEVELOP GUIDELINES EVIDENCE-BASED. MULTIPLE SOCIETIES A YEAR AGO DID COME UP WITH GUIDELINES, AND FOR THE MOST PART THEY TRIED TO BE EVIDENCE BASED BUT AS THEY FULLY ADMITTED MOST OF THIS IS BASED ON SMALL SERIES ANECDOTE. NCCN UPDATED SKYLANDS IN 2019, ON MANAGEMENT OF IMMUNOTHERAPY, I'LL ALLUDE TO THESE TALKING ABOUT LIVER TOXICITY BUT I WANT TO POINT OUT MUCH OF THE EVIDENCE CONSISTS OF OBSERVATIONAL DATA, CONSENSUS GUIDELINES, CASE SERIES AND CASE REPORTS, DUE TO PAUSEICITY, BASED ON EXPERT OPINION. AND THE SOCIETY FOR IMMUNOTHERAPY OF CANCER TOXICITY MANAGEMENT SAID THE RESULTS OF THEIR GUIDE LINES REPRESENT CONSENSUS THINKING BY EXPERTS BUT SHOULD NOT REPLACE EXPERTS. THERE ARE EVIDENCE GAPS, CONSIDERABLE, AND IN FACT CONSENSUS IS NOT ALWAYS REACHED BY EXPERTS. AND THERE ARE MANY QUESTIONS THAT REMAIN UNANSWERED. IN LOOKING AT ANY ADVERSE EVENT, THESE ARE SICK PATIENTS, THERE'S A LOT GOING ON. THERE ARE MULTIPLE DRUGS. SUSCEPTIBLE TO INFECTION. WE NEED TO START BY DOING A LOT OF THINGS UP FRONT, GOOD HISTORY AND PHYSICAL, SOME EXAMS. BUT AGAIN THESE ARE GUESSES, I'LL POINT OUT WHEN WE TALK ABOUT LIVER FUNCTION TESTS THESE ARE NOT SPECIFICALLY MENTIONED IN THE NCCN GUIDELINES YET FORM THE BASIS OF DEFINITIONS OF TOXICITY IN THE LIVER. WE HEARD ABOUT DIARRHEA COLITIS, I'M NOT GOING TO GO OVER THIS EXCEPT TO POINT OUT SOME EVIDENCE FROM OUR INSTITUTION, A FEW POINTS. BUT CERTAINLY AS WAS SAID BEFORE, TOXICITIES VARY BETWEEN IPILUMINAB AND SOME OTHER DRUGS, GRADES OF TOXICITY, A POINT MADE BEFORE, VERY QUICKLY, COLITIS IS A SPECTRUM OF DISEASE, SOME PEOPLE ALWAYS HAVE MILD DISEASE, WE ASSUME, BUT COULD GO ON INEVITABLY TO SEVERE DISEASE, DO WE TREAT PATIENTS DIFFERENTLY, BUT THE PRESENTATIONS CAN DIFFER WITH DIFFERENT DRUGS AMONG DIFFERENT INDIVIDUALS ARE NOT PART OF THE GUIDELINES OF ANY OF THESE SOCIETIES WHICH ARE BASED ON COMMON TOXICITY ELEMENTS. SO, UNLIKE IDIOPATHIC INFLAMMATORY BOWEL DISEASE WE NEED TO PERHAPS START INCORPORATING THESE THINGS INTO OUR GUIDELINES. ONE QUESTION WHICH WE DON'T HAVE AN ANSWER FOR IS DOES ACUTE INFLAMMATION LEAD IN ANY CASE DO CHRONIC INFLAMMATION? AND IF SO, CAN WE PREDICT THAT SUBSET OF PATIENTS, AND TREAT THEM DIFFERENTLY? WE JUST DON'T KNOW. THERE IS SOME EVIDENCE BUT VERY ANECDOTAL IN SOME PATIENTS THERE CAN BE CHRONICITY, HISTOLOGICALLY, AND CLINICALLY, PATIENTS AND KNOW HOW TO TREAT THEM BEST EARLY ON. SO, AS I MENTIONED, COMMON TOXICITY ELEMENTS REALLY ARE BASED ON SYMPTOMS, HOW SICK IS THE PATIENT, BUT DON'T INCORPORATE OBJECTIVE FINDINGS LIKE ENDOSCOPIC FINDINGS, HISTOLOGIC FINDINGS, WE NEED TO DO THAT. PERHAPS WE NEED TO USE SCORING SYSTEMS FOR INSTANCE THAT ARE USED FOR IDIOPATHIC INFLAMMATORY BOWEL DISEASE LIKE THE MAYO CLINIC SCORE, CROHN'S DISEASE ACTIVITY INDEX, WE REALLY ONLY BASE OUR TREATMENT NOW AT LEAST BY GUIDELINES ON CLINICAL SYMPTOMS, AND I KNOW MANY OF US WHO SEE A LOT OF THESE PATIENTS ARE INCORPORATING HISTOLOGIC FINDS BUT WE NEED TO GET BETTER OBJECTIVE SCORING SYSTEMS. THIS WAS -- OH, THIS IS JUST A POINT FROM OUR DATA, M.D. ANDERSON, MANY PEOPLE IF YOU LOOK AT SYMPTOMATIC FINDINGS OR EVEN ENDOSCOPIC FINDINGS MAY HAVE LOW GRADE DISEASE, IF YOU BIOPSY THEM YOU'LL OFTEN SEE HIGHER PERCENTAGES THAT INCORPORATE INFLAMMATION IN TERMS OF THEIR CLONIC FINDINGS, HOW YOU INCORPORATE THIS INTO GUIDELINES FOR FUTURE THERAPY AND RISK STRATIFICATION REMAIN TO BE SEEN. CLINICAL REMISSION DOESN'T ALWAYS EQUATE TO CURE. THIS IS A PATIENT WE SAW WHERE YOU CAN SEE AT THE TOP PRE-TREATMENT, RECEIVED HIGH DOSE STEROIDS, GOT BETTER CLINICALLY BUT ENDOSCOPICALLY NOT MUCH CHANGED. THE ENDPOINT FOR TREATMENT, IS IT SYMPTOMS OR IS IT ENDOSCOPIC OR HISTOLOGIC FINDINGS? TO EMPHASIZE SOMETHING THAT MICHAEL SAID THIS IS A STUDY FROM OUR GROUP, FINDING ULCERATIVE DISEASE ENDOSCOPICALLY DOES SEEM TO PREDICT THOSE WHO WON'T RESPOND TO STEROIDS AND MAY NEED EARLIER TREATMENT WITH THINGS LIKE INFLIXIMAB OR VETALUZAM. FOR THE COLON WE'LL HEAR ABOUT THE MICROBIOME LATER, A PLENARY TALK ABOUT DEAL WITH THIS BUT HOW DOES THE MICROBIOME IN AN IMMUNOGENIC ENVIRONMENT AFFECT DISEASE, RESPONSE TO THERAPY, WE'LL HEAR LATER ON IN THE PROGRAM FROM JEN, RESPONSE TO ANTI-PD-1 IMMUNOTHERAPY, IMPORTANT TO OUR TALK TODAY THERE IS SOME DATA THAT THE INTESTINAL MICROBIOME CAN IDENTIFY PATIENTS AT RISK FOR COLITIS AND I THINK THIS IS AN -- I WON'T SAY EASILY BUT A QUESTION WITH YOU WE SHOULD WORK TO DO THESE STUDIES BECAUSE WE MAY BE ABLE TO PREDICT WHO WILL AND WON'T HAVE CLONIC TOXICITY BASED ON THEIR MICROBIOME. THIS IS FROM ONE STUDY, YOU CAN SEE BASED ON HEAT MAPS THAT THE COMPOSITION OF THE MICROBIOME DIFFERED FROM THE STUDY BETWEEN THOSE WHO WERE COLITIS FREE AND THOSE WHO HAD INFLAMMATORY COMPLICATIONS. LASTLY, VERY ANECDOTAL COULD FECAL TRANSPLANTATION RESULT IN TREATMENT FOR REFRACTORY PATIENTS? THIS IS WORK FROM WANG, WHICH IS NOW PUBLISHED, STILL ANECDOTAL, AND YOU CAN SEE IN THIS PATIENT WHO WAS REFRACTORY, BOTH CENTERED ON AND OTHER IMMUNOSPECIFIC THERAPY, DID RESPOND TO FECAL MICROBIAL TRANSPLANTATION. THIS IS AN EVOLVING PICTURE OF TOXICITY, BECOMING FREQUENTLY REPORTED, BUT GUIDELINES DIFFER AND WE DON'T HAVE GOOD GUIDELINES FOR COLITIS. THIS IS SOME DATA BASED ON UNITED STATES PRESCRIBING INFORMATION, FEEDBACK DATA BASE, YOU SEE FOR IPILUMINAB THE INCIDENCE OF REPORTED TOXICITY VARIES BETWEEN 4 TO 11%, VERY FEW PATIENTS, .2% FATAL COMPLICATIONS, MEDIAN TIME TO ONSET, SOME HAVE LOWER FOR PEMBROLIZUMAB AND NIVOLUMAB. AS WE COMBINE THESE DRUGS I THINK WE'LL NEED TO LEARN MORE ABOUT THE PATTERNS OF TOXICITY. THESE ARE SOME NEWER DRUGS, LOWER PREVALENCE OF TOXICITY REPORTED THUS FAR. SO, THIS IS ONE GRADING SYSTEM FROM UNITED STATES PRESCRIBING INFORMATION, WHERE YOU CAN SEE THAT HEPATOTOXICITY IS BASED ON CTCAE GUIDELINES FOR TRANSAMINASE, NOT HEPATITIS, NO GUIDELINES GRADES HEPATITIS IN GENERAL. MOSTLY BASED ON TRANSANINASE PLUS ELEVATED BULLY RUBIN, FOR PATIENTS WITH HIGHER GRADE DISEASE, HIGHER DOSE OF CORTICOSTEROIDS, THIS IS EMPIRIC. WE DON'T HAVE GOOD EVIDENCE. THIS IS A -- METANALYSIS OF EVENT FROM CTLA-4 AND PD-1 THERAPY, YOU CAN SEE THE OVERALL INCIDENCE OF HEPATOTOXICITY FORMED BY AST ELEVATION WAS RELATIVELY LOW, STATISTICALLY DIDN'T DIFFER FROM TERMS OF MILD TOXICITY, . THIS IS AN INTERESTING STUDY THAT LOOKED AT WORLD HEALTH ORGANIZATION DATA BASE, AS WELL AS METANALYSIS. YOU CAN SEE THIS DATA FROM THE WORLD HEALTH ORGANIZATION DATABASE, THAT TOXICITY SEEMS TO OCCUR MORE QUICKLY SOONER WITH COMBINATION THERAPY, AND WITH ANTI-PD-1 THERAPY, COMPARED TO IPILUMINAB THERAPY, SO THE PATTERN OF TOXICITY MAY DIFFER. ANOTHER WAY OF LOOKING AT THIS AS WE GO TO COMBINATIONS OF DRUGS IS HOW DO THESE CLASSES OF DRUGS COMPARE TO OTHER CHEMOTHERAPEUTIC AGENTS. THIS USED DISPROPORTIONALITY ANALYSIS, LOOKS AT A RELATIVE RISK OF CLASS OF DRUGS TO OTHER CLASSES OF DRUGS, IN THIS CASE IMMUNE CHECKPOINT INHIBITORS, TO OTHER CHEMOTHERAPEUTIC AGENTS, HEPATOTOXICITY WAS EMERGING IN SAFETY PROFILES, SOMETHING WE'LL HAVE TO PAY ATTENTION TO. THIS IS THE RELATIVE ODDS RATIO FOR DIFFERENT EFFECTS FOR DIFFERENT DRUGS, COMPARING IMMUNE CHECKPOINT INHIBITORS TO OTHER ANTI-CANCER AGENTS, YOU CAN SEE FOR HEPATITIS HEPATIC FUNCTION, ET CETERA, ONE POINT, THESE ARE HOW CLINICIANS REPORTED THESE EVENTS. YOU SEE OVERWHELMINGLY REPORTED AS AUTOIMMUNE HEPATITIS. CLINICALLY THERE'S SOME SIMILARITIES BUT ALSO A LOT OF DIFFERENCES. WE HAVE TO LEARN MORE ABOUT WHAT IS THE PATHOGENESIS OF THESE DISEASES. CERTAINLY COMPARED TO OTHER CHEMOTHERAPEUTIC AGENTS, IMMUNE CHECKPOINT INHIBITORS, HIGHER ODDS RATIO FOR HEPATIC DISEASE AND AGAIN IF YOU COMPARE DIFFERENT CLASSES OF DRUGS THEY APPEAR TO BE HIGHER WITH COMBINATION THERAPY OR ANTI-CTLA-4 BUT NOT STATISTICALLY SIGNIFICANT. ONCE AGAIN, WE BASE OUR GRADING OF THESE DRUGS ON COMMON TOXICITY ELEMENTS, THERE IS NONE FOR HEPATITIS. THERE'S ONE FOR OTHER HEPATIC DISORDERS AND COMMON TOXICITY ELEMENTS WHICH LOOK AT CHEMICAL LAB TESTS, AMINO TRANSFERASE, BILIRUBIN, GRADATIONS RELATE TO HOW MANY FOLD OF NORMAL ARE THESE TRANSAMINASE BUT THEY DON'T ALWAYS CORRELATE WITH THE LIVER, ARE THERE HISTOLOGIC PATTERNS THAT PREDICT TOXICITY, PREDICT WHAT WE NEED TO DO FOR THERAPY, ARE THEY DIFFERENT BETWEEN DRUG CLASSES, WE DON'T HAVE A LOT OF INFORMATION. I ASKED A PATHOLOGIST TO GET SLIDES, WE DON'T BIOPSY OFTEN. MOST COMMON IS, THESE PEOPLE RESPOND QUITE WELL TO LOW DOSE STEROIDS. WE ALSO SEE A SMALLER GROUP OF PATIENTS, MORE COMMONLY WITH LOBULAR NECROSIS, ENDOTHELIALITIS, CYTOTOXIC T LYMPHOCYTES, IF YOU STAIN FOR THESE IS THE EVENTUAL COURSE CLINICALLY IN THESE PATIENTS DIFFERENT, WE DON'T KNOW. SHOULD YOU TREAT THEM DIFFERENTLY, WE DON'T KNOW. WHAT IS THE ROLE OF LIVER BIOPSY, WE DON'T KNOW. I'M GOING TO FINISH UP, NCCN GUIDELINES, THEY HAVE TWO CLASSES TO BASE TREATMENT UPON. ONE IS TRANSAMINITIS WITHOUT ELEVATED BILIRUBIN, BASED ON LEVELS OF TRANSAMINASES ELEVATED ABOVE NORMAL, ARBITRARY, MANAGEMENT SIMILAR TO COLITIS. IF YOU HAVE MILD DISEASE, HOLD THE THERAPY, MONITOR TESTS, MAYBE CONSIDER PREDNISONE. ONCE YOU GET TO GRADE 2 DISEASE, GRADE 3 DISEASE, DISCONTINUE THERAPY PERMANENTLY WHICH MAYBE WE SHOULD DO, MAYBE WE SHOULDN'T. GIVE THE PATIENTS LOW DOSE STEROIDS, MONITOR THEM AND ONCE WE GET TO HIGHER ELEVATION OF TRANSAMINASEE PERHAPS A LIVER BIOPSY, TREATED BY GUIDELINES AS YOU TREAT HIGHER GRADE TRANSAMINITIS DISEASE. GUIDELINES ADVISE AGAINST USING THIS. THE ANECDOTAL EVIDENCE IS LIKE WE SEE IN LITERATURE, IF YOU LOOK AT MODERATE TO SEVERE HEPATOTOXICITY, 1.7%, MUCH LESS FOR SEVERE THAN MODERATE TOXICITY. MEDIAN NUMBER OF INFUSIONS, YOU CAN SEE THE TIME FROM INTERVENTION TO HEPATOTOXICITY, VERY SMALL NUMBER OF PATIENTS WERE RESTARTED ON THERAPY, AND FORTUNATELY THE RECURRENT ALT ELEVATIONS WAS LOW, BETWEEN 16 TO 28%, MORE WITH COMBINATION THERAPY, BUT NOT STATISTICALLY SIGNIFICANTLY. I WOULD FINISH WITH A PLEA THAT WE TREAT THESE TOXICITIES AS WE WOULD TREAT OTHER CLINICAL EVENTS WITH SCIENTIFIC RIGOR, THERE'S A DRUG INDUCED LIVER NETWORK ESTABLISHED TO LOOK AT TOXICITY AND STUDY IN A SCIENTIFIC MANNER FOR THESE DRUGS AND ALL DRUGS AND THE ISSUE HERE, THE IDEA IS THAT WE FOLLOW THESE PEOPLE, OBTAIN BIOLOGICAL SAMPLES, TRY TO PROVIDE RIGOR IN LOOKING AT HOW THESE DRUGS ARE TOXIC, AND WHAT WE NEED TO DO ABOUT IT. SO I'LL FINISH WITH A COUPLE THINGS, FOR THE DIARRHEA, WE HAVE A PAUCITY OF HIGH QUALITY PROSPECTIVE EVIDENCE, MOST ANECDOTAL, COLITIS AND DIARRHEA THE MOST COMMON. SIDE EFFECTS CAN RECUR AFTER CESSATION OF TREATMENTS AND BE PROLONGED. SPECIALISTS SHOULD BE INCLUDED IN THE MANAGEMENT OF THESE PATIENTS. I AGREE WITH MICHAEL THAT EARLY COLONOSCOPY CAN HELP WITH TREATMENT OF DISEASE AND PERHAPS PREDICTION OF WHO WILL RESPOND, WHO MAY NEED OTHER TYPES OF THERAPY EARLY, WHILE CURRENTRY IV STEROIDS ARE FIRST LINE TREATMENT FOR EARLY STAGE DISEASE WE USE INFLIXIMAB. ANECDOTALLY STEROID TREATMENT IS FIRST LINE TREATMENT FOR EARLY. THERE'S A GREAT NEED TO DEVELOP IMPROVED MEANS OF DETECTING, FEE DINING, AND STUDYING IMMUNE CHECKPOINT RELATED LIVER TOXICITY. THANK YOU. [APPLAUSE] >> WE'RE GOING TO MOVE TO A PANEL DISCUSSION. WE HAVE DR. MARK ANDERSON JOINING THE PANEL DISCUSSION TO BE GIVING THE TALK IMMEDIATELY FOLLOWING. ONE QUESTION TO GET STARTED, EVERYBODY HAS MENTIONED WHERE WE NEED TO GO NEXT. WHAT DO YOU THINK IS THE MOST IMPORTANT NEXT STEP IN UNDERSTANDING OR TREATING, UNDERSTANDING HOW TO TREAT MUCOSAL TOXICITY OR HEPATITIS, AND NOW I WILL SIT DOWN. >> SO I GUESS WHAT IS THE LOW-HANGING FRUIT, WHAT CAN WE APPROACH? OBVIOUSLY MECHANISMS WE'D LIKE TO KNOW, BUT I THINK THERE ARE APPROACHES THAT WE CAN RIGHT NOW APPROACH IN A SCIENTIFIC MANNER. ONE ISSUE IN DEALING WITH MICROBIOME CAN YOU USE MICROBIOME TO DETERMINE WHO WILL AND WON'T DEVELOP COLITIS? THERE'S SOME PRE-CLINICAL AND EARLY CLINICAL EVIDENCE. I THINK THERE ARE APPROACHES IN A RIGOROUS MANNER SO WE CAN DO THAT. I THINK WE START -- NEED TO GET A BETTER SCORING SYSTEM, THAT INCORPORATE DIFFERENT CLINICAL OBJECTIVE ELEMENTS. WE HEARD ABOUT OBJECTIVE FINDINGS NOT COVERED BY COMMON TOXICITY ELEMENTS. WE WANT TO RELIEVE SYMPTOMS BUT HOW DO WE AVOID DOWNSTREAM CHRONIC EVENTS? >> DR. BARUCH? >> JUST COVERED. I'VE GOT NOTHING ELSE BUT TO AGREE. I WANT TO EMPHASIZE BIOMARKERS, NOT JUST IN TERMS OF MICROBIOME. >> I WOULD LIKE TO ADD ONE MORE THING, I THINK WE DO NEED SOME PROSPECTIVE AND RANDOMIZED TRIALS IN THIS SPACE BECAUSE WE'RE DEALING WITH A SUBSET OF PATIENTS DEALING WITH CANCER, I DON'T THINK ONE INSTITUTION HAS ENOUGH PEOPLE TO GIVE US RIGOROUS ANSWERS. >> I JUST WANT TO TOUCH ON A POINT AND PERHAPS IT'S GOING TO COME UP IN QUESTIONS, ONE HUGE ADVANTAGE, YOU HAVE PATH MATERIAL, WHAT IS GOING ON IN THE BIOPSY, RIGHT? WHAT'S THE GENE SIGNATURE, THE CELLS IN THERE? DOES IT CORRELATE WITH THE CLINICAL PRESENTATION? THAT SEEMS LIKE DEFINING THAT IS CRITICAL ESPECIALLY IF YOU THINK ABOUT A CLINICAL TRIAL OR CLINICAL THERAPY, WHICH PATIENTS ARE YOU DEALING WITH? >> YEAH, IF WE DO THIS, WE NEED TO DO IT WITH RIGOR IN A SETTING OF A CLINICAL TRIAL. LAST WEEK I WAS TALKING TO A JUNIOR FACULTY MEMBER. OH, YEAH, WE'RE GOING TO BIOPSY, HERE, HERE, HERE. HOW ARE YOU GOING TO TRACK THIS? OH, WELL, I DON'T KNOW. YOU NEED RIGOR. NIECE ARE PEOPLE, PATIENTS, SICK PATIENTS. >> I'M ONE OF THE G.I. FELLOWS. COULD THE PANEL BRIEFLY TALK ABOUT WHEN YOU DECIDE TO RESTART CHECKPOINT INHIBIT THERAPY WITH PATIENTS THAT ARE RESPONDING TO IMMUNOSUPPRESSIVE THERAPIES AND A SECOND QUESTION AFTER THAT. >> I MAKE THAT DECISION ENDOSCOPICALLY. PATIENTS WHO HAVE RELATIVELY MILD ENDOSCOPIC DISEASE, I THINK WE CAN RESTART THERAPY QUICKLY. I USUALLY WILL MAKE THAT DECISION BASED ON THEIR SYMPTOMS. SO SYMPTOMS ARE RESOLVED, RESTART THERAPY AND COME UP WITH A PLAN FOR SYMPTOMS THAT OCCUR. ULCERATIVE DISEASE I'M WORRIED ABOUT PERFORATIONS AND TAKE A CAUTIOUS APPROACH, DEPENDING WHETHER OR NOT THEY WERE BENEFITING FROM IMMUNOTHERAPY AND WHAT OTHER OPTIONS, SOMETIMES WE TAKE IMMUNOTHERAPY HOLIDAY AND GO TO A DIFFERENT COURSE AND COME BACK. >> YEAH, IT'S INTERESTING BECAUSE IT'S A GREAT QUESTION, IF YOU LOOK AT THE NCCN OR THE GUIDELINES, ONCE YOU GET TO STAGE 3 AND 4 DISEASE THEIR TALKING ABOUT NEVER RESTART THERAPY, THAT'S NOT PRACTICAL FROM THE POINT OF VIEW OF TREATING THESE PATIENTS, I THINK. AND I AGREE WITH MICHAEL, WHAT'S THE ROLE OF ENDOSCOPY, HAS TAKEN A GREATER -- IT'S BEEN A GREATER ROLE. AND MANY OF US DO REENDOSCOPE. YOU DON'T HAVE TO DO A FULL COLONOSCOPY. PATIENTS WITH SEVERE DIARRHEA I DO NOT PUT THEM THROUGH PREP IF I CAN HELP IT. THEY HAVE ENOUGH ISSUES. YOU CAN OFTEN JUST LOOK, VERY SHORT EXAM, LOOK AT THE MUCOSA, GET A FEELING FOR WHAT'S GOING ON, HOW THEY ARE RESPONDING BUT I THINK IF THEY HAVE RESPONDED -- I START WITH CLINICAL SYMPTOMS, CERTAINLY ULCERATIVE DISEASE, I'D LIKE TO HAVE -- THERE'S BEEN MUCOSAL HEALING, AND WE DO RESTART THESE PATIENTS, DESPITE SOME OF THE PROHIBITIONS AND GUIDELINES WHICH ARE EMPIRIC. >> WE ALMOST NEVER RENEW THERAPY IN PATIENTS WITH GRADE 4, EVEN IF ENDOSCOPY, IT'S AFTER A LONG PERIOD, A WASHOUT TIME, DO YOU HAVE RECOMMENDATION. >> GRADE 4, THERE'S A LOT OF SPECTRUM IN GRADE 4. THE WAY THAT I ADVOCATE IS BASED ON THE EMPIRIC DATA. IF YOU HAD SOMEONE WHO SEEMED REALLY SICK AND THEN YOU GO IN AND SEE THAT THE MUCOSA IS PRETTY NORMAL LOOKING CHANCES ARE SOMETHING ELSE WAS GOING ON AT THAT TIME, MAYBE THEY HAD AN INFECTION THAT YOU DIDN'T CATCH, AND I'D BE MUCH MORE WILLING TO CONSIDER RESTARTING IMMUNOTHERAPY THAN IN SOMEBODY WHO WOUND UP IN THE ICU WITH YOU ULCERATING DISEASE CLOSE TO PERFORATING. >> A LOT OF THINGS ARE GOING ON WITH THESE PATIENTS. WE SEE PATIENTS, POSSIBILITY OF IMMUNE CHECKPOINT, RELATED DIARRHEA OR TOXICITY, FIRST THING IS RULE OUT OTHER THINGS. USED TO BE WE DID LIKE GRAFT-VERSUS-HOST DISEASE, THE NEW ENTITY WITH CALLED ON MOST FREQUENTLY IS IMMUNE CHECKPOINT DIARRHEA BUT YOU NEED TO DO CULTURES, MAKE SURE THEY DON'T HAVE C. DIFFICILE, BEFORE WE GO TO STEROIDS THAT WE RULE OUT OTHER ENTITIS. >> YES, HOWARD FINGERTON, VERY INVOLVED IN INDUSTRY AND MANAGING DIVERSE CLINICAL PROTOCOLS WITH THESE PATIENTS, ESPECIALLY COMBINATIONS. FIRST, ONE-SENTENCE CLARIFYING QUESTION AND MY REAL QUESTION, DR. DOUGAN, WHEN YOU SHOWED DATA ABOUT THE PATIENTS WITH IBD, UNDERLYING IBD, 60+ WHO DID WELL, SOME DID WELL OVER TIME, WERE THOSE PATIENTS ENROLLED TO STUDIES OR WAS THAT RETROSPECTIVE REVIEW OF PATIENTS FOLLOWED BY -- MY REAL QUESTION TO THE PANEL GIVEN THE MATURITY THAT IS GOING ON, IN THIS FIELD, WHAT SHOULD BE CHANGED IN THE WAY WE RUN PROTOCOLS? SO FOR EXAMPLE, THE MERCK COMPANY HAS ADVOCATED AT DIFFERENT TIMES THAT SOME OF THE PROTOCOLS THEY RUN WITH PEMBRO, IMMUNOTOXICITY OR IMMUNOLOGIC DISEASE, OR IF YOU ARE ON A STEROID, CONSTANT DAILY STEROID OVER 10 MILLIGRAMS EQUIVALENT OF PREDNISONE PER DAY, BUT NOW SOME OF THE DATA YOU SHOWED, YOU CAN UNDERSTAND THE QUESTION. SOME OF THESE OLDER ALGORITHMS SHOULD BE CHANGED IN THE WAY WE MANAGE PROTOCOLS, THE WAY WE TRY A INCLUDE MORE PATIENTS GOING FORWARD WITH BETTER MONITORING, ET CETERA, AND THAT'S REALLY THE HEART OF THE QUESTION. >> TO ME I THINK THAT'S -- IT IS THE DIFFERENT QUESTION WITH A LOT OF PATIENTS WITH UNDERLYING AUTOIMMUNE DISEASE, ESPECIALLY LOOKING AT NEW AGENTS. I SHOWED 12 PATIENTS THERE. YES, PEOPLE DID DO WELL. I THINK IF YOU'RE TREATING PEOPLE AS STANDARD OF CARE, THAT MAKES SENSE BUT IF YOU'RE TRYING TO ANSWER A DISTINCT CLINICAL QUESTION, IT COULD BE A SUBGROUP ANALYSIS, NOT NECESSARILY INCLUDED BUT I WOULDN'T INCLUDE THOSE PATIENTS IN THE GENERAL POPULATION EITHER WHEN YOU DON'T KNOW IF THE INVESTIGATIONAL AGENT IS GOING TO BE EFFECTIVE AT ALL OR WHAT THE TOXICITIES COULD BE. >> YEAH, SO YOU BRING UP A GOOD POINT BECAUSE WE REALLY DON'T KNOW, A LOT OF SUPPOSITION, WHAT ARE CLINICAL OF EFFECTS OF PEOPLE WHO ALREADY HAVE UNDERLYING AUTOIMMUNE DISEASE. THERE'S DISCUSSION IN PREAMBLE TO THE GUIDELINES. WHAT CAN YOU TOLERATE IN THESE PATIENTS? THE COMPANIES ARE SHY ABOUT ANY TOXICITY, CERTAINLY IN HEALTHY PATIENTS, EVEN IN SICK PATIENTS, SO HAVING BEEN INTIMATELY INVOLVED IN COX2 ISSUE WITH TOXICITY, CARDIOVASCULAR DISEASE, YOU SAW WHAT HAPPENED THERE, WE'RE VERY CAUTIOUS. I THINK -- I DON'T THINK WE NECESSARILY NEED TO PROHIBIT CONCLUSION OR WE'LL NEVER FIND OUT WHAT THE REAL STORY IS BUT WE NEED TO BE CAUTIOUS IN HOW WE FOLLOW THEM. >> RACHEL CASSPI, NIH. IN THESE GUT TOXICITY CASES THE PANEL MEMBERS TOUCHED SEVERAL TIMES ON THE MICROBIOME AND ITS POTENTIAL INFLUENCE, AND FECAL TRANSPLANT WAS DESCRIBED. SO, I'M WONDERING IF A SHORT COURSE OF ANTIBIOTICS COULD BE USEFUL, IF NOT TO ALLEVIATE THE CONDITION, AT LEAST TO PERHAPS TELL THE DIFFERENCE WHO MIGHT RESPOND TO A FECAL TRANSPLANT? IS THIS ANYTHING THAT HAS BEEN TRIED? >> I'VE TREATED PEOPLE WITH ANTIBIOTICS WHEN THEY HAVE ANYTHING GROWING IN THEIR CULTURE, INCLUDING THINGS THAT ARE NOT THOUGHT TO BE HUMAN PATHOGENS AND REQUIRED STEROIDS. PLENTY DON'T WORK UNTIL I ADD THE ANTIBIOTICS BUT I DON'T THINK ANTIBIOTICS BY THEMSELVES WILL TREAT MANY PEOPLE. >> THERE'S EVIDENCE FROM IDIOPATHIC BOWEL DISEASE, MAY BE EFFECTIVE IN SOME CASES, BUT THE PAUCITY, THERE IS A PAUCITY OF DATA, BUT SOME DATA ON ANTIBIOTICS IN THESE GROUPS NOT EFFECTIVE ALONE BUT WHEN YOU USE THE ANTIBIOTICS YOU'RE NOT JUST ALWAYS CHANGING THE MICROBIOME IN A POSITIVE WAY. YOU MAY CHANGE IT IN A NEGATIVE WAY AS WELL. I WOULD PROBABLY CAUTION AGAINST ROUTINE USE OF ANTIBIOTICS UNLESS THEY ARE REALLY INDICATED. >> IN ADDITION WE DON'T CURRENTLY -- THERE'S ONE WORK FROM SLOAN-KETTERING THAT YOU PRESENT ONE CLINICAL DESCRIBES PATIENTS FROM 2017, PATIENTS WITH COLITIS AND RELATION TO MICROBIOME, WE HAVE NO DATA REGARDING SPECIFIC STRAINS. >> THE WHOLE ISSUE OF HOW YOU DEFINE THE MICROBIOTA, BUT THE MOST COMMON THING IS PEOPLE USE DIVERSITY, I'M NOT SURE I KNOW WHAT THAT MEANS. THERE ARE SOME SPECIFIC STRAINS THAT HAVE COME OUT, SOME PRE-CLINICAL STUDIES, BUT WE HAVE A LOT MORE TO LEARN. >> YEAH, JIM SASSMAN, WESTERN. THE ANTIBIOTIC QUESTION, I MEAN, THERE'S SOME GOOD DATA THAT ANTIBIOTICS ACTUALLY WORSEN THE OUTCOME OF THE DISEASE. NOW OBVIOUSLY THAT'S NOT SIMPLY -- I'D BE VERY CAREFUL ABOUT USE OF ANTIBIOTICS EMPIRICALLY LIKE THAT. A COUPLE QUESTIONS, ONE YOU MAY NOT KNOW ANYTHING ABOUT IS THAT HYPOPHYSITIS EXPERIENCE, I'M NOT QUITE SURE WHEN YOU SAY LOW DOSE STEROIDS WHAT YOU MEAN, SIMPLY REPLACEMENT? >> LESS THAN 7 MILLIGRAMS OF PREDNISONE EQUIVALENT. >> REPLACEMENT DOSE. WITH THE GOAL OF REPLACING ADRENOCORTICAL ACCESS. >> YEAH, WHICH I THINK A LOT OF PEOPLE DO NOW. >> IN HIGH DOSE WAS GREATER THAN 20 MILLIGRAMS A DAY, SO AGAIN IMMUNOSUPPRESSANT DOSE BUT NOT NECESSARILY WHAT WOULD BE USED FOR RHEUMATOLOGIC ADVERSE EVENTS BUT CERTAINLY DOSE THAT'S WHAT WE WOULD USE IN COLITIS OR IN PNEUMONITIS. >> YEAH, I THINK -- I MEAN THAT'S A REALLY IMPORTANT FINDING BECAUSE A LOT OF US GIVE A SHORT COURSE OF HIGHER DOSE STEROIDS WITH THE CONCEPT THAT YOU COULD PRESERVE HYPOHOSEAL FUNCTION. YOU KNOW THERE'S DATA THAT PATIENTS WITH UNDERLYING AUTOIMMUNE DISEASE DO NOT HAVE GRADE INCREASE IN INCIDENCE OF TOXICITY, AND I JUST WONDER WHAT WERE THE DOSES OF STEROIDS IN THOSE PATIENTS, WHERE THEY HAVE TOUGH INFLAMMATORY BOWEL DISEASE, OR WAS THIS A HISTORY OF INFLAMMATORY BOWEL DISEASE? >> SO, I'LL SPEAK TO BOTH, WHAT'S PUBLISHED AND IN OUR EXPERIENCE. IN OUR EXPERIENCE THEY ALL ACTUALLY HAD DOCUMENTED INFLAMMATORY BOWEL DISEASE AT SOME POINT IN THE PAST BY GASTROENTEROLOGIST, THAT'S HOW WE ENDED UPPED -- UP AND INCLUDED THEM. WE VERIFIED DIAGNOSES. GENERALLY DID NOT KNOW IF THEY HAVE ACTIVE INFLAMMATION WHEN STARTED BECAUSE THAT ISN'T NECESSARILY STANDARD OF CARE ALTHOUGH I THINK IT SHOULD BE, TO DOCUMENT BEFORE YOU START IMMUNOTHERAPY ON THESE PATIENTS. ARE THESE PEOPLE WITH DEEP ULCERATION, WE HAD A PERSON ULCERATE IN THE, ILLYO CECUM, THE MOST COMMON SITE OF DISEASE FOR CROHN'S DISEASE. FOR PUBLISHED CASE SERIES FOR PD-1 VERY LITTLE DATA INCLUDED IN THOSE PUBLICATIONS ABOUT WHAT THAT UNDERLYING INFLAMMATORY BOWEL DISEASE WAS, HOW IT WAS DIAGNOSED, WHAT TREATMENTS THEY WERE ON. I SUSPECT THAT BECAUSE THIS IS BIAS TOWARDS EARLIER TREATMENTS, PEOPLE TREATED YEARS AGO, THEY ARE VERY MUCH SKEWED TOWARDS PEOPLE WHO DID NOT HAVE INFLAMMATORY BOWEL DISEASE OR HAD AN UNUSUALLY QUIESCENT VERSION OF THE DISEASE. >> I THINK THE DEFINITION IN MY VIEW IS THOSE WHO ARE ON INTENSE THERAPY AT THE TIME, HIGH DOSE STEROIDS, THOSE I'D BE VERY CAREFUL WITH. >> WE COULD HAVE SOME ANECDOTAL EXPERIENCE WITH REMOCADE AT THE START THAT INDICATES IT'S NOT UNSAFE BUT STEROIDS I WOULD WAIT UNTIL WE'RE OFF. >> I'M AN ENDOCRINOLOGIST. ONE CHALLENGES WITH HYPOPHYSITIS IS REVERSAL, IS IT TRANSIENT AND GOES AWAY, THERE PROBABLY AROUND ENDOCRINOLOGISTS, ONCE THEY START IT'S HARD TO UNRAVEL. IT'S TO THE POINT WE SHOULD STUDY THIS. >> SO I JUST WANT TO BRING ATTENTION TO MOST OF THE PATIENTS IMMUNOTHERAPY IS NOT FIRST LINE BUT RATHER AFTER THE CHEMOTHERAPY IN COMBINATION, ALWAYS RADIATION, SO A LOT OF PREEXISTING CONDITION, YOU ALREADY HAVE A DIRECT DAMAGE TO THE MUCOSAL SURFACE SO I WONDER FOR STUDY BIOLOGY OF PRE-CLINICAL MODELS HOW DO YOU MODEL THIS KIND OF EVENT WITH PREEXISTING DAMAGE TO THE MUCOSA SURFACE AND CAUSE MUCOSAL EROSION, ULCERATION AND YOU HAVE COLITIS AND HEPATITIS EVENTS WITH IMMUNOTHERAPY. >> DIARRHEA IS COMMON WITH MANY DRUGS FOR CANCERS. COLITIS NOT SO MUCH. BUT YOU RAISE A GOOD POINT. SO LIKE EVERYBODY GETS DIARRHEA TREATED FOR CANCER BUT YOU DON'T GET COLITIS. IF YOU LOOK AT GUIDELINES FOR TREATING COLON CANCER, FOR INSTANCEN PATIENTS MICROSATELLITE UNSTABLE THERE'S AN OPTION FOR USING THESE EARLY ON. THESE ARE STARTING TO CREEP INTO EARLIER TREATMENT OF CERTAIN SUBSETS OF TUMORS. WE'LL HAVE TO SEE. >> IT'S A VERY IMPORTANT QUESTION. I DON'T HAVE ANYTHING USEFUL TO ADD. I THINK IT NEEDS TO BE STUDIED. WE DON'T HAVE AN ANSWER IN ANIMAL MODELS OR PATIENTS, IT'S SOMETHING I THINK ABOUT A LOT BUT -- >> (INDISCERNIBLE) DO YOU SEE ANY DIFFERENCE IN PATIENTS WITH MELANOMA OR LUNG CANCER? >> A LOT GOES WRONG IN PATIENTS WHO HAD SOMETHING ELSE FIRST. IT'S MORE COMPLICATED ALWAYS. >> SPEAKS TO THE ISSUE OF COMBINATION THERAPY AND IF THESE PEOPLE -- THE SIGNALS SEEMS TO BE TOXICITY ARE GREATER, BECAUSE YOU'RE CONVERTING COLD TUMORS TO HOT OR SOMETHING ELSE GOING ON IN TERMS OF INTERACTION BETWEEN THE DRUG? >> I THINK WE SHOULD MOVE NOW TO OUR NEXT TALK, SO WE'RE GOING TO HAVE DR. MARK ANDERSON. >> THANK YOU. SO, MY TALK I'M GOING TO CHANGE GEARS AND TALK ABOUT ANOTHER COMPLICATION RELATED TO CHECKPOINT THERAPY, AND THAT IS APPEARANCE OF TYPE 1 DIABETES IN A SUBSET OF THESE PATIENTS SO THESE ARE MY DISCLOSURES. SO BEFORE I GET INTO THE DETAILS, QUICK BACKGROUND. I'M A PHYSICIAN-SCIENTIST, ADULT DIABETESSOLOGYIST. I DON'T THINK I NEED TO SPEND A LOT OF TIME ON THE BACKGROUND OF THE DESTINATION WE'VE REACHED RIGHT NOW WITH AUTOIMMUNITY THE SETTING OF CHECK POINT BLOCKADE BUT A REMINDER OF BASICS HOW T CELLS ARE WIRED. AND THE NEED FOR CO-STIMULATION AND MANIPULATION OF CO-STIMULATION IS KEY TO TAKING BREAKS OFF OF THE IMMUNE SYSTEM OR PUTTING BRAKES BACK ON SO IT'S REALLY NOT A SURPRISE THAT AUTOIMMNITY IS SOMETHING THAT COULD ARISE IN CHECK POINT TREATMENT. EVERY DAY WE'RE GETTING MORE DRUGS APPROVED. THIS GETS AT THE MAIN POINT, THE ONE THING THAT HAS EMERGED, THOUSANDS OF PATIENTS ARE GETTING TREATED WITH THESE DRUGS, THAT WE'RE STARTING TO SEE AUTOIMMUNE TOXICITIES AND HAD A NICE SESSION ON THE G.I. TOXICITY BUT ALL KINDS OF ORGAN-SPECIFIC AUTOIMMUNE PROBLEMS CAN ARISE IN THESE PATIENTS, EVEN VERY UNUSUAL ENDOCRINE MANIFESTATIONS SO HYPOPHYSITIS WHICH I WON'T TALK ABOUT TODAY, SO COMMON IN PATIENTS THAT PARTICULARLY HAVE BEEN TREATED WITH IPILUMINAB AS AN ENDOCRINOLOGIST THIS IS A ONCE OR TWICE IN A CAREER KIND OF DISEASE, BUT THIS IS BEING UNLEASHED BY TREATMENT IS QUITE INTERESTING. A DISEASE NOT LISTED WE SEE CASE REPORTS IS HYPOPARATHYROIDISM AFTER TREATMENT WITH CHECKPOINT BLOCKADE. SO WHEN WE TALK ABOUT THE IREs THAT ARISE IN CHECK POINT BLOCK BLOCKADES, THERE ARE PATTERNS STARTING TO EMERGE, TARGETING CTLA-4 AND PD-1, HIGHER INCIDENCE OF IREs, AND THERE'S ALSO PATTERNS WHEN IT COMES TO ENDOCRINE SIDE EFFECTS, CASES OF HYPO AND HYPER THYROIDISM, HYPER THYROIDISM CAN BE TRANSIENT AND RESOLVE ON IT'S OWN, HYPOTHYROIDISM APPEARS TO BE A PERMANENT CONDITION. THIS IS ANOTHER SLIDE BREAKING OUT -- -- FROM A PAPER ON FREQUENCY OF COMBINATIONS, 10% OF PATIENTS TREATED WITH CHECKPOINT BLOCKADE CAN GET THYROID PROBLEMS. IN THIS PAPER, CALCULATION THAT TYPE 1 DIABETES WAS RARE, AND WE RECENTLY PUBLISHED A PAPER IN DIABETES AND WE THINK THE FREQUENCY IS MORE AROUND 1% OF ALL PATIENTS GETTING TYPE 1 DIABETES, THE MAIN FOCUS OF MY TALK TODAY. SO, IF WE GO BACK AND TALK ABOUT SOME OF THE CLINICAL FINDINGS WITH PATIENTS GETTING WHAT LOOKS LIKE AUTOIMUNE DIABETES IN CHECKPOINT BLOCKADE, WHAT DO WE SEE CLINICALLY AND SUPPORT FROM THE MOONSHOT FUNDING. ONE THING THAT WE'VE DETERMINED IN THE CASE OF TYPE 1 DIABETES, THERE'S A PATTERN THAT RELATES TO EXPOSURE TO CHECKPOINT TREATMENT IN THESE PATIENTS. SO, IT DOES APPEAR THAT IT'S HIGHLY ASSOCIATED WITH EXPOSURE TO ANTI-PD-1 OR ANTI-PD-L1 BLOCKADE AND LESS TO CTLA-4, DIFFERENT FROM PITUITARY HYPOPHYSITIS WITH ANTI-CTLA-4. HERE IS DATA SUPPORTING WHAT I SAID. TWO STUDIES, WE LOOKED AT CASE REPORTS AND VIGIBASE, BREAKING DOWN WHETHER OR NOT TYPE 1 DIABETES OR AUTOIMMUNE DIABETES WAS OBSERVED IN PATIENTS, VERY UNUSUAL TO IDENTIFY PATIENTS THAT ONLY HAVE BEEN EXPOSED TO ANTI-CTLA-4. WE GET CONFOUNDERS, MOST COMMON FOR ANTI-CTLA-4 TO BE GIVEN IN COMBINATION WITH ANTI-PD-1. SO ANOTHER UNUSUAL THING ABOUT THESE PATIENTS, THIS GOES BACK TO WHEN I FOUND OUT ABOUT THIS HAPPENING, A COUPLE YEARS AGO ONE OF THE ENDOCRINE FELLOWS AT UCSF HAD JUST SEEN A PATIENT IN DKA IN THE HOSPITAL, WAS I INTERESTED IN STUDYING? I SAID YES. ONE OF THE THINGS THAT WE'VE NOTICED WITH THE PATIENTS IS ACUITY OF PRESENTATION OF DIABETES IS REALLY UNUSUAL, PARTICULARLY FOR AN ADULT. SO I DO -- I'M AN ADULT ENDOCRINOLOGIST WITH PATIENTS THAT DEVELOP SPONTANEOUS TYPE 1 DIABETES AS ADULT, CLINICAL PRESENTATION IS INSIDIOUS. THEY HAVE PROLONGED PRODUCTION OF C PEPTIDE, NEED TO BE A SMALL DOSES OF INSULIN, GET MISDIAGNOSED AT TYPE 2 RATHER THAN TYPE 1. CHECK POINT ASSOCIATED, CLINICAL PRESENTATION IS REMARKABLY ACUTE, FREQUENTLY COME IN IN DKA, POLY URIC, POLY DIPSIC. THEY ARE COMING FOR INFUSION, YOU CAN GO BACK AND LOOK AT RANDOM GLUCOSES OBTAINED ON THESE PATIENTS AND SO THIS FIGURE IS SHOWING YOU THE RANDOM GLUCOSES OBTAINED ON THESE PATIENTS OVER TIME, AND YOU CAN SEE IF YOU GO BACK INTO TIME, THERE ARE RANDOM GLUCOSES VERY MUCH IN THE NORMAL RANGE AND ALL OF A SUDDEN TAKES OFF. YOU CAN SEE MAYBE A LITTLE BIT OF INFLECTION ON CURVE BEFORE THEIR CLINICAL PRESENTATION. ANOTHER IMPORTANT POINT TO MAKE IS ONSET OF DISEASE. ONSET OF DISEASE AFTER EXPOSURE TO CHECK POINT THERAPY IS HIGHLY VARIABLE. ON AVERAGE SOMEWHERE IN THE BALL PARK OF 15 TO 20 WEEKS AFTER THERAPY THAT WE SEE TYPE 1 DIABETES. YOU CAN SUBSET THESE PATIENT INTO DIFFERENT GROUPS, IF YOU FOCUS ON THE MIDDLE, WE'VE BEEN ABLE TO LOOK ON A PATIENT THAT HAD AUTOANTIBODIES TO CLASSIC TYPE 1 DIABETES, LIKE GAD, INSULIN, IA 2, IF YOU'RE AUTOANTIBODY POSITIVE PERHAPS NOT SHOCKING ONSET WILL BE EARLIER IN PATIENTS AUTOBODY NEGATIVE. ONE THING I WANTED TO BRING UP HERE WAS A SLIDE ABOUT OUR UNDERSTANDING OF THE NATURAL HISTORY OF TYPE 1 DIABETES WITH PEOPLE THAT SPONTANEOUSLY GET IT OUTSIDE OF THE CHECK POINT SETTING. AND SO THIS IS A SLIDE HIGHLIGHTING WHAT MANY OF US CALL THE EISENBAR MODEL, THINGS THAT GO ON BEFORE CLINICAL ATTENTION. WHEN PATIENTS COME TO CLINICAL ATTENTION WITH OVERT HYPO GLEESEMIA WE THINK BETA CELL MASS IS DESTROYED TO THE LEVEL OF 10%. IF YOU HAD ABILITY TO GO BACK IN TIME BEFORE THAT PATIENT CAME IN THERE ARE MARKERS THAT THE IMMUNE SYSTEM HAS BEEN TARGETING THE BETA CELLS FOR QUITE SOME TIME SO THE BEST MARKERS OF COURSE ARE AUTOANTIBODIES, SO THESE ARE THE CLASSIC AUTOANTIBODIES IN TYPE 1 DIABETES. IF WE STUDY PEOPLE IN A PERSPECTIVE WAY WE OFTEN SEE THESE AUTOANTIBODIES YEARS BEFORE CLINICAL PRESENTATION. AND THEN EVEN PRIOR TO THE CLINICAL PRESENTATION THERE'S EVIDENCE THAT THEY HAVE AN ABNORMAL GLUCOSE TOLERANCE TEST. SO OF COURSE WITH THAT KNOWLEDGE IN HAND ONE WOULD WANT TO GO BACK AND LOOK AT THE CASES OF CHECKPOINT BLOCKADE TREATED DIABETES THAT WE'RE SEEING. SO, WE HAVE A COHORT THAT WE'VE DEVELOPED AT UCSF IN COLLABORATION WITH YALE, KEVAN HEROLD, WITH OVER 30 PATIENTS THAT DEVELOPED AUTOMEAN DIABETES AFTER CHECKPOINT BLOCKADE TREATMENT. ONE THING THAT'S INTERESTING IS THE AUTOANTIBODY FREQUENCIES SHOWN ON THE LEFT. YOU CAN SEE THAT IF YOU TAKE ANY TYPE 1 CLASSIC TYPE 1 DIABETES ASSOCIATED ANTIBODIES PREVALENCE IS 40% IN THESE PATIENTS, AND JUST FOR SOME PERSPECTIVE ON WHAT YOU WOULD EXPECT TO SEE IN PATIENTS THAT DEVELOP TYPE 1 DIABETES SPONTANEOUSLY, SHOWN HERE, 80 TO 90% OF TYPE 1 DIABETICS THAT COME IN HAVE AT LEAST ONE AUTOANTIBODY PRESENT. SO EVEN THOUGH THE CLINICAL PICTURE LIKES LIKE AUTOIMMUNE DIABETES PATIENTS ARE INSULIN DEFICIENT, THEY HAVE DKA, UNUSUAL FOR TYPE 2, MANY DON'T HARBOR THE CLASSIC ANTIBODIES AT THE TIME OF DIAGNOSIS. ANOTHER THING THAT WE'VE BEEN DOING SINCE WE PUBLISHED THIS FIRST CASE SERIES A YEAR AGO IS WE'VE BEEN FOLLOWING THESE PATIENTS OVER TIME. WELL, MAYBE THEIR ONSET OF DISEASE IS SO ACUTE WE NEED TIME FOR THE AUTOANTIBODIES TO DEVELOP. THIS IS ANECDOTAL DATA WHERE WE'RE LOOKING AT THREE PATIENTS THAT CAME IN WITH THIS SYNDROME, AUTOANTIBODY NEGATIVE AT PRESENTATION, NOW HOW MANY DAYS SINCE DIAGNOSIS THEY ARE, ONE OR TWO YEARS AGO, THE ONLY AUTOANTIBODY WE SEE THAT POPS UP IN THESE PATIENTS ARE INSULIN AUTOANTIBODIES, CON FOUNDED BY THE FACT PATIENTS ARE TREATED WITH INSULIN, INJECTION MAY BE PROMOTING THIS RESPONSE. THIS IS LOOKING AT 14 PATIENTS. IN THESE 14 PATIENTS THAT WE'VE BEEN FOLLOWING, SOME AS LONG AS 3 YEARS, THE ONLY AUTOANTIBODY WE SEE POP UP IN THESE PATIENTS ARE INSULIN AUTOANTIBODIES, THEY ARE NOT CONVERTING IN A POSITIVE DIRECTION, AT LEAST IN THE SMALL COHORT OF PATIENTS WE'RE FOLLOWING RIGHT NOW. NOW, ANOTHER IMPORTANT THING THAT WE HAVE THE OPPORTUNITY TO LOOK AT IN TYPE 1 DIABETES IS THE GENETICS, RIGHT? GENETICS HAVE BEEN WELL STUDIED, LIKE MANY AUTOIMMUNE DISEASES THE MOST -- HIGHEST RISK GENE MAPS TO HLA ITSELF SO IN OUR SMALL COHORT WE DID HLA TYPING, TO LOOK AT DO WE SEE AN INCREASED PREVALENCE OF CERTAIN HLA TYPES. BLUE ARE TYPE 1, WE'RE SHOWING FREQUENCY OF ALLELES IN CAUCASIANS THAT HAVE TYPE 1 DIABETES, AND THEN IN THE CAUCASIAN AMERICAN HEALTHY POPULATION, SO WHAT WE DO SEE IN CHECK POINT INHIBITORS DIABETES IS ABOVE WHAT'S SEEN IN CAUCASIAN AMERICANS AND HIGHER THAN TYPE 1 DIABETICS. ANOTHER RISK ALLELE IS DQ 8, SAME FREQUENCY AT TYPE 1 DIABETICS, SAME TRUE FOR HLA DR 3. INDEED THESE PATIENTS DO HARBOR SOME OF THE RISK ALLELES FOR THE HLA, PERHAPS SUBTLE DIFFERENCE WITH GARDEN VARIETY TYPE 1 DISEASE. WHERE WE ARE NOW WITH OUR THINKING IS THAT T CELLS ARE LIKELY KEY PLAYER IN WHAT'S DRIVING THE DISEASE, HLA WOULD SUPPORT THAT RESULT. AND WE'RE IN THE MIDST OF DOING A LARGE ANALYSIS OF THESE CELLS. WE DO HAVE SOME TETRIMER DATA AND SO BECAUSE WE KNOW SOME AUTOANTIGENS WITH TIME PEOPLE HAVE DEVELOPED AT TETRIMER REGIONS. UNTIL WE KNEW THE HLA ALLELES THIS BECAME CHALLENGING BUT A CLASS 1 1 TETRIMER, AND KEVIN AT YALE SHOWS THERE ARE DETECTABLE T CELLS BUT IS IT MORE OR LESS? WE'RE WORKING ON THAT RIGHT NOW. WE'RE DOING HIGH DIMENSIONAL CYTOF, THAT'S UNDERWAY BUT I DON'T HAVE DATA AND WE'RE DOING SINGLE CELL RNA-SEQ IN THE PERIPHERAL CELLS, CAN WE IDENTIFY ISLET-SPECIFIC RECEPTORS. WITH THE COMBINATION OF TYPING WE'RE HOPING TO UNEARTH THAT DATA. SO IN TERMS OF SOME OF THE PROGRESS THAT WE'VE MADE THOUGH, ONE OF THE KEY QUESTIONS REGARDLESS OF WHAT AUTOIMMUNE COMPLICATION WE'RE TALKING ABOUT RELATED TO CHECKPOINT THERAPY, WHAT ABOUT SPECIFICITY OF IMMUNE RESPONSE? I THINK THIS IS AN EXTREMELY CHALLENGING PROBLEM, PARTICULARLY WHEN IT COMES TO T CELLS. JUST SO EVERYBODY IS ON THE SAME PAGE, WE KNOW THAT AUTOANTIBODIES ARE VERY USEFUL IN DETERMINING WHAT T CELLS ARE SPECIFIC FOR. IN FACT, ALL OF THE T CELL REAGENTS, THE ORIGINAL ANTIGEN FOR THE MOST PART HAD BEEN FOUND THROUGH USING AUTOANTIBODIES, EVEN THOUGH THE ANTI-BODIES ARE COMING FROM B CELLS, AUTOANTIBODIES ARE OFTEN MARKERS OF WHAT THE T CELLS ARE ACTUALLY GOING TO, ATTACKING, OF COURSE ONE OF THE ADVANTAGES OF AUTOANTIBODIES YOU DON'T HAVE TO DEAL WITH COMPLEXITY OF HLA OR MHC RESTRICTION. I TOLD YOU EARLIER THAT MANY OF THE PATIENTS THAT GET TYPE 1 DIABETES OR AUTOIMMUNE DON'T MANIFEST THE CLASSIC ANTIBODIES SHOULD WE THINK WHAT THEY MIGHT BE RESPONDING TO, IT COULD BE THE STREET LAMP PROBLEM, WE'RE LOOKING UNDER THE THING THAT'S ALREADY KNOWN, COULD IT BE THE PATIENTS ARE MAKING AUTOANTIBODIES AGAINST SOMETHING ELSE THAT'S PROVOKING THEIR TYPE 1 DIABETES? AND SO WE'RE FORTUNATE TO GO INTO COLLABORATION WITH A COLLEAGUE AT UCSF, JOE READ AN INTERESTING APPROACH PUBLISHED BY STEVE ELEDGE, PHAGE DISPLAY, USING PHAGE LIBRARY TO PAN FOR ANTIBODIES AGAINST REACTIVITY SO JOE HAD A BIOINFORMATICIST, OLIGOMERS 50 AMINO ACIDS LONG, EVERY 20 YOU SHIFT OVER, SO THIS LIBRARY HAS OVER 700,000 UNIQUE PHAGE, EACH MAKING A SHORT POLYPEPTIDE, TO GO PANNING YOU TAKE THE ANTIBODIES FROM YOUR PATIENTS, INCUBATE, WASH, ELUTE, DO A COUPLE ROUNDS, ENRICH AND SEND MATERIAL FOR DNA SEQUENCING. IF YOU ALLOW ME TO WALK YOU THROUGH A POSITIVE CONTROL EXPERIMENT TO SHOW IT WORKS. WE HAD ANTIBODY AGAINST GFAP, HUMAN PROTEIN, THIS IS A MONOCLONAL. THIS IS AN EXAMPLE OF THE DATA WE GET BACK, THE ENRICHMENT SCORE VERSUS NUMBER OF READS WE GET BACK, THE ONLY CLONE ON THE TOP RIGHT IS GFAP SEQUENCE ITSELF. SO, WITH THIS TOOL IN HAND ONE OF THE THINGS WE HAVE DONE IS JUST TO SEE IF THIS LIBRARY COULD BE USED TO PAN FOR ANTIBODIES, ALL KINDS OF THINGS. SOME OF YOU MAY KNOW IN THE ROOM A LABORATORY HAS BEEN INTERESTED IN ENDOCRINE IMMUNE POLY GLANDULAR SYMPTOM TYPE 1, THEY DEVELOP MANY DISEASES LISTED ON THIS BUSY SLIDE BUT AUTOIMMUNE DISEASES THESE PATIENTS GET ARE ASSOCIATED WITH AUTOANTIBODIES SO EACH PATIENT WILL OFTEN HARBOR MULTIPLE AUTOIMMUNE SPECIFICITIES AND MANY AUTOIMMUNE SPECIFICITIES ARE KNOWN. SO WE TOOK A COHORT OF APS-1 PATIENTS AND PROBED. THIS IS AN EXAMPLE OF SOME DATA WE GOT BACK. EACH COLUMN IS A PATIENT. AND THEN EACH ROW IS A GENE THAT WE ENRICH FOR IN THE PHAGE DISPLAY IN THE HEAT MAP. RED MEANS ENRICH FOR GENE. I'M SHOWING EXAMPLES HERE IN THE ROWS OF KNOWN AUTOANTIBODY SPECIFICITIES IN THESE APS-1 PATIENTS. THERE IS VARIABILITY FROM PATIENT TO PATIENT BUT YOU CAN CLEARLY SEE WE'RE GETTING ENRICHMENT FOR COHORT OF ANTIGENS KNOWN OVER THAT SEEN IN HEALTHY CONTROLS. AND IN FACT I DON'T HAVE TIME TO GO INTO THIS, WE IDENTIFIED NEW SPECIFICITIES. WE'VE STARTED DOING THIS WITH MATERIAL FROM CHECKPOINT SUBJECTS OVER HERE, IN THE MIDDLE ARE TYPE 1 DIABETICS, NORMAL CONTROLS, I WANT TO SHOW SOME INTERESTING THINGS WE'VE PLUCKED OUT WITH PATIENTS. ONE OF THE THINGS WE SAW IN THE CHECKPOINT BLOCKADE TREATED PATIENTS, THE LITTLE RED SQUARES. ONE THING WE FIGURED OUT ABOUT THESE PATIENTS THAT WERE SCORING POSITIVE FOR ENRICHMENT OF THIS GENE, ALL TREATED WITH NIVOLUMAB. A VERSION OF ANTI-PD-1. THIS IS NOT THE PD-1 GENE. IT'S ANOTHER GENE. WE WENT BACK AND DID PHAGE ENRICH. PEMBRO, IPI, NIVO. WE CAN DETECT CLINICAL INFORMATION ABOUT WHAT THE PATIENTS HAVE BEEN EXPOSED TO. RIGHT NOW WE'RE IN THE MIDDLE OF ANALYZING DATA. THIS IS THE MAIN POINT I WANTED TO MAKE RIGHT NOW, WHEN WE LOOK AT CHECKPOINT-TREATED DIABETICS, WE DO FIND ENRICHMENT FOR GENES OVER HEALTHY CONTROLS, SOME SHARED WITH TYPE 1 DIABETICS, RIGHT NOW WE'RE IN THE MIDST OF TRYING TO VALIDATE SOME OF THESE HITS ARE ACTUALLY POTENTIALLY CORRECT AND MAYBE A NEW BIOMARKER THAT'S RELATED TO CHECKPOINT DIABETES FOR WHICH WE COULD GO AFTER. THIS IS ANOTHER WAY OF LOOKING AT IT. EXAMPLE OF A SINGLE GENE, NOW IN THE SINGLE GENE EXPERIMENT I'M NOW CLUSTERING THE PATIENTS INTO DIFFERENT GROUPS. WE HAVE PATIENTS HERE THAT HAVE CHECKPOINT DIABETES, CHECKPOINT DIABETES AND HYPOPHYSITIS, HERE SOME TYPE 1 DIABETICS, A SINGLE GENE WHERE YOU CAN SEE WE'RE GETTING ENRICHMENT OVER HEALTHY CONTROLS. SO, TO SUMMARIZE , ACUITY OF THE CLINICAL DISEASE ITSELF IS REALLY INTERESTING. IT'S ACUTE ONSET, OFTEN ASSOCIATED WITH DKA AND HOSPITALIZATION OF THESE PATIENTS. THERE'S VARIABILITY IN WHEN PATIENTS COME TO CLINICAL -- WHEN THEY COME TO CLINICAL ATTENTION AFTER THEY HAVE BEEN TREATED. WE DEFINITELY SEE IT'S ASSOCIATED WITH PD-1 OR PD-L1 BLOCKADE MORE THAN CTLA-4 MONOTHERAPY. AND THE AUTOANTIBODIES ARE FREQUENTY NEGATIVE, PERHAPS AS YOU SAW IN THE LAST PART OF THE TALK OTHER SPECIFICITIES WE'RE TRYING TO TRACK DOWN, ALSO POTENTIALLY POSSIBLE THE DISEASE ITSELF IS T CELL MEDIATED DISEASE THAT'S NOT ASSOCIATED WITH AUTOANTIBODIES. WE HAVE ABSOLUTELY NO PATH MATERIAL FROM ANY OF THESE PATIENTS. WE DON'T KNOW WHAT'S GOING ON IN THE ACTUAL ISLETS IN THESE PATIENTS DEVELOPING AUTOIMMUNE DIABETES AND HOPEFULLY WITH TIME WE'LL GET TO THAT DESTINATION AND LEARN MORE. YOU COULD SEE THERE ARE CERTAIN TYPE 1 DIABETES RISK ALLELES ASSOCIATED WITH THIS DISEASE, WE NEED MORE PATIENTS TO LOOK AT THIS. THERE'S NO EVIDENCE THIS DISEASE IS REVERSIBLE IN ANY WAY. ONCE PATIENTS START ON INSULIN THERAPY, THEY NEVER STOP. WE ALSO HAVE ANECDOTAL DATA THAT SOME PATIENTS HAVE GOTTEN OTHER IREs, SMALL HANDFUL OF PATIENTS HAD BEEN TREATED WITH HIGHER DOSE STEROIDS ABOVE 20 MILLIGRAMS A DAY, NO ASSOCIATION WITH DIABETES BEING WORSE OR GETTING BETTER WITH IMMUNOSUPPRESSION. SO WITH THAT I WANT TO THANK PEOPLE THAT CONTRIBUTED TO THIS WORK. I WANT TO HIGHLIGHT ZOE QUANDT WHO HELPED DEVELOPED OUR COHORT. SARAH VASQUEZ DID THE PHAGE DISPLAY EXPERIMENTS, MY COLLABORATORS PARTICULARLY JEFF BLUESTONE AND JOE DERISI AND KEVAN HEROLD AT YALE, AND MIHALIS HERE AT NIH. WITH THAT I'LL STOP AND TAKE A FEW QUESTIONS BEFORE LUNCH. THANK YOU. [APPLAUSE] >> HI. YES, YOUR RECENT DATA SUGGESTS THAT (INDISCERNIBLE) ABLE TO INCREASE LEVELS OF ANTIGENS, INCREASE NO RESPONSE BUT WHAT COULD BE THE MECHANISM OF INCREASED EXPRESSION OF ANTIGENS? >> RIGHT, INCREASE IN AUTOANTIGENS OR JUST AUTOANTIGENS WE HAD NOT DEFINED BEFORE, A SUBTLE DIFFERENCE. ANTI-PD-1 AND ANTI-CTLA-4 ARE TAKING THE BRAKES OFF THE IMMUNE SYSTEM SO THIS MAY BE A WAY FOR US TO ALLOW US TO SEE AUTOIMMUNITY THAT'S ALL SUBCLINICAL, WE HAVEN'T SEEN IT BEFORE, RIGHT? AND ANOTHER IMPORTANT POINT TO MAKE IS HOW DID MANY AUTOANTIGENS GET DISCOVERED? YOU TAKE IN THE CASE OF TYPE 1, TAKE AN ISLET EXTRACT, PROBE WITH SERUM. THE PHAGE DISPLAY SYSTEM IS AGNOSTIC, IT WON'T GET EVERYTHING BUT PERHAPS IS A WAY FOR US TO MORE BROADLY GET IT'S A WHAT'S GOING ON. HELPFUL BEYOND TYPE 1 DIABETES, PERHAPS WE COULD FIND MARKERS OF HYPOPHYSITIS. >> COULD IT BE A LINK WHEN THE MICROBIOME, FOR EXAMPLE? >> OH, ABSOLUTELY. I AGREE WITH THAT. EVENTUALLY WE'LL GET THERE. >> HI. FASCINATING TALK. THANKS SO MUCH. I HAVE TWO QUESTIONS. THE FIRST QUESTION ACTUALLY PIGGYBACKS ON THE PREVIOUS QUESTION. DO YOU THINK THESE AUTOANTIBODIES ARE KIND OF INCREASING AFTER TREATMENT? MEANING ARE THEY THERE IN A PRE-CLINICAL LEVEL, BEFORE THE TREATMENT AND THEN AFTERWARD YOU SEE DEVELOPMENT OF CLINICAL DISEASE, AND THEN THE SECOND QUESTION I HAVE IS DO YOU KNOW WHAT THE FC PORTION OF THE ANTIBODIES IS? IS IT IgM AS SEEN IN NATURAL OR CLASSICAL ANTIBODIES. >> YEP. >> NOT PATHOGENIC OR OF THE IgG ISOTYPE? >> YEAH, YOUR FIRST QUESTION ABOUT THE AUTOANTIBODIES BEING PRE-EXISTING, WE'RE AMPLIFYING ON TOP OF THAT, YOU KNOW, RIGHT NOW I CAN SHARE SOME DATA WE HAVEN'T PUBLISHED YET. TYPE 1 DIABETES AUTOANTIGENS ARE NOT FREQUENTLY CHECKED AS A ROUTINE LAB WORK, RIGHT? ONE THING THAT ACTUALLY IS MORE FREQUENTLY CHECKED ARE THYROID ANTIBODIES. ZOE HAD DONE -- DID A DATABASE POLL FROM EPIC SYSTEM AND LOOKED BEFORE PEOPLE STARTED ON CHECK POINT INHIBITOR TREATMENT AND LOOKED TO SEE WHAT HAPPENED. AND OF COURSE THERE'S SOME BIASES IN THE DATA, BECAUSE YOU WOULDN'T JUST RANDOMLY GET AUTOANTIBODIES ON EVERYTHING BUT THERE WAS NO CORRELATION WITH BEING AT INCREASED RISK FOR THYROID AUTOIMMUNITY USING THAT ANALYSIS SO I THINK IT MAY BE THAT THE AUTOANTIBODIES THEMSELVES MAY NOT BE ACTUALLY PREDICTIVE OF GOING ON TO DISEASE WITH CLASSIC SPECIFICITY. SECOND QUESTION WITH THE ISOTYPES, WE'VE NOT DONE ANYTHING SO I DON'T KNOW THE ANSWER. >> I MEANT FOR THE FIRST PART, I MEANT WITH THE Seq DATA, BUT LOOK BEFORE AND AFTER. >> WE'RE IN THE MIDDLE OF IN A NOW. ONE THING QUITE PRECIOUS THAT WE'RE INTERESTED IN IS SAMPLES ON PEOPLE THAT GOT TYPE 1 DIABETES, INCIDENCE IS 1%, SO LOW RIGHT NOW WE'RE JUST IN THE MIDDLE OF TRYING TO GET THOSE KINDS OF SAMPLES IN OUR HANDS. >> AWESOME. THANKS. >> YES? >> NICE TALK. IT'S NICE TO HEAR THAT KEVAN FOUND A COLLABORATOR ONE OF THE STATEMENTS YOU MADE IT'S MUCH MORE FREQUENT IN PD-1 PATIENTS. HAS IT EVER BEEN SEEN IN CTLA-4? I DON'T KNOW ANYONE WHOSE EVER SEEN IT BUT -- >> MINING THE LITERATURE WE FOUND TWO CASES WITH CTLA-4 MONOTHERAPY, AND THEN AGAIN I WOULD PREDICT GOING ON WITH TIME, CTLA-4 MONOTHERAPY IS PROBABLY SOMETHING IN THE REAR VIEW MIRROR, SO WE MAY NEVER KNOW. DILEMMA IS THE DILEMMA OF A LOT OF PEOPLE WITH VERY RARE AUTOIMMUNE DISEASE. WE'RE INTERESTED IN MYOCARDITIS, AND DOING TROPONIN, EVERYONE DOING EKGs, WHICH ARE EASY AND REASONABLE, YOU KNOW, WILL THEY PICK UP ANYBODY? BECAUSE AS YOU SAID, THESE PATIENTS PRESENT ACUTELY AND THEIR GLUCOSE IS NORMAL TWO WEEKS BEFORE >> IT IS A CHALLENGE. YES? >> WE'RE GOING TO DO ONE MORE QUESTION IN THE INTEREST OF TIME. >> YOU MENTIONED THAT ANTI-PD-1 ANTIBODY CAUSED MORE, YOU COMBINE THE TWO ANTIBODIES IS LESS THAN THE ONE ALONE. I'M WONDERING DO YOU HAVE ANY -- >> THAT'S BASED ON GRABBING WHAT'S OUT THERE, RIGHT? SO I DO THINK THAT IF WE WENT BACK AND DID ANALYSIS ARE YOU AT HIGHER RISK IF YOU HAD COMBINATION THERAPY I THINK THE ANSWER IS QUESTION, FEWER PATIENTS AT THE TIME THAT WE DID THE ANALYSIS WERE GETTING COMBO THERAPY. SO IT HAD TO DO WITH HOW WE GRAB THE SNAPSHOT OF THAT DATA. THANK YOU. [APPLAUSE] >> THANK YOU, DR. ANDERSON. THANKS FOR MENTIONING THIS CANCER MOONSHOT-FUNDED WORKING ON IREs. WE HAVE A GRANT DUE APRIL 25 FOR THE REUP FOR THAT. LUNCH IS GOING ON NOW. PLEASE BE IN THIS ROOM PROMPTLY AT 12:50:00 P.M. IT'S OUR PLEASURE TO INTRODUCE THE AFTERNOON SESSION, WITH DR. JEFF SALSMAN, PROFESSOR MEDICINE NORTHWESTERN UNIVERSITY. HE WANTED TO OPEN THE SESSION WITH A FEW WORDS AND SLIDES DESCRIBING THE GENERAL ISSUES ASSOCIATED WITH ADVERSE HE WANTS SO ITKINE AND AUTO-IMMUNITY. THANK YOU. >> I'M GOING TO TALK FROM HERE, NOT FROM THERE. SO I JUST WANTED TO MAKE A FEW COMMENTS CERTAINLY HAVE BEEN MADE IN DIFFERENT SESSIONS. THAT'S SOME OF THE -- I'M SURE OTHERS WILL MAKE THIS TOO BUT I THINK IT'S REALLY CLEAR HOW WE STUDY THIS DISEASE THAT'S GOING TO ULTIMATELY GIVE US THE BASE FOR ACTUALLY MANAGING IT BETTER. I THINK WHEN PEOPLE LOOK AT THIS YOU CERTAINLY LOOK HOW FACTORS AND CANCER FACTORS. I WOULD SAY THE MOST IMPORTANT FACTOR IS ACTUALLY AN ANNOTATED HISTORY THAT COLLECTS THE INFORMATION THAT CAN BE INTERROGATED AND THIS HISTORY ACTUALLY IS INTEGRATED IN A VERY GOOD TISSUE BANK. OBVIOUSLY THAT BANK CAN CONTAIN TUMOR TISSUE, WE HEARD AND WOULD CONTAIN BUT THERE'S CERTAINLY SOME DIFFICULTIES WITH THAT. AND BLOOD HAS BECOME MUCH MORE REASONABLE OPTIONS WHERE YOU CAN GET A LOT OF INSIGHT. AND THEN TISSUE FROM INFLAMED AREAS, WHICH IS RELEVANT FROM THE DISCUSSION AT THIS MEETING. AND I THINK LASTLY, I DON'T WANT TO REALLY EMPHASIZE YOU SHOULD HAVE SOME TOXIC DEATHS SO YOU CAN GET AUTOPSIES BUT ACTUALLY I WAS A PATH RESIDENT IN MY PAST AND DOING AUTOPSIES WERE REALLY PRETTY WORTHLESS AT THAT TIME. BUT NOW THE VALUE IS JUST INCREDIBLE FOR NUMBER OF THINGS, ONE BEING THAT IN TERMS OF HAVING THOSE WHAT TO STUDY I'M SURE A LOT OF PEOPLE ARE LOOKING AT GERM LINE FEATURES AND WE HEARD SOME OF THAT, OBVIOUSLY THE MICROENVIRONMENT, THE AFFECTED TISSUE, WE HAVE ABILITIES TO LOOK AT CLONAL EXPANSION. IT'S BEEN MENTIONED MICROBIOME AND IT'S EVEN BEEN MENTIONED AUTOANTIBODY PROFILING. THE TUMOR ITSELF CERTAINLY THERE'S A HISTORY THAT WOULD BE IMPORTANT AND GETTING TISSUE IS IMPORTANT BUT ACTUALLY REALLY HAS A CLINICAL INVESTIGATOR IT'S NOT VERY EASY. I THINK THE MOST IMPORTANT AT LEAST FROM MY -- IS STUDYING THE TUMOR, THE GENETICS THE EXPRESSION AND CERTAINLY LOOKING A THE MICROENVIRONMENT, MORE OF THE TUMOR AND AGAIN SOME OF THE SAME TECHNIQUES LOOKING AT T-CELL INFILTRATION AND MICROENVIRONMENT. YOU SAW THIS SLIDE AND I THINK MY POST DOC DID A NICE JOB OVERSEEING THE MAIN CONCEPTS THAT AT LEAST MOST OF US HAVE HAD AND I THINK YOU WILL HEAR ABOUT ALL OF THESE AT THIS MEETING. LASTLY, I WANTED TO EMPHASIZE THE CRITICAL ASSOCIATION BETWEEN ADVERSE EVENTS AND OVERALL SURVIVAL. A LOT OF DATA HERE BUT IF YOU LOOK AT THE DATA, THE OVERALL SURVIVAL, NOW THIS IS FIVE YEARS, WITH THOSE PATIENTS WHO HAD TOXICITY, NOT JUST TALKING ABOUT GRADE 3 AND 4 BUTTOCKSISTY DID SO MUCH BETTER AND MAYBE THE RIGHT WAY TO PUT IT IS THOSE THAT DON'T HAVE ANY TOXICITY DO MUCH WORSE. SO CLEARLY THERE'S A LINK PROBABLY JUST LIKE GRAPH VERSUS HOST DISEASE AND GRAPH VERSUS LEUKEMIA IS NOT GOING TO BE EASY TO BREAK BUT I THINK WE ALL SHOULD THINK ABOUT WHAT WE'RE DOING AS WE TRY TO AMELIORATE THESE TOXICITIES. LASTLY, I'M SURE THIS IS TRUE FOR A LOT OF CENTERS, I THINK WE CAN PERSPECTIVELY TAME THE SPECIMENS ESPECIALLY WITH BLOOD THAT WILL ADVANCE THE FIELD. BUT IT NEEDS TO BE PERSPECTIVE AS MUCH AS IT CAN BE WITH ALL THAT OTHER INFORMATION AND REALLY NEEDS TO BE COLLECTED AT TIME OF PROGRESSION AND TOXICITY. SO THAT'S ALL I WANT TO SAY TO INTRODUCE THE SESSION AND SOMEONE WHO HAS REALLY DONE A GREAT JOB STUDYING ONE OF THE TOXICITYIES, PNEUMONITIS JARUSHKA NAIDOO WHO WILL TALK ABOUT LYM NIGHTIS AND STEROID REFRACTORIES. >> GOOD MORNING, EVERYBODY. A SPECIAL THANK YOU TO LIZ JAFFEE AND ELAD SHARON FOR THEIR KIND INVITATION TO SPEAK TO YOU TODAY. OKAY. SURE. THEY CAN TELL I'M SOMEONE WHO LIKES TO WALK AROUND. SO TODAY I WILL BE TALKING ABOUT AN AREA THAT IS RELEVANT TO MY AREA OF RESEARCH OF IMMUNOTHERAPY FOR LUNG CANCER, PATIENTS WHO DEVELOP REFRACTORY LUNIITIS TO AND USE AS SEG WHAT I TO TALK ABOUT PORE SPECKTIVE STUDIES ADVERSE EVENTS IN GENERAL AND SALIENT TRANSLATIONAL CONSIDERATIONS TO GETTING SOME OF THESE TRIALS UP AND RUNNING. THESE ARE MY DISCLOSURES. IN TERMS OF TODAY I WILL TOUCH ON WHAT WE KNOW ABOUT PD 1 AND PDL 1 FOCUSING ON STEROID REFRACTORY SETTING AND PERSPECTIVE CLINICAL TRIAL I HAVE LED US THROUGH EASTERN COOPERATIVE ONCOLOGY GROUP THAT WILL BE OPEN THROUGH NCTN IN THE THIRD QUARTER OF THIS YEAR, FROM THERE TO TOUCH BRIEFLY ON PERSPECTIVE STUDIES THAT ARE CURRENTLY IN DEVELOPMENT AND ONE LED BY JOHNS HOPKINS THAT IS CURRENTLY IN PRESS AND JNNCN. I'LL CLOSE WITH OTHER RESEARCH PERSPECTIVES IN IRE MANAGEMENT. WHAT DO WE KNOW ABOUT PNEUMONITIS? MOST OF US WHO ARE CLINICAL RESEARCHERS SOMETIMES YOUR RESEARCH PATH IS DETERMINED BY WHO YOU HAPPEN TO SEE IN CLINIC AND SOME OF THE QUESTIONS THAT COME UP IN YOUR EVERY DAY LIFE. SO THIS WAS ACTUALLY -- THESE ARE THE FIRST THREE PATIENTS PHASE 1 IMMUNOTHERAPY CLINIC MEMORIAL SLOAN-KETTERING. BACK TO BACK LUNG PATIENTS DEVELOPED INTERSTITIAL CHANGE IN THEIR LUNG BEING TREATED EARLY PHASE STUDY ON ANTI-PD 1, THIS LED TO THE LARGEST REPORTED SERIES, HIGHLIGHTED IN JCO AND WAS A COLLAORATION BETWEEN MEMORIAL SLOAN-KETTERING AND THE MELANOMA INSTITUTE OF AUSTRALIA. WHAT WE SAW WAS WE ASSESSED OVER 400 PATIENTS, MAINLY WITH LUNG CANCER AND MELANOMA BUT SPANNING ALL SOLID TUMORS WHOSE HAD DEVELOPED CLINICALLY OR PATHOLOGICALLY CONFIRMED ANTI-PD 1 PNEUMONITIS WITH NO EVIDENCE OF ANY INFECTION OR PROGRESSIVE CANCER THAT COULD HAVE CONFOUNDED THIS DIAGNOSIS. WE IDENTIFIED 43 CASES, WITH OVERALL INCIDENCE OF 5% IN PATIENTS WHO ARE TREATED WITH MONOTHERAPY AND 10% IN PATIENT WHOSE ARE TREATED WITH COMBINATION PD 1 BASED IMMUNOTHERAPY REGIMENS. SOME OF THE SALIENT FEATURES THAT WE IDENTIFIED FIRSTLY IS THAT PNEUMONITIS CAN DEVELOP AT ANY TIME DURING A PATIENT CLINICAL COURSE. WHICH IS QUITE DISTINCT FROM SOME OF THE OTHER TOXICITIES. AND IN THIS PARTICULAR SERIES, THE FIRST PATIENT DEVELOPED THIS TOXICITY WITH NINE DAYS AFTER FIRST DOSE IMMUNOTHERAPY AND THE LAST PATIENT APPROXIMATELY 9.2 MONTHS AFTER THE FIRST DOSE. SOME OF THE OTHER IMPORTANT FEATURES WE IDENTIFIED WAS THAT BOTH RADIO LOGICALLY AND CLINICALLY PNEUMONITIS IS NOT ALL CREATED EQUAL. WE IDENTIFIED FIVE RADIO LOGIC SUBTYPES OF PNEUMONITIS THAT APPEAR TO BEHAVE CLINICALLY DIFFERENTLY. PATIENTS WITH MELANOMA APPEAR TO HAVE A CLASSICAL OPACITY TYPE APPEARANCE WHEREAS THOSE WITH LUNG CANCER ENDED UP HAVING A VERY FIRST ITEM THAT YOU SEE AT THE TOP ORGANIZING PNEUMONIA PHENOTYPE WHICH FOR ALL INTENTS AND PURPOSES CAN APPEAR TO LOOK LIKE PROGRESSIVE LUNG CANCER OR PROGRESSIVE CANCER AND REALLY UNDERSCORES THE NEED TO DO A BIOPSY TO ENSURE WE KNOW WHAT WE ARE TREATING. FROM THERE I MOVE TO HOPKINS IS TO START FACULTY POSITION AND DECIDED TO INTERROGATE SIMILAR QUESTIONS IN THAT SPACE. WITH FRUITFUL COLLABORATION WITH OUR PULMONOLOGIST WE HAD TWO PAPERS IN THE JOURNAL OF THORACIC ONCOLOGY LOOKING AT THE EPIDEMIOLOGIC FEATURES OF PATIENTS WITH LUNG CANCER WITH PNEUMONITIS. WHAT WE IDENTIFIED WAS ACTUALLY THE REAL LIFE INCIDENCE OF PNEUMONITIS, PARTICULARLY IN LUNG CANCER PATIENTS. IN WHOM THESE AGENTS ARE NOW LICENSED IN THE STAGE 3 SETTING, THE STAGE 4 SETTING AND THE SECOND NINE SETTING ACTUALLY PROBABLY HAS A REAL WORLD INCIDENCE OF 19% VERY DIFFERENT TO THAT REPORTED IN CLINICAL TRIALS. IMPORTANTLY WE DID A MULTI-VARIANT ANALYSIS AND IDENTIFIED THIS EVEN WITHIN LUNG CANCER PATIENTS THE RISK MAYBE DIFFERENT. AND PATIENT WHOSE HAD ADENOCARCINOMA HISTOLOGY APPEARED TO HAVE A HIGHER RISK FOR SUBSEQUENT DEVELOPMENT OF PNEUMONITIS. I'LL THANK DR. SALTMAN FOR A GOOD SEG WHAT I TO THIS BUT IN TERMS OF SURVIVAL WE KNOW IN MELANOMA AND LUNG CANCER AND OTHER TUMORS PATIENTS WHO TEND TO RESPOND TO THERAPY ALSO APPEAR TO BE POPULATION THAT DEVELOP IMMUNE RELATED ADVERSE EVENTS. I THINK THIS MIGHT BE NUANCED DEPENDING ON WHAT RELATE ADVERSE EVENT WE ARE TALKING ABOUT SO WE ANALYZED OUR LUNG CANCER PATIENTS BY COMPLEX MULTI-STATE MODELING APPROACH AND ACTUALLY IDENTIFIED THAT THOSE PATIENTS WHO DEVELOPED PNEUMONITIS PARTICULARLY EARLY PNEUMONITIS WORK IN THE FIRST THREE MONTHS OF THERAPY ENDED UP WITH POORER OUTCOMES AND POORER OVERALL SURVIVAL. SO WHAT ARE SOME OF THE CHALLENGES AN TREATING PATIENTS WITH THIS PARTICULAR CONDITION? ONE OF THE MAJOR CHALLENGE IS 80 TO 85% OF PATIENTS WHO DEVELOP PNEUMONITIS WILL RESPOND TO STEROIDS MEANING THEY WILL HAVE PNEUMONITIS CLINICALLY IMPROVE OR RESOLVE WITH COURT CORTICOSTEROIDS FOUR TO SIX WEEKS. HOWEVER THERE ARE NO EFFECTIVE SUBSEQUENT IMMUNOSUPPRESS SAN FRANCISCO APPROACHES AND UNIVERSALLY ALL PUBLISHED PAPERS, PATIENTS WHO HAVE BEEN TREATED WITH SUBSEQUENT THERAPIES, HAVE NOT BEEN SHOWN TO HAVE A GOOD OUTCOME WITH ANY IMMUNOSUPPRESSIVE APPROACH. SO REALLY THIS REPRESENTS AN IMPORTANT CLINICAL GAP IN OUR CARE OF THESE PATIENTS. THUS FAR PATIENTS ARE TREATED WITH TNF INHIBITORS ON THE COLITIS EXPERIENCE SHOWING IMPRESSIVE BENEFIT WITHIN PLEXI HAS BEEN FOR CORTICOSTEROID REFRACTORY COLITIS. SAME IS NOT TRUE OF PNEUMONITIS AND OTHER TOXICITIES. AS IN OUR SERIES AS WELL AS OTHERS PATIENTS TREATED WITH INFLEXIMAB WHO HAD PNEUMONITIS HAD POORER OUTCOMES, EITHER DEATH FROM PNEUMONITIS ITSELF OR PROFOUND INFECTION THAT OCCURRED IN 2% OF OUR PATIENTS. ANOTHER CHALLENGE WHICH I THINK IS OBVIOUSLY DIFFERENT DEPENDING ON WHAT TOXICITY IS, AGAIN AS DR. SALSMAN MENTIONED WE LIKE THE GET BIOPSIES SKIN BIOPSIES SOMETIMES LIVER BIOPSIES MAY BE EASY BRONCHOSCOPY NOT SO EASY. IS THIS ROUTINELY DONE IN PATIENTS WHO HAVE SIMILAR TOEMATIC PNEUMONITIS? PARTICULARLY PATIENTS WITH SEVERE PNEUMONITIS WHICH THE BRONCHOSCOPY MAYBE DEEMED A RISKY PROCEDURE. SO THEREFORE THIS REALLY CREATED A DIAGNOSTIC DILEMMA DISCERNING INFECTION PROGRESSION AND PNEUMONITIS AND CONTRIBUTED TO OUR LACK OF MECHANISTIC UNDERSTANDING IN THESE PATIENTS. THEN AGAIN INCIDENCE, SO IMMUNE RELATED TOXICITY HAS A SLIGHTLY LOWER INCIDENCE BUT THIS ALSO REPRESENTS A CHALLENGE IN TERMS OF DOING TRULY RIGOROUS TRANSLATIONAL WORK AND A LIMITED NUMBER OF PATIENTS. SO WITH ALL THIS IN MIND AND WITH ALL THE CHALLENGES IN MIND WE WERE VERY INTERESTED IN TRYING TO REALLY ELUCIDATE IF IN PLEXI HAS BEEN SHOULD BE IMMUNOSUPPRESSIVE OF CHOICE AFTER CORTICAL STEROIDS OF EXAMINING THIS FURTHER WE IDENTIFY REALLY THERE WAS NO PERSPECTIVE DATA AND NO PUBLISHED DATA TO SUGGEST THAT IT HELPED PATIENTS ASIDE FROM THE COLITIS EXPERIENCE AND ONLY SELECTIVE CASE REPORTS HAD SHOWN SCATTERED IMPROVEMENTS AND OFTEN SUBSEQUENT POOR CLINICAL OUTCOMES. ALTERNATIVE APPROACH WOULD BE THE GIVE SOMETHING THAT WAS IMMUNOSUPPORTIVE OR IMMUNOMODULATORY SUCH AS INTRAVENOUS IMMUNOGLOBULIN SHOWN TO BENEFIT SOME PATIENTS WITH APLASTIC IMMUNE CONDITIONS AND ALSO SHOWN TO BE OF BENEFIT FROM A FUNCTIONAL STANDPOINT IN PATIENTS WHO DEVELOP IDIOPATHIC PULMONARY FIBROSIS WHICH IS PURPORTED TO HAVE A SIMILAR MECHANISM OR MAY HAVE A SIMILAR MECHANISM TO PDL 1 RELATED PNEUMONITIS. WITH THIS IN MIND WE HYPOTHESIZE STEROID REFRACTORY PATIENTS MAY BEEN FROM IVIG BUT NEEDS TO BE TESTED IN A RIGOROUS MANNER COMPARED TO WHAT WAS ANECDOTALLY TREATED AS STANDARD OF CARE WHICH WAS INFLEXIMAB, WE USE AS MECHANISM TO LEVERAGE DOING TRANSLATIONAL WORK TO UNDERSTAND IMMUNOLOGIC FEATURES PNEUMONITIS BY LOOKING AT LUNG BIOPSY AS WELL AS BLOOD BASED ASSAYS WHICH IS IN IMMUNOLOGIC CORRELATES. SO THE MAY AIM OF THE STUDY WAS TO CLINICALLY ASSESS WHETHER IVIG IN PNEUMONITIS TO I ASSESS LUNG TISSUE FOR PROGNOSTIC FEATURES AND SERIAL BLOOD SAMPLES AND PATIENTS ENROLLED ON THE STUDY AS WELL AS CONTROL PATIENTS ENROLLED ON INSTITUTIONAL STUDY. SO THIS IS THE TRIAL, OFTEN MANY, MANY ITERATIONS I'LL WALK YOU THROUGH HOW THIS CAME TO FRUITION. SO INITIALLY THIS WAS MEANT TO BE A SINGLE RANDOMIZE STUDY TO INFLEXIMAB VERSUS IVIG WITHOUT PRE AND POST TESTS BUT WE USE IT AS MECHANISM WHICH TO RIGOROUSLY ASSESS HOW PNEUMONITIS IS CHANGING WITH THESE IMMUNOSUPPRESSIVE APPROACHES. SO INCLUSION CRITERIA WAS TO ENROLL ANY PATIENT WHO HAD SYMPTOMATIC PNEUMONITIS WITH ANY SOLID HEMOTO LOGIC MALINGNANCY WITH PD 1 OR P PDL 1 AGENT WITH MONOTHERAPY OR SECOND THERAPY NOT DEEM TO CAUSE ITS OWN PNEUMONITIS. PATIENTS NEEDED TO HAVE FAILED CORTICOSTEROIDS. THIS IS WHERE THE DEFINITIONS FOR MOVING FORWARD BECOME MURKY AND IS SOMETHING I THINK THIS COMMUNITY SHOULD BE ENGAGED IN TRULY RIGOROUSLY DEFINING. AND AFTER I WOULD SAY A YEAR OF DISCUSSIONS, BETWEEN 10, 15 PULMONOLOGISTS 10, 15 MEDICAL ONCOLOGIST, THE NCCN PANEL, ECOG PANEL VARIOUS PANELS, DEFINITION FOR STEROID REFRACTORY BECAME PATIENTS WHO HAD RECEIVED A MINIMUM OF TWO TO TEN DAYS OF CORTICOSTEROID MEDICATIONS AT A HIGH DOSE AND FAILED TO ACHIEVE A CLINICAL IMPROVEMENT. PATIENTS NEEDED TO HAVE NO ACTIVE INFECTION AND WE DEFINE THIS ACTUALLY AS A BASELINE AS BRONCHOSCOPY WITHIN TWO WEEKS OF ENROLLMENT AS WELL AS STANDARD BLOOD TESTS. NO RADIO LOGIC EVIDENCE OF PROGRESSIVE CANCER AND AS MENTIONED BEFORE, BRONCHOSCOPY NEGATIVE PATHOGENS. AT THAT POINT PATIENTS WOULD BE RANDOMIZED WITHIN ONE WEEK BUT MINIMUM OF ONE TO TWO DAYS TO INFLEXIMAB OR IVIG AND AT THAT TIME WITH GET IF PATIENT WAS ABLE TO COMPLETE AND WE ALSO ASSESS FOR HEMOGLOBIN SATURATION OF OXYGEN WITH ARTERIAL BLOOD GAS AND PERFORM A RIGOROUS SET OF PATIENT RELATED OUTCOMES. SO OUR END POINT IS ACHIEVED 14 DAYS AFTERWARDS BY REPEATING THE EXACT SAME ASSESSMENT AND LOOKING FOR CLINICAL IMPROVEMENT. AFTER MUCH DISCUSSION AGAIN THE DEFINITION WAS TO USE OBJECTIVE APPROACH WITH IMPROVEMENT AND PF RATIO ON ARTERIAL BLOOD GAS ASSESSMENT. SOMETHING USED CONSISTENTLY AS END POINT IN IDIOPATHIC FIBROSIS STUDIES AND OTHER RELATED STUDIES OF INTERSTITIAL LUNG DISEASE. AGAIN WE AIM TO USE THIS AS A PLATFORM FROM WHICH TO DO TRANSLATIONAL WORK AND WILL BE COLLECTING SERIAL SERUM AND PDMC FOR MULTI-PARAMETER CYTOKINE ANALYSIS AND AUTOANTIBODY PANEL AS WELL AS T-CELL SEQUENCING. WE WILL USE THIS TISSUE THAT WE OBTAIN WHICH WE AGREE WILL PROBABLY ONLY BE IN A SUBSET OF PATIENTS FOR PATHOLOGIC ASSESSMENT, MULTIPLEXING AND BAL FOR FLOW CYTOMETRY, THIS IS A SCHEMA OF ANALYSES WE PLAN TO DO& AND WORKING WITH COLLEAGUES AT HOPKINS WE ALSO PLAN TO USE SOME OF THIS TISSUE TO CREATE A MOUSE MODEL OF PD 1 PNEUMONITIS AND WE ARE CURRENTLY OPERATIONALIZING THAT WITH SOME ANECDOTALLY COLLECTED SAMPLES FROM OUR PATIENTS. SO I THINK FOR THIS AUDIENCE IN PARTICULAR, THERE WERE VERY IMPORTANT LESSONS LEARNED FROM GETTING THE PROTOCOL WRITTEN, UP AND RUNNING, IRB APPROVED AND WILL BE OPEN THROUGH NCTN IN THE THIRD QUARTER OF THIS YEAR. SO ONE OF THE ISSUES IS SUPPORTING STUDY FEASIBILITY. WHAT IS THE INCIDENCE OF SOME OF THESE TOXICITIES AND HOW CAN WE MAXIMIZE ACCRUAL AND ANSWERING THESE QUESTIONS EVEN IN THE FACE OF A VERY DIFFICULT TO ACCRUE OR RARE PATIENT POPULATION. I THINK THE ANSWER THERE IS TO IDENTIFY THE COLLEAGUE WHOSE ARE INTERESTED IN THIS AND IN THE INSTITUTIONS THAT ARE SET UP TO ANSWER THESE QUESTIONS. SO FOR US WE HAD TO MANDATE HAVING A MEDICAL ONCOLOGY AND PULMONARY CO-PI AT EACH SITE O TO ENSURE BRONCHOSCOPY WOULD BE DONE WITHIN 24 TO 48 HOURS OF IDENTIFYING A PATIENT. ACTUALLY THAT WAS SURPRISINGLY EASIER THAN WE THOUGHT GETTING US ON THE SAME PAGE IS WHAT TOOK LONGER. HOW MANY CENTERS ARE NEEDED, I THINK THIS DEPENDS ON THE QUESTION AND THE CASE OF PNEUMONITIS TRIAL WE HAVE SIX CENTERS THROUGH ECOG AND HAPPY TO EXPAND TO MORE IF PROTOCOL PARAMETERS ARE MET. COMING UP WITH RIGOROUS DEFINITION OF REFRACTORY OR STEROID DEPENDENT IS SOMETHING TO WORK TOWARDS, BEING ABLE TO CREATE A RIGOROUS STUDY, SET UP THE STUDY TO BE ABLE TO TEST THE STATISTICALLY SIGNIFICANT DIFFERENCE BASED ON VERY LIMITED HISTORIC DATA OR ANECDOTAL CASE SERIES IS CERTAINLY A CHALLENGE. SOME PRACTICAL CONSIDERATIONS DEPENDING ON WHAT YOUR IR TOXICITY OF INTEREST IS HOW TO RIGOROUSLY OBTAIN SPECIMENS. WHEN IS THE RIGHT TIME TO OBTAIN A SPECIMEN, SHOULD ONE OBTAIN A SPECIMEN FROM THE INFECTED AREA, THE ADJACENT AREA MULTIPLE AREAS AND WHAT IS CLINICALLY APPROPRIATE AND CLINICALLY FEASIBLE TO ANSWER YOUR QUESTION. IMPORTANTLY, PARTICULARLY IN THE STEROID REFRACTORY SETTING HOW INTERPRETABLE ARE SOME OF THESE TRANSLATIONAL DATA GOING TO BE WHEN A PATIENT MAY HAVE RECEIVED HIGH DOSE STEROIDS. DOING THE P RE POST ANALYSES WHERE PATIENTS ACT AS THEIR OWN CONTROLS IS A POTENTIAL WAY TO LOOK AT THIS OR LEVERAGE EXISTING DATA SETS WHICH WE HAVE SOME NORMAL BANKED SAMPLES WILL BE A WAY TO TRY TO RIGOROUSLY ASSESS THIS. MAKE FRIENDS WITH YOUR COLLEAGUES, VERY IMPORTANT, MOST OF THESE STUDIES ARE GOING TO REQUIRE CLOSE COLLABORATION BETWEEN THE TREATING MEDICAL ONCOLOGIST AND NEIGHBORING PULMO METEOROLOGIST, GASTROENTEROLOGIST NEUROLOGIST, WE HAVE TO REALISTICALLY WORK TOGETHER TO GET THIS DONE, I DON'T THINK THIS IS GOING TO BE ABLE TO BE DONE IN AN ISOLATED SIDE WHETHER MEDICINE OR ONCOLOGY. AND THEN OF COURSE SOME OF THESE TREATMENTS ARE GIVEN BOTH AS INPATIENT AND OUTPATIENT. THIS CAN BE PRESENT LOGISTICAL CHALLENGES IN TERMS OF IRB APPROVAL SO TRYING TO WRITE THIS IN A CREATIVE MANNER THAT IS ALSO FEASIBLE I THINK IS A SEPARATE CONSIDERATION. SO I THINK OUR STUDY HAS STARTED THANKFULLY A WAVE OF INTEREST IN DOING SOME OF THESE STUDIES EVEN IN ABSENCE OF HISTORIC DATA. THIS IS ANOTHER STUDY THAT MY PREVIOUS MENTOR AN PREVIOUS LIFE AT MEMORIAL IS TAKING FORWARD AT COLUMBIA, SO HE AND I PARTNERED TO WRITE ANOTHER STUDY THROUGH THE MCOR MECHANISM, A CLINICAL TRIAL CONSORTIUM THROUGH RASH GENENTECH. THIS PARTICULAR STUDY IMMUNE RELATED ADVERSE EVENTS THAT MAY BE MEDIATED BY THE IL 6 PATHWAY OR AUTOANTIBODY MEDIATED ARE GOING TO BE RANDOMIZED TO EITHER RECEIVING OBSERVATION OR RITUXIMAB OR OBSERVATION AND END POINT HERE IS A CURRENTEN POINT LOOK AT T-CELL AND B CELL SUBSETS. THIS STUDY IS VERY EARLY IN ITS DEVELOPMENT IN DESIGN, PROBABLY CHANGE A COUPLE OF TIMES BUT ALSO SHOWS THAT SOME OF OUR KEY STAKEHOLDERS IN THE FIELD ANSWERING SOME QUESTIONS AND AGREED TO FUND ALL THE CORRELATIVE ANALYSIS AND ALL CLINICAL OPERATIONS. SO AGAIN, ONE OF THE ISSUES HERE IS DEFINITION FOR STEROID REFRACTORY AN STEROID DEPENDENT, THE ISSUE OF INTERPRETING CORRELATIVE END POINTS IN A STUDY WHERE THE POPULATION IS HETEROGENOUS, PATIENTS WHO MAY HAVE RECEIVED DIFFERENT COMBINATIONS MAY HAVE DIFFERENT TUMOR TYPES RECEIVE A DIFFERENT NUMBER OF DOSES, HOW WILL WE ANALYZE THIS IN A RIGOROUS WAY AND TRY TO MAKE MEANINGFUL CONCLUSIONS. AGAIN INCLUSION OF PATIENT WHOSE ARE ON OTHER STUDIES, CERTAIN PERSPECTIVE STUDIES SAY CONCURRENT ENROLLMENT IN OTHER STUDIES IS NOT ALLOWED SO TRYING TO LOOSEN SOME OF THAT LANGUAGE TO ANSWER THESE QUESTIONS WILL BE IMPORTANT. OF COURSE SELECTING THE EASE OF INTEREST. IF WE'RE GOING TO POOL A STUDY, COUPLE OF DIFFERENT FROM DIFFERENT ORGAN SYSTEMS THAT MAYBE AUTOANTIBODY MEDIATED HOW DO WE GRADE THEM EQUITABLY? DOES GRADE ONE OR TWO TOXICITY RELATE THE SAME AS GRADE 1 OR 2 PNEUMONITIS? AND HOW SHOULD WE ANALYZE THAT. SO AGAIN SOME OF THE PRACTICAL CONSIDERATIONS WITH THIS TRIAL AGAIN HAVING PIs THAT REPRESENT MULTIPLE DIFFERENT MEDICAL SPECIALTIES, IS GOING TO BE COMPLEX BUT IMPORTANT. WE NEED TO IDENTIFY A CLINICAL RESEARCH STAFF THAT IS CENTRAL TO TWO DIFFERENT DEPARTMENTS WHICH IS ALSO GOING TO BE A LITTLE BIT TRICKY AND DEFINING IMPROVEMENT ACROSS THESE GROUPS. JUST TO CLOSE I WANT TO MENTION A DIFFERENT ANGLE OF PERSPECTIVE STUDY I THINK IS ALSO IMPORTANT. AT HOPKINS MYSELF AND MY COLLEAGUE IN RHEUMATOLOGY RECOGNIZED THE NEED FOR INTEGRATION BETWEEN MEDICAL ONCOLOGY AND MEDICINE AROUND A YEAR, YEAR AND A HALF AGO AND RECOGNIZE THIS THIS CONVERSATION HOW TO DIAGNOSE AN TREAT PATIENTS WITH ORGAN SPECIFIC IMMUNE RELATED TOXICITIES REALLY IS AN ONGOING DIALOGUE, NOT ONLY INVOLVES MAYBE ONE OR TWO SPECIALISTS, BUT IF A PATIENT DEVELOPS MULTI-SYSTEM IMMUNE RELATED TOXICITY, MAY INVOLVE MULTIPLE SPECIALISTS AS WELL AS OTHER ALLIED SPECIALISTS SUCH AS PHARMACISTS, PATHOLOGISTS, RADIOLOGISTS. SO IN ORDER TO ADDRESS THIS WE DEVELOPED THE CONCEPT OF HOPKINS IMMUNE RELATED TOXICITY TEAM WHICH IS OVER 20 PATIENT TEAM AND THE IDEA WOULD BE TO CREATE THIS VIRTUAL TEAM THAT WOULD CENTRALIZE DISCUSSION OF COMPLEX IRE CASES AND POTENTIALLY BE AN AVENUE WHERE PATIENTS WOULD BE REFERRED TO IDENTIFY NEW IRAEs. FROM THERE WE HOPED THAT IT WILL CREATE A PLATFORM WHICH WE COULD LEVERAGE SOME TRANSLATIONAL RESEARCH. SO REALLY OUR HYPOTHESIS WAS THAT A MULTI-DISCIPLINARY TEAM COULD ASSIST IN DIAGNOSIS AND MANAGEMENT OF THESE PATIENTS IN REAL TIME AND THAT SOME SPECIFIC PATIENT TREATMENT FEATURES WOULD THEN FALL OUT OF THAT THAT WOULD SHOW US WHICH IRA MAYBE MORE LIKELY OR SEVERE IN CERTAIN POPULATIONS. SO WE STARTED THIS PILOT PROJECT LAST YEAR AND WE CREATED A CENTRAL GROUP OF 13 MEMBERS. TWO CO-CHAIRS MYSELF AS MEDICAL ONCOLOGY CHAIR T RHEUMATOLOGIST AS THE MEDICINE CHAIR. WE CREATED A CENTRAL GROUP OF ONCOLOGISTS THAT COULD ACT AS TRIAGE AND FIELD CERTAIN QUESTIONS THAT MAY NOT NEED AN ORGAN SPECIALIST INPUT SUCH AS SHOULD I HOLD THERAPY, WHAT DOSE OF STEROIDS, VERY BASIC QUESTIONS, THIS STARTED BEFORE THE NCCN GUIDELINES WERE IN EFFECT AND WAS REALLY NEED IN A REAL TIME SENSE. THIS IS WHEN THE WRINKLE COMES, WE AGREED TO BE CONTACTABLE ELECTRONICALLY 24 HOURS A DAY SEVEN DAYS A WEEK. THAT WE WOULD CC RELEVANT MEDICINE PROVIDER IF DEEMED CLINICALLY APPROPRIATE. AFTER 24 HOURS, THE RECOMMENDATION WOULD BE SUMMARIZED BY ONE OF THE CO-CHAIRS AND WE WOULD COLLECT HIS DATA IN AN IRB APPROVED DATABASE. THIS WAS SOME OF THE INFORMATION THAT WE COLLECTED. AND WHAT WE FOUND IS -- SO THIS IS THE RESULT OF OUR STUDY, THIS IS OUR SIX MONTH PILOT PROGRAM, PUBLISHED IN JNCCN NEXT MONTH. WHAT WE FOUND IS THAT THE MAJORITY OF PATIENTS THAT WERE REFERRED HAD NOT SURPRISINGLY HAD LUNG CANCERS AND MELANOMAS SO THOSE WERE THE PATIENTS IN WHOM THESE TREATMENTS WERE LICENSED AT THE TIME AND HAS EXPANDED FROM HERE. INTERESTINGLY THE MAJORITY OF PATIENTS WERE TREATED AND MANAGED ON OUTPATIENT BASIS. THERE ARE A LOT OF DIFFERENT INSTITUTIONS APPROACHING THIS AND SLIGHTLY DIFFERENT WAYS AND THAT DOING THIS OPERATIONALLY FROM END PATIENT STANDPOINT FIRST IS EASIER TO OPERATIONALIZE, WE NEED TO EXPAND TO OUTPATIENT SETTING IN A WAY FOR CERTAIN GROUPS OF PATIENTS. THEN WE LOOKED AT THE SPECTRUM OF TOXICITY, WHO WERE THE PATIENTS WE WERE BEING REFERRED TO THE MOST. MOST REFERRALS FOR -- SUSPECTED PULMONARY TOXICITY, THE FACTOR ALSO THAT I WAS CHAIRING PROVIDERS DID KNOW THIS WAS A RESEARCH INTEREST OF MINE BUT INTERESTINGLY WE SEE HERE IN THIS PARTICULAR FIGURE THE YELLOW SUBSET OF THE BAR INDICATES PATIENTS WITH CONFIRMED RELATED IMMUNOTOXICITY AND THOSE IN BLUE PATIENTED REFERRED FOR SUSPECTED TOXICITY THAT DID NOT HAVE IT AT ALL BUT ALTERNATIVE DIAGNOSIS SUCH AS INFECTION OR PROGRESSIVE CANCER. WE SEE HERE IN THIS FIGURE IDENTIFIES THE TOXICITIES THAT REALLY REPRESENT THE HIGHEST DIAGNOSTIC DILEMMA. PATIENTS WITH PNEUMONITIS WE RECEIVED A NUMBER OF REFERRALS FOR BUT JUST OVER HALF ENDED UP HAVING PNEUMONITIS. SO WE HAVE A LONG WAY TO GO IN TERMS OF DIAGNOSTIC ABILITY FOR THESE PATIENTS. THIS WAS EVEN MORE MAGNIFIED IN PATIENTS WITH NEUROLOGIC TOXICITIES WHERE WE RECEIVE SEVEN REFERRALS FOR IMMUNE RELATED ENCEPHALITIS WHICH ONLY ONE PATIENT ENDED UP HAVING ENCEPHALITIS AND THE REST HAD MENINGEAL DISEASE OR INFECTIVE MENINGITIS OR ENCEPHALITIS. SO REALLY A LONG WAY TO GO, PARTICULARLY FOR THOSE TOO. WHETHER IN PARTICULAR TYPES OF PATIENTS THAT WE WERE REFERRED MORE COMMONLY, PATIENT WHOSE RECEIVED COMBINATION CHECK POINT INHIBITORS, THOSE WITH HISTORY OF AUTOIMMUNE CONDITIONS, THEY TENDED TO BE THE PATIENTS WHO DEVELOPED HIGH GRADE TOXICITIES ON MULTI-VARIANT ANALYSIS. WE ALSO CONDUCT AD SURVEY OF PROVIDERS ACROSS HOPKINS TO UTILIZE THE SERVICE AND ASK THEM IF THEY FELT THIS WAS BENEFICIAL IF IT HELP IN THE DIAGNOSIS AND MANAGEMENT OF THESE PATIENTS AND WHERE TO NEXT. WE SAW 97% RESPONSE DENTS FELT THE RECOMMENDATIONS WERE HELPFUL AND THAT SURPRISINGLY THE MAJORITY OF PROVIDERS WHO USE THE SERVICE WERE MDs, WERE SENIOR PROFESSORS AND ASSOCIATE PROFESSORS RATHER THAN PEOPLE WHO MAYBE NOT USED TO USING THESE AGENTS. IMPORTANTLY THE MAJORITY OF THESE RESPONDENTS ALSO SAID THEY FELT THAT A MULTI-DISCIPLINARY WORKING GROUP IN PERSON MEETING COULD ALSO HELP TO FACILITATE SOME OF THESE REFERRALS AND HELP TO DISSEMINATE SOME OF THE INFORMATION THAT WE HAD RECEIVED. HOWEVER, MINORITY THOUGHT IN PERSON CLINIC WOULD WORK BECAUSE OF THE ACUITY OF SOME OF THESE CASES AND NEED FOR REAL TIME FEEDBACK. SO THEREFORE SOME OF THE TAKE HOME MESSAGES WERE WE FELT THAT OUR NEW RESOURCE ALLOW WELL UTILIZED RESOURCE EVEN PIE WILL THE PERIOD, IT'S NOW CONTINUED A YEAR AND IN A YEAR WE RECEIVED 284 REFERRALS. MOST REFERRALS AGAIN WERE OUTPATIENTS LUNG CANCER PATIENTS PULMONARY TOXICITY, COMBINATION CHECK POINT INHIBITORS, AUTOIMMUNE CONDITIONS ASSOCIATED WITH HIGH GRADE TOX. WE SAW DIFFERENCES IN DIAGNOSTIC RECOMMENDATIONS, WHICH IS NOT SURPRISING BASED ON THE GRADE. THEREFORE FROM HERE WE USE THIS TO CONTINUE THE TOX TEAM PLATFORM AND OPERATIONALIZING IT IN MORE FORMAL MANNER GOING FORWARD. SO OF COURSE THIS DOESN'T -- ISN'T IN ISOLATION AN IT TAKES A VILLAGE TO GET SOME OF THIS WORK DONE WITH THAT IN MIND I WOULD REALLY LIKE TO THANK MY COLLEAGUES AND COLLABORATORS WHO HAVE MADE THIS POSSIBLE, PARTICULARLY DR. JAFFEE AND THE CANCER IMMUNOLOGY DIVISION WHO HELPED TO SPEARHEAD SOME OF THIS WORK. AND TO SUPPORT THAT, AT HOPKINS WE ARE RUNNING A CME IRAE MASTER CLASS THAT I WILL BE MEETING TOGETHER WITH MEMBERS OF THE TOXICITY TEAM IN A COUPLE OF WEEKS AND IF ANYBODY WOULD LIKE TO ATTEND, THIS IS A SHAMELESS PLUG, THE LINK IS AT THE BOTTOM. OF COURSE I'M HAPPY TO TAKE QUESTIONS. THANK YOU. [APPLAUSE] >> INTRODUCE KELLY WALKOVICH FROM CS MOTT CHILDREN'S HOSPITAL, WILL BE SPEAKING ON HER WORK LEVERAGING MULTI-DISCIPLINARY CARE MODEL, ESSENTIALLY THE NICER NET WORK WHICH WILL ALSO BE DESCRIBED, IT'S NOT ONLY A GOOD ABBREVIATION IT'S ALSO AN INTERESTING IDEA. >> THANK YOU SO MUCH FOR HAVING ME TODAY. I THINK THAT I'M COMING TO THIS CONVERSATION FROM A DIFFERENT ANGLE. THAN MOST OF YOU, I REALLY WANTS TO HIGHLIGHT THE PRIMARY DEFICIENCY DISORDER GROUP AND ANOTHER GROUP OF CLINICIANS TO UNDERSTAND THE IMMUNE RELATED ADVERSE EVANS. -- EVENTS. I HAVE NOTICE CLOSURES. -- NO DISCLOSURES. I WILL SPEND MAJORITY OF MY TIME CARING FOR PATIENTS WITH PRIMARY DISORDERS WHICH ALSO RECOGNIZE INBORNE ROASTER OF IMMUNITY, MEKNIST LINK DEFINED DISORDERS THAT ENCOMPASS SUSCEPTIBILITY TO INFECTION INCREASE RISK OF MALIGNANCY AND IMPORTANT FOR THE CONVERSATION TODAY REALLY HEIGHTENED TENDENCY FOR AUTOIMMUNE DISORDERS TO DO IMMUNE DISREGULATION. LOOKING AT THE GRAPHIC, THIS DEPICTS OVER TIME A NUMBER OF IN BORNE ERRORS OF IMMUNITY DIAGNOSED AND THERE'S BEEN AN EXPLOSION FROM THE EARLY 2000s TO NOW, PRIMARILY BECAUSE OF ABILITY TO RECEIVE CLINICAL GENERAL IT CAN TESTING. THE MAIN GROUPS THAT HAVE GROWN ARE ANTIBODY MEDIATED DISORDERS DISREGULATION, AUTOINFLAMMATORY SYNDROMES WHICH BROADEN OUR INTEREST IN THIS GROUP BUT ALSO MADE US NEED TO TAKE A PAGE OUT OF THE ANN ARBOR PLAY BOOK FROM FRIENDS IN FOOTBALL REMEMBER THESE PATIENTS CAN BE TREATED IN ISOLATION SO JUST LIKE THEY SAID, THE TEAM, THE TEAM, THE TEAM, WE HAVE TAKEN THAT TO HEART AT THE UNIVERSITY OF MICHIGAN AND WE HAVE A CLINIC THAT'S BEEN ESTABLISHED FOR A DECADE TO CARE FOR PRIMARY IMMUNE DEFICIENCY PATIENTS THAT INCLUDES HEMATOLOGIST ONCOLOGIST AND MY COLLEAGUE TRANSPLANTER, WHO HAVE INFLUX OF GENETICS, INFECTIOUS DISEASE AS WELL AS ROUTINE FELLOW PARTICIPATION FROM THE ALLERGY GROUP AND RHEUMATOLOGY, FOR INDIVIDUAL PATIENTS WE HAVE OUTREACH TO OTHER SUBSPECIALISTS SOME WHICH CROSS THE FEEDS BARRIER TO ADULT MEDICINE AND THE STORY TODAY ABOUT RECOGNIZING IMMUNE RELATED EBBS WE CALL ON OUR FRIEND AND ENDOCRINOLOGIST AND DAVID FROM THE COLLEGE OF PHARMACY. HAS THIS GROUP KNOW, IMMUNE CHECK POINT INHIBITION IS DEPENDENT ON TWO FEATURES, ANTIGEN RECOGNITION AND THEN THE SECONDARY SIGNAL CTLA 4 RECOGNIZING CD8 0 AND PD AND PDL 1 INTERACTION AND WHEN YOU HAVE IMMUNOTHERAPY DISRUPTIVE WITH A DRUG EITHER ANTIBODY CTLA 4 OR P,DL 1 BUT IN A PATIENT I WOULD ARGUE THAT ACTUALLY THERE IS A GENETIC INHIBITION THAT IS REALLY BIOLOGIC MIMICKER OF THE PHARMACOLOGIC INTERVENTION, THIS IS PARTICULARLY TRUE IF YOU CONSIDER CTLA 4 HAPLO INSUFFICIENCY, WHEREAS WITHIN THE DRUG NOT ENOUGH IS PRODUCED ON THE CELL SURFACE. WHILE MECHANISTICALLY THAT IS SIMILAR IT'S IMPRESSIVE CLINICALLY THAT THE -- TO PHENOTYPES OVERLAP SO DRAMATICALLY. SO THIS IS A DIAGRAM OF CTLA 4 HAPLO INSUFFICIENCY PATIENT AND AUTOIMMUNE COMPLICATIONS FROM UVEITIS TO THYROIDITIS TO SKIN MANIFESTATION, TYPE 1 DIABETES, AUTOIMMUNE ARTHRITIS, ET CETERA. WHEN YOU LOOK AT THE COMMON TOXICITIES THAT ARE SEEN, IN IMMUNE CHECK POINT INHIBITION A STRIKING NUMBER OF THEM OVERLAP MEANING WE PROBABLY HAVE SOMETHING TO TAKE FROM THE BIOLOGY OF BOTH INBORNE AREAS OF IMMUNITY AND THE DRUG PHENOTYPES. SO THINKING ABOUT THE CLINIC MY CLINIC WITH PRIMARY IMMUNE DEFICIENCIES WE CAME ACROSS A GIRL WITH CTLA 4 HAPLO INSUFFICIENCY. SHE HAD IMMUNE MEDIATED DISORDERS INCLUDING TYPE 1 DIABETES, ANEMIA, AND AUTOIMMUNE HEPATITIS. THESE ARE FOND IN ASSOCIATION WITH OTHER CLINICAL FEATURES WE DEN HAVE A FULL MECHANISTIC RATIONALE FOR INCLUDING GENERALIZED MUSCULAR DYSTROPHY, MASSIVE MICROCEPHALY, COMPLIMENT KIDNEY FAILURE AND CARDIOMYOPATHY AND THIS IS A PATIENT THAT EMBODIED THE NEED FOR THE MULTI-DISCIPLINARY APPROACH, WHILE ENEMBEDDED IN THE CLINIC MODEL THERE WE CAN'T MANAGE THESE COMPLICATIONS ON OUR OWN. SO BACK TO THE REQUIRED WHICH WAS DIFFICULT TO MANAGE AND REQUIRED SPECIAL MODIFICATIONS TO OVERALL IMMUNE THERAPY PLAN, THIS IS A DISORDER THAT IS CHARACTERIZED BY PROGRESSIVE LOSS OF ADIPOSE TISSUE FOLLOWING BIRTH, AFFECT IT IS ENTIRE BODY LEADING TO SIGNIFICANT METABOLIC REANGLES. THERE'S LOW LEFT HYPERFASCIA ASSOCIATED AND ECTOPIC FAT STORAGE IN MUSCLE AND LIVER. THIS ECTOPIC FAT STORAGE GOES ON TO DEPOSIT IN PLACES THAT CAUSE INSULIN RESISTANCE AND TRIGGER NON-ALCOHOLIC FATTY LIVER DISEASE, INSULIN RESISTANCE LEADS TO THE PHENOTYPIC FEATURES OF DIABETES AND HIGH TRIGLYCERIDE LEVELS. AND WHILE -- HAS BEEN AROUND MANY DECADES THE PATHOGENESIS IS UNKNOWN BUT THERE IS A HINT OR ASSOCIATION WITH AUTOIMMUNE COMPLICATIONS AND WE ARE HOPING THAT WE CAN HELP WRITE IT TO FRUITION. LOOK BACK AT OUR PATIENT STORY FOR AGL DIAGNOSIS, IMAGES YOU CAN GET A SENSE OF WHETHER OR NOT SHE HAS FAT STORAGE AND SHE HAS MINIMAL FAT LOCATED BEHIND HER EYE BALLS AN ALONG THE SPINE BARELY PERCEPTIBLE FAT AND SHE HAS NEAR ABSCESS FAT THROUGHOUT ABDOMEN, HIGH LEPTON LOW LEPTON LEVEL AND HIGH TRIGLYCERIDE LEVEL, HEMOGLOBIN A 1C WAS ELEVATED AND HIGH LEVEL OF INLINS RESISTANCE AND DESPITE CONSTANT HER BMI WAS ONLY 12.1, PHENOTYPICALLY PART OF THE HGL STORY. SHE HAD EXTENSIVE SEQUENCING FOR THE GENERALIZED DYSTROPHY WHEN WE FIRST SAW HER AND OTHER GENES INVESTIGATED WERE ALL NORMAL. WHEN WE EVALUATE THE REST OF HER FAMILY, SHE HAD MANY OTHER FAMILY MEMBERS THAT HAD SIMILAR PHENOTYPES THOUGH NONE AT THE ACQUIRED GENERALIZED LEUKODYSTROPHY, SHE HAD TWO SETS OF COUSIN WHOSE CAME TO ATTENTION FOR THEIR INTEROPATHY AND CYTOPENIA AND THEN AN AUNT WHO HAD MUCH MORE ADVANCED INTEROPATHY AND GENERALIZED IMMUNE DEFICIENCY. SO WITH THAT MULTI-DISCIPLINARY APPROACH WE POOLED TOGETHER GENETICS AND IDENTIFY PATHOLOGIC VARIANT CTLA 4 WHICH WAS A FIVE INSERTION THAT CAUSED A FRAME SHIFT MUTATION DISABLE THE PROTEIN. SHE UNDERWENT VARIOUS TREATMENT TRIALS WITH MANY SAME AGENTS YOU ARE USING, IN THE IMMUNE CHECK POINT INHIBITION SIDE EFFECTS WITH STEROIDS BEING MAIN STAY FOR HER IVIV, AND MOST OFFERED HER SOME IMPROVEMENT IN DISEASE CONTROL BUT SHE DID SUFFER FROM PROGRESSIVE ORGAN DYSFUNCTION AND UNFORTUNATELY DIED IN FEBRUARY SECONDARY TO MULTI-ORGAN FAILURE. SO KEEPING WHAT WE LEARNED FROM HER CASE AND MIND, WE PRESENTED A SECOND CASE AND THAT REALLY HELPED LINK THE TWO TOGETHER. THIS IS A CASE PERHAPS A LITTLE MORE FAMILIAR TO YOU, IT'S A 55-YEAR-OLD MALE WHO HAD A LOCALIZED MELANOMA OF THE RIGHT NECK. THIS WAS DIAGNOSED IN JULY, 2014, EXCISIONAL BIOPSY WITH REGIONAL LYMPH NODE WITH MARGINS. HE RELAPSED IN DECEMBER OF 2017, HAD MODIFIED SECTION WITH ONE LYMPH NODE POSITIVE FOR DISEASE. HE WENT TO RECEIVE STANDARD RADIATION FROM JANUARY TO FEBRUARY 2017 AND THEN LIKE MANY PATIENTS WAS TREATED WITH ANTI-PD 1 THERAPY SPECIFICALLY (INDISCERNIBLE) FROM APRIL 2017 TO FEBRUARY 2018. AND INTERESTINGLY HE TOO WENT ON TO DEVELOP ACQUIRED GENERALIZE LEUKODYSTROPHY. SO LOOK AT HIS PICTURE HERE, PROBABLY SPEAKS A LITTLE BIT TO HIS MELANOMA RISK. BUT WE WANT TO LOOK AT HIS GENERAL PHYSIQUE INCLUDING THE FAT IN THE ABILITY OR INABILITY TO NOTICE THE MUSCLE DEFINITION. AND THEN ALSO THE FORMATTING OF HIS FACE. IF YOU LOOK AT TIME LINE FROM APRIL TO JANUARY RECEIVING EVERY THREE WEEKS AND THEN IN JANUARY HE HAD AN ACUTE ILLNESS WHICH WAS DESCRIBED AS A FLU LIKE TYPE ILLNESS AND THEN ABOUT SIX TO EIGHT WEEKS LATER HAD A SIGNIFICANT LOSS OF FAT IN HIS FACE, MORE LOSS OF DEFINITION, HE WENT THE NEXT TWO MONTHS TO HAVE A TOTAL WEIGHT LOSS OF 20 POUNDS AND ALL OF THIS WAS GENERALIZED SUBCUTANEOUS FAT LOSS. THEN FOLLOWING THAT TWO MONTH PERIOD THE WEIGHT STABILIZED, DIDN'T HAVE ANY FURTHER FAT LOSS BUT YOU CAN TELL OVERALL HE LOOKS VERY DIFFERENT FROM THE FAT LOSS, IN FACT HE LOOKS SIMILAR TO THE REST OF THE AGL COHORT FOLLOWED UP MICHIGAN AND ELSEWHERE WHERE YOU CAN SEE VERY DISCRETE MUSCLE FORMATION AND REALLY THE VEINS POPPING. LOOK AT HIS IMAGES, THIS IS THE ADVANTAGE OF HAVING SOMEONE ON ON COLOGIC STUDY IMAGES BEING OBTAINED FOR OTHER REASONS. WE WERE ABLE TO GO BACK AND ACTUALLY LOOK AT THE FAT DEPOSITION IN THIS LOSS. SO IF YOU LOOK AT ALL OF THE IMAGES HERE ON THE LEFT THOSE ARE FROM APRIL SO PRE-SYMPTOMS AND THEN THESE ARE FROM JULY. SO POST THE WEIGHT LOSS AN POST THE GENERALIZE LEUKODYSTROPHY SYMPTOMMINGS. LOOKING AT ARROW YOU CAN SEE THE LAYER OF FAT IS PROMINENT INNOCENT ON THE SIDE OF THE SKULL. YOU CAN SEE A LARGE LAYER OF ADIPOSE TISSUE HERE AND THEN IN THE POSTERIOR REGION AND THROUGH THE THIGHS, THIS IS ALL APPROPRIATE DISTRIBUTION. WHEN YOU LOOK AT THE OTHER SIDE YOU CAN SEE THAT THE FAT HAS ALMOST ESSENTIALLY MELTED AWAY. AND THAT THE -- HAS BEEN REDUCED SIGNIFICANTLY AS WELL AS THE POSTERIOR FAT HAS ESSENTIALLY DISAPPEARED. THEN ONE AREA WHICH I HAVE TO SAY I NEVER REALLY LOOK AT, ARE THE FEET. BUT THESE ARE IMPORTANT BECAUSE THE ACQUIRED LEUKODYSTROPHY IS GENERALIZED AND YOU CAN SEE THERE IS A DISCRETE AMOUNT OF FAT OR THIS DARK COLOR HERE AROUND THE HEEL AND THE FAT PAD UNDER THE TOES. AND EVEN THIS WAS RECUSED -- REDUCED WHEN LOOKING AT IMAGING LOOK AT HIS LEVELS WHICH WERE DRAWN AFTER RECOGNITION OF THIS PHENOTYPE, HE HAD A LEPTON LEVEL THAT WAS LOW BUT NOT AS LOW AS OUR PATIENT AT .4, HIS TRIGLYCERIDES WERE OTARIES, SO AGAIN NOT AS OUT OF CONTROL AS OUR CTLA HAPLO INSUFFICIENT WHO HAD TRIGLYCERIDES IN THE 5 THOUGHS AND HIS HEMOGLOBIN A 1C WAS FINE BUT FANCIER ENDOCRINOLOGY RATE WHICH WILL IDENTIFY A MODERATE INSULIN RESISTANCE AN BODY FAT SLIPPED 10 AND A HALF PERCENT. WE WENT BACK AND DUG IN THE LITERATURE FOR CTLA 4 PATIENT AS COLLEAGUE OF MINE DESCRIBED A COHORT OF PATIENTS AND IF YOU TAKE THROUGH THE FINE PRINT, ONE OF THE CTLA HAPLO INSUFFICIENT PHI PATIENTS HAS ACQUIRED LEUKODISSTROW TROPHY AND ASSOCIATION NOT MADE. ANOTHER CASE ACQUIRED LEUKODYSTROPHY WAS PUBLISHED SO I THINK THIS LENDS CREDENCE TO OBSERVATION AND SPARKED INTEREST IN OUR GROUP IN TERMS OF POTENTIAL MECHANISMS BECAUSE AS ALLUDED TO TODAY UNDERSTANDING THE MECHANISMS IS PROBABLY THE CRUX OF HOW WE'RE GOING TO RECOGNIZE WHO IS AT RISK BUT ALSO HALT PRODEPRESSION. AS WE -- PROGRESSION. AS WE THOUGHT FROM THE IMMUNE ANGLE THE INHUGE CHECK POINT INH I BIGS ALTERS METABOLISM IN T-CELLS, IT'S SHOWN ALTERED FATTY ACID IN METABOLISM IS DISREGULATED AUTO-IMMUNITY IN OTHER CONDITIONS PARTICULARLY LUPUS, THIS MIGHT TRANSLATE TO OUR POPULATION. IT PRODUCES A PRO APOPTOTIC EFFECT ON ADIPCYTES AND INCREASE UTILIZATION OF LIPID MATERIAL THAT MIGHT EXPLAIN WHY THE FAT TISSUE IN PARTICULAR IS UTILIZED AND IS GONE. THEN THERE'S ALSO THE POSSIBILITY OF AMONG OTHERS THE LIPID METABOLISM -- ACETYL HISTONE ACETYLATIONS FOR INDIVIDUAL, IT IS INTERESTING THE MAJORITY DON'T HAVE THIS PHENOTYPE LIKE THE MAJORITY I HAVE CTLA HAPLO INSUFFICIENT DON'T HAVE THIS PHENOTYPE SO THERE A SECONDSIS HE WANTIBILITY OR PATHWAY HAVE THAT HAPPEN. IT'S NOT JUST MICHIGAN INTERESTED, WE ARE PART OF THE CONSORTIUM KNOWN AS THE NICER CONSORTIUM AND YES YOU HAVE TO BE NICE TO BE ABLE TO PARTICIPATE BECAUSE WE ARE FROM THE MIDWEST. BUT IT IS THE NORTH AMERICAN IMMUNOCLINICAL EDUCATION RESEARCH GROUP AND OUR MISSION SET OUT TO PROVIDE A COLLABORATIVE MULTI-DISCIPLINARY ENVIRONMENT TO ADVANCE EDUCATION CLINICAL CARE RESEARCH WITH PEDIATRIC AND ADULT PATIENTS AND I SEE A LOT OF ADULT PATIENTS BECAUSE RARE DISEASES DON'T RECOGNIZE THE 21-YEAR-OLD CUT OFF. THERE'S THREE AIMS TO ENHANCE CLINICAL COMMUNICATION BETWEEN SPECIALISTS SO PROVIDE PLATFORM FOR EDUCATIONAL OPPORTUNITIES AND REALLY TO CREATE AN OPPORTUNITIES FOR COOPERATIVE RESEARCH STUDIES, ESPECIALLY FOR RARE DISORDERS WHERE YOU NEED EVERYONE'S COOPERATION FOR THE APPROPRIATE END. LOOK AT WHERE THE INSTITUTIONS ARE LOCATED, THE LIGHT PURPLE INSTITUTIONS PRESENT FOR SIX TO SEVEN YEARS PARTICIPATING THE ORANGE LOCATION ONE ARE JUST ON BOARDING NOW AND WE MET OUR GOAL OF BEING TRULY MULTI-DISCIPLINARY, 46% OF US ARE SO ARE TRANSPLANT BASED. SO WHILE IT DOMINATE IT IS GROUP MOST OF THOSE ARE SUPER INTERESTED IN IMMUNOLOGY, WE ALSO HAVE GENETICISTS ENDOCRINE GI ID ALLERGY AND THAT PARTICIPATE QUITE ACTIVELY IN THE GROUP. WHILE FOCUSED ON A WIDE SLOTH OF CLINICAL INTERESTS FROM A RESEARCH PERSPECTIVE WE ARE VERY FOCUSED ON CYTOPENIA, MALIGNANCY AND MORE RECENTLY THE IMMUNE RELATED ADVERSE EVENTS. AS WE SEE OUR ONCOLOGY COLLEAGUES TREATING PATIENTS WITH THE CHECK POINT INHIBITORS, WE HAVE MANY QUESTIONS, WE ARE SUPER EXCITED THAT THIS IS AN OPPORTUNITY TO CURE PATIENTS OF THEIR MALIGNANCY BUT WE SEE THINGS THROUGH SLIGHTLY DIFFERENT GOGGLE AND WE ARE CURIOUS ABOUT LONG TERM COSTS TO THE IMMUNE SYSTEM. CAR T PATIENTS B CELL ALL REALLY MIRROR ANEMIA PATIENTS WITH PROLONGED B CELL DEPLETION THAT IS NOT A SHORT TERM ISSUE BUT MORE A LONG TERM ISSUE. OBVIOUSLY WE HAVE A HISTORY OF EXPERIENCE WITH BREWTON'S PATIENTS AND HOW TO MITIGATE SOME OF THOSE LONG TERM COMPLICATIONS. CAN SOME OF OUR SUPPORTIVE CARE RECOMMENDATIONS FOR PIE PRIMARY IMMUNE DEFICIENCY TRANSLATE TO IMMUNE THERAPY PATIENTS FOR SAFER CARE AND WITH THE DIRECT IMMUNOTHERAPY WITH THE CHECK POINT INHIBITORS THERE'S A HHS OF AUTOIMMUNE MEDIATED PATHOLOGY AND COMPLICATIONS THAT WE'RE HEARING ABOUT IS THERE A POSSIBILITY OR PROBABLY QUITE A LIKELIHOOD BOTH INBORNE ERRORS DEFICIENCIES WE HAVE SEEN MIMICKING BACK AND FORTH AND MIGHT BE ABLE TO WORK TOGETHER TO UNCOVER THE MECHANISM BUT ALSO TO THINK ABOUT TARGETED TREATMENT OPTIONS TO MITIGATE THE IMMUNE RELATED AD VERSION EVENT -- ADVERSE EVENTS. AS PART OF ENHANCING THE MULTI-DISCIPLINARY COMMUNICATION OR CARE, WE HAVE A TOOL THAT I WOULD INHAVE IT ALL OF YOU TO CONSIDER PARTICIPATING IN. WE HAVE THREE SPECIFIC LIST SERVES ONE IS FOR CYTOPENIA WHICH MEANS FOR SOME IMMUNE CYTOPENIAS WOULD BE INTEREST MALIGNANCIES IS AND PRIMARY IMMUNE DEFICIENCY BUT ADVERSE EVANS, FOLKS TON LIST SERVE THERE'S IMMUNOLOGISTS AND A LOT OF HARD CORE SCIENTISTS, Ph.D.s, SOME M.D. Ph.D.s WORKING ON THE BIOLOGY OF T-CELLS, AND THEN THERE ARE WIDE REPRESENTATION FROM MEDICAL SPECIALTIES SO HAVING MORE ONCOLOGISTS ON BOARD I THINK WOULD HELP OPEN THE CONVERSATION. IF YOU WOULD LIKE TO JOIN E I MAIL ADMINISTRATIVE STAFF TOM SMITH OR VISIT OUR WEBSITE FOR MORE INFORMATION. I WOULD DEFINITELY LIKE TO THANK EVERYONE FROM OUR MICHIGAN TEAM, THIS OBVIOUSLY DOESN'T HAPPEN IN ISOLATION. WE HAVE A LARGE TEAM EVEN JUST FOR THIS PRESENTATION, CRITICAL TO IDENTIFYING AND TREATING OUR FIRST PATIENTS AND THEN (INDISCERNIBLE) REBECCA BROWN, WE ARE HELPFUL WITH THE RECRUITMENT AND EVALUATION OF SECOND PATIENT AND BUT HOPEFULLY TODAY'SSOR STORY ENCOURAGED YOU TO OPEN YOUR EYE TO THE TRANSLATION BETWEEN PRIMARY IMMUNE DEFICIENCY PATIENT AND SECONDARY IMMUNE DEFICIENCIES NO JUST FOR RECOGNITION OF VALIDATION OF NEW SIDE EFFECTS BUT ALSO FOR THE ABILITY TO THINK ABOUT DIFFERENT MECHANISTIC TARGETS TOGETHER. I THINK OUR GROUP HAS A LOT TO LEARN FROM YOUR GROUP. THANK YOU. >> THE LAST SPEAKER IS DR. DAVID KLATZMANN, PROFESSOR OF IMMUNOLOGY AT SORBON,NE UNIVERSITY IN PARIS FRANCE, BALANCING IMMUNE TOLERANCE AND LOW DOSE INTERLEUKIN 2. >> THANK YOU FOR THE INVITATION FOR THIS EXCITING MEETING. THE WAS SOMEWHAT DELAYED WHICH GAVE MY TALK ABOUT THE VERY SAME TIME A PRESIDENT ADDRESSING THE COUNTRY BUT ALSO UNFORTUNATELY SAME TIME NOTER DAME IS BURNING AND WE DON'T KNOW WHY. IT'S A TRUE REALITY, I JUST SAW PICTURES. ANYHOW, (INDISCERNIBLE) IL 2. THESE ARE MY DISCLOSURES. I WORK WITH (INDISCERNIBLE) ACTUALLY THE TREATMENT OF AUTOIMMUNE DISEASE WITH IL 2. AS YOU KNOW, THE FIRST EFFICIENT REFRACTORY OF CANCER WOULD BE TO DISCUSS THE WAY IT'S MORE MAYBE WAY TO ALLEVIATE SOME OF THE SIDE EFFECTS OF CURRENT CANCER. I IL 2 WAS HERE AT THE NIH, IT WAS APPROVED AS A TREATMENT FOR CANCER IN 1992. THE DOSE USED TO TREAT PATIENT WITH CANCER WAS SOMEWHERE AROUND 20 TO 40 UNIQUE FOR INJECTIONS, WITH LONG TREATMENT WHICH TOTALLY AMOUNTED TO OVER 2,000, MILLION UNITS FOR COURSE OF THE TREATMENT. THE DIFFERENT STUDY PUBLISHED SHOW THAT THERE ARE REAL ROBUST LONG DURATION DEPENNING ON THE STUDIES SO IT WORKED. THE PROBLEM WAS THAT REMISSION OR CURE WERE EXPENSE OF SEVERE >> MOST IMPORTANT SIDE EFFECT WAS VASCULAR LEAK SYNDROME, AND SIDE EFFECT RECRUITED (INDISCERNIBLE) NEVER MUCH USED IN EUROPE THOUGH QUITE USED HERE IN THE STATES. ONE ISSUE AROUND IL 2, I DON'T KNOW WHY THIS IS THE CASE, APPEARS THERE WERE NEVER SOME REAL IN DEPTH STUDY OF THE EFFECT OF IL 2 TO FIND BIOMARKERS EITHER OF THE RESPONSE OR OF THE SIDE EFFECT. SO TO HAVE A BETTERED USER THAN MOLECULE. ANYWAY, -- DIDN'T WORK IN ALL PATIENTS. IN FACT IT'S PROBABLY RELATED TO THE FACT THAT IL 2 WHICH WAS BY THE WAY INITIALLY BOOST EFFECTED T-CELL RESPONSES TO KILL THE CANCER CELLS, SO THE LIMITATION IN THE TO NOT ONLY STIMULATE EFFECT OF T-CELLS BUT STIMULATE REGULATORY T-CELLS. THESE WHAT WE LEARNED A FEW YEARS AGO IN A CLINICAL TRIAL WE DID IN CANCER TRYING TO TREAT WITH METASTATIC CARCINOMA, WITH CANCER VACCINE, DIDN'T MATTER THE COMPOSITION AND ALSO GIVING TO THIS PATIENT IL 2 BECAUSE FIRST IT WAS IN FOR THIS TYPE OF PATIENT BUT ALSO BECAUSE WE AID AT STIMULATING T-CELL RESPONSE CANCER TO TRIGGER. THE DOSES WERE (INDISCERNIBLE) PER DAY FOR EIGHT WEEKS ALL TOGETHER AROUND A THOUSAND UNITS OF IL 2. THE RESULTS WERE REALLY POOR, IT WAS A HELL OF A TRIAL, VERY DIFFICULT TO PREPARE THE VACCINE. FOR THREE PATIENT WE IN FACT COULD GET SOME OBSERVATION IN CELLS, WE STRUGGLE TO OBSERVE THAT IN THESE PATIENTS THERE WERE MAJOR INCREASE OF TREGS AFTER FOUR WEEKS OF -- AS YOU CAN SEE HERE. (INDISCERNIBLE) AS YOU CAN SEE HERE, IN SOME OF THE PATIENT THERE WAS EVEN THE 20 FOLD INCREASE IN THIS PROPORTION AND HERE FOR EXAMPLE -- IN THESE PATIENTS. AT 45% OF THE CELLS WERE TREGS. AT THE TIME WE WERE DOING THIS STUDY WE WERE INVOLVED IN STUDYING PATHOPHYSIOLOGY OF DIFFERENT DISEASES WITH MY COLLEAGUE, INTERESTED IN VASCULITIS (INAUDIBLE) HCV. WHAT WE SHOWED (OVERLAPPING SPEAKERS) >> THERE WAS A DECREASE IN TREGS IN PATIENT WITH H CV COMPARED TO ALL OTHER CONTROL WE STUDY AT THE TIME. WHAT WAS INTERESTING IS WHEN WE TRIED TO TREAT THIS PATIENT WITH ONE OF THE TWO OPTION FOR THESE SITUATION WHICH IS USER RITUXIMAB, WE OBSERVE THERE WERE PATIENT THAT RESPONDED WELL, IN BOTH WHO DID NOT RESPOND TO RITUXIMAB OR HAD PARTIAL RESPONSE TO RITUXIMAB, AND WHAT WAS STRIKING IS THE FACT THAT THOSE PATIENTS WITH COMPLETE RESPONSE RECOVERED NORMAL NUMBERS OF PERCENTAGE OF TREGS COMPARED TO THOSE WHO DID NOT RESPOND OR HAVE PROPER RESPONSE WITH LOW NUMBERS OF TREG, PRESENTATIONS OF TREGS. THAT'S AN INTERESTING OBSERVATION WHICH IS TYPICALLY THE EGG OR CHICKEN DILIMB MA. WERE PEOPLE RECOVERING TREG CURE FOR VASCULITIS OR CURE FOR VASCULITIS BECAUSE OF TREG. THERE ARE NOT SO MANY WAYS TO ADDRESS THESE QUESTIONS, ONE WAY IS TO JUST ASK IF I JUST TARGET TREG WILL I HAVE A CLINICAL BENEFIT BUT THE QUESTION AT THE TIME IS HOW WE BOOST IN THE PATIENT. WE WANT TO GO CELL THERAPY BUT OF COURSE WE HAVE IN MIND THE STUDY U JUST PRESENTED TO YOU EARLIER SHOWING THAT IL 2 IN FACT CAN BOOST TREG SIGNIFICANTLY, IN PATIENTS AND WE STARTED TO CONSIDER THIS POSSIBILITY. THE PROBLEM WAS IN 206. THE PRIME IS THAT AS YOU KNOW AUTOIMMUNE DISEASE ARE LARGE PART MEDIATED BY T-CELLS WHETHER DETECTORS OR IT'S NOT THE FIRST CHOICE, A RISK TO EXACERBATE THE DISEASE. BUT WE TURN AROUND THE TREGS AND THE FACT THEY ARE CHARACTERIZED BY THE CONSTITUTIVE EXPRESSION OF CD 25, BEING ONE COMPONENT HIGH AFFINITY RECEPTOR FOR INTERLEUKIN 2, MEANING AMONG THE DIFFERENT T-CELLS, TREGS ARE THOSE THAT EXPRESS THE HIGHEST LEVEL SEQUENCE AND RECEPTOR WHILE THE EFFECTOR T-CELLS EXPRESS TRANSIENTLY AND EVEN WHEN THEY EXPRESS TRANSIENTLY AT LOWER LEVEL. IF YOU GIVE LOWER LEVELS IT'S CAP PURRED PREFERENTIALLY BY TREGS. ALSO IT HAS THAT IT WILL BE LIKELY SAFER AND BETTER TOLERATED. PLUS IT WAS FEASIBLE THE TEST BECAUSE OF COURSE IT WAS EVERY HOSPITAL SHELF TO BE USED ON DEMAND. WE STARTED A FILE, TREATED TIN PATIENTS WITH VASCULITIS. THE DOORS WE GET I DON'T HAVE TIME TO EXPLAIN BUT THEY'RE LOWER THAN WHAT YOU GET IN CANCER AT THIS DOSE, IT WAS WELL TOLERATED. THERE WAS A MAJOR TREG INDUCTION IN THIS PATIENT AND IMPROVEMENT IN 8 OF 10 PATIENTS, THIS IS BRIEFLY ILLUSTRATED HERE, YOU CAN SEE THE GRAY BARS ARE COURSES OF IL 2. AND THE TREGS DO GET UP DURING THIS TREATMENT AND STAY UP FOR SOME TIME. THE SYMPTOMS HERE EACH BAR IS ONE SYMPTOM, TEND TO DISAPPEAR FOR THE TIME EXCEPT ORANGE BAARS THAT REPRESENT NEURAL ACTIVITY WHICH TAKE MORE TIME TO BE ABROGATED. IMPORTANTLY ALSO FOR DISCUSSION USING IL 2 IN ANOTHER CONTEXT WE SHOW THIS IS A GLOBAL ANTI-INFLAMMATORY EFFECT. WE LOOK AT THE TRANSCRIPTOME OF PBMC BEFORE AND DURING TREATMENT OF IL 2, WITHOUT GOING INTO DETAIL WE SHOWED THAT SIGNATURES OF INFLAMMATION WERE SIGNIFICANTLY DECREASED DURING THE IL 2 TREATMENT. THIS OBSERVATION WAS ALSO NICELY CONFIRMED THE FACT THE SAME ISSUE WE PUBLISH OUR PAPER THERE WAS AN ACTIVE PAPER BY GROUP SHOWING THAT THEY HAD ALSO IMPROVEMENT IN PATIENTS WITH CHRONIC GRAPH VERSUS HOST DISEASE IN IL 2 AND GRAFT VERSUS HOST DISEASE INFLAMMATORY DISEASE. WHAT ARE THE REAL MECHANISM OF ACTION OF IL 2 THAT WOULD EXPLAIN OUR OBSERVATION? TREG EXPRESS HIGH AFFINITY RECEPTOR AND CAPTURE IL 2 BETTER BUT IN FACT MORE IN THIS. WHILE DOING STUDY AS GROUP SHOWED THAT TREGS WERE EXQUISITELY SENSITIVE TO INTERLEUKIN 2. ISSUE ANALYZE DIFFERENT CELL TYPES AND FIT THEM WITH INCREASING CONSENTVATION OF IL 2 AND LOOK AT STATE 5, THE FIRST DOWNSTREAM ACTIVATION OF IL 2 RECEPTOR. YOU CAN SEE THAT YOU GET SIGNIFICANT PHOSPHORYLATION AT DOSES OF IL 2 WHICH YOU HAVE ABSOLUTELY NO EFFECT ON THE ADVERSE HEALTH POPULATION AND THIS IS FOR TREG, IT'S MORE FOR MEMORY TREG OR EFFECTOR TREG AND YOU CAN SEE THAT THE EFFECTOR MEMORY CD4 CELLS ARE MORE SENSITIVE BUT THEY ARE ACTIVATED STILL AT DOSES OF AT LEAST 20 TIMES HIGHER THAN THOSE THAT ACTIVATE TREGS. EVEN MORE THAN THAT, LOOK DOWNSTREAM PHOSPHORYLATION OF STAT 5, AT THE GENE EXPRESSION PROGRAM TRIGGERED BY IL 2 BINDING TO ITS RECEPTOR, YOU WILL FIND A SERIES OF GENE THAT ARE ACTIVATED AND LOOK AT THE CONCENTRATION AT THE GENE ACTIVATION FOR EXAMPLE LOOKING AT BCL 2 YOU WILL SEE ALREADY WITH ONE UNIT OF IL 2 YOU HAVE FOUR FOLD INCREASE OF THE EXPRESSION OF BCL 2 WHILE EVEN AT HUNDRED UNIT OF IL 2 YOU CANNOT GET TO THIS LEVEL IN THE CD 4 EFFECTOR MEMORY CELLS, WHAT'S TRUE FOR THAT IS TRUE FOR DOZENS OF GENES INVOLVED IN TREG FUNCTION. SO ALL TOGETHER, NOT ONLY TREG CAPTURE BETA IL 2 BUT MORE SENSITIVE TO IL 2 COMPARED TO EFFECTOR CD4 CELLS, 20 FOLD EXPRESSION AND HUNDRED FOLD FOR GENE EXPRESSION. AND NATURALLY AFTER THESE WORKS WERE PUBLISHED MANY GROUPS CAME OUT ONE MECHANISM OF ACTION INTERESTED FOR SETTING TREATK AUTOIMMUNE DISEASE. FOR EXAMPLE, IT'S SHOWN IN EXCELLENT JOURNALS AND REPRODUCED BY MANY GROUP IL 2& BLOCKS DIFFERENTIATION OF NAIVE CD4 POSITIVE CELLS INTO TH 17 CELLS AND INTO TFH CELLS DESIRABLE TO TREAT AUTOIMMUNE DISEASE WITH SOME LEVEL OF INFLAMMATION. AND ALSO TO TACKLE PRODUCTION OF AUTOANTIBODIES. IN FACT VERY NICE PROPERTIES ARE IN THE FACT THAT THERE ARE AT LEAST 30 DIFFERENT MOUSE MODEL OF (INAUDIBLE) WHAT ABOUT THE CLINICAL RESULTS OF IL 2 IS TEST IN MANY DIFFERENT DISEASE. WE HAVE NUMEROUS TRIAL ONGOING AND I WANTED TO SHOW ONE ONGOING TRIAL WHICH IS THE OPEN TRIAL SO I HAVE ACCESS TO THE RESULTS ON TIME, BECAUSE IT'S ALSO VERY RELEVANT TO WHAT WE ARE DISCUSSING HERE TODAY. THIS TRIAL IS TRANSFERRED WE CALL IT A DISEASE FINDING TRIAL BECAUSE WE -- THE NEED THE TRY DECIDING WHICH WE'RE GOING TO CONTINUE THE DEVELOPMENT OF INTERLEUKIN 2, A PHASE 2 TRIAL, WE ARE TREATING 1 IN 32 PATIENT, ONE OF 11, NOT 14 SELECTED AUTOIMMUNE DISEASE. THE LIST IS HERE. I DON'T HAVE THE TIME TO GO INTO DETAILS OF WHY WE CHOSE THE DISEASE BUT IF WE HAD THE TIME WE COULD ALSO SEE MANY DISEASE ARE RELATED TO TISSUE ORGANS THAT APPEARS ON THE SLIDE SHOWED BY OTHERS RELATED TO THE TARGET ORGAN FOR IMMUNE RELATED ADVERSE EVENT OF CANCER AND IMMUNOTHERAPIES. IMPORTANTLY THESE PATIENTS RECEIVE EXACTLY THE SAME TREATMENT WITH IL 2 AND WE SELECTED WITH MILD TO MODERATE DISEASE ACTIVITY BECAUSE WE DON'T WANT TO ADD TOO MANY CLINICAL TREATMENT AT HIGH DOSE THAT AFFECT ALSO THE UNION INVESTIGATION WE ARE CARRYING WITH THESE PATIENT. THE TREATMENT IS A SERIES OF FIVE INJECTION FOR WHAT WE CALL INDUCTION PHASE AND MAINTENANCE PHASE ONE INJECTION EVERY TWO WEEKS FOR SIX MONTHS IN THIS TRIAL. THE QUESTION WE ARE ASKING, WILL EFFECT OF TREG SPECIFIC AND SIMILAR AMONG DIFFERENT DISEASES, WILL THE TREATMENT BE SAFE ACROSS THE DIFFERENT DISEASE DIFFERENT CONCOMITANT TREATMENT THIS PATIENT RECEIVE, WILL THE CLINICAL BENEFIT WILL BE SIMILAR OR DIFFERENT ACROSS THE DISEASES. FIRST TREG CRITERIA FOR THE TRIAL, AS YOU CAN SEE HERE THESE ARE PATIENT WITH DIFFERENT TYPE OF AUTOIMMUNE DISEASE AND MORE OR LESS RESPOND AS WE EXPECT TO IL 2 WITH DOUBLING OF TREGS AFTER FIVE INDUCTION INJECTION AN MAINTENANCE OF TREG BOTH BASELINE FOR THE REST OF THE TRIAL. I DON'T HAVE THE TIME TO DISCUSS IN TOO MANY DETAILS BUT WE WANTED TO ALSO USE THIS PATIENT TO REALLY ADDRESS THE QUESTIONS OF WHETHER WE ARE HAVING AN EFFECT VERY SPECIFIC FOR TREGS AND NOT AFFECTING EFFECTED T-CELLS WHICH YOU DON'T WANT TO DO. WHEN YOU TREAT AUTOIMMUNE DISEASE, WE USE UNSUPERVISE METHOD TO ANALYZE IMMUNOPHENOTYPING OF THE PATIENT IL 2. WITHOUT GOING INTO THE DETAILS WE USE A -- TO DEFINE THRUSTERS AND YOU GET SUBCLUSTERS AGAIN AFTER AUTOMACK CLUSTERING AND WHAT YOU CAN SEE HERE IS THAT ONLY TREG ARE SIGNIFICANTLY MODIFIED BY THE TREATMENT AND NAIVE TREG AND THE MOST ACTIVATED TREGS, THIS IS WHAT'S IMPORTANT IN THE EFFECTED T-CELLS, REALLY NOTHING SIGNIFICANTLY EFFECTIVE THAT REALLY CHANGE IN AN INDIVIDUAL WAY. WHAT ABOUT THE CLINICAL EVALUATION OF THIS PATIENT? BECAUSE THE TRIAL WAS DESIGNED AROUND THE CROSS EVALUATION WANTED TO FIND A WAY TO CROSS EVALUATION THE PATIENT FOR CLINICAL RESPONSE TO THE DRUG OF COURSE, FOR SOME TREATING THERE ARE WELL KNOWN SPECIFIC SCORES MONITORING BUT WE WANT AD SCORE THAT WOULD HELP US ANALYZE ALL THE PATIENT ALL TOGETHER. WE FOUND IN THE LITERATURE THAT THERE IS THIS GLOBAL IMPRESSION SCALE DEVELOP MOSTLY TO EVALUATE A DRUG PSYCHIATRIC DISEASE TO DESCRIBE IT IN IF DETAIL, WE DECIDED TO TRY TO I ADAPT THIS SCALE -- ADAPT THE SCALE TO THE EVALUATION OF OUR PATIENT BUT ALSO OF COURSE WE FOLLOWED THE DISEASE SPECIFIC SCORES. GLOBALLY ACROSS THE PATIENT DISEASE, ANALYZE ALL TOGETHER WE CAN SEE THAT THERE IS A MARK DECREASE OF A DISEASE ACTIVITY SCORE, WITH DISEASE SEVERITY SCORE THAT IS SIGNIFICANT FOR SIX MONTHS PERIOD OF THE TREATMENT AND WHEN YOU ACTUALLY STOP THE TREATMENT AT SIX MONTHS AND DO A EVALUATION TWO MONTHS THEREAFTER THERE IS A TENDENCY FOR SOME REAPPEARANCE OF SOME OF THE SYMPTOMS BUT ALL TOGETHER ACROSS VERY DIFFERENT DISEASES THERE WAS A MARKED -- AN EFFECT OF IL 2, CLINICAL BENEFIT OF IL 2. I AM OUT OF TIME BUT THE DISEASE SCORE ALSO IMPROVED. ONE OBSERVATION WE MADE WHICH I THINK IS REALLY SIGNIFICANT IN THE MANY DIFFERENT TRIALS WE HAVE DONE AND THAT WE HAVE ALREADY ANALYZED WE HAVE ALWAYS OBSERVED THAT THERE IS A VERY GOOD CORRELATION BETWEEN THE CLINICAL RESPONSE IN A PATIENT AND IN FACT THE TREG RESPONSE TO IL 2, BECAUSE OF COURSE WHEN I SHOW THE GLOBAL SCORE IN THE SLIDE PRECEDING THIS ONE WE LOOK AT THE PATIENT ALL TOGETHER, OF COURSE THERE ARE RESPONDERS AND NON-RESPONDERS. SO WHEN YOU LOOK AT THE RESPONDERS AND NON-RESPONDERS SEPARATELY, YOU SEE THIS IS FROM THREE DIFFERENT TRIALS, FOR EXAMPLE IN THE TRANSFER TRIAL I JUST DESCRIBE HERE WE REANALYZE THE RESULTS OF PATIENT WITH -- DISEASE, (INAUDIBLE) DISEASE OR SCLERODERMA. AND WE DEFINE THEM AS RESPONDERS AND NON-RESPONDER BASED ON PRE-SPECIFIED CLINICAL PARAMETERS. YOU CAN SEE VERY CLEARLY THOSE WHO ARE RESPONDERS IN GREEN HAVE A MUCH MORE ROBUST RESPONSE TO IL 2 IN TERMS OF TREG INCREASE IN PRESENTATION BUT THIS IS ALSO TRUE IN NUMBER, IT IS ALSO TRUE WHEN YOU LOOK AT ACTIVATION MARKER EXPRESSION ON TREGS. WITH CORRELATION BETWEEN CLINICAL BENEFIT OF THE -- EXPECTING FROM YOUR DRUG WHICH IS ALWAYS GOOD. ANOTHER STUDY THAT WE HAVE NOT PRESENTED YET, THIS WAS A PHASE 2 DEVELOP LINE PLACEBO CONTROL STUDY OF PATIENT SLE. WE DO PATIENT WITH EITHER A DRUG OR WITH PLACEBO. THIS IS WHAT WE OBSERVED AT MONTH 3 IN GREEN ARE THE PATIENT WHO RECEIVE PLACEBO IN ORANGE PATIENT THAT RECEIVED THE DRUG. THE STRAIGHT LINE GOES WITH RESPONDERS AND DOTTED LINE GOES WHO ARE NON-RESPONDERS AND AS YOU CAN SEE HERE AGAIN YOU HAVE MUCH MORE MARKED AND ROBUST RESPONSE TO IL 2 IN THE RESPONDERS TO IL 2 IN THE CLINICAL RESPONDERS THAN IN THOSE WHO DID NOT RESPOND. FINALLY, ONE MORE EXAMPLE OF A TRIAL WE RECENTLY ANALYZE WE ARE GOING TO HOPEFULLY FINISH SOON, THIS IS A TRIAL IN TYPE 1 DIABETES. THIS WAS A DOSE TIMING TRIAL WHERE WE TREATED CHILDREN FROM SIX TO 14 WITH RECENT ONSET TYPE 1 DIABETES WITH IL 2 DEVELOP LINE PLACEBO TRIAL AND WE GAVE SOME VERY LOW DOSE, VERY FEW PATIENT FINALLY HAD A DOSE THAT COULD EXPECT TO BENEFIT FROM. WHEN WE STRATIFY THE PATIENT AS HIGH RESPONDERS TO IL 2 IN TERM OF TREG ELEVATION, AND LOW RESPONDERS TO IL 2, WE CAN ALSO SEE THAT IN THOSE WHO RESPOND WELL TO IL 2 IN TERMS OF TREG ACTIVATION THERE'S A BETTER PRESERVATION OF PRODUCTION OVER TIME THAN IN THOSE WHO RESPOND LESS WELL TO IL 2. WITH THIS I WILL CONCLUDE. AND MAYBE OPEN DISCUSSION, WE'RE GOING TO HAVE. BASICALLY CANCER IMMUNOTHERAPY ARE AIM TO HELP THE EFFECTED T-CELLS OVERCOME TUMOR TOLERANT ENVIRONMENT THAT IS IN LARGE PART TREATED BY TREGS BUT ALSO PRE-DETERMINE ENVIRONMENT FOR NORMAL TISSUES. AND IT'S NOT SO SURPRISING THAT EMANCIPATING TF FROM CONTROL OF TREGS INTERACTIONS ARE SOMETIME UNLEASHED. A COUPLE OF INTERVENTION HAVE BEEN DISCUSSED ALREADY, FOR CONTROLLING THE IMMUNE ADVERSE EVENT NONE AIMED AT STIMULATING TREG, IT'S A PAUCITY THAT SHOULDN'T BE IGNORED AND I'LL LET YOU THINK ABOUT THIS THAT I L TWO NOT ONLY BE FIRST IMMUNE CANDIDATE ALSO OF HELP TO CONTROL SIDE EFFECT OF OTHER CANCER IMMUNOTHERAPIES. THESE ARE MY COLLABORATORS OF THE NUMEROUS CLINICAL TRIALS AND BEFORE I FORGET, I WANT TO DO A LITTLE TIDING HERE,, WE ARE HAVING -- ADVERTISING HERE. WE ARE HAVING A MEETING ON INTERLEUKIN 2 IN BOTH REFRACTORY DISEASE AND CANCER IN PARIS IN NOVEMBER. WE HAVE A GREAT LIST OF SPEAKERS. AND YOU CAN FIND INFORMATION WITH THE NEWLY RELEASED WEBSITE HERE. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] Q. THANKS VERY MUCH, IT WAS A VERY EXCITING SESSION. WE ARE AVAILABLE TO TAKES QUESTIONS FROM THE AUDIENCE AND MAYBE AS PEOPLE ARE COMING UP, CURIOUS FOR DR. KLATZMANN COULD YOU CONCEIVE OF A SITUATION IN WHICH INDIVIDUALS PERHAPS HAVE SEVERE AUTOIMMUNE DISEASE ONE WOULD USE CYTOKINES OR IN ORDER TO HELP CONTROL THAT IN A BETTER FORMAT? >> SAY SOMEBODY HAD SEVERE ADVERSE EVENT AS A RESULT OF AN IMMUNE CHECK POINT INHIBITOR OR OTHER CANCER IMMUNOTHERAPY, TYPICALLY WE ARE USING SOME BLOCKING ANTIBODY WITH IL 6 CYTOKINE RELEASE SYNDROME BUT COULD YOU SEE THAT USED MORE ROUTINELY PERHAPS A LOW DOSE IL 2 OR SOME OTHER CONCOCTION BASICALLY. >> I WAS ADVOCATING WE SHOULD THINK ABOUT WAYS TO TRANSIENTLY BOOST, BECAUSE YOU ALSO WANT TO PRESERVE THE EFFECT OF THE CANCER IMMUNOTHERAPY SO IT'S ALL ABOUT THE BALANCE. BUT I WANT TO SAY THE REASON I PRINT THE SLIDE WHEN WE STARTED TO THINK ABOUT THIS PROCESS WE CAME TO USE IL 2, MORE OR LESS SAME SITUATION IN AUTO-IMMUNITY, YOU WANT TO BOOST EFFECTOR CELLS AND YOU WANT TO FIND THE RIGHT DOSAGE, HERE YOU HAVE IMMUNE ADVERSE EVENTS IN BY OBVIOUSLY TREGS PLAY A ROLE TO CONTROL THEM TRANSIENTLY, THE GOOD THING IS IL 2 HAS SHORT HALF LIFE SO YOU CAN PLACE -- I WOULD THINK THAT IT'S WE SHOULD CONSIDER THAT. THEN IT'S A MATTER OF DOSE AND DURATION OF TREATMENT AND THEN PARAMETERS. >> I HAVE TWO QUESTIONS TO JARUSHKA. AS A RHEUMATOLOGIST I TREAT LOT OF PATIENTS WITH AUTOIMMUNE DISEASE AND SOME WITH (INDISCERNIBLE) WE DO KNOW IN THESE PATIENTS TTNF AND INNFLEXIMAB DON'T WORK AT ALL. EVEN THOUGH MAY INDUCE SOME -- THUS I AM A LITTLE SURPRISE ABOUT CHOICE OF INFLEXIMAB, EVEN I CAN UNDERSTAND IN COLITIS, BECAUSE (INDISCERNIBLE) BUT WHY CHOOSING INFLEXIMAB IN THIS SIDE EFFECT PD 1 THERAPY? >> ALL I CAN SAY IS YOU ARE PREACHING TO THE CHOIR, I'M WITH YOU ON THAT. I THINK IN GENERAL THE CLINICAL FIELD WAS VERY IMPRESSED WITH THE CLINICAL RESULTSES OF USING INFLEXIMAB IN PATIENTS WITH COLITIS. ANECDOTALLY IT'S BEEN SHOWN TO BE VERY BENEFICIAL AND THE NUMBER OF CHECK POINT ININHIBITORS TOXICITIES NOT JUST COLITIS, JUST STARTED WITH COLITIS. PNEUMONITIS WAS THE FIRST SET OF SEVERE TOXICITIES FROM PD 1 IMMUNOTHERAPY AND ANECDOTALLY PROVIDERS USE THAT IN THE HOPE IT COULD RECAPITULATE THE BENEFICIAL EFFECTS SEEN WITH COLITIS. RHEUMATOLOGISTS AND PULMONOLOGISTS SUCH AS YOURSELF, IT HAS BEEN NOW NOTICED THAT THESE PATIENTS DON'T DO WELL BUT BECAUSE IT'S ACTUALLY WRITTEN INTO MANY OF THE PRESCRIBERS GUIDELINES AS AN OPTION FOR THERAPY THAT IS WHAT HAS PREPET WAITED ITS USE. AND NOW IT WOULD VERY MUCH BE SEEN AS ALMOST A UNIVERSAL STANDARD OF CARE THOUGH NOT BASED ON ANY OBJECTIVE DATA AND FOR THAT REASON THIS UNDERSCORES THE NEED TO COMPARE IT IN A TRIAL SETTING. INITIALLY WHEN WE PROPOSED OUR TRIAL WE PROPOSE A THREE ARM STUDY WHICH WE WOULD COMPARE PATIENTS WHO WERE TREATED WITH INFLEXIMAB IVIG BECAUSE AS YOU KNOW MICROFEN LATE MAKES SENSE AND HAS BEEN USED IN UIP AND NUMBER OF INTERSTITIAL DISEASES. BUT AGAIN RELATED TO THE ISSUE OF THE INCIDENCE OF STEROID REFRACTORY PNEUMONITIS BEING RARE, THERE WAS CONCERN ABOUT ACCRUAL FOR THAT. THE STUDY WAS THEN CHANGED TO IV,G VERSUS MICROFEN LATE AND ONCE AGAIN NUMBER OF REGULATORY BODIES DIFFERENT BODIES WHO HAVE USED AND CONTINUE TO USE INFLEXIMAB INSIST ON IT BEING USED AS THE CONTROL ARM. BUT THE STUDY HAS BEEN WRITTEN IN SUCH A WAY THAT IT IS TREATING A SMALL NUMBER OF PATIENTS INITIALLY IF A LEAD IN SHOWS INFLEXIMAB ARM SAYS HIGH ADVERSE OUTCOMES HAS BEEN REACH IN 14 DAYS WE WILL CLOSE THE ARM AND HAVE OUR ANSWER IN A SHORT TIME FRAME FROM A VERY SMALL NUMBER OF PATIENTS. AND I'M HOPEFUL THAT THAT'S WHAT WE WILL SEE. I COMPLETELY AGREE WITH YOU. >> I HAVE A QUESTION TO THE PANEL. WE ARE -- AUTOQUESTION ABOUT SAFETY OF HIGH DOSE STEROIDS IN THE CONTEXT OF TREATMENT. IN HUE PUS WE HAVE TRIAL -- STEROIDS AND 20 NEW VARIETIES WITH ONLY RITUXIMAB AND -- WITHOUT ANY STEROIDS. DON'T YOU THINK NOW IT'S TIME IN THIS ADVERSE EVENT OCCURRING WITH IMMUNE CHECK POINT INHIBITORS MAYBE TO TEST MAYBE MORE AMBITIOUS CLINICAL TRIAL WITH NO STEROID VERSUS RITUXIMAB VERSUS IPILIMUMAB. >> I WILL TAKE A RESPONSE, THAT'S A GREAT QUESTION AND DEFINITELY THE FIELD SHOULD APPROACH. ONE OF THE CHALLENGES TO THAT IS THAT PATIENTS DO VERY WELL WITH STEROIDS ALONE. IT WOULD BE A HIGH BAR TO TRY TO REACH AND TAKE A LOT OF PATIENTS AND WOULD HAVE TO BE DONE IN A O STRAYTIVE MANNER WITH THE DIFFERENT TYPES OF IMMUNE RELATED TOXICITIES BUT DEFINITELY A QUESTION THAT IS ASKED. >> I THINK THERE'S A PROBLEM WITH THE NUMBER OF DIFFERENT SIDE EFFECTS AND HOW TO LOOK AT SOME -- IN COLITIS IT IS A GOOD EXAMPLE, A LOT OF PEOPLE WOULD LIKE TO SEE A TRIAL LOOKING AT STEROIDS VERSUS INFLEXIMAB STUDY, YOU ARE RIGHT. STEROIDS MAYBE THE WORST OF ALL OF THESE DRUGS THAT WE CHOOSE. >> I AM AWARE, RITUXIMAB IS IN LINE WITH CHECK POINT INHIBITORS IN HEMATOHODGIC DISEASE. I AM AWARE OF ONE TRIAL THAT IS BEING STARTED AT EMORY, BY THE GROUP ACTUALLY LOOKING AT APRIORI, LARGELY TO DEAL WITH SUPPRESSIVE -- SUPPRESSOR B CELLS AS USING RITUXIMAB AS A MEANS OF REDUCING SUPPRESSOR B CELLS BUT IT WOULD BE INTERESTING TO LOOK AT EFFORTS LIKE THAT TO SEE PERHAPS IF CERTAIN ADVERSE EVENTS ARE REDUCED IN PARTICULAR COMPLETED TRIALS WELL CONDUCTED AND COLLECT THAT INFORMATION APPROPRIATELY. >> MY QUESTION IS FOR DR. NAIDOO. CONGRATULATIONS YOUR TITLE WAS EXCELLENT. I THINK PNEUMONITIS IS PROBABLY THE MOST CHALLENGING TOXICITY MORE THAN MYOCARDITIS BECAUSE WITH THAT WE HAVE THE HEART BIOPSY AS GOLD STANDARD BUT IN PNEUMONITIS WE DON'T HAVE ANYTHING YOU MENTIONED UNTIL THE MONTH AGO THE RECOMMENDATIONS FOR GRADE 3 AND 4 PNEUMONITIS ACCORDING TO THE GUIDELINES WAS TO START ANTIBIOTIC THERAPY AND STEROIDS ON THESE PATIENTS AND CONSIDER BRONCHOSCOPY IF THERE WERE DIFFERENT POSSIBILITIES ON -- I THINK THIS IS NOT HELP TESTIMONY PNEUMONITIS IS ONLY DIAGNOSE NOSEYS FEE WITH START ON BOTH THERAPIES WE DON'T KNOW WHAT'S GOING ON AND WHAT WE ARE TREATING. IN THE LAST UPDATED VERSION OF THE NCCN GUIDELINES, THEY FINALLY ADVISE TO CONSIDER BRONCHOSCOPY SINCE THE BEGINNING AND START PATIENTS ON ANTIBIOTIC THERAPY ONLY WHENNEN INFECTION HAS NOT BEEN SUCCESSFULLY PLOTTED. SO I SOMETHING WE SHOULD TRY TO BRING ALL THESE PEOPLE BECAUSE THAT'S THE BEST WAY TO KNOW WHAT'S GOING ON THERE. EVEN DELAY OF 24 HOURS IS NEEDED, IF PATIENTS ARE STABLE WE SHOULD WAIT. I WOULD LIKE TO KNOW WHAT'S THE CLINICAL PRACTICE IN YOUR INSTITUTION, HOW DO YOU MANAGE THESE PATIENTS WHEN THEY COME TO THE EMERGENCY DEPARTMENT. >> I WISH I COULD HIRE YOU ALL TO COME O TO HOPKINS. THAT'S MY CLINICAL PRACTICE IS I WOULD ADVOCATE FOR BRONCHOSCOPY AND I DO THAT AT EVERY PATIENT IN WHOM I HAVE THIS QUESTION WHO IS SIMILAR TOEMATIC. GREAT ONE PNEUMONIGH AT THIS CASE ADVOCATING FOR INNOVATIVE TASTE ASYMPTOMATIC IT'S TRICKY BUT START STEROIDS OF ANTIMICROBIALS THAT MAKES SENSE, THAT IS MY PRACTICE. HAVING SAID THAT, I DO WORK IN A MULTI-DISCIPLINARY TEAM WITH THREE INTERVENTIONAL PULMONOLOGISTS WHO WILL BRONC PEOPLE 24 TO 48 HOURS, SO I APPRECIATE COMMUNITY PROVIDERS WHO DON'T HAVE THAT IMMEDIATE LINK TO SOMEONE WHO IS ABLE TO DO A BRONCHOSCOPY AND MORE IMPORTANTLY HELPED MECAL ONCOLOGIST INTERPRET THOSE FINDINGS. SO I THINK IN CONTEXT OF GUIDELINES, THAT IS WHERE THE RECOMMENDATIONS OR WIGGLE ROOM COMES FROM, THAT IT IS FELT FEASIBILITY NEEDS TO BE FACTORED INTO THE GUIDELINES AND HENCE THE PUSH BACK FOR NOT PUTTING THE BRONCHOSCOPY FOR EVERY PATIENT. THAT IS DEFINITELY I AD VOTE KATEED FOR AND HAPPY THE NCCN DID IN THE GUIDELINE. >> I THINK ALSO WITH GI TOXICITY, IT'S VERY SIMILAR IN TERMS OF EVALUATION. I CERTAINLY TRY NOT TO START STEROIDS UNTIL WE HAVE THE DIAGNOSIS WITH BIOPSIES. WHAT YOU HAVE TO DO IS GET A REALLY MOTIVATED SPECIALIST THAT'S ALMOST KEY WITH PULMONARY OR GICS. WITH PULMONARY, ONE PROBLEM I HAVE HAD IS ACTUALLY PROBABLY A GOOD PROBLEM TO HAVE, IS THAT MANY PERSONS GOD -- PATIENTS GET ADMITTED. CLEARLY NEED TREATMENT, AND WE DO START STEROIDS, THEY ARE BETTER BY THE NEXT MORNING AND THEN IT'S VERY HARD TO PERSUADE ANYONE TO DO A BIOPSY. CAN I ASK WHEN WILL HE'S COMING UP? A QUESTION FOR KELLY IN THE SPIRIT OF THE MEETING. WHERE THE CONNECTIONS BETWEEN AUTO-IMMUNITY AND CANCER, IT'S SO FASTNATING THERE ARE PATIENTS WITH CTLA 4 HAPLO INSUFFICIENCY, HOW COME WE HAVEN'T FOUND A HUMAN WITH PD 1 MUTATION OR PROBLEM? ARE WE NOT LOOKING CORRECTLY? IT'S BAD LUCK? DOESN'T HAPPEN? >> SO RARE IF I DON'T KNOW IF IT'S LETHAL SO THERE ARE HETEROZYGOUS POLYMORPHISMS THAT CTLA 4 AND PD 1 AUTO-IMMUNITY. BUT IN TERMS OF HAVING A DISEASE PHENOTYPE THAT'S EQUIVALENT TO THE CTLA 4 HAPLO INSUFFICIENCY OR WE HAVEN'T IDENTIFIED PART IS RECOGNITION BUT ALSO CENTER PLACE THAT CAN DO THE DIAGNOSTICS BEFORE THAT PATIENT DIES AND WHEN THEY ARE RECOGNIZE A LOT OF PATIENTS DIE OF SEPSIS OR OTHER INFECTIONS OR AUTOIMMUNE COMPLICATION WITHOUT HAVING THEIR GENOME INTERROGATED. SO HOPEFULLY IF THEY ARE OUT THERE WE WILL FIND THEM. GUIDELINES THEN QUESTION. AS I UNDERSTAND ONE OF YOUR FULL PROFESSORS AT HOPKINS SPENDS 30% OF HIS TIME HELPING AUTHOR GUIDELINES, I DO WONDER WHETHER OR NOT THERE'S OPPORTUNITIES HERE TO ENCOURAGE ENROLLMENT AND THE IDEA OF THE SHOULD BE FURTHER STUDIES WITHIN THE GUIDELINES THEMSELVES, THEY ARE BEING ADOPTED INTERNATIONALLY, CHINA. WE CAN TALK OFFLINE BUT IF YOU WANT I THINK YOU KNOW WHAT I'M TALKING ABOUT. IN YOUR HONOR PROTOCOL DESIGN, I DON'T THINK YOU SHARED WITH US THE END AND EXPECT TED DATA OF THE OUTCOME, BASED ON ENROLLMENT PROJECTION, OPERATION. >> I SHOULD HAVE SAID THAT. IT'S 16 PATIENTS PER ARM. AND WHICH IS VERY AMBITIOUS. BUT IN THE SIX CENTERS WE ARE HOPING WE WILL ENROLL IN TWO YEARS. >> SO IT'S I DON'T KNOW HOW IT'S POWERED BUT SEEMS LIKE LOW NUMBERS TO MAKING INFIRM DECISIONS. WONDERING ABOUT THE CAPACITY AND INTEREST TO COLLABORATE WITH INDUSTRY. I SHOULD SAY I'M HOWARD FINGER FULL DISCLOSURE, I'M IN INDUSTRY AND I WORK ON MULTIPLE PRE- PERSONAL PRIVATE AND INDUSTRY PUBLIC PRIVATE ORGANIZATIONS. SO I HAVE BEEN VERY LUCKY TO SEE TIMES TRIALS LIKE THIS WERE PEOPLE REALLY AGREE ON TRYING TO HELP WITH THE SAFETY OUTCOMES. CAN BE SOMETHING THAT INDUSTRY CAN GET TOGETHER ON AND I WOULD ADVOCATE, GETTING ENROLLMENT DONE I PRISON YOU FOR DOING THIS BECAUSE THIS IS NET DOTES AROUND SAFETY AND HOW TO MITIGATE INTERVENTIONS. I HAVE MAJOR CONCERNS ABOUT (INDISCERNIBLE), WITHOUT SEEING MORE RANDOMIZE FULL DATA OFF LABEL USE, ET CETERA, MAY NOT BE THE WAY TO GO WITH THAT DRUG. SO THANK YOU FOR THAT, MAKE THE OFFER IF YOU WANT TO TALK ABOUT IT OFFLINE, WHEN SAFETY COMES IN, THERE'S A LOT OF OPPORTUNITY AMONG PEOPLE IN INDUSTRY INCLUDING COMMITTEE CHAIR FOR PULMONARY, FROM ECOG NOW RUNNING THE PULMONARY DEPARTMENT IN ONE OF THE BIGGEST ONCOLOGY PD 1 PROGRAMS IN THE WORLD. YOU ALSO KNOW WHO I'M TALKING ABOUT SO WE CAN TALK OFFLINE BUT I DO THINK IT'S -- THESE ARE OPPORTUNITIES TO CONSIDER, I DON'T KNOW IF YOU HAVE CONSIDERED OR IF YOU HAVE COMMENTS. >> THAT WOULD BE WONDERFUL WE WILL TAKE ANYONE THAT CAN HELP. SO THE CORRELATES OF ANALYSES ARE FUND BY INDUSTRY FOR THIS PARTICULAR PROTOCOL. I HEAR YOU IN TERMS OF NUMBERS BUT I THINK ANYBODY WHO WORKED IN THIS SPACE CLINICALLY KNOWS THAT THE QUESTION OF FEASIBILITY IS AN ISSUE AND EVEN THOUGH THE NUMBERS ARE SMALL, AND I APPRECIATE THIS IS NOT GOING TO BE 100, 200 PATIENT STUDY, IN ABSENCE OF ANY PERSPECTIVE DATA IT'S A START AND WE WOULD BE MORE THAN HAPPY TO EXPAND TO LARGER GROUP IF WE DO SUCCESSFULLY ACCRUE. >> I THINK BEING ON THE COMMITTEE, I WOULD SAY I DON'T EVEN GO FARTHER. IT'S ALL ANECDOTAL AND THERE'S VERY LITTLE DATA SO I THINK THESE KINDS OF STUDIES EVEN ONE ARM LOOKING AT REALLY OUTCOMES OF SOME OF THE ESTABLISHED APPROACHES OR AT LEAST WE THINK ESTABLISHED WOULD BE USEFUL. >> I WANT TO MAKE COMMENT DILEMMA WAITING FOR PATHOLOGY AND THIS IDEA, OBVIOUSLY WE TRY TO WAIT FOR CULTURES BUT BEST CASEY ANYWHERE OWE TAKES THREE DAYS TO GET PATHOLOGY BACK. THERE'S A BIG PUSH TOWARDS DOING SOMETHING. IN THE COLON IT'S NOT PATHOFUME MONIC OF COLITIS. SO IT'S A DILEMMA, I AGREE WITH YOU, WOULD BE NICE TO GET BACK AS MUCH INFORMATION AS POSSIBLE BUT WHEN YOU DEAL WITH ABOVE STAGE 2 DISEASE IT BECOMES A CLINICAL DILEMMA. Q. THIS IS A QUESTION TO DR. CLASS NANO. -- DR. KLATZMANN, THE NOTION IS REALLY SUPER BUT IF YOU ARE DOING IN CONTEXT OF CANCER WHERE THIS IS EXACTLY THE OTHER SIDE OF THE COIN IT WOULD SEEM KIND OF RISKY. >> YOU MEAN YOU WOULD ACTUALLY BLOCK ME RESPONSE TO CANCER -- WOULD YOU SAY? >> YOU COULD ENHANCE THE CANCER. >> ACTUALLY I JUST WANTED TO ADD, WE SPENT ABOUT TEN YEARS DOING JUST THAT. THERE WERE NUMEROUS STUDIES LOOKING AT INTERLEUKIN 2 AS AN ANTI-CANCER AGENT. I THINK THAT IS FASCINATING WHAT YOU ARE DOING. BUT IT SHOWS YOU HOW YOU CAN IN THE PAST WHILE WE DID -- WHILE WE THINK WE WERE DOING, WE VERY MUCH WEREN'T. >> IN LOW DOSE IL 2 ESPECIALLY. >> IT WILL BE -- YOU CAN HAVE ALSO OFFLINE, YES, IT'S TRUE TREG CONTROL ARE IN PART RESPONSIBLE FOR CANCER NOT ELIMINATED BY TREG AT THE TIME SEVERE ADVERSE EVENT YOU HAVE TO FACE TO CONTROL THEM. SOMEONE MENTIONED EARLIER THIS DILEMMA OF BIMODAL IMPLEMENTATION WHERE THE T-CELLS MEDIATE INITIAL EFFECT, ALSO THAT ARE RESPONSIBLE FOR SEVERE SIDE EFFECT OF GRAFT VERSUS HOST DISEASE GVHD AND YOU HAVE TO BALANCE THAT AND TUNE THAT AND I WAS JUST CONSIDERING THAT FROM LISTENING TO YOU AND WHAT WAS PRESENTED MAYBE AT SOME POINT SOME TRANS GENT BOOSTING OF TREG COULD ACTUALLY HELP BALANCE ALL THIS. IT WOULD HAVE TO BE TESTED. FROM [APPLAUSE] >> THANK YOU ALL. WE'LL BE BACK IN -- NO BREAK. >> I WANT TO THANK THE PANEL VERY MUCH, WE ARE KEYING UP FOR THE NEXT SESSION, WE ARE RUNNING BEHIND BUT PROBABLY HAVE TO CUT TEN MINUTES OUT OF OUR BREAK. IN ADDITION OF COURSE IT WILL BE REWIRED TO STAY FOR THE POSTER SESSION AT 5:30, INCLUDING FOR THE 300 PEOPLE WHO ARE WATCHING THIS ONLINE. THANKS VERY MUCH. SCOPY PLEASURE TO INTRODUCE DR. DAVID HAFLER FROM YALE UNIVERSITY (INAUDIBLE) IMMUNE SYSTEM IN THE BRAIN AND MODERATE THE REST OF THE SESSION. >> THESE ARE MY DISCLOSURES. I'M EGOING TO PRESENT -- GOING TO PRESENT SOME NEW DATA THAT IS TOTALLY UNPUBLISHED AND I RECEIVED SOME OF THESE DATA ABOUT AN HOUR, TWO HOURS AGO FROM MY GRADUATE STUDENTS. VERY MUCH REAL TIME. THIS IS MORE UNDER THE PART OF IMMUNOLOGY THAN ANYTHING ELSE. PART OF MY QUESTION, WHAT DO CHECK POINT INHIBITORS REALLY DO? HERE IS THE REVIEW. I'M NOT GOING TO TALK MULTIPLE SCLEROSIS OTHER THAN TO SUMMARIZE THE DISEASE BY SAYING IT'S A COMPLEX GENETIC DISEASE, MAPPING TO THE IMMUNE SYSTEM WITH B CELLS DRIVING THE FLAMED MYELIN SPECIFIC T-CELLS WHICH MAKE 17 GMCSF GAMMA AND CXCR 3 POSITIVE CELLS WHICH MIGRATE TO CENTRAL NERVOUS SYSTEM. LET ME TELL YOU WHAT I'M GOING TO SHOW YOU. YOU WILL NOT BE SURPRISED TO HEAR THAT WHEN WE COMPARE SINGLE CELL RNA SEQUENCING AND BLOOD TO MS SPINAL FLUID, THE SPONDYLFLUID WAS INCREDIBLY INFLAMED. THEN WE DID THE THING ONE SHOULD NEVER DO IN SCIENCE. WE DID CONTROLS. WE STARTED DOING HEALTHY YOUNG YALE STUDENTS SAME FOR NIH STUDENTS AND TURNED OUT THAT WE REALLY CAN TELL THEIR SPINAL FLUID FROM MS PATIENTS, WHICH MANS THE PAST 40 YEARS I HAVE BEEN STUDYING MS SPINAL FLUID ARE REALLY STUDY NORMAL SPINAL FLUID, HEALTHY SPONDYLFLUID THE T-CELLS ACQUIRE TH 1 PHENOTYPE, DRIVEN TO BEST GAMMA INTERFERON HOST OF OTHER MOLECULES. THE ENTRY OF THE T-CELLS INTO THE SPONDYLFLUID CNS IS VERY TIGHTLY REGULATED. THIS FUNCTION OF RESIDENT T-CELLS IS IN FACT REGULATED BY ASTROCYTES. AND FINALLY THE TH 1 SIGNATURE IS ALSO SEEN IN HEALTHY BRAIN, YOU WILL BE DELIGHT TO KNOW THAT WAS NOT FROM YALE STUDENTS. THE WHAT WE FOUND IN T-CELL RECRUITMENT IN CSF. SO WE HAVE KNOWN FROM WORD FROM DIANE MATHIS, NUMBER OF YEARS AGO LOOKING AT MUSCLE TISSUE, THAT AS T-CELLS ENTER INTO THE TISSUE, THEY MOVE INTO A HOMEOSTATIC STATE AND I MEAN TO SAY THIS IS WORK DONE BY REALLY THE INTELLECTUAL WORK OF INCREDIBLY TALENTED GRADUATE STUDENT WHO IS SOON TO GRADUATE. THERE SHE IS. SAYING WHAT AM I THINKING ABOUT. IN EACH TISSUE YOU HAVE DIFFERENT CHEMOKINE RECEPTORS WHICH BRING THAT IMMUNE CELL INTO THAT TISSUE. AND BRAIN ALPHA 4 BETA 1. IT IS KNOWN DIFFERENT DRIVING FACTORS IN EACH TISSUE IL 33 AND LIPID AND FAT TISSUE, VITAMIN D FOR SKIN, ET CETERA. I WOULD LIKE TO SHOW YOU THAT FOR THE BRAIN CHOLESTEROL AND TGF BETA DRIVING ASTROCYTES. SO THIS TIGHT HI RECKLATED RECRUIT -- REGULATED RECRUITMENT OF T-CELLS CRCX 3 C CR POSITIVE FROM THE CHORIOPLEXUS INTO THE CENTRAL NERVOUS SYSTEM CXCL 10, THEN THE RESIN T-CELLS ARE FURTHER SHAPED BY TISSUE, VERY HIGH EXPRESSION OF T BET, AND TGF BETA. THIS INVOLVES A WELL DESCRIBED MECHANISM OF ASTROCYTES SECRETING FACTORS FROM MICROGLIAL SURVIVAL SHOWING HOMEOSTATIC COMMUNICATION MEDIATED BY ASTROCYTES, THAT'S WHAT THE TALK WILL BE. SO WE DID SINGLE CELL RNA SEQUENCING OF PAIRED BLOOD CSF FROM HEALTHY INDIVIDUALS AS WE MOVED ON FROM MS PATIENTS, WE TOOK TOTAL PERIPHERAL BLOOD SPINAL FLUID CELLS TECHNIQUE BY ALEX SETE ALEX SHELIX AND CHRIS LOVE AT MIT AND BROAD INSTITUTE AND LOOKED AT THE BLOOD CSF CONTINUUM. WHAT WE STORY PROFILE WE FOUND HOMEOSTATIC STATE IN THE SPINAL FLUID. THERE ARE 18 CLUSTERS INCLUDING TH 1 GENES GRANZYME O MUST, MODULATORY PATHWAYS SUCH AS TGF BETA RECEPTOR AND VARIOUS CO-INHIBITOR RECEPTORS, I'LL SHOW IN MORE DETAIL. PREDOMINANTLY COMPOSED T-CELLS, THERE ARE IN PERIPHERAL BLOOD, LARGE NUMBER OF NAIVE T-CELLS IN SPINAL FLUID, THEY ARE PREDOMINANTLY MEMORY CELLS WITH SOME DENDRITIC CELLS, MONOCYTES, VERY FEW B CELLS, NK CELLS AND NON-CLASSIC MONOCYTES, WHEN THE GRAD WAITS LOOK AT THE LOOKED AT THAT TIME LITERATURE, THAT WAS BEFORE SHE WAS BORN IN 1985. WHAT IS THE PROPER COMPOSITION OF BLOOD AND SPINAL FLUID? CELLS ARE EXCLUDED FROM HAVING THE CSF. CELLS NEED TO BE AXVATED EXPRESS CXCR 3. THE CELLS NECESSARY FOR TRAITS NECESSARY SPORE SPONDYLFLUID ENTRY. THESE CELLS ARE NOT UNDERSTOOD GONE TISSUE SPECIFIC CHANGES, THEN THERE ARE CELLS WHICH ENTERED BRAIN AND UNDERGO TISSUE DEPENDENT CHANGES, USING THE CENTRAL NERVOUS SYSTEM AS THE EXAMPLE, THIS MECHANISM IS OPERATIVE IN EVERY TISSUE. SO WE USE THIS IS WORK DONE IN COLLABORATION WITH (INAUDIBLE) AND DAVID VAN DIKE IN YOUR GROUP, MATHEMATICIAN. WHO IS REALLY BROUGHT INCREDIBLE INCITE HOW TO LOOK AT SINGLE CELL DATA. WE USE A TECHNIQUE CALLED FATE, WITHIN HERE WE HAVE THIS SAME COLOR WILL BE USED RED IS BLOOD, BLUE IS SPINAL FLUID AND THIS IS CELL PROGRESSION OF BLOOD AND CSF T. THE CSF CELLS. WE USE A TISSUE SCORE, AND THE TISSUE SCORE DIFFUSION OPERATOR WHICH IS BASICALLY THE PROBABILITY TRANSITIONING FROM ONE CELL TO ANOTHER AND RAN DOOM ORDER, READ -- RANDOM ORDER. READ OUT OF CELL CELL SIMILARITY. YOU DO A PLOT TAKE THE DATA AND SMASH IT DOWN, DOESN'T PROVIDE THAT MUCH INFORMATION AND RANDOMLY CLUSTERS BUT WITH TISSUE SCORE, YOU CAN ASK HOW CSF LIKE OR BLOOD LIKE IS PARTICULAR CELL WHICH IS THE PROBABILITY ONE CELL GENE TO ANOTHER. YOU SEE CELLS IN CENTRAL NERVOUS SYSTEM WHICH ARE VERY CSF LIKE, SOME VERY BLOOD LIKE AND MANY IN TRANSITION. IF WE USE NELD WHICH IS A MEASURE OF LOOKING AT WHAT THE POPULATION, SO HERE IS TISSUE SCORE LOOKING AT THE TOP EXPRESSED YOU CAN SEE AS REALITY CHECK CCR 7 MARKER T-CELLS ABSENT FROM BLOOD ABSENT FROM SPONDYLFLUID BUT VERY MUCH IN BLOOD. WHEREAS FOR EXAMPLE CXCR 3 OR BLA 4 ITGA 4 WHICH IS TARGET FOR IN LIZ MAP TREATMENT FOR MS IS HIGHLY EXPRESSED IN THE CENTRAL NERVOUS SYSTEM. WE THEN WISH TO IDENTIFY RELEVANT CHANGES IN THE HOMEOSTATIC T-CELL STATE ACROSS THE BLOOD SPONDYLFLUID ACCESS. SO THE GENE EXPRESSION WAS IMPEDED WITH A TECHNIQUE CALLED MAGIC TO VISUALIZE GENE EXPRESSION PATTERNS ACROSS TISSUE SCORES, THERE ARE 18 CLUSTERS THAT WERE GENERATED. HERE IS TISSUE SCORE AGAIN SPINAL FLUID, HERE ARE INTERMEDIATE STAGES. THIS REPRESENT IT IS ORIGINAL STATE OF THE TISSUE. FROM THIS, WE GENERATED SHAPE BASED CLUSTERING TO STRATIFY PATTERNS OF GENE EXPRESSION BASED ON TIMING, AND MAGNITUDE OF RELATIONSHIP WITH THE TISSUE SCORE. SO FOR EXAMPLE, IN GRANZYME B THIS REPRESENTS -- THIS IS EXPRESSION ON THE Y AXIS THIS IS TISSUE SCORE ON THE X WAXY, MORE TO THE RIGHT, THE MORE CSF IT IS AND THIS IS HOW MUCH EXPRESSION IS. SO FOR EXAMPLE, GRANZYME B IS NOT EXPRESSED AT ALL IN THE CSF CELLS, PREDOMINANTLY EXPRESSED IN THE BLOOD. IN CONTRAST YOU LOOK AT GAMMA INTERFERON, TISSUE SCORE HERE IS MORE SPINAL FLUID, THIS IS THE EXPRESSION, THIS VERY HIGH GAMMA INTERFERON EXPRESSION TRANSITION GOING INTO SPONDYLFLUID. SAME FOR T BET, TGF BETA RECEPTOR THREE, TGIT LIPID RECEPTORS AND PD 1, HIGH EXPRESSION PD 1 ON CSF CELLS. TWO DIFFERENT PATTERNS. IL 6 AND 7 RECEPTOR AND WHEN WE COLOR FOR THE EC 8 EXPRESSION HERE, THIS IS CD 8 EXPRESSION YOU CAN SEE IL 6 RECEPTOR WHICH IS NOT WELL -- NOT WELL EXPRESSED ON CD8 CELLSABLE REASON WE HAD TAIL HERE IS REPRESENT CD8 CELLS, WITH IL 7 RECEPTOR, SEE THIS TAIL HERE, SO THE REASON WHY THEY'RE TWO NOT EXPRESS IL 7 RECEPTOR. DID- SO YOU CAN SEE THE POWER OF THIS TECHNIQUE. ACROSS CELLS WE LOOK AT SO THESE ARE NOT DATA WE ANALYZE THIS MORNING, NOT JUST A SINGLE CELL TYPE ANALYSIS LOOKING AT RNA, IN THIS EXPERIMENT TOOK SPONDYLFLUID DIRECTLY FROM THE CSF, HEALTHY INDIVIDUAL, POPPED OPEN THE MEMBRANE, STAINED ANTI-GAMMA INTERFERON AND HERE IS BLOOD, .067% AND 4 -- 5% TO CELLS IN SPONDYLFLUID HAD GAMMA INTERFERON EXPRESSION. SO THE PROTEIN DATA VERY MUCH REFLECTS WHAT WE ARE SEEING BY SINGLE CELL RNA SEQ. I FIND THE DATA REMARKABLE THAT FROM A HEALTHY YOUNG INDIVIDUAL YOU TAKE OUT T-CELLS, AND ABOUT FIVE PERCENT EXPRESSED IN GAMMA INTERFERON. SO LOOK AT THE CONTINUUM SOME OF THE MAJOR CLUSTERS, WE SAW TH 1 GENES SUCH AS T BIT GAMMA CXCR 3, CR 5, RESTIN T-CELLS, CLUSTER HOMEOSTASIS, AGAIN THE BRAIN IS PREDOMINANTLY LIPID, TGF BETA PATH BAY, CO--- PATHWAY AND CO-INHIBITORY RECEPTORS. SO THIS RAISES A FUNDAMENTAL QUESTION TO THIS MEETING. WE KEEP LOOKING AT AUTOIMMUNE DISEASE BUT WE ARE HEARING THAT THE CHECK POINT INHIBITORS ARE NOT GIVING US IN MANY INSTANCES THE CLASSIC AUTOIMMUNE DISEASE THAT WE SEE. WE TALK ABOUT A PD 1 FOR EXAMPLE AS BEING A MARKER OF EXHAUSTION BUT THESE DATA RAIDS THE QUESTION THAT DO THE CO-INHIBITORY RECEPTORS ALLOW FOR GAMMA INTERFERON EXPRESSION WHILE REGULATING TISSUE EXPANSION? IF YOU HAVE THIS HOMEOSTATIC STATE WHERE THE T-CELLS ARE BEING TURNED ON TO MAKE GAMMA INTERFERON IF IT WASN'T SOME CHECK TO KEEP THE CELL CYCLE, THEY ARE MAKING GAMMA BUT NOT ENTERING CELL CYCLE, THAT WOULD BE BAD. AND THIS RAISES AN OBVIOUS QUESTIONS ABOUT TO DO THE SAME EXPERIMENTS, IN INDIVIDUALS WITHOUT -- AFTER ANTI-PD 1, WHAT'S HAPPENING IN THAT SITUATION. SO LET LOOK AT MS LOOK AT SIGNATURES ASSOCIATED WITH INFLAMMATION BASICALLY WE CAN'T FIND THE DIFFERENCE BETWEEN MS AND HEALTHY INDIVIDUALS, HERE ARE THE OVERLAPPING GENES I SHOWED YOU. THIS IS FROM A FEW WEEKS -- FROM A WEEK AGO BUT LAST NIGHT BASICALLY FINISHED THE ANALYSIS NUMBER OF TECHNIQUES. REALLY CAN'T FIND A SIGNIFICANT DIFFERENCE BETWEEN MS AND HEALTHY CONTROLS. WHAT IS GOING ON, I'LL ISSUE ONE PIECE OF DATA. THIS IS CORE OVERLAPPING T-CELL STATE, EXIST IN HEALTHY PATIENTS, PATIENTS WITH INFLAMMATION IN THE CNS AND REPRESENT STEADY STATE, TRAFFICKING REQUIREMENTS AND WITH BRAIN MILIEU WHICH ARE PRESERVED DURING INFLAMMATION. IN OTHER WORDS WITH DRIVING THE SYSTEM ARE THE ASTROCYTES MORE THAN ANYTHING ELSE SO THEN WHAT IS GOING ON WITH MS AND I THINK IT COMES DOWN TO EAA OBSERVATION CAUTIONED YEARS AGO, LET ME JUST SAY THE FREQUENCY OF -- THEMSELVESES ARE SAME IN SPINAL FOR MULTIPLE DIFFERENT DISEASES T. WHEN ONE ACTUALLY LOOKS WITH CLASS 2 TETRAMER IN SPINAL FLUID OF MS PATIENTS HERE IS ONE EXAMPLE THIS IS TWO AND A HALF PERCENT TETRAMER POSITIVE. WE DIDN'T BELIEVE THIS, WE PREVIOUSLY SEEN HIGH FREQUENCIES OF AN EVENTUAL SPECIFIC CELLS IN THE PERIPHERAL BLOOD. BUT THIS IS ONE IN 30 CELLS ANTIGEN SPECIFIC AND THIS IS A MINIMAL OBSERVATION MINIMAL DETERMINANT USING A NUMBER OF CLASS 2 TETRAMERS LIKELY TO BE OTHERS, GROUP OF PATIENTS MS HEALTHY CONTROLS PATIENT WITH -- WHAT IS PROBABLY GOING ON THE ANTIGEN SPECIFIC CELLS, THAT GET INTO THE CSF. WE HAVE BEEN DOING SINGLE CELL RNA SEQ AND THEY HAVE A STRONG GAMMA SIGNATURE AND NOW WE KNOW WHY. IN THE PERIPHERY THEY ARE MAKING 17 GM CSF GO INTO THE CENTRAL NERVOUS SYSTEM, CLEARLY CHANGING. JUST LIKE TO SHOW THIS, THIS IS AGAIN LOOKING AT ORIGINAL TISSUE IN A GIFT PLOT YOU CAN SEE CHANGING TISSUE SCORE, YOU CAN NICELY SEE THE DIFFERENCES, IN TERMS OF SPINAL FLUID TRANSITION AND BLOOD WE THEN BEGAN TO LOOK FOR PRO MOW EXPANSION. SO HERE WE HAVE THE EXPANSION OF CELLS IN -- GET RID OF THESE THINGS. EXPANSION OF CELLS IN. SO WE HAVE EXPANSION OF CELLS IN THE CSF SO THE BLUE DOTS REPRESENT CELLS THAT EXPAND, I'LL SHOW IN MORE DETAIL IN A SECOND SO HERE IS THE GAMMA EXPRESSION, THESE ARE PREDOMINANTLY IN CELLS EXPAND IN THE CSF. SO LET ME SHOW THAT IN MORE DETAIL. SO WE LOOK AT THE CVR 3 BETA CHAIN WE FIND CLONAL EXPANSION HERE IS DONOR 1, DONOR 2, YOU CAN SEE MAJORITY OF CELLS WERE UNIQUE BUT ONE CLONE IN EACH TISSUE BLOOD AND SPINAL FLUID, OR SHARED BETWEEN NUMBER CLONES BLOOD AND SPINAL FLUID AND DONOR 2, UP TO SIX DIFFERENT CLONES EXPANDED SPINAL FLUID SHARE IN PERIPHERAL BLOOD. HERE IS WHAT DATA LOOK LIKE ON FAKE PLOT THE RED IS BLOOD, BLUE IS SPINAL FLUID. ONE IS IMMEDIATELY SEE AND THE COLOR CODES REPRESENT HOW MANY CLONES THERE WERE, THERE'S MARKER CLONAL EXPANSION IN SPINAL FLUID COMPARED TO PERIPHERAL BLOOD AND SOME CLONES WERE SHARE IDENTICAL BEING BLOOD -- CAVEAT BEING CR 3 BETA CHAIN BUT REPRESENTED WHAT WE SEE WITH THE ALPHA CHAIN. ONE CAN ASK WHAT IS THE DISTANCE BETWEEN DIFFERENT CELLS, IF YOU LOOK AT ALL THE RNA EXPRESSION HOW SINGLE THEY ARE, BETWEEN BLOOD AND SPINAL FLUID YOU CAN DISTANCE BETWEEN TERMS OF RNA EXPRESSION VERY DIFFERENT IN BLOOD COMPARED TO CSF. THAT IS EVEN THOUGH THE CLONE MAYBE IDENTICAL IN THE SPINAL FLUID CHANGES, WE QUESTION DISTANT IN THE NERVOUS SYSTEM MUCH MORE SIMILAR. SAME PARIS WITH SAME CDR 3 EXPANDED TISSUES ARE SEPARATED BY LARGER DISTANCE COMPARED TO CELL PAYERS WHICH ARE PRESENT IN THIS CSF. SUGGESTING WHEN THE CELLS GO IN, THEY CHANGE. THEN WE LOOK AT THE EXPRESSION SCORE, THE TOP 500 DIFFERENTIAL EXPRESSION GENES IN BLOOD AND SPINAL FLOOD AND BASICALLY CSF T CELLS HAVE LOW EXPRESSION SCORE T DIFFERENT FROM BLOOD HIGHER CSF SCORE SUGGESTING MORE SIMILAR TO EACH OTHER LOCKING AT THE 500 MOST EXPRESSED GENES. SO JUST SPECIFICALLY LOOK AT T-CELLS TISSUE ENVIRONMENT OVER TIME, CAN HEAR TWO DIFFERENT VIEWS OF THESE PLOTS, RED BEING BLOOD CSF AND TISSUE SCORE OF WHAT IS MORE SPINAL FLUID TRANSITION AND BLOOD. WE THEN LOOKED AT THE CLONE -- AT THE TISSUE SCORE DISTRIBUTIONS IN RELATIONSHIP TO THE EXPANDED CELLS. YOU CAN SEE WITH P VALUE TEN TO THE MINUS 15, THE CLONE EXPANDED T-CELLS WHEN CSF CONVERGE ON HIGH CSF TISSUE SCORE ON TOTAL CSF SCORES HERE IN GRAY. AS THE CELLS ENTER INTO THE NERVOUS SYSTEM THE LONGER THEY ARE THERE, THE MORE CLONAL THEY ARE, THE MORE THEY BECOME CSF LIKE. WHAT IS MECHANISM FOR THIS? SO WE WISH TO IDENTIFY T-CELL GLIAL CELL COMMUNICATIONS. WORK FROM THE -- AT STANFORD UNIVERSITY SHOWS ASTROCYTES THE SECRETING FACTORS LED TO SURVIVAL OF MICROGLIA. YOU CAN SAY THEN I HAD BARBARA AS A CHIEF RESIDENT NEW YORK HOSPITAL, JUST TO SAY NO MATTER WHAT -- BARBARA HOW BRILLIANT SHE'S BEEN. THE ASTROCYTES REQUIRED FOR MICROGLIA SURVIVAL. IF U YOU DON'T KNOW ABOUT BARRIER SEASON SECOND SPEC TACK LAR YOU SHOULD READ IT'S CONTRARIAN IN NATURE. INCLUDING CHOLESTEROL LIPID GLEE CO-PROTEINS FOUND WITHIN THE CSF. WE WISH -- (INAUDIBLE) TAKE ASTRO SITE DISH MEDIA AND MIX WITH CXCR 3 POSITIVE CELLS AND YOU CAN SEE THAT INDUCED EXPRESSION OF GAMMA INTERFERON. AGAIN SUGGESTING THAT THERE IS THIS COMMUNICATION ASTROCYTES NOT ONLY MICROGLIA BUT T-CELLS INDUING GAMMA INTERFERON. SO THE MAIN OBSERVATION IS TGF BETA IN CHOLESTEROL INDUCE MICROGLIA SURVIVAL SO WE THEN WISH TO LOOK AT CHOLESTEROL TGF BETA, RELATIVE EXPRESSION, GAMMA MESSAGEND YOU CAN SEE THERE'S ALMOST A THOUSAND -- UP TO A THOUSAND FOLD INCREASE OF GAMMA MESSAGE WITH TGF BETA AND THE MARKET INCREASE OF PD 1 WITH THIS CRUST ROLL TGF BETA. WHO KNEW THAT CHOLESTEROL AND TGF BETA WOULD BE SUCH A DRIVER OF GAMMA INTERFERON EXPRESSION AND PD 1 EXPRESSION. LOOKING AT THESE PLOTS, WHICH SHOWED EARLIER, THE GAMMA INTERFERON VARIOUS CSF LIKE AND PD 1 ALSO VERY CSF LIKE. WE HAVE DONE A NUMBER OF OTHER GENES AND BASICALLY THE CHOLESTEROL TGF BETA INDUCES A RNA EXPRESSION PATTERN WHICH LOOKS VIRTUALLY IDENTICAL TO WHAT WE SEE OUT OF THE SPINAL FLUID. WE SUGGEST TGF BETA AND CHOLESTEROL ARE DRIVING THIS PHENOTYPE IN HEALTHY INDIVIDUALS. FINALLY WANT TO ASK WHAT ABOUT BRAIN? AS I MENTION WE USE BRAIN NORMAL BRAIN FROM PATIENT HAVING EPILEPSY SURGERY AS SURGEON GONS IN, THEY GO THROUGH NORMAL BRAIN, THEY GO THROUGH MORE NORMAL BRAIN, WE DID SEQ ON THE BRAIN ISOLATING T-CELLS AND BASICALLY INCREDIBLE OVERLAP CSF BRAIN T-CELLS OVER 1300 GENES AND WHAT WE ARE SEEING IN THE BRAIN IN HEALTHY BRAIN, IN THE CELLS THAT ARE THERE REFLECT WHAT WE ARE SEEING IN THE SPINAL FLUID. SO THE NEXT QUESTION, DOES THIS RELATE TO A VIRAL INFECTION? AND T-CELLS THAT HAVE GONE INTO THE CENTRAL NERVOUS SYSTEM OR IS THIS INVOLVED IN NEURONAL DEVELOPMENT SO WE LOOK AT NEWBORNS WITH SINGLE CELL SEQ DATA FROM THE CSF DRAIN HYDROCEPHALUS. BASICALLY THERE ARE ALSO CXCR 3 POSITIVE THAT APPEAR TO HAVE THE SAME SIGNATURE AS HEALTHY YOUNG INDIVIDUALS. SO IN SUMMARY, THIS TIGHTLY REGULATED RECRUITMENT OF CELLS I SHOWED YOU INTO THE CENTRAL NERVOUS SYSTEM, BY FACTOR OF AS SITES REQUIRE T BIT GAMMA INTERFERON SIGNATURE TISSUES EX-VIVO IN THE SPINAL FLUID MAKE SIGNIFICANT AMOUNTS OF GAMMA INTERFERON AND AGAIN THIS LIKELY INVOLVE WE BELIEVE ASTROCYTES WE MEDIATED MICROGLIA SURVIVAL INVOLVED IN HOMEOSTATIC COMMUNICATION. SO IT RAISES THE QUESTION DO CO-INHIBITOR RECEPTORS ALLOW GAMMA INTERFERON SECRETION BY INTERFERING CELL CYCLE, THERE'S QUESTIONS THAT COME UP SUCH AS THESE BUT WHEN GIVING ANTI-PD 1 TO INDIVIDUAL WITHOUT CNS DISEASE ARE WE UNLEASHING THESE CELLS TO HAVE ENTER. WE HAVE LOOKED THE PATIENT WITH GLIOBLASTOMA IF THIS WAS HEALTHY CONTROL DONE BY DAN IN OUR LABORATORY PUBLISHED TWO, THREE YEARS AGO. FITS A LOT, LOOK THE LITERATURE, WE DID THIS ON TREG, IF ANYONE HAS DONE THIS EXPERIMENT IN REGULAR T-CELLS WE TOOK THE PD 1 HIGH CELL SIMILAR TO WHAT WE DID WITH IL 2 RECEPTOR TO IDENTIFY TREG. YOU CAN'T TAKE THE INTERMEDIATE BUT THE PD 1 HIGH TREG AND NEGATIVE YOU CAN SEE THE PD 1 HIGH TREG DO NOT ENTER CELL CYCLE DO NOT SUPPRESS BUT MAKE A LOT OF GAMMA INTERFERON. SO SUGGESTING THAT PD 1 HIGH LEADS WITH TREGs, COME UP TO ME AFTERWARDS, WE'RE NOW DOING THIS EXPERIMENT IN HEALTHY INDIVIDUALS, IS WHAT'S HAPPENING PD 1 HIGH CELLS IN THE NERVOUS SYSTEM ARE COMPETITOR MEANTING CELL CYCLE AND MAKE GAMMA. SO FINALLY WITHIN KNOWN FUNCTION OF GAMMA INTERFERON CNS, INVOLVED IN CHEMOKINE PRODUCTION, NOT LIKE GAMMA INTERFERON HAS NEUROPROTECTIVE FUNCTION IN TERMS OF GLUTAMATE CLEARANCE IN SURVIVAL AND SYNAPTIC PRUNING. WE KNOW GAMMA INTERFERON WORKS OF MICROGLIA, RAISES THE QUESTION, WE LIVE LONGER ON LAMP POST, ALONG THE LINE, IF CARLA CHATS DISCOVERED CLASS ONE NEURONS, WE WOULD HAVE SAID HOW INTERESTING, A NEURONAL MARKER OF THE IMMUNE SYSTEM, NIGHTURE USES CASSETTES OVER AND OVER AGAIN FOR DIFFERENT FUNCTIONS WE KNOW THAT AND IT SUGGEST IT IS GAMMA SECRETION BY THE T-CELLS ARE PART OF PHYSIOLOGY AND NERVOUS SYSTEM DEVELOPMENT KNOW GAMMA INTERFERON KNOCK OUT MOUSE ARE DEPRESSED. I DON'T KNOW HOW THEY MEASURE DEPRESSION BUT THEY ARE DEPRESSED. CCR 5 INFLUENCES NEURONAL MIGRATION CONNECTION. SO NUMBER OF INTERESTING THINGS TO LOOK AT AND REALLY EXAMINE WITH T-CELLS MICROGLIA EARLY DEVELOPMENT OR DIRECTING NEURODEVELOPMENT IN THE NERVOUS SYSTEM. END WITH PEOPLE WHO DID THE WORK AND JUST AGAIN THIS REPRESENTS NOT JUST THE HANDS BUT THE INTELLECTUAL (INDISCERNIBLE) MANY OTHER PEOPLE INVOLVED, WORKING CLOSELY WITH SMITH AND DAVID AND CHRIS LOVE AT THE BROAD INSTITUTE, PEOPLE FROM MS CLINIC. I'LL STOP THERE. THANK YOU. [APPLAUSE] SO NOW WE WILL CONTINUE. THE NEXT TALK IS NEUROTOXICITY IMMUNE CHECK POINT INHIBITORS. OKAY. >> DEAR FRIEND AND COLLEAGUE BUYIAN DA SANTOMASSO FROM MEMORIAL SLOAN-KETTERING. -- BIANCA SANTOMASSO. Q. HELLO, EVERYONE WE ARE GOING TO BE MORE CLINICAL NOW MOVING FROM SCIENCE, REALLY, AS DAVID MENTIONED I'M A NEURO-ONCOLOGIST AT MEMORIAL SLOAN-KETTERING CANCER CENTER. HOWEVER I DID MY Ph.D. IN IMMUNOLOGY WITH BOB DARNELL, THERE'S UNUSUAL INTERSECTION THAT CAME TO PLAY WITH THIS WHOLE NEUROLOGIC IMMUNE RELATED ADVERSE EVENTS AND MY Ph.D. CAREER WHICH I WILL CLUE YOU IN ON. THESE ARE MY DISCLOSURES. I RECEIVED CONSULTING HONORARYIA RELATED TO NEUROTOXICITY FOR CAR T-CELLS, NOT THIS, I'LL DISCUSS THE OFF LABEL VALUES OF -- AT LEAST MENTION IGIF RITUXIMAB AND CYCLOPHOSPHAMIDE. WHEN I FIRST STARTED MY CAREER, THESE WERE NEUROLOGIC IMMUNE ADVERSE RELATED EVENS WERE RARE, AT THE LEVEL OF CASE REPORTS, SO A SINGLE CASE REPORT THAT ACTUALLY CAME OUT OF OUR INSTITUTION AND OTHERS HERE. SINGLE PATIENTS DEVELOPING AND ARRAY OF NEUROLOGIC SIGNS AND SYMPTOMS AFFECTING MULTIPLE LAYERS OF THE NERVOUS SYSTEM. MORE RECENTLY THERE'S LARGER CASE SERIES WHICH ARE HELPFUL AT LEAST AS FAR AS PROVIDING SCRIPPED INFORMATION ABOUT THE INCIDENCE, MORE DETAILS ABOUT THE RESPONSE TO THERAPY. STILL LEFT US WITH UNANSWERED QUESTIONS, WE DO KNOW NEUROLOGIC IMMUNE RELATED EVENTS ARE DIVERSE,, THEY CAN AFFECT THE PERIPHERAL NERVOUS SYSTEM, WE ARE TALKING ABOUT SENSORY NERVES DORSAL ROOT GANGLIA, YOU CAN BASICALLY GET A -- WHAT HAS BEEN DESCRIBED IN CASE REPORTS ARE SENSORY NEUROPATHIES, SENSING ARE MOTOR NEUROPATHIES, PLEXITIS MICE THENIA GRAVES, DISEASE OF THE NEUROMUSCULAR JUNCTION AN NEUROLOGISTS THAT LIKE TO TAKE OVER THE MUSCLE AS WELL, IT'S KIND OF RHEUMATOLOGIST ALSO LIKE MUSCLE BUT MYOSITIS IS ALSO SEEN WITH THESE CHECK POINT INHIBITORS AND CENTRAL NERVOUS SYSTEM, ASEPTIC MENINGITIS, PROS STEER YOUR REVERSIBLE ENCEPHALOPATHY SYNDROME, AND MORE RECENTLY PERINATAL PALACIC SYNDROMES -- SO THE PREVIOUS EXPERIENCE WITH NEUROLOGIC THESE ARE PROBABLY UNDERREPORTED IN CLINICAL CLINICAL TRIALS, THE RATE WAS REPORTED AS LESS THAN 1 PERCENT, AROUND .1% AND IN FACT ONE OF THE LARGE TRIALS WITH INLIB MAP IN ADVANCE MELANOMA DIDN'T REPORT ANY TOXICITY. THE LARGER CASE SERIES HAVE GIVEN A LITTLE MORE OF HANDLE THAT THERE IS SOME SIGNAL HERE, THESE ARE RARE EVENTS COMPARED TO PNEUMONITIS AND COLITIS. BUT ARE SIGNIFICANT, THESE ARE MOVING MORE INTO THE FOUR AND MORE PATIENTS BEING TREATED WITH COMBINATION THERAPIES AS WELL INCLUDING NEW COMBINATIONS, THERE'S A NEED TO BE AWARE OF THE DIVERSE PHENOTYPES ESPECIALLY. WE DO KNOW THAT AT LEAST THERE SEEMS TO BE INCREASE INCIDENCE OF COMBINATION CT LARKS 4 AND PD 1 INHI DIGS. AND COUPLE OF -- INHIBITION. THE SEVERE EVENTS ARE RARE, LESS THAN 1%. AT MSK WE TREATED PATIENTS SO WE SAID CAN WE GO BACK AND LOOK AGAIN, THIS IS -- THIS IS A RETROSPECTIVE STUDY SO OBVIOUSLY HAS ITS LIMITATIONS BUT WE THOUGHT AT LEAST WE COULD GET A HANDLE AND WE HAVE A LARGE NEUROLOGY CONSULTATIVE SERVICE, WE FOLLOW THESE PATIENTS SO WHAT HAVE WE LEARNED FROM THE PATIENTS THAT WE HAVE ALREADY TREAT IN SO WE DID A RETRO SPOKETIVE REVIEW LOOK BACK TO 2010 WITH PATIENTS TREATED WITH DIVERSITY OF TUMOR TYPES, AND LOOKED AT A NUMBER OF FACTORS INCLUDING THE DEMOGRAPHICS, TIME TO ONSET, AND RESPONSE THE TREATMENT. WE IDENTIFIED ABOUT 5,000 PATIENTS WHO RECEIVE THESE CHECK POINTS INHIBITORS WE EXCLUDED PATIENTS WHO RECEIVE INHIBITORS FOR PRIMARY BRAIN TUMORS AND ALSO WHO WERE -- BLIND TO STUDY RECEIVED. IDENTIFIED TOTAL OF 81 PATIENTS WITH NEUROLOGIC TOXICITIES WE CHARACTERIZED FURTHER. SO WHAT WE FOUND OVERALL WAS THE INCIDENCE SIMILAR TO WHAT'S BEEN REPORTED, IN SOME OF THE LARGER CASE SERIES. THOUGH THIS IS AT LEAST THE LARGEST THAT WE KNOW OF. THERE IS INCIDENCE OF 1.6%. WE FOUND AT THE TIME TO ONSET WAS RELATIVELY EARLY, THERE'S A CLASSIC CURVE AT THE TIMING OF THE OTHER IRE RASH TENDS TO OCCUR EARLY, HYPOTHESIZETIS MORE LONGER COURSE DIARRHEA COLITIS OCCURS EARLY. AND WHAT WE FOUND WAS THAT THE TIME TO ONSET RANGED FROM THREE DAYS, SO THREE DAYS AFTER THE FIRST TREATMENT TO 17 MONTHS BUT THE MEDIAN WAS QUITE EARLY, IT WAS USUALLY AFTER THE SECOND DOSE. OTHER THINGS WE FOUND WERE THERE IS HIGHER INCIDENCE WITH COMBINATION CHECK POINT BLOCKADES SO COMBINING CTLA 4 PD 1 VERSUS MONOTHERAPY, THERE'S IN DIFFERENCE IN AGE STRATIFIED FOR PATIENT OLDER THAN AGE 65 AND YOUNGER. AND THE ONE YEAR INCIDENCE IS VERY SIGNIFICANTLY BY DISEASE TYPE SO MELANOMA, MORE THAN LUNG, BLADDER CANCER, PROSTATE CANCER, SMALL CELL LUNG CANCER AND MIRACLE CELL CARCINOMA DEMONSTRATING HIGHER INCIDENCES. OF THE PATIENTS WHO DEVELOPED NEUROLOGIC, 60% WERE HOSPITALIZED AND 6% REQUIRED IN ICU LEVEL OF CARE. AND THE OTHER THING THAT WAS VERY INTERESTING AND INFORMATIVE WAS LOOKING AT THESE CASES ABOUT 60% HAD CONCURRENT NON-NEUROLOGIC IRE. IN OTHER WORDS AT THE SAME TIME HAVING NEUROLOGIC SYMPTOMS THEY HAD ANOTHER IRE AFFECTING ANOTHER ORGAN SYSTEM. MOST EVENTS WERE REVERSIBLE 70% REVERSE WITHHOLDING DRUG THERAPY AND IMMUNOSUPPRESSION. WE SAW AS WELL THAT THE EVENTS INVOLVED BOTH PERIPHERAL AND CENTRAL NERVOUS SYSTEM, PREDOMINANTLY PERIPHERAL NERVOUS SYSTEM, SO THAT'S CHARACTERIZED HERE THE SENSORY NEUROPATHY, THE MYOSOTIS, SENSORY MOTOR AIDP MICE THENIA GRAVES. WE ALSO SAW QUITE A FEW PATIENTS WHO DEVELOPED ABOUT 14 PATIENTS WHO DEVELOPED ENCEPHALITIS, ASEPTIC MENINGITIS AND PERINEOPLASTIC NEUROLOGIC DISORDERS. SO I THINK THAT ONE OF THE THINGS THAT WAS HELPFUL GOING THROUGH THE CASES IS CHARACTERIZING THE RESPONSE TO TREATMENT. AND SEEK HOWEVER WE STILL HAVE TO GO -- HOWEVER WE HAVE TO GO WITH MANAGEMENT OF SOME OF THESE MORE SEVERE TOXICITIES SO I WILL GO THROUGH A COUPLE OF CASES. THIS IS AN ACTUAL CASE FROM REVIEW, THIS WAS A PATIENT WHO I SAW 54-YEAR-OLD WOMAN UNDERGOING COMBINATION CHECK POINT BLOCKADE FOR MELANOMA, SHE DEVELOPED A FEVER AND STIFF NECK WITH PHOTO PHOBIA, PHOTO PHOBIA, NAUSEA, VOMITING AS WELL. ON EXAM THERE WAS NO ENCEPHALOPATHY WITH CRYSTAL CLEAR HISTORY AND NO OTHER FINDINGS SO GETTING TO THE POINT OF WHAT WAS POINTED OUT BY SOME OF THE EARLIER PRESENTATIONS, I THINK THAT BECAUSE OF THE DIVERSITY OF NEUROLOGIC IMMUNE RELATED ADVERSE EVENTS IT'S CRITICAL IF WE'RE GOING TO BE ASKING WHAT ARE THE BIOMARKERS OF RESPONSE THAT WE HAVE A VERY GOOD PHENOTYPIC MEANING CLINICAL EVALUATION OF WHAT THE PATIENT IS GOING THROUGH WHICH MEANS THAT WE HAVE OUR DIFFERENTIAL DIAGNOSIS SQUARED AWAY. MAKING SURE THIS PATIENT DOESN'T HAVE A CNS INFECTION. OBVIOUSLY THE DIFFERENTIAL BACTERIAL OVER VIRAL WOULD BE POSSIBLE. OTHER IMMUNE RELATED EVENTS SEVERE HEADACHE. AND ASEPTIC MENINGITIS IS WHAT WE'RE THINKING IN THIS CASE. SO SHE HAD AN MRI BRAIN NORMAL INCLUDING PITUITARY PROTOCOL. ALL LABS ARE NORMAL AND LUMBAR PUNCTURE WHICH IS THE CRITICAL TEST, WHITE BLOOD CELL COUNT WITH LYMPHOCYTIC PREM DOCUMENT INNOCENCE AND CYTOLOGY AND CULTURES WERE NEGATIVE. BASED ON THAT WE START ANTIBIOTIC WAITING FOR CULTURES, WE ALSO STARTED HER ON STEROIDS AND ON RELATIVELY LOW DOSE STEROIDS HER SYMPTOMS IMPROVED. THEY OCCURRED WHEN WE TAPERED THE STEROIDS BUT WE ABLE TO INCREASE STEROID DOSE. AND SHE WAS ONE MONTH STEROID TAPER. SO BASED ON THIS WE NOW HAVE GUIDELINES WHICH ARE AGAIN JUST THEIR RECOMMENDATIONS FOR STARTING POINT. AND MANY OF THESE ARE INCLUDED PUBLISHED IN A UP THE OF PLACES -- COUPLE OF PLACES BUT ASEPTIC MENINGITIS HAS TO BE ONE CASE WHERE CSFS IS HELPFUL AND ALL CASES IN OUR SERIES WERE EXQUISITELY RESPONSIVE, YOU DON'T HAVE TO BLAST PATIENTS WITH STEROIDS, YOU CAN GET AWITH LOW DOSE PREDNISONE. ? CONTRAST WE SEE CASES MORE SEVERE, 467-YEAR-OLD METASTATIC BLADDER CANCER, AFTER FOUR DOSES TWO WEEK VEER VALUES BROUGHT TO THE HOSPITAL WITH WEAK OF CONFUSION, SHALL REMEMBER TERM MEMORY LOSS, GENERALIZED WEAKNESS, MIGHT HAVE HAD A MILD FEVER, AND ON EXAM, THE MOST REALLY TELLING THING WAS THAT HE HAD NO SHORT TERM MEMORY, COULDN'T RECALL THE DOCTOR'S NAME, HIS ONCOLOGIST NAME, OR CANCER DIAGNOSIS, THERE'S NO OTHER FINDINGS SO THERE'S A DIFFERENTIAL HERE AS WELL. YOU CAN THINK INFECTION, VIRAL ENCEPHALITIS, STROKE OR SEIZURE, LEPTOMENINGEAL DISEASE OR -- SO THE WORK UP CAN INCLUDE MRI IMAGING AND LUMBAR PUNCTURE IN ADDITION THE STANDARD TESTING. IN HIS CASE EVERYTHING WAS NORMAL. AT LEAST FROM THE LABORATORY STANDPOINT, HOWEVER, HE DID HAVE AN MRI THAT SHOWED THESE MEDIA TEMPORAL FLAIR HYPERINTENSITIES. NOT IMMUNE CHECK POINT CASES ENCEPHALITIS SUCH AS VIRAL ENCEPHLITTIES AND PERINEOPLAST TIC SYNDROMES, THE VIRAL CULTURES WERE NEGATIVE AND THE PERINEOPLASTIC PANEL IS ALSO NEGATIVE. SO HE DID HAVE AGAIN A PLEOCYTOSIS, NOT AS MUCH AS ASEPTIC MENINGITIS CASE AND NORMAL PROTEIN. WE STARTED HIM ON WHAT WE CONSIDER TO BE A HIGH DOSE OF STEROIDS FROM THE IRAE STANDPOINT, ONE KID PER DAY OF METHYL PREDNISONE BUT HIS EXAM GOT WORSE SO THEN WE ACTUALLY GOT AN EEG WHICH SHOWED HE WAS HAVING FOCAL SHARP WAVES SO WE DECIDED TO USE PULSE DOSE STEROIDS WHICH IS A VERY HIGH DOSE METHYL PREED ONE GRAM A DAY THAT'S USED FOR A LOT OF NEUROLOGIC AUTOIMMUNE ENCEPHLITTIES AND WE ADDED IVIG FIVE DAYS HE IMPROVED COMPLETELY TO BASELINE CLINICALLY. BASED ON THESE AND OTHER PUBLISHED EXPERIENCES, WE HAVE SLIGHTLY DIFFERENT TREATMENT DEPENDING UPON CLINICAL PRESENTATION OF THESE PATIENTS. THESE PATIENTS IF THERE'S NO IMPROVEMENT WITH LOW DOSE STEROIDS YOU IMMEDIATELY GO TO HIGHER DOSE PLUS IVIG AND EVEN IN SOME CASES, THERE ARE DISCUSSIONS ABOUT CONSIDERING ESCALATION TO RITUXIMAB. WE ALSO HAVE SEEN OTHER CASES THIS IS ONE OF MAN WHO WAS TREATED WITH MSI HIGH COLORECTAL CANCER WITH ANTI-PD 1, HE DEVELOPED ATAXIA AND UNSTEADY GATE AND FELT HE COULDN'T FEEL HIS FEET AND DIMINISHED SENSATION. THE ROMBERG TEST WAS POSITIVE, DIDN'T HAVE THE PROPRIA SECTION TO FEEL THE FLOOR. THE DIFFERENTIAL DIAGNOSIS IS LEEP UNTIL MENINGEAL DISEASE AND IN FACT WE GOT AN MRI OF THE SPINE WHICH SHOWED MENINGEAL DISEASE BUT IS IT LEPTOMENINGEAL DISEASE? THIS MR. CASEY: CAME TO THE TUMOR BOARD BECAUSE THERE WAS CONCERN FOR THIS BUT WE SAID THE TUMOR TYPE IS STRANGE, THIS PATIENT IS ON IMMUNOTHERAPY, AND IN FACT AGAIN, THE CSF WAS CRITICAL IN THIS POINT, FOR THIS CASE AS WELL. REVEALING AGAIN A LYMPHOCYTIC PLY OWE SIGH SEWSIS. SIGH -- PLY OWE CYTOSIS. WE STARTED LOW DOSE NEGATIVE AND STEROIDS CUB TAPERED OVER A MONTH. WE HAVE SEEN OTHER CASES WHICH HAVE MORE REFRACTORY TO TREATMENT. SO THIS IS A CASE THAT WE SAW A 74-YEAR-OLD MAN UNDERGOING COMBINATION IMMUNE CHECK POINT BLOCKADE, AFTER HIS FOURTH INFUSION HE DEVELOPED BILATERAL LEG NUMBNESS WHICH ASCENDED RAPIDLY. WORSENING OVER DAYS AND HAD SEVERE MID LOWER BACK PAIN. HE HAD FALLEN TIMES AT HOME AND HAD BRUISING ON HIS LEGS AND DEVELOPED ELEVATED HYPOTHYROIDISM. ON EXAM HE HAD CLEAR WEAKNESS BILATERAL FOOT DROP, DECREASE SENSATION UP TO IS UPPER LEGS, DECREASE PROPRIA SECTION AT ANKLES AND HE HAD ABSENT DEEP TEN TON REFLEXES SO AGAIN, THE DIFFERENTIAL INCLUDES LEPTOMENINGEAL DISEASE BUT TIMING WAS TOO FAST, OR SPINAL CORD COMPRESSION. IN OUR SITUATION WE WERE CONCERNED ABOUT GEOM BERRAY SYNDROME, NEUROLOGISTS KNOW THIS IS CLASSIC. UP LIKE CLAY I CAN IS GBS WHICH USUALLY YOU HAVE AN ALBUMIN OF SITE LOGIC ASSOCIATION MEANING THERE AREN'T ELEVATED CELLS IN CSF BUT ELEVATED PROTEIN. IN EVERY CASE OF SYNDROME RELATED TO IMMUNE CHECK POINT INHIBITOR WE HAVE SEEN ELEVATED WHITE BLOOD CELL COUNT. THE PROTEIN WAS ELEVATED BUT THE WHITE BLOOD CELL COUNT WAS STRIKING AND DIFFERENT FROM IDIOPATHIC SYNDROME. CONDUCTION STUDY SHOWED THE CLASSIC FINDINGS DEMONSTRATING A SEVERE POLYNEUROPATHY WITH DEMYELINATING FEATURES AND THE PSYCHOLOGY WAS NEGATIVE. SO HE WAS STARTED ON IV,G, PLUS STEROIDS, STEROIDS BEING ADDED BECAUSE OF THE ELEVATED CELL COUNT. AND HE ALSO WERE COVERED. FROM IT I'M GOING TO SKIP THIS CASE. JUST TO SAY WE ALSO HAVE SEEN CASES OF MICE THENIA GRAVES AND THESE CASES ARE QUITE SIMILAR TO NON-IMMUNE CHECK POINT INHIBITOR RELATED CASES OF MYASTHENIA GRAVES WITH THE EXCEPTION OF OVERLAP SYNDROMES WITH MYOSITIS AND MYOCAR DITIS. YOU HAVE A PATIENT COMING IN WITH WEAKNESS AND SHORTNESS OF BREATH YOU MIGHT ASSUME TO BE DUE TO THE MYASTHENIA GRAVES ALONE, WE THEN CHECK THE PATIENTS TO COMPLETE THE WORK UP AND FOUND ELEVATED CPK, TROPONIN AND THEN ECHOCARDIOGRAM AND SEE THERE IS MYOCARDITIS AS WELL. WE HAVE GOTTEN SOME HANDLE ON THE MECHANISMS OF THESE IRAEs NEUROLOGIC AND NON-NEUROLOGIC, OBVIOUSLY BIOPSIES HAVE BEEN CRITICAL TO THIS EFFORT. THIS IS AN EXAMPLE OF A MUSCLE BIOPSY FROM ONE OUR PATIENTS, WHO PRESENTED WITH THE SYMPTOMS OF MYOSOTIS BUT DIDN'T HAVE ELEVATED CPK AND WHAT YOU CAN SEE INSTEAD IS LYMPHOCYTIC INFILTRATION OF THE BLOOD VESSEL. EVEN IF YOU HAVE CASES THAT FITTED A CLINICAL SYNDROME YOU MIGHT HAVE A SLIGHTLY DIFFERENT PATHOLOGY, AND IT'S IMPORTANT TO ON STAIN THE BIOPSY WHEN POSSIBLE IF THE LABORATORY TESTING DOESN'T FIT YOUR NORMATIVE VALUES. WE HAVE ALSO SEEN CASES CLEARLY WITHIN THE NEUROLOGIC WORLD WHERE IT APPEARS TO BE NEUROLOGIC IMMUNE RELATED ADVERSE EVENTS APPEAR ENHANCEMENT OF ANTIBODY MEDIATED DISEASE. WHAT DO I MEAN BY THAT? MISTHINK SYNDROME IMMUNE CHECK POINT INHIBITORS YOU SEE PRESENCE OF ACETYLCHOLINE RECEPTOR ANTIBODY AND IF NOT THAT, YOU CAN SEE STRIATED MUSCLE ANTIBODY WITH MYOSOTIS. THERE'S BEEN A CASE REPORT IN THE LITERATURE OF ENCEPHALITIS WITH NMDA RECEPTOR ANTIBODIES AND PATIENT RECEIVING COMBINATION IMMUNE CHECK POINT INHIBITION FOR MELANOMA. IN THE CASE IMPROVED ONLY AFTER IVUG AND RITUXIMAB. PAPER THAT WAS MENTIONED EARLY, THIS IS WORK BY (INDISCERNIBLE) NOW AT EMORY THEY SAW EARLY B CELL CHANGES PREDICTING AUTO-IMMUNITY FOLLOWING IMMUNE CHECK POINT BLOCKADE WHICH BEGS THE QUESTION, IF THEY ARE USING RITUXIMAB UP FRONT FOR B CELL TOLLERRIZING B CELLS THEY MAY BE HELPING THE IMMUNE CHECK POINT RELATED TOXICITIES AS WELL. THIS WAS KIND OF MY INTERSECTION THE PERINEOPLASTIC NEUROLOGIC SYNDROMES BEFORE IMMOWN CHECK POINT, INHIBITOR THAT THERE WERE THESE CASES WHERE PATIENTS WOULD HAVE SPONTANEOUS REGRESSION OF TUMORS ALONG WITH NEUROLOGIC SYMPTOMS. THIS IS A PATIENT PUBLISHED BY TWO OF MY MENTORS, BOB DARNELL AND JERRY POSENER, BOB Ph.D. MENTOR AND JERRY CLINICAL MENTOR AT MSK, OF A WOMAN WHO BASICALLY GOT THIS CAT SCAN FOR COUGH WHILE HAVING NEUROLOGIC SYMPTOMS AND WHAT YOU CAN SEE HERE IN THIS BLURRY CAT SCAN IS ACTUALLY A SMALL CELL LUNG CANCER SPONTANEOUSLY REGRESSING. AND AS THE TUMOR REGRESSED PER NEUROLOGIC SYMPTOMS ALSO IMPROVED. WE HAVE NOW SEEN CASES FOR PERINEOPLASTIC NEUROLOGIC SYNDROMES WITH IMMUNE CHECK POINT BLOCKADE, THIS IS IN I SAW 78-YEAR-OLD MAN WITH SMALL CELL PROSTATE CANCER SINGLE DOSE AND FIVE DAYS LATER DEVELOPED ATAXIA, FACIAL DROOP, WORSENING NEUROPATHY, HE WAS CLASSIC FOR CELL BELL LAR DEGENERATION SO WE HAD TO SEND A PERINATAL PALACIC PANEL, WE FOUND TWO CLASSIC ANTIBODIES, WHICH HAVE BEEN ASSOCIATED WITH THESE SYNDROMES, THESE ARE ANTIBODIES THAT DEFINE THE SYNDROME, HOWEVER MOST P AND D TUMOR IMMUNITY IS THOUGHT MEDIATED BY CYTOTOXIC T-CELLS, ANTIBODY BEING A MARKER FOR THE IMMUNE RESPONSE. HE STARTED IMMUNOMODULATION WITH SEROUS AND IVIG AND AT THIS POINT HE WAS HAVING AN EXCELLENT RESPONSE ON HIS CAT SCAN WITH MANY OF HIS LYMPH NODES RESOLVING. AND HAVE SIGNIFICANT PR HOWEVER EVENTUALLY OCCURRED. WE WERE ABLE TO GET A SLIDE OF TUMOR AND STAIN FOR HU, ONE OF THE ANTIBODIES THAT SHE HAD AND SAW IN FACT HIS TUMOR DOES EXPRESSION HUD. FROM THIS IS ANOTHER CASE, A WOMAN WHO HAD MERKEL CELL CARCINOMA WITH ANTI-PDL 1, RECEIVED THREE DOSES ANTI-PDL 1 AND REMARKED AFTER HER SECOND DOSE THAT HER AXILLARY NODE BOTHERING HER WAS MUCH IMPROVED. BUT THEN SEVEN DAYS AFTER HER THIRD DOSE SHE DEVELOPED RAPIDLY ATAXIA, VISION PROBLEMS AND PROFOUND PERSONALITY CHANGES AND SHORT TERM MEMORY LOSS. SHE FIT THE BILL FOR A CLASSIC PERINATAL PLASTIC NEUROLOGIC SYNDROME BASED ON HER CLINICAL PRESENTATION SO WE SEND OFF THE PANEL AND BLOOD AND CSF AND AGAIN FOUND PERINEOPLASTIC ANTIBODIES, WE FOUND VOL THAN GATED POTASSIUM CHANNEL ANTIBODY AS WELL. AND CLONAL BANDS. SHE STARTED MODULAR -- IMMUNOMODULATION WITH HIGH DOSE STEROIDS, IVUG SHY CASH FLOW PHOSPHAMIDE, RITUXIMAB AND SHARED CLINICAL SYNDROMES IMPROVED, HOWEVER, SHE DID NEVER RECOVERED FULLY NEUROLOGICALLY, MENTAL STATUS IMPROVED HOWEVER SHE STILL HAS ONGOING ATAXIA. SHE'S IN A CR FOR HER CANCER SO THIS WAS PET CT THAT WAS DONE A MONTH AFTER HER TREATMENT. WE WERE ABLE TO GET A SAMPLE OF HER BLOOD BEFORE SHE DEVELOPED NEUROLOGIC SYMPTOMS AND FOUND SHE DOES HAVE A LOW DOSE, THIS IS CRIM 5 IN LIMITED CSF SOLUTION, HIGH TITER ANTIBODY, SHE HAS ANTIBODY BLOOD HIGHER TITER ALONG WITH SEVERAL OTHERS THAT REACT WITH MOUSE WHOLE BRAIN LYSATE. HER PLASMA HARBORED A LOW TITER ANTIBODY BEFORE SHE WAS NEUROLOGICALLY SICK, THIS WAS ACTUALLY AFTER HER FIRST DOSE. SO GENERAL PRINCIPLES OF NEUROLOGIC IRA MANAGEMENT WERE SLOWLY -- ARE SLOWLY COMING INTO FOCUS FUNDAMENTALLY PEOPLE SHOULD CONSULT NEUROLOGY IF UNSURE AND HOSPITALIZE THE PATIENT IF THEY HAVE MODERATE TO SEVERE SYMPTOMS OR RAPIDLY PROGRESSIVE. I WOULD LIKE TO UNDERSCORE ALONG WITH THE THEME OF BIOPSY, CSF IS HELPFUL IN CLINICALLY DETERMINING WHETHER THIS IS A NEUROLOGIC IMMUNE RELATED AVERSE EVENT OR NOT AND ALSO POTENTIALLY FOR UNCOVERING THE PATHOGENESIS AS WELL. IN CONCLUSION NEUROLOGIC IMMUNE RELATED AVERSE EVENTS ARE DIVERSE WITH CENTRAL AN PERIPHERAL NERVOUS SYSTEM, THE OPTIMAL MANAGEMENT IS NOT DEFINED CERTAINLY HOLDING THE CHECK POINT INHIBITOR AND STARTING STEROIDS IS THE BASELINE BUT OTHER PRACTICE INVOLVE PULSE STEROIDS IGIV RITUXIMAB AND OTHERS. AND PRESENTATIONS OF CLASSIC CONDITIONS SUCH AS MICE TEENIA GRAVES MAYBE ATYPICAL, IN THE CASE OF MYASTHENIA GRAVES THERE'S OVERLAP SYNDROME AND YOU CAN FIND CELLS IN THE CSF OF GBS. SOME NEUROLOGIC IRAE ARE STEROID RESPONSIVE, RAISING THE QUESTION OF WHETHER THESE ARE HAVE A COMMON PATHOGENESIS OR NOT AND BIOMARKERS ARE NEEDED TO PREDICT PATIENTS AND IDENTIFY PATIENTS FOR EARLY INTERVENTION. SO WITH THAT, I WOULD LIKE TO THANK MY COLLEAGUES, THIS WAS ACTUALLY A HUGE UNDERTAKING, LED BY A GREAT TEAM. LOTS OF CHART REVIEW, ESPECIALLY (INDISCERNIBLE), JETTED, MY LAB MENTOR LISA DEANGELES AND JERRY POSENER AND MY FUNDING AS WELL. THANK YOU. [APPLAUSE] >> THE LAST TALK IS OCULAR TOXICITIES, FROM THE NATIONAL INSTITUTE -- NATIONAL EYE INSTITUTE. >> THANK YOU FOR THE INVITATION. IT'S A PLEASURE TO BE SUCH A MULTI-DISCIPLINARY GROUP. I WILL TRY TO SUMMARIZE VERY QUICKLY IN THE INTEREST OF TIME THE OCULAR TOXICITIES WE OBSERVE. NO FINANCIAL RELATIONSHIPS AND I WILL MENTION A FEW OFF LABEL USE OF MEDICATIONS. THANKS THE WONDERFUL SPEAKERS SO FAR, MY FIRST FIVE FLUIDS ARE REDUNDANT AND NOT NECESSARY RIGHT NOW SO I'M GOING TO SKIP THROUGH THOSE. WE KNOW UNLEASHING THE IMMUNE SYSTEM LED TO MULTIPLE AUTOIMMUNE SYNDROME, SO FAR. SO I'M GOING TO GO STRAIGHT TO OCULAR SIDE EFFECTS. SO MOST COMMON OCULAR SIDE EFFECTS NOTED WITH IMMUNE CHECK POINT IS DRYIOCIN CHROME, ALREADY MEDIATED THE RATES RANGE FROM ONE TO TWO TO 24%. AND UVEITIS RATES RANGE BETWEEN .3 TO 6% OF THOSE WHO USE ICI. THERE HAVE BEEN MULTIPLE OTHER SYNDROMES THAT INVOLVE INFLAMMATORY CONDITIONS IN THE EYE, KERRY TIETIS, OPTIC NEUROPATHY, MUSCLE MYOSITIS AS WELL. MOST OF THESE HAVE BEEN MANAGED WITH TOPICAL OR PERIOCULAR STEROID INJECTIONS. I PROVIDED A CROSS SECTION OF THE EYE, JUST AS A REMINDER FROM MED SCHOOL DAYS, THIS IS THE HEAR ME SITING. THIS IS VITREOUS, MIDDLE PART OF YOUR EYE AND THIS IS THE RETINA CAPILLARIES WHICH IS THE VASCULAR LAYER OF THE EYE. WE KNOW WHY IT MATTERS TO RECOGNIZE THESE SYNDROMES BECAUSE THINK ARE GO -- THEY'LL BECOME MORE COMMON, THIS SLIDE MANLY FROM OPHTHALMOLOGY COLLEAGUES, IT IS IMPORTANT TO US HISTORY AND MEDICATION USE TO THESE PATIENTS SO THAT WE CAN ACTUALLY RECOGNIZE THE RELATIONSHIP. JUST TO GIVE YOU A BACKGROUND BEFORE I GO ON TALKING ACTS UVEITIS ON AND ON, IT IS THE EWE OWE LA TISSUE OF THE EYE, THE VASCULAR LAYERS OF THE EYE, RETINA, CHOROID, CELLULAR BODY, IT'S A RARE DISEASE, WITH INCIDENCE OF 52 IN HUNDRED PERSON THOUSAND YEARS BUT IT IS RESPONSIBLE UP TO 15% OF BLIND FINANCE THE U.S.. AND -- BLINDNESS IN THE US. WE HAVE THE PRIVILEGE OF LOOKING INTO THE TISSUES WE ARE EXAMINING AND MICROSCOPY WE CAN SO CELLS, THESE WHITE BLOOD CELLS, IN ANTERIOR SEGMENT OF THE EYE WHICH IS HERE, ANTERIOR CHAMBER, AND THEN THE DRESS ARE MEN THEY CAN FORM A LAYER. THESE CELLS ACCUMULATE STICK TO BACK OF THE CORNEA. AS YOU CAN SEE HERE. OR FROM NODULES ON THE IRIS WHICH IS TIPPEDLY SEEN IN -- CAN CAUSE POSTERIOR ADHERENCE OF THE IRIS, COLORED PART OF YOUR EYE TO THE LENS. AND IT CAN CAUSE CATARACTS AND OTHER COMPLICATIONS. THE VITREOUS CELLS FORMENING THE MIDDLE TESTIFY EYE, AS I MENTIONED BEFORE, I OBSERVE MICROSCOPY LIKE THIS, THESE ARE SMALL WHITE BLOOD CELLS THAT ARE IN VITREOUS AN UP CLOSE YOU CAN SEE THE CELLS MORE CLEARLY. I HOPE MY MOUSE IS SHOWING THERE. FOR REFERENCE, NORMAL EYE. THIS IS A NORMAL EYE RETINAL VASCULATURE AND THIS IS A CROSS SECTION TOMOGRAPHY OR CT, THAT SHOWS YOU THE CROSS SECTIONAL RETINA, THIS IS THE CHOREROID DEEPER TISSUE OF THE RETINA EPITHELIUM, THIS CORRESPONDS TO YOUR CENTRAL -- IS RESPONSIBLE FROM YOUR PERFECT CENTRAL VISION. THIS IS A NORMAL INDIVIDUAL WE SHOWS RETINOL BLOOD VESSELS, VERY SHARP AND DO NOT LOOK FUZZY, IN CONTRAST, THIS IS A FLOOR PROGRAM FROM A PATIENT WITH UVEITIS, YOU CAN SEE HOW DIFFERENT IT IS, YOU DON'T HAVE TO BE AN OPHTHALMOLOGIST TO TELL THE DIFFERENCE BETWEEN THE TWO A IMAGES. I WANT TO INTRODUCE YOU TO A CONCEPT OR SYNDROME CHARACTERIZED BY POLIOSIS, STEN TENONITIS (INDISCERNIBLE) PRIMARILY EFFECTS SOMEVINGS WITH SOME PIGMENT SO NOT SEEN THE NORTHERN EUROPEAN ETHNICITY CAUCASIAN PATIENTS. IT WILL BECOME RELEVANT WHEN TALKING SYNDROME IN CONTEXT OF ICIU. IT IS CHARACTERIZED BY SUBRETINAL FLUID IN THE RETINA ACCUMULATION OF FLESH SCENE AND LEAKAGE, THESE ARE AREAS THE FLUID ACCUMULATES UNDER THE RETINA, WHICH IS NOT NORMAL. AND THESE PATIENTS CAN HAVE POLIOSIS OR TENONITIS AT THE SAME TIME, THE MECHANISM IS PROPOSED RELATED TO T-CELL RESPONSE, TOWARDS ME LANCYTE DERIVED ANTIGENS OR PROTEINS. IN AND OTHER WISE GENETICALLY PRONE INDIVIDUAL WHICH IS TYPICALLY HLA DR 4 POSITIVE INDIVIDUALS. SO THE OSTY OF THE PATIENTS THE SUBRETINAL FLUID UNDER RETINA, THE SECTION OBTAINED HERE AND THICKENING OF THE CHOROID THAT INDICATES INFLAMMATION AND ENGEORGEMENT OF THE VASCULAR PLEXIS OF THE EYE. YOU CAN SEE PULSE TREATMENT NORMALIZES, THIS IS A NORMAL CHOROIDAL THICKNESS OPPOSED TO THIS ONE. PUTTING THINGS IN PERSPECTIVE, SIDE EFFECTS IN CONTEXT OF ICI. SO WE WANTED TO LOOKED OUR EXPERIENCE WITH CHECK POINT INHIBITORS AND UVEITIS. WE HAD TO COMBINE COURSES WITH OUR COLLEAGUES AT THE VETERAN HOSPITAL AND (INAUDIBLE) HARVARD. BECAUSE THESE ARE RARE. WE DID A RETROSPECTIVE SEARCH, WE LOOKED AT PATIENTS RECEIVING IMMUNE CHECK POINT INHIBITORS BUT NOTE THAT THESE PATIENTS REFERRED OPHTHALMOLOGY FOUR VISUAL OR OCULAR SO WE CAN'T FOCUS ON PREVALENCE CALCULATIONS. WE WERE ABLE TO IDENTIFY 11 PATIENTS THESE THREE CENTERS WITH OCULAR IRAE WHILE BEING TREATED WITH ICI ONE HAD NOW OPPOSITE DRY EYE SYMPTOM, ONE UVEITIS. DRY EYE SEEMS LIKE NOT SO IMPORTANT SYNDROME BUT CAN BE CHRONIC AND DEBILITATING IF SEVERE. IS BACK TO UVEITIS PATIENTS FOUR HAD ANTERIORITIS A MILDER FORM OF UVEITIS. ONE HAD INTERMEDIATE, AS SOON AS YOU CROSS THE LENS TO THE BACK OF THE EYE, IF YOU WILL, CALLED POSTERIOR SEGMENT UVEITIS AND MOST LIKELY TO CAUSE VISION LOSS. YOU CAN SEE ESSENTIALLY ALL RESPOND TO TOPICAL CORTICAL STEROIDS. WE HAD ONE ON THE UVEITIS THAT RESPONDED TO INJECTIONS TWICE. IT REQUIRED INJECTIONS TWO INJECTIONS IN A ROLE. AND THREE POSTERIOR EYE EYE AT THIS WHICH CARRY CHARACTERISTICS OF BKH SYNDROME PICTURES I HAVE SHOWN A LITTLE BIT AGO. KNEED LOCAL OR SYSTEMIC CORTICOSTEROIDS TO CONTROL THEIR DISEASE. WE LOOK HOW SOON AFTER CHECK POINT INHIBITOR USE THESE SYNDROMES PRESENTED, IT'S RANGED ANYWHERE BETWEEN 10 TO 24 WEEKS. ALL GRADE 2 OR 3 BASED ON TCCAE CRY TOO TIERIA, -- CRITERIA, NO GRADE 4 ESSENTIALLY FOR EYES QUALIFIES AS BLINDNESS. WHEN WE LOOK AT THESE PATIENTS, THAT CAGE LIKE REACTION YOU CAN SEE THAT THEY WERE EXCLUSIVELY IN THE MEL MONA PATIENTS WHICH IS NOT TERRIBLY SURPRISING GIVEN THE MECHANISM OF THE DISEASE INVOLVES MELANOCYTE DERIVED ANTIGENS. HERE IS ONE OF THOSE PATIENTS. 62-YEAR-OLD WHO PRESENTED WITH -- (INDISCERNIBLE) A CENTRAL VISUAL AFFECT YOU CAN SEE WHY SHE'S HAVING A CENTRAL VISION PROBLEM AND PHOBIAIA, SHE HAD FLUID UNDERLYING UNDER HER RETINA. SHE WITNESS TO BE DIAGNOSED THISES A I SOCIOIATED WITH IMMUNE CHECK POINT INHIBITORS AFTER APPROPRIATE WORK UP, WE GAVE HER PERIOCULAR CORTICAL STEROID INJECTION, IMMUNOTHERAPY HELD BY ONCOLOGIST ANDK SEE COMPLETE RESOLUTION OF FLUID AND HER VISUAL ACOWTY DID IMPROVE LIVING A LITTLE CHANGE NOT UNEXPECTED. THEN SHE RESUMED IMMUNOTHERAPY, IT STARTED AGAIN, KIND OF CHALLENGE, RECHALLENGE APPROACH OF DRUG RELATED EVENT. ANOTHER CASE OF 50-YEAR-OLD CAUCASIAN FEMALE WITH SEVERAL DAYS, WEEKS OF BLURRY VISION ON AND OFF IN BOTH EYES, SHY HAD THREE CELLS IN BOTH ANTERIOR CHAMBERS AND SHE HAD -- AS YOU CAN SEE, TWO PLUS CELLS IN THE SRI TREE YOUS AS WELL. -- VITREOUS AS WELL. NOTE BOTH CAUCASIAN, IN WHOM VKH DOES NOT OCCUR. THIS PATIENT HAD METASTATIC MELANOMA, BEING TREATED WITH CYSTIC IMMUNOTHERAPY, A RECENT COLITIS TREATED WITH PREDNISONE AND IPILIMUMAB WAS HELD AFTER EFFECT BUT CONTINUED ON IT. THIS IS A IMAGE OF THESE PATIENTS YOU CAN SEE LITTLE HAZY BECAUSE OF THE CELLS, THE SPLIT LAMP PHOTOGRAPHY CANNOT GET A PERFECT VIEW WHEN INFLAMMATION IS IN THE EYE. THIS IS THE OLD CT THAT DOESN'T SHOW A LOT OF NUDE, MAYBE A VERY SMALL SLIVER THERE, AND HER VASCULATURE WAS ESSENTIALLY NORMAL IN THE EYE WITH HAP NERVE, A LEAKY INFLAMED NERVE. IN THE LEFT EYE A LITTLE LEAKAGE FROM THE PERIPHERAL VESSELS. SHE WAS TREATED WITH A STRONGER STEROID DROP THAT IS BELIEVED TO PENETRATE TO POSTERIOR SEGMENT OF THE EYE AND AFTER APPROPRIATE WORK UP. HER LEAKAGE IN THE IMPROVED AFTER TREATMENT AND SHE RECOVERED. AFTER FOLLOW-UP SHE DEVELOPED POLIOSIS, COMPONENT OF THE CK SYNDROME NORMALLY, THAT'S NOT OCCURRING TYPICALLY IN CAUCASIAN ETHNICITY. WE WANTED TO RECRUIT MORE PATIENTS AND ANNOUNCE STUDY PARTICIPATION OVER ON THE AMERICAN UVEITIS SOCIETY. APPROXIMATELY 5 CENTERS CONTRIBUTED AND STAND AND ALL THOSE THAT CONTRIBUTED MAJORITY OF THOSE WERE MALIGNANT MEL MONA. YOU CAN SO SEE THE PANUVEITIS IN THE FORM OF VKH SYNDROME ALL OCCURRED IN PATIENTS WITH MALIGNANT MELANOMA, INDICATING THAT WHILE THE CAGE LIKE REACTION MAYBE RESTRICT TO PATIENTS TREATED FOR METASTATIC MEL -- MELANOMA, NOT ALL DEVELOP CAGE LIKE UVEITIS. THERE'S MORE RECENT PUBLICATION FROM FRANCE WHERE THEY DID A PROSPECTIVE COHORT IMMUNOTHERAPY TREATED PATIENTS AND IDENTIFIED A PREVALENCE OF .4% IN AN INCIDENCE OF .7 PER HUNDRED THOUSAND PATIENT MONTHS OF TREATMENT. IT IS IMPORTANT TO NOTE THAT THIS DID NOT INCLUDE SYSTEMATIC EXAMINATION SO THE PREVALENCE AND INCIDENCE MIGHT BE UNDER-REPRESENTED. THEY ALSO LOOKED AT A DECLARATIVE PHARMACO VIGILANCE REGISTRY WHERE THEY IDENTIFIED ANOTHER FIVE CASES AND ALL IN ALL IDENTIFIED EIGHT CASES, SIMILAR TO OUR FINDINGS THEY FOUND HALF OF THESE TO BE GRADE 2, HALF OF THE PATIENTS THAT WERE IDENTIFIED, HAD GRADE 3 OCULAR TOXICITIES, 50% CASES DEVELOPED SYMPTOMS AFTER THEIR SECOND CYCLE. THEY ALSO ARE ABLE TO MANAGE OVERWHELMING MAJORITY OF PATIENTS USING LOCAL OR SYSTEMIC CORTICAL STEROIDS. THEY NOTED 65% PATIENTS EXPERIENCED ADDITIONAL EXTRAOCULAR IMMUNE RELATED ADVERSE EVENTS. MYOSITIS. AND APPROPRIATE WORK UP IS NOT BEING DONE, MYOCARDITIS WOULDN'T HAVE BEEN IDENTIFIED. OBVIOUSLY THE OCULAR SIDE EFFECTS WILL NOT KILL YOU, IT MAY MAKE YOU BLIND BUT IN MOST CASES IT DOESN'T SO CONCURRENT IMMUNE RELATED ADVERSE EVANS ARE IMPORTANT TO NOTE -- EVENTS ARE IMPORTANT TO NOTE. THEY FOUND THE MAJORITY OF THEIR PATIENTS WERE COMPLETE RESPONDERS, BEGGING THE QUESTION WHETHER IMMUNE RELATED ADVERSE EVENTS ARE ASSOCIATED WITH BETTER ANTITUMOR EFFICACY. NOT GOING TO GO INTO DETAILS OF THE SLIDE, MANY SPEAKERS HAVE ADDRESSED THIS QUESTION PRIOR TO ME. IN CONCLUSION ADVERSE EVENTS OCCUR LAST SIX MONTHS MAJORITY BEFORE THEN, MAJORITY RESPOND WELL TO TOPICAL OR LOCAL CORTICOSTEROIDS WHICH IS A FAVORABLE THING FOR US HOWEVER THIS GETS IN THE WAY OF BEING US BEING ABLE TO TRANSLATIONAL WORK IN THESE PATIENTS BECAUSE NORMALLY WE COULD TAP THESE PATIENTS AND IDENTIFIED CELLS INFILTRATING THE EYE, THEY ARE LIKELY TO RESPOND TO TOPICAL STEROIDS, THE RISKS OF TAPPING THE EYE MIGHT EXCEED THE RISK POSED BY DISEASE ITSELF. THE CAGE LIKE REACTION IS OBSERVED IN MELANOMA PATIENTS. AND IT IS IMPORTANT TO INVESTIGATE CONCURRENCE SYSTEMIC IRAEs, IT IS CRITICAL NOT TO CONFUSE METASTATIC DISEASE OR INFECTION WITH INFLAMMATORY SIDE EFFECT OF IMMUNOTHERAPY AS PREVIOUS SPEAKERS HIGHLIGHTED. THANK YOU AND HAPPY TO TAKE ANY QUESTIONS IF THERE ARE ANY. [APPLAUSE] >> QUESTIONS? >> MY QUESTIONS IS FOR DR. SANTOMASSO, GREAT TALK VERY INTERESTING. I HAVE A COMMON QUESTION, WE AT PENN HAVE RESIDENT THERE, HAD A RECENT CASE OF A PATIENT WHO DEVELOPED SEVERE ATAXIA NEUROPATHY, APOPTOSIS AFTER HIS FIRST INJECTION PD 1 MERKEL CELL AND WE ACTUALLY HAD A PERINATAL PLASTIC DONE A FEW MONTHS EARLIER BY NEUROLOGISTS AND HAD POSITIVE ANTI-HU ANTIBODIES AND DIDN'T HAVE ANTI-HU INIS CHROME UNTIL HE GOT PD ONE INHIBITOR, GOING ALONG WITH YOUR CASE OF HAVING THE ANTIBODY AT LEAST PRESENT BUT WE KNOW OBVIOUSLY A LOT ARE PRESENT IN THESE PATIENT WHOSE DON'T HAVE THESE SYNDROMES. 40% SMALL CELL LUNG CANCER, THAT'S VERY INTERESTING SO I WOULD LIKE YOU TO COMMENT ON THAT. >> YOU BRING UP AN IMPORTANT POINT. THERE'S PROBABLY IN THE WORLD OFFERER NEOPLASTIC NEUROLOGIC DISORDERS THERE'S HIGH TITER ANTIBODY PATIENT WHOSE HAVE NEUROLOGIC SYMPTOM AND WHO HAVE ANTITUMOR IMMUNITY. THIS IS WITHOUT CHECK POINT INHIBITORS. THERE WAS DESCRIBED IN THE LITERATURE THIS INTERMEDIATE TITER ANTIBODY, PROBABLY YOUR PATIENT BUT THE TITER OF THE HU ANTIBODY WAS BUT THE PSEUDOAPOPTOSIS THE PATIENT DEVELOPED AFTER WAS MOST DEFINITELY ATTRIBUTABLE TO THE DORSAL ROOT GANGLIONOPATHY FROM THE ANTIBODY AND PATIENTS WHO DON'T HAVE ANY ANTIBODY AT ALL. THE QUESTION IS, AS YOU KNOW, THESE AREN'T THOUGHT TO BE -- THESE ARE INTRACELLULAR ANTIGENS NOT DIRECTLY TARGETED BY THE ANTIBODY, SO THE QUESTION IS A, COULD THEY BE A MARKER, SHOULD WE BE DOING THIS FOR OUR ENDOCRINE TUMOR PATIENTS. AND B, IS IT A MARKER ALSO OF THE ANTITUMOR IMMUNE RESPONSE? DID YOU TREAT YOUR PATIENT ACTUALLY DID GET TREAT IN >> HE HAD A SEVERE DISEASE AFTER DISCUSSION WITH ONCOLOGY WE KEPT HIPT ON ANTI-PD ONE BECAUSE -- SUCH A DEFENDANT -- USUALLY DOESN'T HAVE MUCH RESPONSE, SO WE KEPT THEM ON TO FINISH THE CYCLE, HE'S NOW LIKE REMISSION AND HASN'T WORSENED AT ALL BUT NOT IMPROVED. ANOTHER QUESTION BRIEFLY, >> REASON BEING WE ARE HALF HOUR BEHIND. I WAS TOLD IT WOULD BE VERY BRIEF. >> THIS QUESTION IS FOR DAVID HAFLER. GREAT TALK. BY THE WAY. WHAT ABOUT THE DIFFERENTIAL GENOMIC PROFILE OF THE CNS TISSUE IN MS PATIENTS VERSUS NORMALS. >> LOOKING PAPERS EMERGING ON -- SEQ OUT OF THE BRAIN. CLEARLY IT'S INFLAME COMPARED TO NORMAL BRAIN. THERE ARE NOT A LOT OF T-CELL NORMAL BRAIN DEFINED. THOSE DATA ARE EMERGING. IN TERMS OF THE RNA PROFILING THAT'S THERE. IMPORTANT QUESTION. >> ANY KEY THINGS THAT YOU KNOW? >> (INAUDIBLE) PAPER NAYTURE LOOKING AT OLIGODENDROCYTES GO OVER ALL THE DETAILS. WE'RE IN THE PROCESS OF TRYING TO ISOLATE DETAILS FROM SEQ. >> SUPER FAST TECHNICAL QUESTION FOR DR. HAFLER. HOW DUD YOU GET HEALTHY T-CELLS FROM HEALTHY CSF? PLY OWE CYTOSIS IS A MARKER OF INFLAMMATION, NOT HEALTHY BY DEFINITION SO WHERE DID YOU GET THEM FROM? >> SPINAL TAPS. SO HERE IS THE THING. WHEN -- AS A CLINICIAN ONE DOES A SPINAL TAP, THEIR NUMBER COMES BACK 0 TO 1, WHATEVER. WHAT I HAVE BEEN DOING A NUMBER OF YEARS ROUTINELY TAKE 30 CCs OF SPINAL FLUID, LITERATURE IF YOU TAKE OUT 30 CCs WITH A -- DOESN'T MAKE A WHOLE LESS LIKELY TO HAVE HEADACHE. YOU CAN TAKE OUT LESS. WHEN YOU TAKE OUT 30 CCs AND COUNT THE NUMBER OF CELLS THAT ARE THERE, THERE'S A LOGARITHMIC DIFFERENCE. A HEALTHY INDIVIDUAL HAS BETWEEN 15 AND 30,000 T-CELLS AND 30 CCs. THEY JUST TRUST ME, WE DO. SPINAL TAP SUBPAR I PROMISE TO GET ONE DONE. MS PATIENTS HAVE A FEW HUNDRED THOUSAND, THE TROUBLE IS WHEN YOU TAKE SPINAL FLUID WITHOUT CONCENTRATING FROM THE CALENDAR 0 TO 1 IS A VERY BROAD NUMBER. WE HAVE BEEN MISLED BY THAT NUMBER FOR A LONG TIME, WE SHOULD RETHINK HOW WE DO SPINAL FLUID COUNTS. THAT'S MY OWN BIAS. ANY OTHER QUESTIONS BEFORE WE TAKE A BREAK? WE HAVE A FEW MOMENTS. GO AHEAD. >> HI. I DREAM OF A WORLD IN WHICH IF I GO TO A DOCTOR AND I AM DIAGNOSED WITH CANCER, THE DOCTOR WILL DO A BATTLE OF TESTS AND WILL BE ABLE TO ASSESS ROUGHLY WHAT ARE THE RISK TO DEVELOP THIS SIDE EFFECT IF I GET X TREATMENT AND THAT SIDE EFFECT IF I GET Y TREATMENT. I AM JUST WONDERING WHAT DO YOU THINK COULD BE DONE TO HAVE A MORE PRECISE ASSESSMENT OF THE PROBABILITY TO GET SIDE EFFECTS? THANK YOU. >> THAT'S A GREAT QUESTION, WE DON'T NOW WE ARE STARTING TO ASK ABOUT TO INCREASE AND HISTORY OF PRIOR AUTOIMMUNE DISEASE BUT AS WE HAVE SEEN WE HAVE TREATED PATIENTS WITH HISTORY OF AUTO-IMMUNITY AS WELL. I THIS I THAT THAT'S KIND OF WHAT EVERYONE IS TRYING TO DETERMINE WHETHER THERE ARE PRE-EXISTING BIOMARKERS, I DON'T THINK WE KNOW YET. FORTUNATELY THE VERY SEVERE EVENTS ARE RARE. STILL, EVEN NEUROLOGIC EVENT, THOUGH IT'S MORE THAN WAS REPORTED, THEY ARE STILL RARE AND OCULAR EVENTS SIMILAR HARLEY ARE RARE. AND OFTEN IF CAUGHT EARLY, AND MANAGED WITH STEROIDS, THEY CAN BE TREATED AND REVERSED. VERY RARE THE SEVERE ONES ARE THE ENCEPHALITIS, MYASTHENIA GRAVES CASES BECAUSE OF MYOCARDITIS WITH IT AND THE GEOM BERET CASES AND SOME HAVE MORE ASSOCIATION WITH CERTAIN TUMOR TYPES. GEE I DON'T WE CAN LOOK AT PREEMPT IN THOSE PARTICULAR TUMOR TYPES. GEE I DON'T MEAN BEAR RAY OR GENETIC MARKERS. >> IT BECOME AS FUNDAMENTAL QUESTION OF ARE THESE REALLY AUTOIMMUNE -- ARE THESE REALLY AUTOIMMUNE DISEASES, ARE THEY JUST UNLEASHING OF THE IMMUNE SYSTEM, REMEMBER THIS DISCUSSION, CTLA 4 KNOCK OUTS. WELL, IT'S INFLAMMATION TISSUE IS AUTO-IMMUNITY, ISN'T CLEAR, VERY INTERESTING QUESTION. >> JUST A QUICK QUESTION. HAVE YOU EVER TREATED MS PATIENT OR HAS -- (INAUDIBLE) I WOULD LOVE TO HEAR WHAT YOUR THOUGHTS ARE. >> I DO. I AM FOLLOWING A PATIENT WHO HAS MS WHO WAS TREATED, I JUST DISCUSSED THE PATIENT WITH DR. HAFLER WHO DID DEVELOP AN IMMUNE RELATED AVERSE EVENT THAT WAS A SKIN TOXICITY, HE HAS EOSINOPHILIC FAST SHYTIS. HE'S FINE NEUROLOGICALLY, HIS -- HAS BEEN STABLE AND HE'S ON NS THERAPY SO, GO FIGURE T MAIN TOXICITY IS THE SKIN. I DON'T KNOW THAT I WOULD HAVE BEEN COMFORTABLE DOING IT BUT I HAVE HEARD OF PEOPLE ANECDOTALLY TREATING AND NOT HAVING PROBLEMS. >> WE TREATED A FEW FM PATIENTS WITH ANTI-PD 1. SO FAR HAVE ESCAPED THE WRATH OF THE DRUG. WE HAVE A CLINICAL TRIAL WE ARE DOING, WE'RE GOING TO FOLLOW PATIENTS PERSPECTIVELY AND SEE WHAT HAPPENS. IF NO FURTHER QUESTIONS, WE ARE ORDERED TO GET BACK ON TIME, THERE WILL BE A BREAK. WE WILL RETURN HERE AT 4:00 P.M. SHARP FOR THE LECTURE. NEXT LECTURE. IT IS MY GREAT HONOR AND PLEASURE TO HELP OUR CO-NOTE SPEAKER DR. LIZ JAFFEE, GOT HER MEDICAL DEGREE FROM NEW YORK MEDICAL COLLEGE, DID RESIDENCY AT PRESBYTERIAN UNIVERSITY HOSPITAL IN PITTSBURGH. SHE IS A WIDELY RESPECTED AND WELL KNOWN FIGURE IN THE FACULTY AT JOHNS HOPKINS ASSISTANT PROFESSOR ONCOLOGY NOW HOLDS THE DANA PROFESSORSHIP IN ONCOLOGY AND DEPUTY DIRECTOR OF THE COMPREHENSIVE CANCER CENTER AT HOPKINS. AS A WORLD RENOWN EXPERT IN CANCER IMMUNOLOGY LIZ LED HE WAS ON THE TESTING AND DEVELOPMENT OF ALLOGENEIC CANCER VACCINES, THE GV ACTIONX VACCINE FOR PANCREATIC CANCER, NOW DEFINING BIOMARKERS REQUIRED FOR PANCREATIC CANCER ONSET AND PROGRESSION, LIZ AS MANY OF YOU KNOW IS THE IMMEDIATE PAST PRESIDENT OF AACR HANDLE OVER HER TITLE A FEW WEEKS AGO AT ANNUAL MEETING TO DR. MARTES AND WE HAVE BEEN HONOR TO HAVE HER ON OUR ORGANIZING COMMITTEE AS THE CHAIR. THANK YOU. ON TO LIZ. >> THANK YOU. I HOPE EVERYONE IS ENJOYING THE MEETING SO FAR. A LOT OF GOOD INFORMATION, STILL HAVE A LOT TO DO IN THIS FOLD AND WE LEARNED FROM THIS MEETING TO HELP US MAKE SOME DECISIONS. SO I'M GOING TO TALK ABOUT COMBINATION IMMUNOTHERAPIES AND THIS WILL START OFF THE SESSION FOR THIS AFTERNOON, THESE ARE MY DISCLOSURES, I WILL BE TALKING TWO VACCINES LICENSED TO A DURA BIOTECH MYSELF AND JOHNS HOPKINS HAS POTENTIAL TO RECEIVE ROYALTIES IN THE FUTURE AND I'M ON A NUMBER OF SCIENTIFIC ADVISORY BOARDS. JUST TO START OUT WITH COMBINATIONS, I THINK MOST HAVE SEEN THAT'S SPECIALLY ONCOLOGIES AND MY NOLNIST JUSTS IN THE FIELD. -- ONOLOGIST IMMUNOLOGISTS IN THE FIELD. IT WAS A COMBINATION STUDY INVOLVING -- TO SEE THE GROUP THAT DID THE STUDY COULD IMPROVE ON THE RESPONSE RATE AT THAT TIME IPIMIMLAB ALONE THAT, THE FIRST APPROVED FOR MELANOMA. IN THE ORANGE CURVE IN FACT THERE WAS IMPROVEMENT. BUT AS YOU WOULD GUESS FROM WHAT WE ARE LEARNING TODAY, THERE IS MORE TOXICITY THAT WE OBSERVE AS WELL WHEN YOU COMBINE THESE TWO AGENTS. IN FACT WITH THAT WE SAW MANY MORE TREATMENT RELATED BOTH LOW GRADE AND HIGHER GRADE AEs AND THEY WERE MOSTLY THE HIGHEST RATE WAS IN COLITIS AND ALSO DIARRHEA. THE MEDIAN TIME TO ONSET WE LOOKED AT THIS, IN OTHER CIRCUMSTANCES, WITH SINGLE AGENT IMMUNOTHERAPIES, DURING SOME OF THE SESSIONS TODAY. IT CAN HAPPEN ANY TIME. SO WE CAN'T PREDICT, WE HAVE NO BIOMARKERS TO TELL US WHEN THESE DIFFERENT ADVERSE EVENTS ARE GOING TO HAPPEN. IT COULD HAPPEN AFTER THE FIRST DOSE, COULD HAPPEN AFTER SIX OR EIGHT MONTHS. SO THAT'S ONE OF THE NEW CHALLENGES NOT ONLY SINGLE AGENT BUT AS WE START TO DO COMBINATIONS AND NOW THE ADVERSE EVENTS WILL INCREASE RATE AS WELL AS SEVERITY, IT WOULD BE HELPFUL TO PREDICT WHOSE IS GOING TO BE HIGHER RISK AND HOPEFULLY INTERVENE AT EARLIER TIME POINT. THESE ARE SCIENTIFIC CHALLENGES THAT WE HAVE AS WELL AS THE ADVERSE EVENT CHALLENGES THAT WE HAVE, BUT I'M GOING TO TALK ABOUT PANCREATIC CANCER AS A WAY TO TALK ABOUT WHY YOU NEED TO START THINKING MORE SCIENTIFICALLY ABOUT COMBINATIONS. PANCREATIC CANCER IS A CANCER THAT DOESN'T ACTUALLY RESPOND TO IMMUNOTHERAPY, ABOUT 80% OF CANCER SUBPAR DON'T RESPOND TO IMMUNOTHERAPY SO WE HAVE ONLY HIT THE LOW HANGING FRUIT. SO SOME OF THE SCIENTIFIC CHALLENGES INCLUDE THE TUMOR MICROENVIRONMENT, PDL 1 SIGNALING VERY IMPORTANT OF COURSE BUT IN THE OTHER CANCER THERE'S SIGNALS THAT WE THINK MAY ALSO BE DOMINATING THAT WE MAY HAVE TO BYPASS BEFORE WE GO INTO SEE AN OPTIMAL ANTITUMOR IMMUNE RESPONSE. WE NEED TO BETTER UNDERSTAND THE COMPLEXITIES OF THE TUMOR MICROENVIRONMENT AND IT GOES WITHOUT SAYING THAT BECAUSE THERE ARE A NUMBER OF DIFFERENT SIGNALS WE'RE GOING TO HAVE TO DO AT LEAST TWO COMBINATION, MAYBE THROUGH OR FOUR, IT MAYBE AT ONCE OR MAYBE OVER TIME SEQUENTIALLY BUT AGAIN, THIS IS ALL SCIENTIFICALLY QUESTIONS WE NEED TO ADDRESS. CURRENTLY WE HAVE A FEW BIOMARKERS, WE HAVE HIGH MUTATIONAL BURDEN, PDL 1 EXPRESSION, THEY ARE NOT PERFECT, THEY DO WORK. THEY HAVE BEEN SHOWN TO BE APPROVED IN CERTAIN SIXER TO PREDICT WHO WILL RESPOND. BUT AGAIN THAT'S IN THE MINORITY, NOT MAJORITY OF PATIENTS RECEIVING IMMUNOTHERAPY, WE NEEDED BIOMARKERS TO PREDICT NOT ONLY SINGLE AGENT BUT PREDICT WHO ARE GOING TO RESPOND TO COMBINATIONS. SO IN ORDER TO BOTH PREDICT TOXICITIES AND ALSO OPTIMIZE OUR COME COME COMBINATIONS WE HAVE TO THINK ABOUT THE TUMOR MICROENVIRONMENT, WHAT ARE SIGNALS AND WHAT BIOMARKERS HELP US DETERMIE WHO IS GOING TO BEST BENEFIT FROM THESE AGENTS. THIS IS WHAT PANCREATIC CANCER LOOKS LIKE. LET ME SEE IF I HAVE -- THERE WE GO. ONE OF THE SHIRE US OF PANCREATIC CANCER IS THAT ONLY ABOUT TEN TO 40% ARE TUMOR CELLS. THE REST IS REACTIVE INFLAMMATORY AS WELL AS NON-INFLAMMATORY CELLULAR COMPOSITION THAT WE CALL THE PLASTIC STROMA, IT'S A DYNAMIC PROCESS, IT'S NOT STAGNANT, NOT JUST SITTING THERE, IT'S NOT INERT, IT TAKES MANY CELLS CONSTANTLY CHANGING IN COMPOSITION. EARLY IN PANCREATIC CANCER DEVELOPMENT WE SEE MONOCYTES, REGULATORY T-CELLS, THESE START TO CHANGE, WE SEE THE FIBROBLAST CO-OPTED BY THE CANCER ASSOCIATED FIBROBLAST. THEY ARE SIGNALING, HELPING THE CANCER GROW, THEY ARE EXCLUDING T-CELLS THROUGH EITHER GETTING IN OR FROM FUNCTIONING ONCE THEY GET IN. SO THIS IS AN EXAMPLE OF THE CANCERNA NATURALLY RESPONDS TO SINGLE AGENT IMMUNOTHERAPY, THIS IS ONE OF THE HIGH TUMORS, THIS IS COLON CANCER AND THIS IS A PATIENT WHO GIVE ANTI-PD 1 RESPONDED RIGHT AWAY. THIS IS WHAT WE WANT PANCREATIC KAREN TO LOOK LIKE. WE DON'T SEE EFFECTOR T-CELLS COMING IN H, CD8 EFFECTER T-CELLS. WE SEE FOX P 3 POSITIVE REGULATORY T-CELLS, MYELOID DERIVED CYPRESSSOR CELLS, TUMOR I A CERTAINIATED MACROPHAGES. EFFECTOR T-CELLS AND IF WE SEE CD8 T-CELLS, THEY ARE NOT FUNCTIONING SO THE GOAL WITH THESE COLD TUMORS, THEY ARE INFLAMMATORY, THEY'RE JUST NOT THE RIGHT INFLAMMATION BUT PEOPLE CALL THEM COLD TUMORS BECAUSE EFFECTOR T-CELLS HAVEN'T GOTTEN IN SO THE GOAL IS TO TURN A PANCREATIC CANCER INTO ONE THAT IS SUSCEPTIBLE TO THESE IMMUNE ONCOLOGY AGENTS. SO IF YOU START OUT WITH THIS TUMOR, LOTS OF STROMA, SOME LYMPHOCYTES NOT ACTIVATED DENDRITIC THAT ARE STARTED TO BECOME PRO CARCINOGENIC, THE FIRST STEP IS TO INDUCE GOOD T-CELL AND GET IT TO INFILTRATE TO YOU CAN DO THAT IN A NUMBER OF WAYS, WE ARE LOOKING AT VACCINES, WE HAVE SOME OLDER TYPE VACCINES, TUMOR CELL VACCINES, WISTERIA, CONTAINING TUMOR ASSOCIATED ANTIGENS BUT NEOANTIGEN VACCINES ARE RECENT ADVANCE AND THESE MAY ALSO BE VERY IMPORTANT EVEN IN PANCREATIC CANCER BECAUSE PANCREATIC CANCERS DO HAVE MUTATIONS, JUST NOT AS HIGH MUTATIONAL BURDEN AS MELANOMA OR A LUNG CANCER BUT ONCOLYTIC VIRUSES MAY RELEASE TUMOR ANTIGENSES AND TUMOR MICROENVIRONMENT, WE HAVE BEEN TESTING EPIGENETIC MODIFIERS AN THEY CAN UNCOVER NEOANTIGENS, RADIATION MAY RELEASE ANTIGENS ND CHEMOTHERAPY MAY RELEASE ANTIGENS, I FOCUS ON VACCINES BECAUSE IN THE INFECTIOUS DISEASE WORLD VACCINES ARE THE WAY TO EXGAIN DIRECT DEBTIC CELLS, THEY ARE THE DIRECTOR OF THE ORCHESTRA, THEY ARE THE ONES THAT TAKE UP THE ANTIGEN AND THEY ARE THE ONES THAT DECIDE WHAT IMMUNE RESPONSE SHOULD HAPPEN IN INFECTION WE CAN TAKING ADVANTAGE OF THE NATURAL IMMUNE RESPONSE TO ACTIVATE IMMUNE RESPONSE AGAINST CANCER. NOW THAT YOU GET A T-CELL IN, NOW WE START TO SEE THE LYMPHOCYTES COMING IN, WE WANT TO NOW GET A BETTER ACTIVATED LYMPHOCYTE SO STEP ONE, WE ACTIVATE T-CELL GET IT IN, STEP TWO IS TO MANIPULATE THE STROMA AND ACTIVATE THE T-CELL FULLY. THAT IS GOING TO HAPPEN BY GIVING CHECK POINT BLOCKING AGENTS, ANTI-PD 1 ANTI-PDLA 1, ANTI-CTLA 4, GIVING ANISTS, ARLENE MENTIONED WE HAVEN' BEGUN TO EXPLORE THE AGONIST YET. THEY ARE IN THEICALLY IN THIS CASE, STARTING TO EXPLORE THEM. WE DON'T KNOW WHICH ARE THE BEST COMBINATIONS AND WHETHER THEY'RE GOING -- WHETHER IT'S DEPENDENT ON THE TUMOR TYPE, THE SITE WHERE THE TUMOR IS, PANCREAS MAYBE DIFFERENT FROM THE LIVER, FROM THE LUNG, THAT'S SCIENCE WE STILL DON'T KNOW. WHAT WE DO KNOW WE NEED TO AT LEAST MODULATE ONE OTHER SINGNAL BESIDE ACTIVATING T-CELL AN MORE THAN LIKELY IT WILL BE MULTIPLE SIGNALS. SO WE HAVE BEEN TESTING A NUMBER OF VACCINES AND THEN VACCINE COMBINATIONS AND PATIENTS WITH PANCREATIC CANCER. AND WE ARE JUST BUILDING ON SCIENCE THAT WE STARTED QUITE A FEW YEARS AGO. AND THIS WAS THE FIRST STUDY TO SHOW THAT WE CAN GET A T-CELL INTO THE PANCREATIC TUMOR. THIS WAS A NEOADJUVANT, AN EVENTUAL STUDY, WE PUBLISHED BACK IN 2014, THIS IS DONE WITH MY COLLABORATORS MEDICAL ONCOLOGY AN CHRIS WOLFGANG IN SURGERY ANDER I CAN ARE LUTZ IMMUNOLOGY. SO MULTI-DISCIPLINARY TEAM, WE TEST THE OLDER VACCINES TWO GENERAL TECH LICK ENGINEERED ALLOGENEIC TUMOR CELLS IN GRANULOCYTE STIMULATING FACTOR WHICH ACT INVESTIGATES RECRUITS AND ACTIVATES DENDRITIC CELLS, DENDRITIC CELL TAKES UP THE TUMOR ANTIGEN AND DECIDES ARE THE MOST IMPORTANT ANTIGENS WHICH TO USE TO ACTIVATE A T-CELL RESPONSE. WE GAVE PATIENTS THIS VACCINE TWO WEEKS BEFORE SURGERY. ONE VACCINE WE GET THE TUMOR, WE GET TO TAKE A LOOK COMPARED TO THE VACCINE BIOPSY, THEN GO ON TO ADJUVANT CHEM RADIATION AND MORE VACCINE IN REMISSION. WE DID REPORT THIS STUDY, WE SAW THERE WAS A SIGNIFICANT IMPROVEMENT IN DISEASE FREE OVERALL SURVIVAL, WE HAD ASSOCIATION OF EXPANDED GOOD QUALITY MESOTHEE LYNN T-CELL RESPONSE. THAT'S SO IMPORTANT, ARLENE ALLUDED TO THE FACT WE KNOW ABOUT T-CELL SIGNALING NOW AND YOU DON'T WANT TO MAKE A T-CELL, IT HAS TO BE AN OPTIMAL QUALITY T-CELL. WHICH I THINK MANY PEOPLE IN IN THE FIELD ARE STARTING TO DEFINE WHAT WE FOUND IN OUR FIRST LOOK WAS THAT IN 85% OF THE PATIENTS, WE TREATED OVER 60 PATIENTS, WE SAW HIMFOID AGGREGATES COMING IN, THERE IS A DIFFERENT LOOKING TUMOR WHAT I'M SHOWING BEFORE. THIS IS THE PANCREATIC TUMOR THE LYMPHOID AGGREGATES COMING IN. EARLY ON WE HAVE SINGLE AGENT IMMUNOHISTOCHEMISTRY WE CAN LOOK AT THAT'S WHAT WE DID. WE LOOK TO TRY TO DEFINE WHAT SOME OF THE POPULATIONS WERE AND THESE REALLY LOOKED LIKE NEW LYMPH NODES FORMENING THE PANCREAS, TERTIARY LYMPHOID AGGREGATES, THEY HAD BOTH B CELLS IN THE MIDDLE, T-CELLS ON THE SURROUNDING EDGE, THEY SEEM LIKE THEY WERE DYNAMICALLY OCCURRING. SO THEY WERE ACTIVE HI FORMING BECAUSE WE HAD BOTH ANTIGEN INEXPERIENCE AN ANTIGEN EXPERIENCE T-CELLS, THEY EXPRESS CXCR 3. T-CELL TRAFFICKING MARKERS. THEY EXPRESS EARLY T-CELL ACTIVATION MARKER CD 69, WHAT THEY DIDN'T EXPRESS IS EVIDENCE T-CELLS COULD KILL A CANCER, NO GRANZYME B OR PORPHYRIN. WE SAID THESE ARE AGGREGATES IMMUNE ACTIVATING AND REGULATING BUT NOT AREAS OF SITE OF LYSIS YET. IN THE SAME STUDY, AFTER ONE VACCINE, IF IN FACT WE SAW THE T-CELLS COMING OUT OF THOSE LYMPHOID AGGREGATES AND INFILTRATING THE TUMOR THESE PATIENTS WENT TO LONG TERM SURVIVE. THE ONE WHOSE DIDN'T HAVE A TYPICAL SURVIVAL RATE OF 1.5 YEARS ON AVERAGE. SO WE WANTED TO BETTER UNDERSTAND WHAT'S HAPPENING AND AS ANY IMMUNOLOGIST IF THE AUDIENCE WOULD EXPECT WE FOUND THAT IN FACT NOW THAT A T-CELL CAME IN, THE T-CELL MAKING GAMMA INTERFERON AND UP YESSINGLATION OF THE PDL 1 PATHWAY. WE GOT UP REGULATION OF THE IDO PATHWAY, IDA 1 SEVERAL PATHWAYS I'M SHOWING YOU THE ANTI-PDL 1. THE INTERESTING PART, REMEMBER THIS IS 2012, 2013, IT WAS HAPPENING IN THE LYMPHOID AGGREGATES. YES, THE TUMOR EXPRESSED THE PDL 1 BUT THERE WERE LOTS OF CELLS IN THE LYMPHOID AGGREGATES EXPRESSING IT. IN FACT WE HAD PD 1 ON THE T-CELLS. SO WE WANTED TO BETTER UNDERSTAND WHAT WAS GOING ON. SO WHAT WE DID WAS COLLABORATED THROUGH OUR NEXT GRANT MECHANISM STAND UP TO CANCER, AACR, GRANT, THIS ALLOWED US TO DEVELOP A MULTIPLEX IMMUNOHISTOCHEMISTRY APPROACH DONE IN COLLABORATION WITH LISA COUSINS AT OHSU AND HER POST DOC TAKAHIRA IS THE FIRST NAME. WE WANTED TO BE ABLE TO STAIN AS MANY MARKERS AS POSSIBLE ON ONE SLIDE OFF THE TISSUE. SO WE WENT TO THAT FIRST STUDY I SHOW YOU TO WORK THE CONDITIONS OUT, AND WHAT WE WERE ABLE TO DO IS DO UP TO 12 MARKERS ON ONE SLIDE. WHICH IS GOOD BEFORE YOU START TO LOSE THE TISH SHOE, LOOKS LIKE IT'S ON ITS OWN TIMER. BEFORE YOU LOSE THE TISSUE INTEGRITY. SO BASICALLY WE WOULD DO A PRIMARY STAINING, WE WOULD THEN DIGITALIZE IT, SCAN IT, AND ASSIGN A COLOR THEN STRIP AND DO THAT 12 TIMES BEFORE LOSING TISSUE INTEGRITY. THEN WE GET THESE PRETTY PICTURES, WHICH ARE NICE BUT DOESN'T TELL A LOT OTHER THAN THEY'RE PRETTY BUT WHAT WE WERE ABLE TO DO IS 12 LYMPHOID BIOMARKER, 12 MYELOID BIOMARKERS AND 12 FUNCTIONAL MARKERS. AND NOW WE ARE ABLE TO DO ANALYSIS, THIS IS ACTUALLY USING COMPUTATIONAL APPROACHES TO QUANTIFY CELL TYPES, WHICH WERE EXPRESSING WHAT AND WE CAN GET A PRETTY HEAT MAP AND LOOK AT ALL DIFFERENT AREAS OF THE SLIDE AND START TO DO ANALYSES TO PREDICT RESPONDERS. SO THE FIRST THING WEAPON FOUND IS WHEN YOU ROOK AT THE T-CELL -- LOOK AT T-CELL TO MYELOID RATIO, CD 68 POSITIVE CELLS, WE FOUND IF IT HAD A HIGH CD8 TO CD 68 OR LOW MYELOID POPULATION, YOU ARE GOING TO BE IN THAT GROUP THAT DOES WELL, LIKELY IN THE GROUP T-CELLS GET OUT AND KILL THE CANCER. HOWEVER, IF YOU HAD A HIGH MYELOID PROFILE THAT WAS NOT GOOD. IN A ADDITION THE T HELPER ONE AND TWO PREDICTED YOU WOULD BE ABLE TO DO WELL. THE FIRST PARAMETER WE WERE ABLE TO LOOK AT. WE LEN LOOKED WHO WAS EXPRESSING PDL 1 IN LYMPHOID AGGREGATES AND COMPARED IT TO THE NEOADJUVANT CHEMOTHERAPY THE OTHER GROUP IN COHORTS AND WHAT WE FOUND IS FIRST NEOADJUVANT CHEMOTHERAPY DIDN'T UPREGULATE PDL 1. SO AT LEAST THIS PARTICULAR CHEMOTHERAPY -- THERE MAYBE OTHERS THAT WOULD WE LOOKED AT THE T CELL, B CELLS WHICH YOU ARE SEEING CSFR 1 POSITIVE CD 68 POSITIVE CELLS, CD 63 POSITIVE, CD 68 POSITIVE CELLS AND THE DC SIGN POSITIVE AND CD8 3 POSITIVE CELLS WERE UPREGULATING PDL 1 IN RESPONSE TO T-CELLS COMING IN, AND IF YOU UPREGULATED YOUR PDL 1 IN THIS CASE ON THE MONOCYTES WERE GOING TO BE DOING BETTER. THAT WAS NOT THE CASE FOR THE CHEMOTHERAPY GROUP, IT DIDN'T MATTER IF YOU HAD PDL 1 OR NOT. SO BASED ON THAT WE HAD A HYPOTHESIS. WE HAVE NON-IMMUNOGEN UK BASELINE AT ENVIRONMENT, BM DENDRITIC CELLS AN ABLE TO TAKE UP ANTIGEN AND ACTIVATES T-CELL, T-CELL ARE ACTIVATED, THEY INILTRATE THE TUMOR SORRY, THERE WE GO. PDL 1 UPREGULATED IN THE MICROENVIRONMENT, THE T-CELLS ARE INACTIVATED. SO THE NEXT STEP IN THE NEOADJUVANT SETTING IS TO DO ANTI-PD 1 BLOCKADE WITH YOUR VACCINE TO SEE IF WE CAN ALTER WHAT HAPPENS IN THE MICROENVIRONMENT. THIS STUDY IS ONGOING I DON'T HAVE THE DATA YET BUT WE WILL PROBABLY HAVE THE DATA IN THE NEXT SIX MONTHS. JUST TO FINISH UP ON THIS PARTICULAR PATIENT POPULATION, WE ARE ALSO ABLE TO TAKE A BETTER LOOK AT THE TYPE OR THE QUALITY OF THE T-CELLS, SO WE STARTED LOOKING AT WHO WAS EXHAUSTED WHO WAS AN EARLY EFFECTOR, WHO WAS NAIVE MEMORY CELL SO THE FIRST THING YOU SEE IF YOU HAVE LOW MYELOID YOU HAVE ALMOST DOUBLE THE NUMBER OF CD8 T-CELLS INTO THE TUMOR MICROENVIRONMENT COMPARED TO HIGH MYELOID. THE MOST IMPORTANT IS THERE'S LESS EXHAUSTION, ONLY 4.6 OPPOSED TO 21% GETTING EXHAUSTED IN THE HIGHER MYELOID POPULATION. WE ALSO HAVE A NICE POPULATION OF THE LATE EFFECTOR AND EARLY EFFECTOR. POPULATION. SO THE NEXT STUDY WE DID SIMULTANEOUSLY AT THE TIME WAS TO COMBINE OUR VACCINE WITH ANTI-CTLA 4 GOING BACK QUITE FEW YEARS, AFTER CTLA WAS APPROVED IN 2011 BUT IN THE METASTATIC PANCREATIC CANCER STUDY. THE CLINICAL TRIAL WAS PUBLISHED THIS WAS WORK DONE BY YOUNG LEE WHO IS ONE OF OUR EXPERT CLINICAL RESEARCHERS WHO DOES THE COMBINATION IMMUNOTHERAPY STUDIES IN THE GROUP. WHAT YOU ARE LOCKING AT HERE IS THE COMPARISON BETWEEN GVAX VACCINE AND PLUS ANTI-CTLA 4 VERSUS ANTI-RTRA 4 ALONE, OBVIOUSLY IT DIDN'T WORK. THESE ARE PATIENT WHOSE FAILED TWO OR MORE CHEMOTHERAPIES ON AVERAGE THREE MONTHS TO LIVE, WE HAD A 27% 12 MONTH SURVIVAL IN THE ONES THAT DID LIVE, WE ONLY HAD 7% 12 MONTH SURVIVAL IN ONE WHOSE GOT CTLA 4. HERE IS THE IMPORTANT THING. IF YOU CAN WAIT LONG ENOUGH IN THIS PATIENT POPULATION, WE START TO SEE REGRESSION. HOWEVER TAKING A LOOK AT THE CAT SCAN OF THE LUNGS THIS IS BASELINE THREE DIFFERENT CUTS YOU CAN SEE TUMORS ALL THROUGH HERE. AT WEEK SEVEN THIS IS TWO MONTHS INTO IT, WE ARE SEEING GROWTH. THIS IS TYPICAL, THIS IS NOT ATYPICAL. THERE'S BIOMARKERS THERE'S A CHEMICAL BIOMARKER IN THE BLOOD GOING UP THEN COMES DOWN, IT COMESES DOWN BY WEEK 14, THIS IS AFTER THREE MONTHS OF THERAPY. SO IF THE PATIENTS CAN WAIT THAT LONG, ABOUT HALF THE PATIENTS HAD SOME SORT OF RESPONSE ON BOTH CAT SCAN AND ALSO BY BIOMARKER. SMALL STUDY, ALL SCIENCE IN THE PATIENTS, NOT TRYING TO TELL YOU THAT ANYONE HAS BEEN CURED OR WE MADE GREAT PROGRESS BUT WE ARE MAKING PROGRESS ON THE SCIENCE I WILL SHOW YOU. SO OUR SECOND STUDY WAS DONE WITH ANTI-PD 1 AND OUR VACCINE GVAX ADDS A PRIME AN CRS TO A 7 GIVEN A BOOST WHICH IS MONOCYTOGONY VACCINE ALTERED SO THAT IT CAN'T MOVE FROM CELL TO CELL. IT'S A NATURAL WAY TO GET INTO THE ANTIGEN INTO A DENDRITIC CELL, WE STUDIED THIS PRE-CLINICALLY AND PUBLISHED ON IT AND WE GENETICICALLY ALTERED IT WITH BIOTECH TO EXPRESS MESOTHELIN, THE ANTIGEN IDENTIFIED AS T-CELL ANTIGEN AND PANCREATIC CANCER. PRIME GVAX BOOST WITH WISTERIA, THAT WAS VACCINE ALONE VERSUS VACCINE PLUS ANTI-PD 1, THAT WAS THE STUDY, PET PATIENTS, RANDOMIZED ONE TO ONE, YOUNG LEE THIS IS CHEMOTHERAPY RESISTANT METASTATIC PANCREATIC PATIENTS AND AGAIN, LOOKING AT THE CLINICAL OUTCOME, WE SAW EVEN PARTIAL RESPONSES AT THIS POINT, THE OTHERS OR IMMUNE RESPONSES NEVER REACHED PARTIAL RESPONSE, WE SAW PARTIAL RESPONSE BY RESIST IN THE STUDY GETTING READY TO PUBLISH. WE'RE ANALYZING ALL THE DATA. YOU CAN SEE BASELINE GROWING AT WEEK TEN, NOT TO WEEK 30, THIS PATIENT HAD NEAR CR WEEK 30. SIX MONTHS. HOWEVER WE GOT SPATTERRER, WE FIGURED WHEN TO DO THE SECOND BIOPSY SO WE HAD PRE-TREATMENT BIOPSY S DURING TREATMENT BIOPSY AND BASED ON THE CTLA 4 STUDY WE DO IT AT WEEK TEN, GOOD POINT SEEING PROGRESSION. SO WHAT DID WE SEE? WE DID IMMUNOHISTOCHEMISTRY, MULTIPLEXING WITH LISA'S GROUP, THIS HAS NOT BEEN PUBLISHED YET, IT'S GETTING READY TO BE PUBLISHED SO WE SAW CD8 AND CD4 COMING TO THE GROWING TUMOR. AND WHEN WE QUANTITATE IT THESE ARE PROLIFERATING KI 67 PRE-, POST, YOU CAN SEE POST CD4 AND CD8 POPULATION AND IMPORTANTLY WHEN YOU LOOK AT REINVIGORATED CELLS, THE POSITIVE PD 1 NEGATIVE POPULATION, HAS INCREASED IN THE POST AND PATIENT WHO HAS DONE WELL, THIS IS AN EXAMPLE, THIS IS AN EARLY EXAMPLE, WE HAVE NOW ASSESSED ALL THE PATIENTS AND WE HAVE A COUPLE OF LEARNING POINTS SO PATIENT WHOSE HAD SHORT TERM OVERALL SURVIVAL, VERY HIGH TUMOR ASSOCIATED MACROPHAGESS FROM THE START. THOSE -- THOUGH THEY GO DOWN THEY DON'T GO DOWN ENOUGH WHERE Z IF YOU HAD LONGER SURVIVAL YOU HAD LOW, YOU STARTED OUT PRE-TREATMENT WITH LOWER TUMOR ASSOCIATED MACROPHAGES. AND THEY STAYED LOW. SUGGESTING THAT MAYBE THE APPROACH HERE IS TO RECONDITION OR REPROGRAM TUMOR ASSOCIATED MACROPHAGES FIRST AND COMMIT WITH IMMUNOTHERAPY, SOMETHING WE THINK ABOUT FOR OUR NEXT STUDY. IN FACT THE T-CELLS GO UP IN PATIENTS WHO HAD LOWER TAM SO WE SHOWED THAT IN NEOADJUVANT SETTING, THEN THE METASTATIC SETTING, OVERALL SURVIVAL, SOME T-CELLS AND THEY GO WAY UP AFTER CYCLE THREE ON AVERAGE IN THE PATIENTS WHO HAD LOW TAM. SO TO SUMMARIZE THIS PART OF THE TALK, LONGITUDINAL CHANGES IN THE IMMUNE CELL COMPLEXITY CAN BE PROFILED AND WE CAN CORRELATE AT LEAST MAKE SOME HYPOTHESES FROM THOSE CORRELATIONS WITH SURVIVAL, WE ARE SEEING EXPANSION OF THE CD8 T-CELLS AND REINVIGORATING THEM IN SOME OF THE PATIENT WHOSE GO ON TO DO BETTER. WE DO SEE INCREASED EXHAUSTED POPULATION IN THOSE PATIENTS WHO HAVE SHORTER SURVIVAL, THAT GOES ALONG WITH HIGHER TAM FREQUENCY, SO AGAIN THIS WOULD SUGGEST MAYBE THE WAY TO GO IS PRE-CONDITION THESE TUMORS TO TRY TO MODIFY THE MONOCYTES BEFORE WE DO ANYTHING ELSE WITH IMMUNOTHERAPY. SO THE FINAL PART OF THE TALK HAS TO DO WITH LOOKING AT T-CELL RECEPTOR SEQUENCING, I SHOWED YOU THE TWO TRIALS, CTLA 4 PLUS VACCINE AND THE PD 1 BLOCKING PLUS VACCINE SO WE HAVE PBL AND TUMORS TO EVALUATE PRE AND DURING TREATMENT FROM THESE TWO STUDIES. I WILL ONLY SHOW YOU THE PBL BECAUSE TURNS OUT THE TUMOR DIDN'T GIVE EXTRA INFORMATION. THESE ARE BULK SEQUENCING NOT SINGLE CELL ANALYSES. THE PATIENTS AGAIN WERE TREATED WITH IPILIMUMAB PLUS VACCINE OR WITH THE PRIME BOOST ALONE OR PRIME BOOST PLUS (INAUDIBLE). THIS IS DONE BY ALEX HOPKINS GRADUATE STUDENT IN MY LAB, WE LOOK AT NUMBER OF PARAMETERS WE PUBLISHEDDED THIS THIS PAST FALL. THIS WAS WITH THE ORIGINAL TECHNOLOGICAL ABILITIES, WE DIDN'T REALLY KNOW WHAT THE PARAMETERS WERE THAT WERE BEST THAT WERE GOING TO CORRELATE. WE LOOKED AT A NUMBER OF THEM AND AT LEAST FOR ANTI-CTLA 4 BLOW KID WE FOUND THE NUMBER OF EXPANDED -- BLOCKADE WE FOUND THE NUMBER OF CLONES EARLY ON VACCINATING WAS A PREDICTOR OF WHO WAS GOING TO GO TON RESPOND. THIS EXPANDED NUMBERED OF CLONES DID NOT PREDICT THE PD 1 GROUPS, SO NON-RESPONDERS CTLA 4 RESPONDER NON-RESPONDER PD 1 RESPONDER. SO THEN WE LOOK AT SURVIVAL WE SAW THERE WAS INCREASE IN DIVERSITY OF T-CELLS, THAT CORRELATED WITH THAT SURVIVAL BENEFIT AND THIS IS OVER A YEAR WITH MORE THAN TWO CHEMOTHERAPIES. IN THIS PATIENT POPULATION THAT WAS REALLY UNEXPECTED. WHEREAS IN THE ANTI-PD 1 GROUP IT WAS ACTUALLY AN INCREASE IN THE CLONAL POPULATION AFTER THEY GOT ANTIGEN EXPERIENCE SO YOU CAN SEE HERE THIS IS GOING OUT PAST ALMOST TWO YEARS AT THIS POINT. SO IF YOU EXPANDED CLONAL POPULATION, NOT YOUR EXPANDED THE NUMBER OF CLONES BUT THE CLONES THAT WOULD NOW COMMITTED TO ANTIGEN RESPONSES YOU DID BETTER WITH ANTI-PD 1. WITH THAT THERE WERE TWO ISSUES WE WERE THINKING THAT WELL MAYBE WE HAVE TO EXPAND FIRST NUMBER OF T-CELLS AVAILABLE FOR VACCINE ACTIVATION, AND THAT WOULD BE WITH AN EARLY TREATMENT OF ANTI-CTLA 4 TO GET THAT EXPANSION. THEN COME IN WITH A VACCINE AND ANTI-PD ONE AND WE PROBABLY NEED TO GIVE ANTI-CTLA 4 LONG TERM, HOPE ANY NOT ONLY SEEING MORE RESPONSES BUT REALLY LOOKING FOR A FASTER RESPONSE RATE BECAUSE THE FASTER THE RESPONSE RATE THE MORE PATIENTS THAT MAY BENEFIT FROM THE IMMUNOTHERAPY. SO THAT'S WHAT'S ONGOING, METASTATIC CHEMOTHERAPY, RANDOMIZED ONE TO ONE, WE'RE GIVING IPILIMUMAB LOW DOSE ONE MILLION GRAM TWO DOSES EVERY SIX WEEKS FOR TWO DISS AND THEN FLOP WITH EVERY THREE WEEKS SO WE ARE GIVING THIS WITH OUR PRIME BOOST OR WITH JUST WISTERIA BECAUSE WE HAD DATA TO SUGGEST THAT WISTERIA MAYBE GOOD ENOUGH FROM A PRIOR VACCINE STUDY THAT'S ALREADY BEEN PUBLISHED. AGAIN I DON'T HAVE THE DATA, EARLY, HYPOTHESIS TESTING IN PATIENTS. WHAT WE ARE FINDING IS THAT AGAIN THIS IS YOUNG LEE AND MYSELF DOING THIS, WE ARE FINDING A QUICK RESPONSE. SO WE HAD FOUR RESPONSES OUT OF 15 ALREADY SO YOU CAN SEE THE CTN 99'S BIOMARKER GOING DOWN IMMEDIATELY, WE HAVE NEVER SEEN THIS BEFORE WITH THE IMMUNOTHERAPY. YOU CAN SEE THE TUMOR MASS IN THE LIVER, ONLY SIX WEEKS, THIS IS AFTER TWO DOSES NIVO ONE DOSE IPILIMUMAB. WE ARE SEEING FAST RESPONSE IT IS PATIENTS STARTING TO RESPOND IN THIS TRIAL. SO I DON'T THINK WE'RE -- THIS IS NOT THE END ALL BUT I THINK IF THERE'S ANY POINT I WANT TO TRY TO MAKE IS THAT WE DO NEED TO LEARN FROM THE SCIENCE. WE HAVE TO DO THIS IN THE PATIENTS, THEY'RE WILLING TO GIVE BIOPSIES. WE DON'T WAIT TO THE END WHEN THEY FAIL, THEY WON'T GIVE US BIOPSIES WHEN THEY FAIL, WE ARE DOING IT AT A TIME POINT WE'RE GOING TO SEE SOMETHING AND IN THIS CASE WE'RE DOING IT TIME WE EXPECT TO SEE PROGRESSION BUT IN FACT WE ARE SEEING REGRESSION. SO JUST GOING TO SUMMARIZE NON-IMMUNOGENIC CANCER LACK ADEQUATE NUMBER OF EFFECTOR T-CELLS. THEY ALSO DON'T HAVE THE QUALITY THAT WE EXPECT. SO WE NEED A TWO STEP APPROACH AT MINIMUM, ONE WOULD BE TO ACTIVATE A GOOD T-CELL, AND THE OTHER WOULD BE TO REPROGRAM THE TUMOR MICROENVIRONMENT. I THINK THESE NEW TECHNOLOGIES ARE REALLY LETTING US INTERROGATE THE TUMOR MICROENVIRONMENT, REALLY SMALL, TISSUE BIOPSIES, SO THAT'S REALLY MADE A BIG DIFFERENCE IN MY FIELD. IMMUNE CHECK POINT AGENT COMBINATIONS ARE ONGOING. WE'LL SEE SOME THAT ARE GOING TO BE FDA APPROVED HOPEFULLY WE'LL HEAR MORE FROM THE PANELIST. BUT I THINK THAT WE REALLY NEED TO STOP COMBINING THESE AGENTS AND SAYING IF ONE WORKS MAYBE TWO WILL BE BETTER. AND WE NEED TO BETTER UNDERSTAND WHICH CANCERS WILL BENEFIT FROM WHICH COMBINATIONS. AS ARLENE SHOWED IT MAYBE SEQUENCING AS WELL AND OUR DATA SUPPORTS THAT. BIOMARKERS ARE NEEDED TO PROVIDE GUIDANCE NOT ONLY IN DEVELOPING THE SCIENTIFICALLY DRIVEN COMBINATIONS BUT I'M FIGURING OUT WHO IS GOING TO RESPOND AND WHAT TOXICITIES WE HAVE TO BE THINKING ABOUT. I'LL STOP THERE AND THESE ARE MY SCIENTIFIC PARTNERS AT HOPKINS AND THE FUNDING MECHANISMS. THANK YOU. [APPLAUSE] SO WE'LL MOVE ON AND TAKE QUESTIONS AFTER. THE FIST PERSON IS DR. JONATHAN SCHOENFELD WHO WILL TALK ABOUT TOXICITIES OF RADIATION AND THERAPY COMBINATIONS. >> THANKS VERY MUCH, LADIES AND THANKS LIZ AND THE OTHER ORGANIZERS FOR INVITING ME, IT'S REALLY A PRIVILEGE TON HERE. -- TO BE HERE TO SPEAK ABOUT TOXICITIES OF RAYIATION IMMUNOTHERAPY, COMBINATIONS. HERE ARE MY DISCLOSURES. SO FOR ANYBODY THAT'S NOT AWARE RADIATION IMMUNOTHERAPY COMBINATIONS ARE OF INTEREST. THAT'S BOTH BECAUSE OF PROMISING PRE-CLINICAL DATA SUMMARIZED ON THE LEFT, THAT SUGGESTS THAT RADIATION AND SPECIFICALLY TARGETED RADIATION CAN CAUSE IMMUNOGENIC CELL DEATH AND GIVE RISE TO TUMOR SPECIFIC ANTIGEN RESPONSES. THERE'S ALSO A GROWING AMOUNT OF CLINICAL DATA. PERHAPS THE MOST PROMISING CLINICAL DATA IS CAME RECENTLY WITH THE PUBLICATION OF THE PACIFIC TRIAL. WITH ANYBODY NOT AWARE THE PACIFIC TRIAL TESTED THE PDL 1 INHIBITOR FOLLOWING COMBINED CHEMOTHERAPY AND RADIATION IN PATIENTS WITH STAGE 3 NON-SMALL CELL LUNG CANCER AS YOU CAN SEE FROM THE PROGRESSION FREE SURVIVAL CURVE ON THE RIGHT THERE WAS A HUGE BENEFIT IN FAVOR OF -- AND UNSELECTED PATIENT POPULATION FOLLOWING INITIAL CHEMORADIATION TREATMENT. SO I DO THINK EVALUATING GAINED RADIATION IMMUNOTHERAPY TOXICITY IS AN IMPORTANT QUESTION. IF YOU LOOK AT THE NUMBER OF COMBINATION TRIALS, THIS WAS A PUBLICATION A COUPLE OF YEARS AGO, IN 2017, THAT LOOKED AT ALL THE DIFFERENT AGENTS THAT PD 1 AND PDL 1 AGENT WERE BEING COMBINED WITH, YOU CAN SEE THAT RADIATION MAKES UP ONE OF THE MAJOR COMBINATIONS AS DOES CHEMORADIATION THERAPY I CAN TELL YOU NUMBERS OF COMBINATION TRIALS INVOLVING RADIATION IN CHEMORADIATION HAS CONTINUED TO INCREASE OVER THE LAST COUPLE OF YEARS. IRRESPECTIVE OF CLINICAL TRIALS, MORE THAN HALF OF ALL ONCOLOGY PATIENTS RECEIVE RADIATION AT SOME POINT DURING THEIR CARE. IT'S A KEY COMPONENT OF ORGAN PRESERVATION THERAPY OR ADJUVANT THERAPY IN PATIENTSES WITH LOCALIZED OR REGIONALLY ADVANCE DISEASE, ESPECIALLY AS IMMUNOTHERAPY MOVES TO EARLIER STAGES OF CANCER TREATMENT. IT'S AN IMPORTANT COMBINATION TO EXAMINE. ALSO RADIATION IS COMMON IN THE PALLIATIVE TREATMENT OF CANCER PATIENTS INCLUDING PATIENTS WITH BONE, BRAIN AND LUNG METASTASIS AMONG OTHERS. WHAT ARE THE SPECIFIC CONCERNS WITH COMBINATION OF RADIATION THERAPY AND IMMUNE THERAPY, FIRST TO THE EXTENT THAT RADIATION CAN STIMULATE IMMUNITY THERE'S A POTENTIAL ENHANCEMENT OF AUTOIMMUNE RISK. ADDITIONALLY THERE'S BEEN CONCERN ABOUT IMPACTS ON SOME OF THE MORE COMMON AND SEVERE OVERLAPPING TOXICITIES THAT CAN BE SEEN IN RADIATION AND IMMUNOTHERAPY AND SPECIFICALLY IMMUNE CHECK POINT BLOCKADE. FOR EXAMPLE, RADIATION CAN GIVE RISE TO DERMATITIS, YOU CAN SEE EXAMPLE OF HEAD AND NECK DERMATITIS FOLLOWING HEAD AND NECK RAID YES THERAPY THAT CAN INCLUDE RADIATION. IT CAN CAUSE PNEUMONITIS. YOU CAN SEE LINEAR CONSOLIDATION WITHIN A LUNG INDICATIVE OF RADIATION PNEUMONITIS AND AS WE HAVE HEARD IT'S VERY MUCH CONCERN WITH IMMUNE CHECK POINT INHIBITORS AND SPECIFICALLY PD 1 AND PDL 1 INHIBITORS. YOU CAN SEE GI EFFECTS WITH RAILIATION AS WELL, YOU CAN SEE WITHIN THE COLON, BLEEDING, AS WELL AS LINEAR HYPODENSITY IN THE LIVER HERE WITHIN THE RADIATION TREATMENT FIELD THAT CAN BE INDICATIVE OF RADIATION HEPATITIS. SO OF COURSE ALL THESE CONCERNS WITH IMMUNE CHECK POINT THERAPY AS WELL AS WE HAVE HEARD SO THE OVERLAP OF THE TWO TOXICITIES IS AREA OF POTENTIAL CONCERN. I'LL POINT OUT FOR ANYBODY NOT FAMILIAR WITH RADIATION, IT IS NOT CREATED EQUAL. IT'S IMPORTANT IMPACT OF NUMBER OF RADIATION FACTORS THAT IMPACT TOXICITY. SO RADIATION DOSE, FRACTIONATION HOW RADIATION IS GIVEN, FOR EXAMPLE 50 GRAY DELIVERED IN FIVE FRACTIONS OF TEN GRAY, IS DIFFERENCE THAN 50 GRAY DELIVERED IN TEN FRACTIONS OF FIVE GRAY BIOLOGICALLY, AND THAT HAS RAMIFICATIONS FOR TOXICITY AS WELL, OF COURSE WHERE RADIATION IS TARGETING SO THE RADIATION FIELD LOCATION AND SIZE, THE WAY RADIATION IS GIVEN SO THE TREATMENT TECHNIQUE AS WELL AS EVEN BEFORE IMMUNOTHERAPY THE ADMINISTRATION OF CONCURRENT SYSTEMIC THERAPY IS VERY MUCH APPRECIATED TO IMPACT THE RISK OF RADIATION TOXICITY. I'LL ALSO POINT OUT CONCERN ABOUT ENHANCEMENT OF THE IMMUNE RISKS WITH ADDITION OF RADIATION TO IMMUNOTHERAPY WE HAVE TO THINK ENHANCEMENT OF LOCAL EFFECTS WITH IMMUNOTHERAPY AS WELL. WE KNOW THE IMMUNE SYSTEM VERY MUCH IMPACTS THE EFFECTS OFCAL RAID CONGRATULATION, PRE-CLINICAL DATA FROM THE UNIVERSITY OF CHICAGO DEMONSTRATING WILD TYPE E-16 MICE, THE TUMOR ITSELF WITHIN THE RADIATION FIELD IS MORE SENSITIVE IN THE WILD TYPE MICE COMPARED TO THE IMMUNODEFICIENT NUDE MICE. THIS LOCAL SENSITIVITY IS DEPENDENT ON CD8 T-CELLS IN TERMS OF CLINICAL REPORTS, THERE HAVE BEEN PREVIOUSLY WITH AN OLDER IMMUNOTHERAPY OBVIOUSLY INTERFERON TREATMENT REPORTS OF ENHANCED LOCAL TOXICITIES, THOUGH SOME CONFLICTING DATA ABOUT THAT, AND THAT INCLUDES INCREASE MUCOUSSITIS, RADIATION NECROSAYINGS GRADE 3, 4, DERMATITIS NEUROPATHY AND STRUCTURE. FOR THE REST OF THE TIME I HAVE THIS AROUND WHAT I WANT TO DO WHAT ARE EXISTING EMERGING CLINICAL DATA IN REGARD TO COMBINATION OF IMMUNE CHECK POINT BLOCKADE RADIATION AND HOW TO MOVE FORWARD IN WHAT ARE SOME OF THE CHALLENGES ASSOCIATED WITH THIS. FIRST IN TERMS OF THE DATA THAT EXISTS TODAY, THIS IS A QUESTION WE HAVE BEEN INTERESTED IN IN A FELLOW BY NAME OF DR. ANDREW BENEFITING WHO LOOKED ANOTHER -- BE IN,NING, HE -- BENNING, OVER 130 CONSECUTIVE PATIENTS WITH MELANOMA, RENAL CELL AND LUNG CANCER WHO RECEIVE STANDARD OF CARE PALLIATIVE RADIATION CTLA 4 PD 1 BLOCKADE. WE ARE INTERESTED IN OVERLAP BETWEEN RADIATION TREATMENT FIELD AND POTENTIAL TOXICITIES SO WE HAD A NUMBER OF PATIENTS THE RADIATION FIELD OVERLAP ORGANS WE WERE PARTICULARLY INTERESTED IN, SUCH AS LUNG BATTLES AND BRAIN. WHEN WE LOOK AT TOXICITIES IN PATIENTS THEY WERE SIMILAR TO PATIENTS HISTORICALLY TREATED WITH IMMUNE CHECK POINT BLOCKADE ALONE, WE SAW FEW SEVERE GRADE 3 OR HIGHER RELATED ADVERSE EVEN AND NO RELATION BETWEEN THESE AND SITE DOSE OR TIMING OF RADIATION. LOOK IN THE BAR GRAPH YOU CAN SEE TOXICITY IN PATIENTS THAT HAD ASSOCIATED SITE OF RATEIATION IN BLUE, NOT SURPRISINGLY WE SAW INCREASE IN ANY GRADE PNEUMONITIS IN PATIENTS THAT RECEIVE LUNG DIRECTED RADIATION. BUT RELATIVELY MILD CASES IN MOST PATIENTS. WE DIDN'T SEE ANY INCREASE IN COLITIS OR TRANSEMANITIS IN PATIENTS AD RADIATION FIELDS THAT OVERLAP THE ABDOMEN. PERHAPS THE MOST REASSURING DATA IN TERMS OF COMBINATION OF RADIATION IMMUNOTHERAPY, WE CAN LOOK TO THE RECENT PUBLICATION TO THE SPECIFIC TRIAL WHICH TO REMIND EVERYBODY WAS ADDITION OF THE PDL INHIBITOR FOLLOWING CHEMORADIATION FOR STAGE 3 NON-SMALL CELL LUNG CANCER, THINK OF A PATIENT POPULATION THAT MIGHT BE PARTICULARLY LIKELY TO GET PNEUMONITIS, MIGHT BE THESE PATIENTS RECEIVE FULL DOSE RADIATION TO THE LUNG BEFORE STARTING A PDL 1 INHIBITOR. REASSURINGLY WHEN WE LOOK AT RATES OF PNEUMONITIS, RADIATION PNEUMONITIS, THERE WAS ONLY SLIGHT INCREASES, SO IN TERMS OF SEVERE EVENTS GRADE 3, 4 PNEUMONITIS, INCREASED 2 # .4% WITH P PUBLICATION AN ANTI-GRADE TOXICITY WAS 25% WITH PLACEBO AND 45% WITH ADDITION OF (INDISCERNIBLE). WE ARE STARTING TO SEE A MOST CONSISTENT PATTERN OF RETROSPECTIVE AND MORE RECENTLY PROSPECTIVE STUDIES. IN GENERAL COMBINATION RADIATION AND IMMUNOTHERAPY SPECIFICALLY IMMUNE CHECK POINT BLOCKADE RESULTS IN LIMITED RATES OF TOXICITY. I WILL MENTION THERE'S A NUMBER OF DIFFERENT TYPES OF RADIATION THAT HAVE NOW BEEN TESTED IN COMBINATION WITH IMMUNE CHECK POINT BLOCKADE, THAT INCLUDES HYPOFRACTIONNATED RADIATION, WHICH IN PRE-CLINICAL MODELS HAS BEEN DEMONSTRATED PARTICULARLY IMMUNOGENIC, IT INCLUDES HIGHER DOSE OR FOCAL RADIATION, SO STEREO TACTIC BODY RADIOTHERAPY OR SBRT TREATMENT AND MORE RECENTLY WITH PUBLICATION OF SPECIFIC TRIAL INCLUDES FRACTIONATED CHEMORADIATION, WHICH IS I THINK AS A PARTICULARLY IMPORTANT TYPE OF RADIATION OR TREATMENT TO EVALUATING COMBINATION WITH IMMUNE CHECK POINT BLOCKADE BECAUSE AGAIN, THIS IS COMMONLY ADMINISTERED FOR PATIENTSES WITH LOCALLY ADVANCED KAREN. CANCERS. WHILE WE DON'T HAVE A NUMBER OF OTHER PUBLICATIONS THAT LOOK AT COMBINATION OF CONVENTIONALLY FRACTIONATED CHEMORADIATION OR RADIATION WITH IMMUNE CHECK POINT BLOCKADE THERE ARE MANY ONGOING STUDIES COMBINING FRACTIONATED RADIATION AND IMMUNE CHECK POINT BLOW KID ACROSS A NUMBER OF DIFFERENT DISEASES IN PATIENTS WITH LOCALIZED OR REGIONALLY ADVANCE DISEASE. SORRY THE TEXT IS SMALL BUT THESE ARE SOME OF THE STUDIES PREDOMINANTLY IN LUNG CANCER HEAD AND NECK CANCER, THOUGH WE DON'T HAVE THE PUB ACCOMPLISHED SAFETY DATA YET, A NUMBER OF THESE STUDIES ARE STARTING TO BE PRESENTED, AND AT LEAST THE DATA THAT HAS BEEN PRESENTED SO FAR, HAS LOOKED REASSURING IN TERMS OF RATES OF DOSE LIMITING TOXICITIES, BEING FUELED IN FAR BETWEEN AND RATES OF SEVERE TOXICITIES SEEM TO BE CONSISTENT WITH EITHER RATES FROM RADIATION OR CHEMORADIATION ALONE OR IMMUNE CHECK POINT MONOTHER THERAPY. DESPITE THIS REASSURING DATA WE HAVE CONTINUED TO PAY ATTENTION TO POTENTIAL INCREASES IN TOXICITY. FOR EXAMPLE I MENTION WE WERE INTEREST IN RADIATION TREATMENT OF THE BRAIN PARTICULARLY FOCAL RADIATION OR STEREOTACTIC RADIATION TO BRAWN WE ARE INCREASINGLY USING SO IN A STUDY LED BY DR. ISER AND ALLISON MARTIN THERE WAS ANALYSIS OF 480 PATIENTS TREATED WITH SRS, 115 RECEIVED IMMUNE CHECK POINT BLOCKADE. AS YOU CAN SEE IN KAPLAN MEYER CURVE ON THE RIGHT THE CHECK POINT BLOCKADE WAS ASSOCIATED WITH SYMPTOMATIC RADIATION NECROSIS AFTER ADJUSTING FOR TUMOR HISTOLOGY, PARTICULARLY MELANOMA PATIENTS WHO RECEIVE IPILIMUMAB SO POTENTIAL ENHANCEMENT TO LOCAL EFFECTS AS I MENTIONED PREVIOUSLY. THERE HAVE ALSO BEEN INTERESTING CASE REPORTS OF RECALL REACTION. SO RECALL IS A PHENOMENON THAT WE HAVE OBSERVED WITH CERTAIN ANTIBIOTIC WITH CHEMOTHERAPY, AND SO PERHAPS IT'S -- IT CAN HAPPEN WITH IMMUNOTHERAPY AS WELL. SO WHAT I MEAN BY THIS IS THERE ARE TWO CASES PUBLISHED MANY THE ANNULS ON ONCOLOGY A COUPLE OF YEARS -- ONCOLOGY, A COUPLE OF YEARS AGO YOU CAN SEE RADIATION ISOCURVINGS ON THE LEFT LUNG ON THE TOP AND RIGHT LUNG ON THE BOTTOM. THESE PATIENTS WENT COUPLE OF YEARS BEFORE THEY DEVELOPED METASTATIC DISEASE, AT THE TIME THEY STARTED PD 1 INH I BIGS, THERE WAS NO EVIDENCE PNEUMONITIS SYMPTOMATICALLY OR RADIO GRAPHICALLY. HOWEVER THESE PATIENTS WENT ON TO DEVELOP BOTH CLINICAL AS WELL AS RADIOGRAPHIC PNEUMONITIS WHICH IN AND OF ITSELF IS NOT REMARKABLE GIVEN IT CAN HAPPEN WITH IMMUNE CHECK POINT MONOTHERAPY BUT WHAT WAS INTERESTING IS RADIOGRAPHICALLY THE PNEUMONITIS WAS LOCALIZED WITHIN THE PRIOR RADIATION TREATMENT FIELD PREDOMINANTLY WHICH OF COURSE IS NOT THE USUAL PATTERN FOR IMMUNE CHECK POINT RELATED PNEUMONIGH AT THIS WHICH IS MORE DIFFUSE AS I WILL TALK ABOUT LATER. I ALSO THINK WE NEED TO TALK TOXICITIES WE HAVEN'T THOUGHT SO MUCH IN REGARDS TO RADIATION THERAPY, THERE'S HOPE THAT RADIATION CAN STIMULATE ANTITUMOR IMMUNE RESPONSES BUT WE ALSO HAVE TO REMEMBER THAT RADIATION IS POTENTIALLY IMMUNE SUPPRESSIVE AS WELL. DR. PIKE LOOKED AT THE RISK OF RADIATION INDUCED LYMPHOPENIA WHO WENT ON TO RECEIVE CHECK POINT BLOCKADE AND NOT SURPRISINGLY THERE WAS AN ASSOCIATION WITH MORE PROTRACTED RADIATION REGIMENS WITH RADIATION REGIMENS DELIVERED TO LARGER FIELDS, OVER LONGER COURSE IN TIME AND THAT INCLUDED MORE BONE MARROW AND CIRCULATING BLOOD. THIS HAS A REAL WITH LYMPHOPHONEPENIA, THIS IS A POTENTIAL IMPACT IN ERA OF IMMUNE CHECK POINT BLOCKADE BECAUSE WE SAW WHEN PATIENTS WENT ON TO RECEIVE IMMUNE CHECK POINT BLOCKADE THE PATIENTS WHO HAD LOWER LYMPHOCYTE COUNTS DID WORSE IN TERMS OF SURVIVAL. HOW DO WE MOVE FORWARD AND WHAT ARE SOME OF THE CHALLENGES WE FACE THINKING ABOUT COMBINATION RADIATION IMMUNOTHERAPY TOXICITIES. IN TERMS OF CURRENT CLINICAL PRACTICE AN PERHAPS GOES WITHOUT SAYING BUT AT LEAST RIGHT NOW, THERE'S NO EVIDENCE TO WITHHOLD OR DELAY STANDARD OF CARE TREATMENT, EITHER RADIATION OR IMMUNE CHECK POINT BLOCKADE BECAUSE OF THE CONCERNS ABOUT TOXICITY. YOU OBVIOUSLY HAVE TO BALANCE THESE THEORETICAL OBSERVED TOXICITIES AGAINST KNOWN CLINICAL BENEFIT. I'LL JUST POINT OUT, I MENTION THERE MIGHT BE AN INCREASE RADIATION NECROSIS IN THE BRAIN BUT WE ALSO HAVE TO REMEMBER A HUGE BENEFIT THAT OUR PATIENTS ARE NOW GETTING WITH THE COMBINATION OF RADIATION AND IMMUNE CHECK POINT THERAPY, I THINK MANY PEOPLE ARE PROBABLY FAMILIAR WITH THE DISMAL OUTCOMES FOR PATIENTS WITH BRAIN METASTASIS, PARTICULARLY MELANOMA PATIENTS WITH BRAIN METASTASIS PRIOR TO ERA OF IMMUNE CHECK POINT BLOCKADE WITH SURVIVAL MEASURED IN MONTHS. NOW THERE'S BEEN MANY STUDIES THAT HAVE SHOWN IMPROVED SURVIVAL, WITH IN THE IMMUNE CHECK POINT BLOCKADE ERA IN MELANOMA PATIENTS WITH BRAIN METASTASIS. AS AN EXAMPLE IN OUR RECENT SERIES LOOKING AT PATIENTS TREATED WITH STEREOTACTIC RADIO SURGERY TO THE BRAIN AND IMMUNE CHECK POINT BLOCKADE WE HAD MEDIAN SURVIVAL OF OVER FOUR YEARS OR 52 MONTHS THIS THESE PATIENTS -- IN THESE PATIENTS. THERE'S NO EVIDENCE TO SUPPORT ARBITRARY TIME CUT OFF BETWEEN RADIATION IMMUNE CHECK POINT BLOCKADE AS WAY OF MITIGATING TOXICITY RISK. THAT WAS AT ONE POINT IN TIME SOMETHING THAT WAS RECOMMENDED AND REALLY BECAUSE THE TOXICITIES THAT CAN DEVELOP AFTER RADIATION AND IMMUNE CHECK POINT BLOCKADE ARE LONG LASTING AND BECAUSE POST RADIATION AND IMMUNE CHECK POINT BLOCKADE HAVE LONG TERM EFFECTS REALLY HARD TO IMAGINE HOLDING RADIATION OR DRUG FOR A FEW WEEKS WOULD HAVE ANY MAJOR IMPACT ON THE SUBSEQUENT RISK. SO IN TERMS OF OUTSTANDING QUESTIONS, AS BEEN MENTIONED BEFORE WE NEED TO DO A BETTER JOB IDENTIFYING THE PATIENTS THAT ARE AT RISK FOR COMBINED TOXICITIES, HOW DOES THE TYPE OF IMMUNE THERAPY IMPACT THE RISK. HOW DOES THE IMPACT OF THE RADIATION PARAMETERS AS AN EXAMPLE OF HOW THESE RADIATION IS VERY DIFFERENT YOU CAN SEE THIS IS LUNG SPRT SO SMALLER FIELD DELIVERED TO HIGHER DOSE AND YOU MIGHT IMAGINE THE TOXICITIES ARE DIFFERENT THAN SOMEONE WITH HODGKINS LYMPHOMA, RECEIVING FRACTIONATED RADIATION TO LARGER FIELD BUT BEING DELIVERED AT A LOWER DOSE. THEN WE ALSO DON'T KNOW IF THEY'RE RELEVANT RISK WITH OTHER NOVEL IMMUNOTHERAPIES THAT ARE COMBINED WITH RADIATION SO FOR EXAMPLE NEW IMMUNE CHECK POINT INHIBITORS IN COMBINATIONS, INTRATUMORAL IMMUNE THERAPIES AS WELL AS CAR T-CELLS AND OTHER IMMUNE THERAPIES. IN TERMS OF THE CHALLENGES THE TIME COURSE OF SIDE EFFECTS CAN BE DELAYED WITH IMMUNOTHERAPY AND RADIATION AND THAT REALLY SPEAKS TO THE IMPORTANCE OF MULTI-DISCIPLINARY EXTENDED FOLLOW-UP AFTER INITIATING COMBINED THERAPY TO IDENTIFY LONGER TERM EFFECTS. I ALSO THINK THAT MULTI-DISCIPLINARY FOLLOW-UP HELPS WITH ATTRIBUTION OF THESE SIDE EFFECTS BY COULD BE DIFFICULT AND THAT CAN BE OF CLINICAL RELEVANCE TO PATIENTS FOR EXAMPLE DECIDING WHETHER TO A PATIENT SHOULD CONTINUE IMMUNE CHECK POINT BLOCKADE WHO HAS LYM NIGH AT THIS THAT HAS RADIATION OR IMMUNE CHECK POINT RELATED. AS AN EXAMPLE HOW WE MIGHT GO ABOUT SOME OF THE QUESTIONS REGARDING ATTRIBUTION, I MENTIONED BEFORE THAT THE PATTERNS OF RADIATION INDUCED LUNG TOXICITY, TEND TO BE LOCALIZED WITHIN THE RADIATION TREATMENT FIELD. SO HERE IS AN EXAMPLE OF STEREO TACTIC RADIATION TREATMENT FIELD WITH LOCALIZED RADIATION AND YOU CAN SEE THE RADIOGRAPHIC CHANGES LARGELY SUBSEQUENTLY LOCALIZED AT LEAST INITIALLY SO WITHIN THE RADIATION TREATMENT FIELD, THAT IN MOST CASES CONFERS FROM IMMUNE CHECK POINT PNEUMONITIS WHICH CAN HAVE A VARIETY OF MANIFESTATIONS BUT TENDS TO BE DIFFUSE THROUGHOUT THE LUNGS. HOWEVER CAN BE CHALLENGING ESPECIALLY WHEN DEALING WITH POTENTIAL OVERLAP WITH TOXICITIES. THIS IS CASE OF A PATIENT WE TREATED, IT WAS A GENTLEMAN WHO BECAUSE OF HIGH RISK FEATURES RECEIVED RIGHT AXILLARY RADIOTHERAPY, AFTER RESECTION OF MULTIPLE INVOLVES LYMPH NODES IN THE RIGHT AXILLA, YOU CAN SEE RADIATION TREATMENT PLAN DOES OVERLAP PERIPHERY OF THE RIGHT LUNG. THIS PATIENT WENT ON TO RECEIVE PD 1 INHIBITION WITH -- THERAPY AND DEVELOPED CLINICAL SYMPTOMS AND RADIOGRAPHIC FINDINGS CONSISTENT WITH PNEUMONITIS. YOU CAN SEE INITIALLY THE PNEUMONITIS WAS LOCALIZED WITHIN A LOT OF THIS OVERLAP OF THE RADIATION TREATMENT FIELD IN THE PERIPHERY OF THE RIGHT LUNG. HOWEVER, OVER TIME THE CHANGE EVOLVED AND THERE WAS CONSOLIDATION AND OPACITIES THAT OCCURRED OUTSID THE RADIATION TREATMENT FIELD BUT YET CONFINED TO THE IPSA HALL LATERAL LUNG THAT MIGHT HAVE BEEN INFLUENCED BY RADIATION AND IMMUNE CHECK POINT BLOCKADE THERAPY. I THINK THE CHALLENGES CAN BE ILLUSTRATED BY THE UPDATED SPECIFIC DATA PUBLISHED IN NEW ENGLAND JOURNAL OF MEDICINE HERE. THERE WAS A MORE COMPREHENSIVE ATTEMPT TO ATTRIBUTE PNEUMONITIS AND RADIATION PNEUMONITIS THAT WAS EXPERIENCED OR OBSERVED DURING THE STUDY, I THINK THE DATA ARE OFFERALL FAVORABLE FROM THE STUDY IN TERMS OF TOXICITY RISKS BUT SOME OF THE CHALLENGE YOU CAN SEE HERE THAT ACTUALLY WHEN YOU LOOK AT PNEUMONITIS THAT WAS ATTRIBUTED TO THE RADIATION THE INCREASE IN GRADE 3, 4 WAS RELATIVELY MILD, 1.7 TO 1.9 ANTI-GRADE 7.7 TO 12.6%. WHEN YOU LOOK AT THE PNEUMONIGH AT THIS ATTRIBUTED TO THE RADIATION, THE GRADE 3, 4 EVANS WERE 0.4 AND INCREASE TO 1.5, AND THEN 15.8 INCREASE TO 20.2% IN TERMS OF ANTI-GRADE PNEUMONIGH AT THIS. IT IS GOING TO TAKE CAREFUL LOOK AT THE PROSPECTIVE DATA AS IT'S DEVELOPED IN TERMS OF PATIENT WHOSE ARE TREATED WITH IMMUNE CHECK POINT BLOCKADE AND RADIATION LOOK AT THE RADIATION TREATMENT FIELD TO BETTER QUANTIFY THE RISK OF COMBINING THESE TWO THERAPIES AS WELL AS PROBABLY BETTER BIOMARKERS TO TRY TO TEASE OUT WHAT IS RADIATION PNEUMONITIS RISKER WHAT IS RADIATION PNEUMONITIS, VERSUS WHAT IS PNEUMONITIS FROM IMMUNE CAN HE CAN POINT BLOCKADE VERSUS EFFECT OF BOTH TREATMENTS. TO SUMMARIZE, IMMUNOTHERAPY TOXICITIES OVERLAP WITH POTENTIAL RADIATION EFFECTS THE INITIAL DATA SUGGESTS STANDARD OF CARE OF EXPERIMENTAL APPROACHES THAT COMBINE RADIATION IMMUNE CHECK POINT BLOCKADE ARE GENERALLY SAFE THOUGH WE NEED TO COLLECT DATA AND DATA WITH LONG TEAR FOLLOW-UP. I THINK THE CHALLENGES MOVING FORWARD INCLUDE THE ACTIVITY ATTRIBUTING THESE TOXICITIES THE VARIABILITY AND TIME COURSE WITH WHICH SIDE EFFECTS DEVELOP BOTH AFTER RADIATION IMMUNOTHERAPY AS WELL AS TOXICITIES THAT MIGHT OCCUR WITH THE DEVELOPMENT OF NEW DRUGS AN THERAPIES. AND I DO THINK IT'S IMPORTANT TO HAVE INPUT FROM THE MULTI-DISCIPLINARY TEAM AS SEEN BEFORE AS THEY CONTINUE TO RECEIVE IMMUNOTHERAPY AND RADIATION IN IN THE THE DEFINITIVE SETTING. WITH THAT, THANK YOU VERY MUCH. GUESS WE'LL TAKE QUESTIONS AT THE END. [APPLAUSE] >> THANKS JOHN, OUR NEXT SPEAKER IS DR. NICOLE DREZNER FROM THE FDA WHO WILL TACK TO US ABOUT COMBINATIONS. >> GOOD AFTERNOON, MY NAME IS NICOLE DREZNER. I AM GOING TO BE TALKING ABOUT REGULATORY PERSPECTIVES ON COMBINATION IMMUNOONCOLOGY TRIALS AND APPROVALS. I HAVE NO FINANCIAL RELATIONSHIPS TO DISCLOSE AND I WON'T BE DISCUSSING OFF LABEL USE AND/OR INVESTIGATIONAL USE IN THIS PRESENTATION. SO I FIRST WANT TO MENTION A GUIDANCE PUBLISH BY THE FDA ON THE CO-DEVELOPMENT OF TWO OR MORE DRUGS, RELEVANT TO APPROVALS DISCUSSING A LITTLE LATER THE PRESENTATION WITH STUDY DESIGN. CO-DEVELOPMENT OF TWO OR NEW DRUGS NOT PREVIOUSLY DEVELOPED FOR ANY INDICATION TO BE USED IN COMBINATION TO TREAT DISEASE OR CONDITION. THE RECOMMENDATIONS IN THE GUIDANCE ARE SPECIFICALLY RELEVANT TO DEMONSTRATING THE CONTRIBUTION OF COMPONENTS DISTRIBUTION EACH INDIVIDUAL NEW DRUG TO EFFECTIVE COMBINATION AND APPLIES ONLY TO THE THINKING IN CDER OR CENTER FOR DRUG I VALUATION AND RESEARCH WHERE -- EVALUATION AN RESEARCH WHERE I WORK. CO-DEVELOPMENT PROVIDES LESS INFORMATION ABOUT THE CLINICAL SAFETY AND EFFECTIVENESS AND DOSE RESPONSE OF THE INDIVIDUAL NEW DRUGS INTENDED TO BE USED IN COMBINATION, THEN WOULD BE OBTAINED IF INDIVIDUAL DRUGS WERE BEING EVALUATED ALONE. FOR EXAMPLE IN CO-DEVELOPMENT SCENARIOS WHICH RAPID DEVELOPMENT OF RESISTANCE TO MONOTHERAPIES IS A MAJOR CONCERN, IT WOULDN'T BE POSSIBLE TO OBTAIN CLINICAL DATA FOR THOSE DRUGS BEYOND MUCH BEYOND THE PHASE 1 TESTING. BUT BECAUSE CO-DEVELOPMENT GENERALLY PROVIDES LESS INFORMATION ABOUT THE INDIVIDUAL DRUGS, IT MAY PRESENT GREATER RISK TO PATIENTS, COMPARED TO CLINICAL DEVELOPMENT OF INDIVIDUAL GROUP. AND GIVEN THIS CONCERN, FDA BELIEVE CO-DEVELOPMENT SHOULD BE RESERVED FOR THE SITUATIONS THAT ARE LISTED ON THE SLIDE. FIRST COMBINATION IS INTENDED TO TREAT SERIOUS DISEASE OR CONDITION, SECOND THERE'S A STRONG BIOLOGIC RATIONALE FOR USE OF COMBINATION. THIRD THAT NON-CLINICAL EVIDENCE SUGGESTING COMBINATION MAY PROVIDE ADVANTAGE OVER AVAILABLE THERAPY AN SUPERIOR TO THE INDIVIDUAL AGENTS ALONE. AND FINALLY THERE'S A COMPELLING REASON WHY THE DRUGS CANNOT BE DEVELOPED INDEPENDENTLY. AN EXAMPLE, THIS WOULD BE MONOTHERAPY FOR DISEASE OF INTEREST LEADS TO RESISTANCE ORAL ONE OR BOTH AGENTS EXPECT TO HAVE LIMITED ACTIVITY COMPARED TO THE COMBINATION WHEN USED AS MONOTHERAPY. SO THE APPROPRIATE STUDY DESIGN FOR COMBINATION STUDIES IS GENERALLY DETERMINED ON A CASE-BY-CASE BASIS LATER IN DEVELOPMENT AND COMES AFTER WHAT'SIOUSLY -- PREVIOUSLY DONE AS DRUGS FEASIBILITY OF MONOTHERAPY AND STANDARD OF CARE ALONE TREATMENT ARMS AND OTHER FACTORS SO THERE'S THREE CLINICAL SCENARIOS LISTED HERE FOR EXAMPLES OF APPROPRIATE STUDY DESIGNS. IN THE FIRST SCENARIO, THIS WOULD BE RELEVANT FINDINGS FROM IN VIVO OR IN VITRO MODELS AND/OR PHASE 2 TRIALS ADEQUATELY DEMONSTRATE CONTRIBUTION OF EACH NEW DRUG TO THE COMBINATION. RANDOMIZED TRIALS COMPARING COMBINATION OF STANDARD OF CARE PLACEBO ARE GENERALLY SUFFICIENT TO ESTABLISH EFFECTIVENESS OF COMBINATION. IN THE SECOND SCENARIO IF THE COMBINATION OF INDIVIDUAL DRUGS IS NOT CLEAR AND IS ETHICALLY FEASIBLE TO USE ONE OR MORE OF THE INDIVIDUAL DRUGS AS MONOTHERAPY IN STUDY ARM THE CONTRIBUTION OF DRUGS ARE DEMONSTRATED USING A FACTORIAL STUDY DESIGN, FOR EXAMPLE, A B COMBINATION A B VERSUS DRUG A, VERSUS DRUG B. THIS IS ADEQUATE TO DEMONSTRATE CONTRIBUTION OF EACH NEW DRUG BUT NOW BE ABLE TO DIRECTLY MEASURE OVERALL TREATMENT EFFECT OF THE COMBINATION. HOWEVER IF EFFECT OF STANDARD OF CARE IS WELL ESTABLISHED AND KNOWN TO BE SMALL IT MAYBE POSSIBLE TO ESTIMATE TREATMENT EFFECT OF CONTRIBUTION WITHOUT CONCURRENT STANDARD OF CARE OR PLACEBO ARM. FINALLY THIRD SE GNAR I DON'T HAVE PHASE 2 E DATA DO NOT PROVIDE SUFFICIENT EVIDENCE OF COMBINATION OF EACH DRUG COMBINATION BUT DO PROVIDE STRONG EVIDENCE COMBINATION IS SPHERE YOUER TO ONE OF THE DRUGS ALONE, A TWO ARMED DESIGN COMPARING THE COMBINATION TO MORE ACTIVE DRUG ALONE FOR EXAMPLE A B VERSUS DRUG A ONLY, MAYBE NEEDED TO DEMONSTRATE THE LESS ACTIVE DRUG B CONTRIBUTES TO THE ACTIVITY OF THE COMBINATION. I LIST HERE OPT SLIDE THREE MAJOR CATEGORYPS OF COMBINATION THERAPIES AN NEWSPAPER ONCOLOGY, I WILL BE TALKING ABOUT COMBINATION STUDIES TWO AGENT BEING EVALUATED AND THOSE WHICH THERE'S ONCOLOGY BEING EVALUATED IN COMBINATION WITH CHEMOTHERAPY. SO WE NOTED BROADLY SPEAKING IMMUNE CHECK POINT BLOCKADE REMOVE INHIBITOR SIGNALS OF T-CELL ACTIVATION AND ADDITION OF SECOND IMMUNOONCOLOGY AGENT MAY ADDRESS ISSUE OF COMPANYTORY UP REGULATION OF IMMUNE CHECK POINT MOLECULES. THERE'S INCREASE TOXICITY IN COMBINATION STUDIES COMPARED TO SINGLE AGENT THERAPY AND WE KNOW THAT FDA APPROVAL IS THUS FAR HAVE BEEN IN COMBINATION PD 1 AND ANTI-CTLA AGENT STUDIES THOSE THERE'S MU STUDIES ONGOING USING ANTI-TIM 3 AND ANTI-LAG THREE COMBINATIONS AMONG MANY OTHERSES. SINGLE AGENT IMMUNOONCOLOGY AGENTS ARE APPROVE IN A BROAD RANGE OF TUMOR TYPES AND COMBINATIONS ARE APPROVED IN LESS SLIGHTLY LESS BROAD RANGE. THEN MOVING ON TO IMMUNOONCOLOGY AGENTS IN COMBINATION WITH IMMUNOTHERAPY HISTORICALLY WE THINK OF CHEMOTHERAPY IN TERMS OF ITS CONVENTIONALLY CYTOTOXIC EFFECT. BUT WE KNOW CHEMOTHERAPY AGENTS MAY ALSO HAVE IMMUNOREGULATORY PROPERTIES, THAT MAY CONTRIBUTE TO THEIR ANTITUMOR EFFECTS. THESE INCLUDE INCREASING TUMOR ANTI-GENICITY, ANGIOGENIC CELL DEATH, DISRUPTING IMMUNE PATHWAYS AND DISRUPTING IMMUNE T RECEPTOR RESPONSE. THEREFORE WITH CHECK POINT INHIBITORS MAY ENHANCE CYTOTOXIC T-CELL ACTIVITY. HOWEVER, CHALLENGES EXIST IN CHOICE OF CHEMOTHERAPY REGIMENS AND AGENTS AND SEQUENCING SCHEDULE DOING OF TWO TYPES OF THERAPIES. IN MOST CLINICAL TRIALS CLINICAL TRIALS NOW, CHEMOTHERAPY AND MINE ONCOLOGY THERAPY ARE CONCURRENT. BUT THERE'S PRE-CLINICAL WORK IN TOW MORE MODELS THAT SHOW BENEFIT IN GIVING THERAPIES SEQUENTIALLY RATHER THAN CURRENTLY. THE CURRENT APPROVALS IN CHEMOTHERAPY AND GIVEN CONCURRENTLY ALL IN LUNG CANCER. HOWEVER, THERE ARE COMPLETED OR ONGOING STUDIES OF DIFFERENT COMBINATION REGIMEN AND OTHER TUMOR TYPES INCLUDING MEL MELANOMA AND ESOPHAGEAL CANCER. SO THIS SLIDE LISTS THE APPROVALS IN IN IMMUNOONCOLOGY COMBINATIONS USING THE IPILIMUMAB COMBINATION. AND I JUST WANTED TO DRAW YOUR ATTENTION MAINLY TO THE TREATMENT ARMS BECAUSE THAT WILL BE RELEVANT WITH CONTRIBUTION OF COMPONENT TO OFALL EFFECT BUT THE FIRST APPROVAL OCCURRED IN 2015 IN PATIENTS WITH BRAF WILD TYPE UNRESECTABLE OR METASTATIC MELANOMA FROM THE STUDY CHECK MATE 069 IN WHICH PATIENTS WERE RANDOMIZED TO TO RECEIVE IPILIMUMAB VERSUS PLUS PALACE POE. THIS WAS ACCELERATED APPROVAL SO THE OUTCOME MEASURE WAS THE RESPONSE RATE OF OF PATIENTS IN (INDISCERNIBLE) AND IPILIMUMAB ARM, B RAF WILD TYPE GROUP WHICH DEMONSTRATED AN OR OF 60% VERSUS 11 IN THE IPILIMUMAB ONLY GROUP. LESS THAN A YEAR LATER THE COMBINATION WAS APPROVED FOR WITH APPROVAL WIDENED TO INCLUDE PATIENTS WITH BRAB WILD TYPE MUTATION POSITIVE ON RESECTABLE OR METASTATIC MELANOMA. THIS WAS A REGULAR APPROVAL BASED ON RESULTS OF CHECK MATE 067 IN WHICH PATIENTS WERE RANDOMIZED TO ONE OF THREE ARMS LISTED THERE. IN THIS CASE THE OUTCOME MEASURES WERE PFS AND OS WITH STATISTICALLY SIGNIFICANT BENEFIT IN THE EBOLAM ABOUTB AND IPILIMUMAB ARM. THE SECOND TWO OF THE LAST TWO APPROVALS OCCURRED IN 2018, FIRST IN PATIENTS WITH RENAL CELL CARCINOMA BASED ON RESULTS OF CHECK MATE 214 WHICH PATIENTS RECEIVED COMBINATION WERE RANDOMIZED TO COMBINATION OR STANDARD OF CARE SINITNIB AND OUTCOME MEASURE IN THIS TRIAL WAS OVERALL SURVIVAL AND IN JULY 2018 THERE WAS ACCELERATED APPROVAL IN PATIENTS WITH MSI HIGH OR MISMATCH REPAIR DEFICIENT METASTATIC COLORECTAL CANCER IN PATIENT WHOSE RECEIVED PRIOR TREATMENT BASED ON STUDY CHECK MATE 142. THIS WAS NOT A RANDOMIZE STUDY, IT FELT A MULTI-COHORT STUDY SO THE APPROVAL WAS BASED ON COHORT OF PATIENT WHOSE RECEIVED COMBINATION AND AGAIN, THE OUTCOME MEASURES IN ACCELERATED APPROVAL WAS O RR WITH OR 46% IN IPILIMUMAB GROUP. SO YOU WANT TO TOUCH ON EFFICACY ISSUES THE REVIEW TEAMS GRAPPLED WITH FOR EACH OF THESE OR SOME APPROVALS SO BRIEFLY MENTION THE SMALL PATIENT SAMPLE SIZE IN CHECK MATE 069 WHICH WAS THE FIRST MELANOMA APPROVAL, BECAUSE OF THE SMALL SAMPLE SIZE, THERE WAS SOME UNCERTAINTY REGARDING RISK OF THE ADDITION OF NEBOLAMAB TO THAT COMBINATION. IPILIMUMAB WAS ALREADY APPROVED SINGLE AGENT THERAPY MELANOMA IN 2011 TO GIVEN THE HETEROGENEITY OF IMMUNE MEDIATED ADVERSE EVENTS A FULLER PICTURE OF TOXICITY WAS NOT POSSIBLE WITH THAT SMALL NUMBER OF PATIENTS. FURTHER SHOW YOU THE RESULTS TOKER THE ENTIRETY INTENT TO TREAT POPULATION BUT THOUGH THOSE WERE SIMILAR TO THE BRAF WILD TYPE PATIENTS IN WHOM APPROVAL WAS BASED THE FDA TEAM WAS NOT ABLE TO EXTRAPOLATE THOSE RESULTS TO THE MUTATION POSITIVE PATIENTS AND SO THAT'S WHY THE APPROVAL WAS ONLY IN THE BRAF WILD TYPE PATIENTS UNTIL THE LARGER STUDY READ OUT IN THE FOLLOWING APPROVAL THE NEXT YEAR. THEN I WANTED TO TALK ABOUT THE ISSUES OF CONTRIBUTION OF COMPONENTS PRIMARILY WITH THE CHECK POINT 214 AND CHECK POINT 142 STUDIES SO CHECK POINT 2014 YOU REMEMBER WITH STUDY IN RENAL CELL CARCINOMA PATIENTS WITH RASH RANDOMIZED TO COMBINATION VERSUS STANDARD OF CARE, DID NOT INCLUDE MONOTHERAPY ARM AND THEREFORE ISOLATING THE C CONTRIBUTION OF EFFECTIVE -- THE IPILIMUMAB COMPONENTS OF THE COMBINED THERAPY WAS CHALLENGING FOR REVIEW TEAM, SO THE REVIEW TEAM ACTUALLY DID WAS COMPARE THE ORR THAT WAS OBSERVED IN CHECK MATE 214, IN COMBINATION TO MONOTHERAPY COHORTS OF -- HAS BEEN OBSERVED IN SMALLER TRIALS. SO THEY WERE LOOKING AT AN OR OF 11% IN MONOTHERAPY, COHORT OF PATIENTS AND FIVE PERCENT IN IPILIMUMAB MONOTHERAPY COHORT OF PATIENTS. ADDITIONALLY THEY LOOKED AT MONOTHERAPY VERSUS COMBINATION IMMUNOTHERAPY TRIALS ACROSS A LOT OF OTHER TUMOR TYPES, AND NOTED THAT IPILIMUMAB MONOTHERAPY ARMS DEMONSTRATED RELATIVELY MODEST ORRs THAT INCREASED BY ABOUT 10% ACROSS TUMOR TYPES WHEN TWO DRUGS WERE GIVEN IN COMBINATION. FINALLY, THE TEAM ALSO NOTED THAT THE ORR ASSOCIATED WITH NEBOLAM A,B OR IMALMOST HAS BEEN MONOTHERAPY TEND TO INCREASE DESPITE DIFFERENT LINES OF THERAPY SO THEY LOOK -- COMPARED TO A 20% ORR THAT HAD BEEN OBSERVED IN A RENAL CELL CARCINOMA COHORT OF PATIENTS IN THE SECOND LINE SETTING. WHICH WAS LESS THAN THE ROUGHLY 40% OR THAT WAS OBSERVED IN CHECK MATE 214 SO ALL THAT TOGETHER IN ADDITION TO THE ADDED TO THE EFFECT IN OS THAT WAS OBSERVED IN THIS TRIAL, THE FDA CONSIDERED FOR APPROVAL OF COMBINATION REGIMEN FOR THE STUDY POPULATION. CHECK MATE 142 COLORECTAL CARCINOMA TRIAL, THEY WERE SIMILAR ISSUES WITH THE CONTRIBUTION OF COMPONENTS. THIS WAS A NON-RANDOMIZE TRIAL AS YOU RECALL, IT WAS -- WITH MULTIPLE DIFFERENT COHORTS SO IT WAS NOT DESIGNED TO ISOLATE THE CONTRIBUTION OF EITHER -- IPILIMUMAB TO OBSERVED TREATMENT EFFECT OF COMBINATION. HOWEVER, THE FDA WAS ABLE TO COMPARE THE RESULTS THAT WERE OBSERVED IN -- MONOTHERAPY COHORT IN THAT SAME TRIAL IN WHICH 53 PATIENTS WHO RECEIVED PRIOR TREATMENT WITH CHEMOTHERAPY REGIMEN WERE FOUND TO HAVE LOWER ORR THAN THOSE IN THE COMBINATION ARM. IN ADDITION FDA WAS ALSO LOOKED BACK AT THE APPROVAL FOR -- AS MONOTHERAPY FOR THE METASTATIC COLORECTAL CANCER COMBINATION IN WHICH WAS ALSO LOWER. AGAIN THEY COMPARED THE DATA THAT HAD BEEN OBSERVE IN MULTIPLE DIFFERENT TUMOR TYPES ESPECIALLY MELANOMA WHICH DID NOT FIND THAT THE ADDITION OF IPILIMUMAB TO NEVOLAMAB ADDED MUCH TO THE COMBINATION. SO OVERALL, THE REVIEW TEAM CONCLUDED IT WAS HIGH LIE UNLIKELY THAT IPILIMUMAB ALONE COULD BE DRIVING THE OBSERVED TREATMENT EFFECT OF THE COMBINATION. AGAIN THIS WAS ACCELERATED APPROVAL BASED ON OVERALL RESPONSE RATE. SO THIS SLIDE SHOWS THE FOUR IMMUNOONCOLOGY AGENT AND CHEMOTHERAPY COMBINATION APPROVALS STARTING WITH MOST RECENT AT THE TOP AND SMALL CELL LUNG CANCER THAT JUST HAPPENED LAST MONTH. THE TWO IMMUNOONCOLOGY AGENTS THAT THESE APPROVALS HAVE OCCURRED IN HAVE BEEN (INDISCERNIBLE) ALL IN LUNG CANCER AS I MENTIONED, THESE WERE ALL REGULAR APPROVALS SO THEY WERE EACH BASED ON AN EFFECT NOTED IN OVERALL SURVIVAL AND PROGRESSION FREE SURVIVAL. SO THE ONLY EFFICACY ISSUE I WANT TO MENTION WITH THE IMMUNOONCOLOGY AGENT AND CHEMOTHERAPY COMBINATION STUDIES ANTIBODIES NOTED WITH USE OF -- SO IMMUNOGENICITY REFERS TO IMMUNE RESPONSE OF HOST TO BIOLOGIC PROTEIN PRODUCT IN THIS CASE A TISO, THE IMMUNOGENIC RESPONSE INCLUDES CELLULAR AND HUMORAL ARMS OF THE IMMUNE RESPONSE AND ANTIBODIES DIRECTED AGAINST THE PRODUCT CONSIST OF IGG IGA IGE ISOTYPES. IN PRACTICE THIS IS ASSESSED BY DETECTION OF ADA AND THESE ARE CHARACTERIZED BY BINDING ANTIBODY OS OR ISOTYPES CAPABLE OF BINDING TO PRODUCT. NEUTRALIZING ANTIBODIES ARE A SUBPOPULATION OF THE TOTAL BINDING ANTIBODIES THAT INHIBIT FUNCTIONAL ACTIVITY OF THE PRODUCT WHICH IS HYPOTHETICALLY POTENTIALLY SERIOUS PROBLEM. THIS WAS FIRST OBSERVED IN THE MONOTHERAPY STUDY, OAK, IN 565 PATIENTS WITH NON-SMALL CELL LUNG CANCER, WHOM 30% TESTED POSITIVE FOR WITH MEDIAN TIME TO ONSET OF THREE WEEKS. THIS RESULTED IN A REDUCE SYSTEMIC EXPOSURE TO -- AND EXPLORATORY ANALYSES OF THE EFFICACY, THE SUBSET OF PATIENTS WHO ARE ADA POSITIVE BY WEEK FOUR, 21% OF THE PATIENTS APPEARED TO HAVE LESS EFFICACY OR EFFECT ON OS COMPARED TO PATIENTS WHO TESTED NEGATIVE FOR ADA BY WEEK FOUR. SIMILAR ADA OBSERVED ONE OF THE STUDIES THAT LED TO APPROVAL, IN COMBINATION CHEMOTHERAPY, BUT EXPLORATORY ANALYSIS OF EFFICACY DID NOT DEMONSTRATE ANY LESS EFFICACY OF THAT GROUP. THROUGH THE NEXT SLIDES QUICKLY BECAUSE WE DISCUSSED THE SAFETY UNIQUE GROUP OF IMMUNORELATED ADVERSE EFFECTS THAT COME FROM THESE AGENTS. LISTED IMAE AND RATE OF SEVERE IMAE HERE, ANTICTLA 4 TOXICITIES SEEM DOSE DEPENDENT WHICH IS NOT THE CASE IN PDL 1 AGENTS. I PULLED THESE DATA FROM DIRECTLY FROM THE LABEL SO IN THIS CASE THE NEVOLAMAB LABEL WHICH SHOWS THE DIFFERENCES IN TOXICITIES BETWEEN THE RENAL CELL CARCINOMA AND THE COLORECTAL CANCER TRIALS VERSUS THE MELANOMA TRIALS SEPARATED LIKE THAT BECAUSE OF THE DIFFERENT DOSES OF IPILIMUMAB WITH HIGHER DOSE MELANOMA. YOU CAN SEE HIGHER INCIDENCE OF DERMATITIS OR RASH HEPATITIS AND COLITIS. IN THE MELANOMA TRIALS WITH THE HIGHER DOSE IPILIMUMAB. THIS SLIDE IS SET UP A LITTLE BIT DIFFERENTLY BUT GIVE BROAD OVERVIEW OF THE SAFETY -- IN THE IMMUNOONCOLOGY CHEMOMOW COMBINATION STUDIES. JUST WANTED TO HIGHLIGHT HERE THERE'S SOME DIFFERENCES IN HEPATITIS AND COLITIS BETWEEN THE TWO POEMBROLIZMAB WHEN COMPARED WITH (INDISCERNIBLE) THERE'S SIGNIFICANTLY MORE OR THERE WAS MORE HEPATITIS AND COLITIS IN THE -- PLUS CHEMO STUDIES. SO THE ASSESSMENT OF IMMUNE MEDIATED ADVERSE EVENTS IN CLINICAL TRIALS IS IMPORTANT TOPIC. THERE ARE WELL ESTABLISHED MANAGEMENT GUIDELINES FOR THESE IMMUNE MEDIATED AE. CLINICAL TRIAL DESIGN REQUIRES SOME TYPE OF STANDARDIZATION OF DEFINITION OF IMAE AND ADVERSE EVENTS OF SPECIAL INTERESTS ACROSS STUDIES, THE ADVERSE EVENTS OF SPECIAL INTEREST ARE GENERALLY CHARACTERIZED AS EVENTS THAT ARE DIRECT RESULT OF ACTIVATION OF IMMUNE SYSTEM AND I JUST WANTED TO POINT OUT ONE OF MY FDA COLLEAGUES WILL BE SPEAKING TOMORROW MORE ABOUT THIS BUT IMAE ARE ANY AESI THAT REQUIRES CONSIDERATION OF SYSTEMIC INTERVENTION WITH STEROIDS OR ENDOCRINE THERAPY RATHER THAN REQUIREMENT FOR THE USE OF STEROIDS AND SOMETHING FDA HAS MOVED ABAY FROM A LITTLE BIT. THERE'S A NEED FOR CLEAR DEFINITION IN TRIAL DESIGN PREFERRED TERM THAT COME PRIDES GIVEN IMAE AND THERE'S ALWAYS SOME DIFFICULTY USING NCI CTCA GRADING SYSTEM DESIGNED FOR USE WITH CYTOTOXIC DRUGS AND MAY NOT FULLY CAPTURE THE IMAE. ON THE FDA END THERE'S A PUSH TO STANDARDIZE LABELING, ESPECIALLY THE WARNINGS AND PRECAUTION SECTION OF THE LABEL FOR THESE AGENTS, THEY LOOK SIMILAR AND YOU CAN FIND SIMILAR INFORMATION. WITH THE LAST FEW MOMENTS I WANT TO TALK ABOUT THE MAJOR BIOMARKERS THAT ARE BEING USED IN IMMUNOONCOLOGY STUDIES SO PDL 1 WHICH WE KNOW EXPRESS IN SERVICE O OF TUMOR CELLS VARIOUS MALIGNANCIES CORRELATION WITH PROGNOSIS IS UNCLEAR, DIFFERS BETWEEN TUMOR TYPES, THERE ARE DIFFERENT CUT OFFS FOR POSITIVITY BETWEEN DIFFERENT PDL 1 ASSAYS, DIFFERENT AREAS OF MEASUREMENT, SOME STUDIES LOOK AT TUMOR CELLS VERSUS INFILTRATING LYMPHOCYTES OR BOTH AND MANY ASSAYS ARE USED TO ASSESS PDL 1 POSITIVITY. I PUT DURATION OF TREATMENT DOWN THERE JUST TO BRING UP THE POINT THAT THERE IS A QUESTION OF WHAT THE OPTIMAL DURATION OF TREATMENT IS PDL 1 AGENTS GIVEN POTENTIAL DELAYED EFFECT AND RARE PHENOMENON AND PSEUDOPROGRESSION AND STUDY IT IS HAVE SHOWN SMALL SUBSET OF PATIENTS MAY DERIVE SOME BENEFIT FROM BEING TREATED BEYOND PROGRESSION, TO THIS AND THE I RESIST CRITERIA ARE DEVELOPED THOUGH NOT YET CLINICALLY VALIDATED FOR USE IN REGISTRATIONAL TRIALS. THIS SLIDE SHOWS TWO DIFFERENT STUDIES BOTH SAME POPULATION OF PATIENTS, METASTATIC NON-SMALL CELL LUNG CANCER PATIENTS WHO NOT RECEIVED PRIOR TREATMENT RANDOMIZE ON THE LEFT TO RECEIVE -- VERSUS CHEMOTHERAPY, VERSUS ON THE RIGHT NEBOLAMAB VERSUS CHEMOTHERAPY CHECK MATE 026 ON THE LEFT PATIENTS SELECTED FOR PDL 1 TUMOR PROGRESSION SCORE GRATER THAN 50% AND IT RESULTD IN GREATER SIGNIFICANTLY SIGNIFICANT BENEFIT IN THE PEMBRO ARM LIEDING TO APPROVAL VERSUS ON THE RIGHT IN CHECK MATE 026 PATIENTS THAT MAIN OUTCOME MEASURE WAS PFS AND PATIENTS WITH PDL 1 EXPRESSION GREATER THAN 5% AND THEY DIDN'T FIND A STATISTICALLY SIGNIFICANT BENEFIT OF NEBOLAMAB MONOTHERAPY. TUMOR MUTATION BURDEN, MEASUREMENT OF MUTATIONS CARRIED BY TUMOR CELLS IS IN SOME WAYS GOING WAY OF PDL 1, IT MAY PREDICT OUTCOMES WITH IMMUNOTHERAPY, BEING EVALUATED IN MULTIPLE COMBINATION THERAPY APPROACHES. 'S TYPICALLY MEASURED THROUGH EXOME SEQUENCING BUT NOT USED VERY ROUTINELY IN CLINICAL USE SO THERE ARE MANY PRECISION ONCOLOGY PLATFORMS NOW USING NEXT GENERATION SEQUENCING OF TARGETED GENE PANELS. AGAIN, THERE ARE DIFFERENT PLATFORMS FOR THE ASSESSMENT OF TNB, NO CLEAR CUT OFF ACROSS STUDIES AND DISEASE TYPE, SIMILAR TO THE PDL 1 RAY SAYS. SO WITH THAT, I WILL FINISH UP AND ACKNOWLEDGE SOME OF MY COLLEAGUES AT THAT TIME FDA, AND THORACIC TEAM AND I THINK WE'LL TAKE QUESTIONS NOW. THANK YOU. [APPLAUSE] >> WE'LL TAKE QUESTIONS. THANK YOU BOTH FOR GREAT TALKS. FIRST QUESTION. >> >> MY QUESTION IS FOR DR. JAFFEE. YOU SAID THAT WE SHOULD IN -- WE SHOULD TAKE CARE OF MACROPHAGE BEFORE TAKING CARE OF T-CELLS. SO MY QUESTION IS, HOW CAN WE TAKE CARE OF MACROPHAGES. IS IT INHIBITING MACROPHAGES IMMUNE CHECK POINT LIKE CR 1 ALPHA? CD 47 LIKE LYMPHOMA OR KILLING THEM WITH CHECK MATE INHIBITORS? >> GREAT QUESTION, THERE'S MANY WAYS TO ALTER OR REPROGRAM THE MONOCYTES. SO YES THEY EXPRESS CSCFR 1, THERE ARE AGENT FOR THAT. CD40 IS AN AGONIST THAT WILL CHANGE THE MDSC POPULATION. AND HAD GOOD ACTIVITY IN THE CLINICS. THERE ARE A NUMBER OF DIFFERENT CD 47 CERTAINLY, WE RECENTLY PUBLISHED PRE-CLINICAL DATA SHOWING THAT H STACK INHIBITORS CAN REPROGRAM IN DSCs AND MAKE THEM MORE FUNCTIONAL AS ANTI-CANCER MONOCYTES. SO THAT'S THE QUESTION. AND I THINK THAT ONE OF MY -- CERTAINLY YOU'LL DEFER TO COLLEAGUES -- I'LL DEFER TO COLLEAGUES AS WELL BUT ONE OF MY GOALS IS TO ASK THAT QUESTION IN A SCIENCE PATIENT CLINICAL TRIAL TRYING TO DESIGN RIGHT NOW. >> ONE QUESTION FOR YOU, DR. JAFFE AND OTHER QUESTION FOR DR. DREZNER IF I MAY. FOR YOU WHAT DO YOU THINK THE ROLE IS OF TREG EPITOPES IN THE MUTANOME OF PATIENT? IS THAT A FACTOR IN TERMS OF OUTCOME? >> YES. I THINK TREGs ARE IMPORTANT COMPONENT OF PANCREATIC TUMOR MICROENVIRONMENT, WE HAVE SHOWN THAT BOTH IN PRE-CLINICALLY IN NUMBER OF PATIENT AND ALSO CLINICALLY. WE HAVE BEEN -- OUR VEENA DIDN'T MENTION THE LOW DOSE SIDE WE USED THAT IN THE PAST BUT IPILIMUMAB IS ALTERING THE TREG AND WE HAVE DATA TO SUGGEST WE REVERSE THAT. I WANT TO START LOOKING AT SPECIFIC EPITOPES WE HAVEN'T GOTTEN TO THAT POINT BUT I BELIEVE THAT WE'RE GOING TO SEE THAT. >> DR. DREZNER I WAS WONDERING IF YOU THOUGHT THE ANTI-DRUG ANTIBODIES WERE AGREE BAITING EFFICACY OF THESE DRUGS WHEN USED IN COMBINATION, WE KNOW THAT WHEN YOU ADD ANTI-TREG CTLA 4 ANTIBODY TO THE PEMBRO YOU MIGHT INCREASE THE ANTIBODIES TO THOSE ANTIBODY, ARE YOU SEEING CORRELATION BETWEEN OUTCOME AND ANTI-DRUG ANTIBODIES? IS THAT SOMETHING YOU CAN PEOPLE TO MONITOR? >> I DON'T THINK WE'RE SEEING CORRELATION IN OUTCOME, ALL -- THESE WITH EXPLORATORY ANALYSES SO THERE'S NOT ENOUGH INFORMATION YET IN MONOTHERAPY MUCH LESS WHEN THERAPIES ARE COMBINED BUT YES, IT IS SOMETHING WE ARE LOOKING AT WE ASK FOR PEOPLE TO AS BEST THEY CAN COLLECT AD ACTION INFORMATION DURING THE CONDUCT OF A TRIAL SOMETHING I THINK MORE INFORMATION WILL COME OUT. >> I HAVE A QUESTION FOR DR. SCHOENFELD. YOU POINTED OUT THAT RADIATION CAN BOTH INCREASE IMMUNE RESPONSES AND ALSO BE IMMUNOSUPPRESSIVE. SO WHAT IS THE POLICY OF BEST WAY TO DEAL WITH SEQUENCE OF TREATMENT WITH IMMUNOTHERAPY AND RADIATION? ESPECIALLY IF YOU ARE FRACTIONATING. >> I THINK THAT'S A GREAT QUESTION. AND I THINK WE REALLY DON'T KNOW TODAY, THERE'S SOME PRE-CLINICAL STUDIES THAT LOOK AT TIMING OF RADIATION IN COMBINATION WITH IMMUNE THERAPY, IMMUNE CHECK POINT BLOCKADE AND LOOK CONCURRENT THERAPY, MAYBE SEEING A BENEFIT THERE, DEPENDENT WHAT TIP OF IMMUNOTHERAPY YOU ARE USING. THOSE ARE HELPFUL. BUT THEN RIGHT NOW THE CLINICAL DATA AS I MENTION SPECIFIC DIDN'T DO THAT, THEY FRACTIONATED RADIATION THERAPY, TO SOME CASES PRE-TY LARGE TUMOR, AND THEN WEIGHTED ANYWHERE FROM FEW WEEKS TO EVEN MORE BEFORE STARTING PDL 1 INHIBITION, THERE'S A HUGE BENEFIT. SO I THINK RIGHT NOW WE REALLY DON'T KNOW, THERE ARE STUDIES LOOKING AT THAT QUESTION THAT ARE DIRECTLY COMPARING AND UNTIL WE HAVE RESULTS FROM THOSE STUDIES, BIOMARKER RESULTS ADS WELL AS CLINICAL RESULTS WE WON'T KNOW WHICH TIMING IS THE BEST. BUT THOSE ARE OUR CONCERNS WITH THE COMBINATION. HOPEFULLY SEE THESE STIMULATING EFFECTS AS I MENTION WE SHOULDN'T FORGET ABOUT THE INHIBITOR EFFECTS EITHER. AND HAVE TO THINK ABOUT THOSE WHEN LOOKING IN COMBINATIONS. >> I WOULD LIKE TO ASK THE PANEL ABOUT TOPIC RELATED TO OUR ABILITY TO IMPROVE ON UNDERSTANDING COMBINATION THERAPIES AND HOW TO PRIORITIZE, MANAGE THEM GOING FORWARD, WHAT I'M PARTICULARLY THINKING ABOUT IS HIGH NUMBER OF SINGLE ARM STUDIES, THAT ARE DEEMED POSITIVE LIKE DR. DREZNER'S PRESENTATION BASED ON HISTORIC EXPERIENCE WITH SINGLE AGENTS ALONE. THERE ARE BETTER WAYS OF DOING THAT GOING FORWARD, WHAT ARE THE KINDS OF THINGS THAT MAYBE CHANGING AS THERE'S BEEN MORE EXPERIENCE WITH EACH OF THESE DRUGS GOING FORWARD? FROM WHAT I HEARD FROM FRIENDS IN THE INDUSTRY IS PD 1 MONOTHERAPY TREATED IN THE SAME POPULATION TODAY WILL GIVE YOU MUCH DIFFERENT RESULTS IN TERMS OF EFFICACY OR DISCONTINUATION RATES DUE TO ADVERSE EVENTS ET CETERA, BECAUSE PEOPLE USE THE DRUG BETTER HOW TO MANAGE THE PATIENTS BETTER TODAY THAN THEY DID BEFORE SO THAT IMPACT IT IS SUCCESS OR THE FAILURE OF THE PHASE 3 TRIAL THAT'S RUN TODAY. IT'S A COMPLICATED QUESTION BUT IT'S IMPORTANT. >> ADDRESS PART OF THAT. I AGREE, IT'S DIFFICULT TO USE HISTORICAL CONTROLS, I DIDN'T MEAN TO SUGGEST THAT SOMETHING HAPPENED, I THINK THE ACCELERATED APPROVAL PROGRAM IS A GREAT WAY FOR THE FDA TO ALLOW DRUG DEVELOPMENT TO TAKE PLACE QUICKER BUT STILL PROVIDE MEASURE TO ULTIMATELY DEMONSTRATE EFFICACY OF WHATEVER THE STUDY DRUG IS ON A VALIDATED OUTCOME MEASURE LIKE OVERALL SURVIVAL SO FOR ACCELERATED APPROVAL THESE SORTS OF QUESTIONS COME IN TO PLACE WHETHER THERE'S ADEQUATE HISTORICAL CONTROL, WHETHER WHAT THE END POINT IS, ALL THE ACCELERATED APPROVALS ARE TYPICALLY IN LUNG CANCER ON OVERALL RESPONSE RATE WHICH IS THOUGHT TO BE SURROGATE FOR CLINICAL BENEFIT. SO BUT I STILL THINK THAT ALLOWS DRUGS TO COME OUT TO MARKETS QUICKER THAN THEY WOULD BUT ALSO REQUIRES DRUGS SPONSORS TO DO THE WORK TO SHOW BENEFIT OF THEIR DRUG OR COMBINATION ON A VALIDATED MEASURE. >> I THINK IT'S REALLY IMPORTANT, ONE CONCERN I HAVE IS NOT ONLY HOW FAST WE ARE LOOKING AT THIS -- IS THERE A WAY TO DO MORE ADAPTIVE TYPE OF CLINICAL TRIAL OR ACTUALLY ACR SPONSORING A COMBINATION THERAPY WORKSHOP THINK TANK, IT'S A THINK TANK, IN JUNE TO ADDRESS SOME OF THESE IMPORTANT QUESTIONS, NOT THAT TOXICITY SO MUCH AS THE SCIENTIFICICALLY DRIVEN COMBINATIONS AND MECHANISMS AND HOW YOU GET THERE FASTER TRIAL DESIGNS AND FDA IS INVOLVED IN THIS AS WELL. BUT THE OTHER THING THAT HASN'T COME OUT THAT I WORRY ABOUT, THAT HASN'T COME OUT SO FAR IN THIS SESSION THAT I WORRY ABOUT ALL THE TIME, WE'RE ALSO THINKING ABOUT WHAT'S HAPPENING IN IN ONE TIME POINT. AND WE ARE ONLY ASSESSING TUMORS AT ONE OR TWO TIME POINTS. SO FOR INSTANCE, WITH RADIATION, I WONDER ARE WE MISSING, YOU ARE SAYING SOMETIMES IT'S INHIBITOR, SOMETIMES ACTIVATING AND ABSOLUTELY. BUT WHEN IS THE BEST TIME TO COMBINE THEM WITH OTHER AGENTS BECAUSE ARE WE MISSING, WE CAN'T BIOPSY EVERY DAY OR EVERY WEEK EVEN WHAT IS GOING ON. SAME THING WITH COMBINATIONS YOU INDUCE A T-CELL, COMBINATION OF IO, YOU INDUCE A T-CELL AND NOW THE WHOLE TUMOR MICROENVIRONMENT WILL CHANGE WHEN IT GETS IN THERE BECAUSE CYTOKINES AND THEN YOU ALTER THE MONOCYTES AND THE CYTOKINES AND CHEMOKINES CHANGE. >> I WOULD ECHO THAT AND SAY THOUGH THE RESPONSE WE DON'T HAVE PERFECT WAYS OF ASSESSING THE RESPONSE, THE DATA KEEPING PATIENTS SO ON AND SEEING RESPONSE OVER TIME, I THINK MANY APPRECIATE THE PROBLEMS WITH PSEUDOPROGRESSION, PARTICULARLY MELANOMA, IN SOME CASES, I THINK IT'S A CHALLENGING, I AGREE WITH EVERYTHING YOU SAID, IT'S HARD IN A SINGLE ARM STUDY PHASE 2 STUDY USING HISTORICAL CONTROLS, HARD TO MAKE INFORMED COMPARISON AND I THINK SOME OF THOSE ASPECTS MAKE IT MORE CHALLENGING. THANK YOU. >> I HAVE A QUESTION FOR EACH OF YOU. LIZ. ONE OF MY CONCERNS ABOUT ALL OF THOSE STUDIES IS -- IT'S NOT JUST PANCREAS. IS THE BIOPSIES ARE INCREDIBLY SMALL. FROM WHAT I KNOW. IN PANCREATIC CANCER. WHEN WE KNOW ALREADY THAT THE PRESENCE OF A VIBRANT IS A GREAT PROGNOSTIC FACTOR PERIOD OR PREDICTIVE -- I GUESS SO MY CONCERN IS HOW DO YOU KNOW AT LEAST FOR THOSE STUDIES THAT YOU'RE ACTUALLY INDUCIN THAT EFFECT. THE EFFECT IS GOOD BUT ARE YOU INDUCING. >> I THINK AGAIN, DOING HUMAN STUDIES THAT'S ONE OF THE CHALLENGES AND I HAVE ANOTHER CHALLENGE TRYING TO THINK ABOUT THE PATIENTS. WELL BEING AND SAFETY. BUT WE ARE GETTING A BIOPSY OF JUST ONE MATTER, ONE LIVER AND THINGS ARE HAPPENING. THEY ARE HAPPENING IN DIFFERENT PARTS OF METASTASIS BUT ALSO METASTASIS. SO ABSOLUTELY IT'S TOUGH. WE USUALLY GET 4 TO 6 BIOPSIES FROM ONE TUMOR SITE TO WE HAVE A FEW TO LOOK AT WHICH HELPS A LITTLE BIT. YOU ARE RIGHT. WE HAVE TO BE THINKING ABOUT THAT. >> ACTUALLY JONATHAN, TWO THINGS, ONE, I'M HAPPY THAT YOU MENTIONED RADIATION NECROSIS IN THE BRAIN. THERE'S A LOT OF RADIATION ONCOLOGIST TO STRONGLY FEEL THAT AT LEAST IN MELANOMA, YOU HAVE TO TREAT EVERYONE WITH SRS, EVEN IF YOU YOU HAVE A ACTIVE IMMUNE THERAPY. >> THERE'S GREAT DATA ABOUT THE EFFICACY OF CHECK POINT INHIBITORS IN THE BRAIN. SO I WOULD IN GENERAL AGREE, WE HAVE TO BE VERY CAREFUL BECAUSE WE KNOW SRS IS AN EFFECTIVE MODALITY FOR BRAIN METASTASIS, WINDOW WHICH IT'S MORE EFFECTIVE. BEFORE BRAIN METASTASIS GROW TO YOUR KNOWLEDGE, I THINK THAT AS LONG AS THERE'S REALLY CARFUL OBSERVATION,INGS I WOULD AGREE WITH THAT. >> THE OTHER QUESTION, HAS THERE BEEN A PHASE 3 STUDY, LOOKING AT RADIATION TO SITE X, THAT REALLY ISN'T YOUR TREATMENT, SO SOME SITE THAT YOU DON'T NEED TO RADIATE, LIKE THE LUNG CANCER AND COMPARE THOSE PATIENTS WITH THOSE THAT JUST RECEIVE IMMUNE THERAPY. EVERYONE BELIEVES THIS. IS IMPORTANT BUT I HAVEN'T SEEN ANY ACTUAL OBJECTIVE DATA TO SHOW IT. >> WHAT YOU ALLUDE TO, THERE'S BEEN A LOT OF SINGLE ARM PHASE 2 STUDIES, SOME -- IT'S HARD, TO ANSWER THE PREVIOUS QUESTION TO COMPARE THOSE HISTORICAL CONTROLS, I THINK ULTIMATELY WE NEED PROSPECTIVE DATA AND IDEALLY PROSPECTIVE RANDOMIZE DATA. I WOULD SAY PEOPLE WITH THE EFFECTS OF RADIATION, I DON'T WANT PEOPLE TO BE OVERLY FOCUSED RADIATING ONE AREA IN THE PINKY AND THEN LOOKING FOR SYSTEMIC RESPONSE IN A PATIENT THAT FAILED, FIVE DIFFERENT LINES OF THERAPY AND COUPLE OF DIFFERENT IMMUNOTHERAPIES THAT'S TALL ORDER, I THINK DATA FROM PACIFIC IS SUFFICIENTLY EXCITING FOR THE COMBINATION IN GENERAL OF RADIATION AND CHEMOTHERAPY. BUT IT'S NOT -- THE QUESTION YOU ARE ASKING WHICH IS IN TERMS OF RANDOMIZED DATA, THERE'S SOME PRESENTED BUT NOTHING THAT I KNOW THAT'S A LARGE RANDOMIZE PHASE 3 STUDY. >> QUICK EDITORIAL COMMENT. T OVERALL GROWTH TO GET DRAMATIC RESULTS. STAGE 4 DISEASE RURAL RESPONSES YOU HAVE PANCREATIC CANCER WHERE ONCE YOU GET BEYOND LOCALIZED OR LOCAL REGIONAL DISEASE, WHICH MAYBE MORE LOCAL DISEASE, THE GAME IS KIND OF OVER. YOU CAN PROLONG SURVIVAL FOR SHORT PERIODS OF TIME. WE SHOULD BE DOING THESE TRIALS IN PATIENTS WHO WOULD LIKELY MOST BENEFIT, REGIONAL DISEASE MENTIONED IN TERMS OF RADIATION IS A GOOD OPPORTUNITY TO DO THAT. THOSE ARE THE KINDS OF TRIALS WE SHOULD BE DOING. >> INTERESTING SO WE ARE DOING THOSE, I SHOWED YOU THE NEOADJUVANT STUDIES WE ARE BUILDING ON BUT UNFORTUNATELY WE ARE TALKING 30% OF PATIENTS TOLL. WE STILL -- TOTAL. WE HAVE 70% WHO UNFORTUNATELY PRESENT WITH METASTATIC. THAT'S THE CASE FOR A LOT OF CANCERS. FROM I THINK WE ARE LEARNING AND WE ARE HAVING THE TUMOR AVAILABLE ALLOWS US TO ALSO LEARN WHAT'S HAPPENING. NO OTHER QUESTIONS? WELL THANK YOU, BOTH. THAT'S TERRIFIC. [APPLAUSE]