>>> GOOD AFTERNOON, EVERYONE WELCOME TO THE WEDNESDAY AFTERNOON LECTURE, A SPECIAL LECTURE. THE G BURROUGHS MIDER LECTURE. YOU CAN READ MORE ABOUT HIM ON THE BACK OF THE SHEET FROM TODAY. THIS IS ALWAYS A SPECIAL OPPORTUNITY TO RECOGNIZE AN INTRA MURAL SCIENTIST WHO HAS MADE OUTSTANDING CONTRIBUTIONS BY MEDICAL SEARCH AND THIS YEAR I THINK WE'VE DONE VERY WELL IN CHOOSING DR. LOUIS STAUDT FOR HIS CONTRIBUTIONS TO CANCER RESEARCH PARTICULARLY IN THE AREA OF LYMPHOMA. AND IT'S A PLEASURE FOR ME TO BE ABLE TO INTRODUCE SOMEBODY I'VE HAD THE PRIVILEGE OF KNOWING FOR QUITE SOME TIME AND LEARNING IN THE WAY IN WHICH HE HAS BEEN A LEAD IN THIS WHOLE IDEA OF PRECISION MEDICINE BEFORE IT STARTED GETTING THROWN AROUND SO LOOSELY BY SO MANY PEOPLE, LOU WAS DOING IT. MUCH TO THE ADVANTAGE OF PATIENTS THAT HE HAS HELPED BY HIS DISCOVERIES IN THE WAY IN WHICH THEY'VE POINTED TO SPECIFIC THERAPIES THAT ARE APPROPRIATE FOR SUB GROUPS THAT WERE NOT APPARENT JUST BY LOOKING THROUGH THE MICROSCOPE. LOU GOT HIS DEGREE AT HARVARD COLLEGE AND P PPHP. HE ENDED UNUP A VERY INTERESTING PLACE, NAMELY THE WHITEHEAD INSTITUTE WHERE HE CARRIED OUT A POST DOCTORAL FELL O.SHIP. IT'S QUITE A NICE CONNECTION HERE BETWEEN THE WHITEHEAD IN THE '80s AND THE NIH IN THE 2010s, WHICH IS I GUESS WHERE WE ARE. HE CAME TO NIH IN 188 AS -- 1988 AS A SENIOR STAFF FELLOW. TOOK ADVANTAGE OF THIS REMARKABLE FACILITY AND ALL THE CAPABILITIES THAT HAPPENED HERE, BRINGING TO THAT HIS OWN EXCEPTIONAL INTELLIGENCE AND CREATIVITY AND VISION TO PRODUCE AN INCREDIBLE SERIES OF PRESENTATIONS AND DISCOVERIES ABOUT CANCER AND NOW SERVES AS THE CO-CHEER OF THE MALIGNANCIES BRANCH AND THE SENT FOR CANCER GENOMICS. HE IS AN ELECTED MEMBER OF THE NATIONAL ACADEMY OF SCIENCES, AND IN 2009 RECEIVED THE PRIZE FROM THE AMERICAN SOCIETY OF HEMATOLOGY. SO A DISTINGUISHED SCIENTIST IN OUR MIDST. WE'RE LUCKY TO HAVE HIM HER. [ APPLAUSE ] >> THANK YOU. WELL, IT SHOULD BE OBVIOUS, IT WAS NOT CLEAR TO ME I'D HAVE THE PRIVILEGE OF BEING INTRODUCED BY FRANCIS TODAY, BUT WE'RE GLAD HE'S HERE TO DO MANY THINGS FOR US, AND MORE GENERALLY, I THINK YOU'LL SEE THAT REALLY MY CAREER WOULD NOT HAVE BEEN POSSIBLE WITHOUT THE HUMAN GENOME PROJECT. I WAS SORT OF LIVING THROUGH IT AND INSPIRED BY IT. I JUST USED IT THROUGHOUT, AND I'M GOING TO TRY TO TELL YOU SOME SORT OF AN ARC OF -- I'M GOING TO DO IT A LITTLE BIT OF HISTORY, BUT THERE'S GOING TO BE A FAIR AMOUNT OF NEW DATA IN THIS LECTURE AS WELL. BUT THE IMPORTANT THING AND THE SPECIAL THING I THINK ABOUT ONE OF THE SPECIAL THINGS ABOUT BEING HERE ANYWAY IS OUR ABILITY TO SEAMLESSLY THINK ABOUT DISEASE PROCESSES, WORK ON THEM IN THE LABORATORY, AND THEN TRY SOME THINGS OUT AND HOPEFULLY HELP SOME PEOPLE ALONG THE WAY, AND SO THAT'S WHAT I'VE TRIED TO DO, AND I'LL GIVE YOU SOME EXAMPLES OF PING PONGING BETWEEN THE LAB AND THE CLINIC THROUGHOUT. AND AS FRANCIS SAID, THERE WAS NOT A NAME OF WHAT I WAS WORKING ON AT THE BEGINNING. BUT IT'S NOW GOT A NAME, PRECISION MEDICINE, AND I'M EMBRACING THAT. I WANT US ALL TO GO IN THAT DIRECTION, AND THIS IS AN ILLUSTRATION OF WHY. AFTER I GOT MY FEET ON THE GROUND AS PRETTY MUCH A BASIC SCIENTIST IN DEVELOPMENTAL IMMUNEOLOGY. WHEN I CAME HERE IT DAWNED ON ME THEY DID RECRUIT ME TO THE CANCER INSTITUTE, AND WHAT WAS THIS PROBLEM OF CANCER AND SO I SAID I -- THIS FIRST WITH THIS MICROSCOPE I HAVE TO SAY IS NEAR AND DEAR TO MY HEART. THIS IS MY DAD'S MICROSCOPE IN MEDICAL SCHOOL. HE GAVE IT TO ME WHEN I WAS A YOUNG LAD, AND I LOOKED AT A LOT OF POND SCUM IN THIS THING AND OTHER THINGS TO PASS THE TIME, AND HONESTLY HOW LYMPHOMA WAS DIAGNOSED WHEN HE WENT TO MEDICAL SCHOOL WAS HOW IT WAS BEING DIAGNOSED IN THE MID '90s. PEOPLE WERE LOOKING UNDER THE MICROSCOPE AND THIS SAID THE CELLS ARE LARGE AND DIFFUSED IN THEIR DISTRIBUTION SO WE'LL CALL THIS DIFFUSE LARGE B CELL LYMPHOMA. SO THAT SEEMED TO NOT HAVE A MONTHLY CULTURE -- I WAS A DYE TO THE WALL MOLECULAR BIOLOGIST AT THAT POINT AND THOUGHT THERE MIGHT BE SOME OPPORTUNITIES. SO FAST FORWARD TO 2015, AND IT'S SORT OF REMARKABLE THAT IN THOSE ENSUING MAYBE 15 TO 20 YEARS, THIS IS A FIGURE TAKEN, A CARTOON FROM ONE OF MY PAPERS FROM MY LAB LAST YEAR IN SOME INCREDIBLE MOLECULAR DETAIL. IT'S PROBABLY NOT ON THE RIGHT, BUT IT'S A GOOD MODEL WHERE WE ARE, AND YOU CAN SEE A LOT OF PROTEINS AND THEIR INTERACTIONS. AND THAT'S WHAT WE THINK LYMPHOMA IS. IT'S NOT THESE CELLS UNDER THE MICROSCOPE, AND IT IS THIS KIND OF MOLECULAR UNDERSTANDING THAT LEAD US TO HAVE AN IDEA ABOUT THERAPY. YOU DON'T GET AN IDEA ABOUT THERAPY SEEMS BY LOOKING AT THE SHAPE OF THE CELLS, BUT THIS GIVES YOU SOME GOOD ONES. AND SO THEM AS I MENTIONED I WAS GROWING UP IN SCIENCE AS THE HUMAN GENOME PROJECT WAS DEVELOPING. NOW YOU GUYS ARE JUST GOING TO THE INTERNET, ALL OF YOU, TYPING IN YOUR GENE, LEARNING EVERY XON. WE DIDN'T AT ALL KNOW THIS. WE FORTUNATELY KNEW THE STRUCTURE OF THE GENOME. WE DIDN'T KNOW HOW MANY THERE WERE. WE DIDN'T HOW THEY THEY WERE EXPRESSED. WE DIDN'T KNOW SQUAT REAVMENT WE STARTED WITH NOW I SAY FROM THE MUSEUM OF ANTIQUE GENOMICS, THIS TECH TEETH IS NOT USED TOO MUCH AT ALL BUT IT'S A CDNA MICRORAY AND EVERY SPOT HERE WAS A LOVINGLY PCR'D IN MY OWN LAB, 18,000 HERE. THE FIRST INCARNATION OF THIS WAS DONE IN COLLABORATION WITH A GREAT SCIENTIST PAT BROWN AT STANFORD, AND THEN WE BROUGHT IT HERE. AND YOU CAN SEE THE PENNY IS 1999. THIS IS WHEN WE WERE ALL BREAKING FOR US. WE TURNED TO USE THIS GENE EXPRESSION TOOL TO LOOK AT EXPRESSION DIFFERENCES IN LYMPHOMA SAMPLES. WITHOUT BELABORING IT, WE ISLEY FOUND THAT THERE WERE TWO LARGE CLUSTERS OF SAMPLES ASSOCIATED WITH DIFFERENT GENE EXPRESSION PROFILES AND WE CALLED ONE FOR REASONS THAT WILL BECOME CLEAR THE ACTIVATED D-CELL LIKE OR ABC TYPE AND ONE THE GERM NAIL BCB DIFFUSED LYMPHOMA. I'M HAPPY TO SAY THIS IS PART OF THE WORLD HEALTH ORGANIZATION CLASS IFICATION. THE INITIAL CLUE WAS THAT THERE WAS ALSO A DIFFERENCE IN SURVIVAL PATIENTS WHO WERE TREATED WITH CHEMOTHERAPY. SO IT'S SAID THAT BIOLOGICALLY WE'RE SOMEWHERE ON THE RIGHT TRACK, AND THOSE TUMORS OF THE ABC TYPE WERE THE REAL BAD APPLES. WE COULD ONLY CURE THEM IN ABOUT 40% OF THE PATIENTS WITH CHEMOTHERAPY, AND THEN THE GERM NAIL CENTER ITEM SURGEON BETTER AT 75% CURE RATE, BUT OF COURSE THERE'S STILL A LOT OF PEOPLE DYING FROM THE GCB TYPE OF LYMPHOMA. ANOTHER PART OF THE UNDER PINNING WAS TUMORS AROSE FROM NORMAL BC DEVELOPMENT. SO HERE WAS THE GERMINAL CENTER REACTION WHICH A BCELL PROLY RATE QUITE A LOT FROM A SLIGHTLY DIFFERENT CELL ALSO BURKETTE LYMPHOMA ARISES FROM HERE, ANOTHER AGGRESSIVE LYMPHOMA. THE ABC, ARISED FROM A CELL ON ITS WAY TO BECOMING A PLASMA CELL BUT IT PROBABLY STOPPED AT THE PLASMA BLASTIC STAGE. IF YOU DO DEEP GENETICS OF ALL THESE TUMORS, YOU FIND THESE YIN AND YANG KIND OF DIFFERENCES IN FREQUENCIES. SO, FOR EXAMPLE, IN THE GCB TYPE LYMPHOMA, 45% HAVE A TRANCE LOCATION OF THE FAMOUS BCL2 ONCA GENE. SO THERE'S NO SELECTIVE PRESSURE FOR THE -- AND THERE ARE MUTATION MUTATIONS THAT I'LL TELL YOU ABOUT IN GREAT DETAIL. AND THEN BURKETTE HAS ITS OWN SET OF CHARACTERISTIC ABNORMALITIES. SO I WAS TELLING YOU THIS IS NOT ONE OF MANY WAYS TO SLICE AND DICE THESE TUMORS. THESE ARE PATHO GENETICALLY DIFFERENT. THEY MAYBE NEED BECAUSE OF THAT A DIFFERENT WAY THAT BECOME MALIGNANT BASED ON THAT STARTING POINT. ANOTHER BIT OF BACKGROUND BEFORE I LAUNCH INTO THE DATA IS THIS B CELL RESPECTER IS KEY TO WHAT I'M GOING TO BE TELLING YOU ABOUT. WITHOUT IT YOU CAN'T EACH MIKE A B LYMPHO CITE. YOU KNOW WELL. SO THAT WE KNOW, BUT ONLY IMMUNOLOGISTS KNOW ABOUT IS RESENTER SIGNALING, AND THIS DOES NOT INVOLVE INDUCE CLUSTERING OF THE B-CELL RESPECTER. IF YOU CONDITIONALLY DELETE THE RESENTER FROM A MATURE B CELLS FROM THE MOUSE, ALL MATURE B CELLS ARE GONE FROM THAT MOUSE IN SEVEN TO 14 DAYS. œTHESE ARE TWO MODES AND OF COURSE WE WERE INTERESTED TO SEE WHETHER THEY WERE BEING UTILIZED IN LYMPHOMAS. SO NOW OUR TECHNOLOGY COMES IN TWO FLOSSERS IN THE LAB. WE HAVE LIKED FOR MANY YEARS GENETIC SCREENS INVOLVING ITEMS LIKE RNA I/CRISPR SCREENS. SEQUENCING CANCER GENOMES AND WE DISCOVER MUTATIONS THAT OFTEN GIVE US INSIRVETLE INTO WHY PARTICULAR PATHWAYS WE FOUND IN THE FUNCTIONAL SCREENS WE FOUND WERE SO IMPORTANT. WE'RE SORT OF CONVERGING ON THESE ESSENTIAL CANCER PATHWAYS AND WE'RE JUST AS ENAMORED. IT CAN BE USED IN A GENETIC SCREEN SEASON AS THIS. YOU MIEBLG A LIBRARY OF VECTORS THAT TARGET CAS TO A DIFFERENT COLOR HERE. YOU THEN INFECT A CANCER CELL LINE, SO EVERY CELL LINE GETS ON AVERAGE ONE OF THESE AND IS INACTIVATED ONE HUMAN GENE. OURS IS THE SIMPLIST ONE YOU CAN IMAGINE. CAN THAT CELL SURVIVE AND PRO LIG RATE FOR THREE WEEKS IN CULTURE? SO THIS TURQUOISE WOULD HAVE HIT AN ESSENTIAL GENE, AND BECAUSE IT DID, THAT CELL DROPPED OUT OF THE CULTURE. YOU JUST DO NEXT GEN SEQUENCING AND VOILA, YOU FIND THE ESSENTIAL GENES IN YOUR CELL. THIS IS A FEW OF OUR DATA, NOT GOING TO SHOW A LOT OF IT. BUT WE'RE EXTREMELY EXCITED ABOUT IT, AND THE MOST EXCITING THING IS THIS CONTROL EXPERIMENT. IT'S EFFECT IN TWO DIFFERENT CELL LINES. ONE IN BLUE AND ONE OF THE GCB IN ORANGE. THE ZERO SHOWS THERE WAS NO AFFECT WHICH IS REMARKABLE BECAUSE THERE WERE OFF-TARGET EFFECT OFF THE WAZOO, AND THIS DIDN'T PREVENT US FROM MAKING PROGRESS BUT IT DIDN'T HELP MUCH EITHER. THIS IS A GREAT NEW DAY WITH THIS CRISPR CAS. WHAT DID WE LEARN? WE LEARNED A LOT THAT WE KNEW. BUT FIRST WHAT WE ALREADY KNEW WAS THE PATH WAY WAS VERY IMPORTANT IN THE ABC TUMOR. HERE ARE THERE COMPONENT OF THE KEY REGULATING ENOUGH CAPPA B. THE BLUE DOTS GOING DOWN, MEANING THIS IS AN ESSENTIAL GENE IN THE ABCs BUT NOTHING IS HAPPENING IN THE GCB CELL LINE. A 20 IS A NEGATIVE REGULATOR AND WHEN IT IS DELETED YOU SEE THE DOT ARE GOING UP. THAT MEANSES OF BEHAVING AS A TUMOR SUPPRESSER. IT'S MAYING THESE WEED CELL LINES GROW FASTER WHEN DELETED. WE'VE NEVER SEEN THIS WITH INTERFERENCE. SO THEN WE LOOK AT THE B CELL RESENTER PATHWAY. WHAT WE KNEW WAS THE COMPONENTS WERE ON-LINE ESSENTIAL IN ABC. SO HERE WE HAVE A BTK, VERY IMPORTANT FOR A FEW SHREWD FROM NOW. TOGETHER MAKE A LITTLE ADAPTER SIGNALING ADAPTER COMPLEX. ALL ABC, NOT GC. SO THAT WAS WHAT WE KNEW. STRIDES, SURPRISE. THIS WAS A BIG SURPRISE TO US. WE HAD NOT SEEN THIS WITH RNA INTERFERENCE. WHEN WE KNOCKED DOWN THE B CELL RESENTER ITSELF OR A VERY PROXIMAL NOW WE DID HAVE AN EFFECT IN THIS GCB CELL LINE ALONG WITH THE ABC. WE THINK WE DIDN'T SEE THIS BEFORE BECAUSE YOU ONLY GET A PARTIAL LOSS OF THE EXPRESSION, THE CHRIS -- CRISPR CASGIVES YOU A FULL LOCKOUT. THE DATA IS COLOR CODED SUCH ON THE LEFT SIDE THE BLUER YOU GET, THE MORE ESSENTIAL THAT IS IN AN ABC TYPE CELL LINE, AVERAGE IS CROSS SAFE. ON THE RIGHT THE ORANGER YOU GET, IT'S THE MORE ESSENTIAL IN THE GCB. SO WHAT YOU'LL SEE NEAR THE TOP HERE IS THE B CELL RESPECTER SUB UNITS ARE ALL IMPORTANT IN BOTH GCP AND ABC AND THERE'S SOME DIFFERENCES THOUGH IN SOME OF THE PROXIMAL. IN FACT, SOME OF THE APPROXIMATE NAIL SIGNALING MEMBERS ARE MORE IMPORTANT. THEN YOU CLEARLY SEE SIGNALING DOWN IS IMPORTANT IN BOTH OF THESE TYPES, BUT AS WE SORT OF KNEW AND HAS REALLY BORNE OUT HERE, ALL THESE COMPONENTS ARE ONLY JEWISH IS IN THE ABC. SO WE'VE GOTTEN SOME CLARITY AROUND THIS NOW SO SAY THAT THE ABC SUB TYPE HAS THIS PARTICULAR MODE WHEREAS THE GCB HAS MORE THIS TOPIC AND WE FOUND THIS WAS THE CASE IN BURKITT LYMPHOMA. IF YOU HAVE EITHER FORM, A PROXIMAL INHIBITOR OF SYK KINASE MIGHT WORK. SO NOW PIVOTING THEN TO TRYING OUT SOME OF THESE CONCEPT IN THE CLINIC. SO CAN WE TARGET THE CHRONIC B CELL WITH A DRUG, IBRUTINIB. THE PATHWAY THAT IS ACTIVE FROM A-C, THROUGH SOME KINAISE, THE CBM COMPLEX. BY SEQUENCING GENOMES FROM CANCERS OF THE ABC VARIETY, WE FOUND A BEVY OF MUTATIONS THAT ALL IN ONE WAY OR ANOTHER ACTIVATE THIS SIGNALING PATHWAY, AND MANY OF THESE ARE EXCLUSIVE TO THE ABC TYPE OF LYMPHOMA. JUST TO SHOW YOU THE ONES IN THE B CELL RESENTER, THE SUB UNITS AND WE FOUND EVERY POSSIBLE AMINO ACID SUBSTITUTION. AND HOW THAT WORKS NOW IS UNDERSTOOD THAT IT ENHANCES B CELL RESENTER SIGNALING IN TO WAYS, PREVENTS THE RECYCLING OF THE B CELL RESENTERS SO YOU GET AN INDOE SIGH TOES IS, SO WITH THE MUTATION IN THE B CELL RESENTER, THIS DOESN'T HAPPEN AS READILY. AND THAT FOR REASONS THAT ARE NOT SO CLEAR DOESN'T WORK AS WELL IF YOU HAVE THIS MUTANT FORM OF THE B CELL RESENTER. BUT THE REASON I'M TELL YOU THIS IS THESE ARE SORT OF BACK SEAT DRIVER MUTATIONS. WHAT DO I MEAN. IT'S ONE THAT IS RESPONSIBLE. IT'S IN THE DRIVER'S SEAT. THESE MUTATIONS WHEN PUT UP A CELL THAT HAS NO B CELL RESENTERS SIGNALING DO NOTHING. BUT IF YOU PUT THEM INTO A CELL THAT HAS ONGOING B CELLS, THEY ARE SORT OF PACK SEAT DRIVERS, THEY ARE ENABLERS. SO HERE WE WERE GRACED WITH THE PRESENCE OF A DRUG, IBRUTINIB THAT WAS BEING DEVELOPED FOR OTHER REASONS, AUTOIMMUNE. FANTASTIC DRUG. IT'S GOING TO BE ONE OF THE BLOCKBUSTER DRUG OR IS ONE OF THE BLOCKBUSTER DRUGS UNCANCER AND SO IT'S VERY STRONG AND GREAT WHARM -- PHARMIC. I ALREADY HAD BEEN WORKING WITH MY FRIEND AND COLLEAGUE VERY CLOSELY BUT THIS WAS OUR REAL MOMENT TO TEST SOME OF THE IDEAS OF THE LABORATORY. VERY QUICKLY AFTER WE MET, WE DID A TEN PATIENT TRIAL HERE IN THE CLINICAL CENTER AND THIS WAS A TRIAL IN IBRUTINIB IN PATIENT RELAPSED AND REFRACTORY IN THEIR DISEASE AND INITIALLY WE RECRUITED ONLY ABC PATIENT AND THIS WAS ONE OF THEM. SHE WAS A 52-YEAR-OLD FEMALE WELL THIS ABC LYMPHOMA. LIKE MANY PATIENT WITH LYMPHOMA, HAD HAD SOME SUCCESS WITH SOME CHEM AND THEN IT RELAPSE WILLED, ANOTHER CHEM AND THEN IT RELAPSED. SO SHE CAME TO US ON THIS CLINICAL TRIAL. ONE PILL A DAY, NO APPARENT SIDE-EFFECT AND HERE ARE HER TUMOR IN HER ABDOMEN IN THIS PET CT SCAN. THESE TWO HAD GONE AWAY BY WEEK EIGHT. SHE IS WITH US STILL MORE THAN SIX YEARS LATER AND IS A HAPPY CAMPER, HAPPY WITH HER SERVICE HERE AT THE NIH AND WE'RE ABSOLUTELY THRILLED FOR HER. SO THAT THE FIRST AND SECOND AND THIRD THOUGHT IS ARE YOU JUST SHOWING ME YOU'RE AN EXCEPTIONAL RESPONDER AND YOUR RESULTS MAY VARY. SO OF COURSE WE PUT THIS TO A FORMAL TEST AND THERE WAS A 70 PATIENT NATIONAL TRIAL LOOKING AT ALL COMERS AND THEN PREDICTED, HOPED THAT IT WOULD BE THE ABC ITEM IRES THAT WOULD BE RESPONSIVE. WE DID SEE THAT. WE HAD A 37% RESPONSE RATE IN ABC AND ONLY A 5% IN GCB. BOTH COMPLETE AND PARTIAL RESPONSES. SOME OF THEM WERE QUITE GOOD. THIS IS OUR SURVIVAL CURBS. INCREASE IN OVERALL SURVIVAL OF 10.3 MONTHS FOR THE ABC VERSUS .333 FOR THE GCB. NOT A HOMERUN I WOULD PAUSE ITS FOR THESE PAY SUBJECT. I MENTIONED THE ONE LADY OUT PAST SIX YEARS. WE HAD ONE GENTLEMEN MADE IT TO . YEARS. WE REALLY DID MOVE THE BALL JUNE FIELD FOR ABOUT ONE AND SEVEN PATIENT OF THE APC. WE'LL GET IT AT THE END OF THE TALK HOW WE'RE GOING TO DO BETTER THAN THE MAJORITY. NONETHELESS, A FAIRLY HIGH RESPONSE RATE IN A VERY BAD SET OF CANCERS, SO WE WERE ENCOURAGED. SO, BUT BEING THE SCIENTIST THAT WE ALL ARE, WE WANTED TO KNOW WHY WORK WASN'T 100%. YOU WERE WILLING THIS AS THE MOST IMPORTANT THING OF FOR ABC, WHY WASN'T IT 100% RESPONSE RATE. COULD IT BE SOMETHING IN STORY IN THE ACTUAL MUTATIONS. OF COURSE THE FIRST THOUGHT IS MAYBE IF YOU HAVE THE RESENTER, THEN YOU'LL RESPOND MORE OFTEN. YOU SORT OF DID. 55% RESPONSE RATE. HOWEVER, I WAS TAKEN BY THE IN FACT 30% OF THE CASES THAT RESPONDED. IN FACT, THE MAJORITY OF RESPONDERS DIDN'T HAVE A FEW STATION. SO THIS MADE ME THINK ABOUT OUR DATA AND ESPECIALLY THAT THIS WAS NOT WHAT'S SEEN IN SOME CASES THAT YOU MUST HAVE RAY MUTATION TO GET A RESPONSE. THIS DIDN'T PLAY OUT IN A CASES. THIS IDEA OF A NON-GENETIC FORM OF B CELL RESENTERS SIGNALING, AND WE SORT OF ALREADY KNEW THIS. IN OUR FIRST PAPER ON THE SUBJECT WE HAD TEAMED UP HERE WITH SUE PIERCE WHO HAD BEEN STUDYING B CELL RECEPTORS. AND FOUND IN RED THESE BRILLIANT DOT OF THE BENEFIT CRECEPTORS. THAT WAS NOT SEEP IN THE GCB CELL LINES AND SAMPLES. SO THIS WAS AT IF YOU WOULD SEE IN A NORMAL B CELL EXPOSED TO AN AN TOE -- ANTOGEN BE? WE THEN WENT OUT TO PROVE THAT EACH OF OUR CELL LINES RELIES ON INTERACTION BETWEEN THE B CELL RECEPTOR. ANOTHER CASE IN ANDOGEN RELEASED. AND IN THE CUTEST EXAMPLE, THE B CELL RECEPTOR IS WHAT I WORKED ON IN GRADUATE SCHOOL. AND THEN SOMETIMES YOU GET A MUTATION THAT WE THINK AUGMENTS THIS PROCESS. ALL RIGHT. SO NOW I HAVE TO TELL YOU ABOUT ONE OTHER THING THAT I'VE NEGLECTED ON PURPOSE JUST NOT TO CONFUSE YOU. BUT THE MOST IMPORTANT, THE MOST PREVALENT MUTATION IN THESE LYMPHOMAS IS IN THE SIGNALING ADAPTER MONTHLY CULTURE MYD88. SO WE DISCOVERED IN 38% OF THESE TUMORS THERE WERE ACTION SIEVE ATERS THAT ON ENOUGH CRAPPA B. AND OBVIOUSLY THAT MIGHT IMPINGE ON WEATHER A CELL RESPOND OR NOT. JUST TO SHOW YOU THESE FOR A SECOND, HERE'S THE MYD88 DOMAIN SEQUENCE AND THE TIR DOMAIN. WE HAD MANY RECURRENT MUTATIONS BUT THERE WAS ONE EVOLUTIONARY WINNER THAT IS NOW CALLED L265 P. AND THIS IS BECOMING ONE OF THE MOST IMPORTANT IMPORTANT ONCAGENES. SO WHEN YOU PUT IT INTO CELLS HERE, IT SIGNALS A COMPLEX INVOLVING TWO KANAISE. AS YOU SEE, DON'T SEE THAT WITH WILD TYPE. SO IT'S A FUNCTION. HOW DID IT PLAY OUT IN A TRIAL? IT WAS SORT OF A WASH. SO NOTHING GOING ON THERE. LET'S MOVE ON. EXCEPT THAT WE NOTICED THAT WERE FIVE TUMORS THAT HAD BOTH B CELL RECEP TYES TOR. SO THAT WAS A SIGNIFICANT DIFFERENCE AND IT DID JIBE WITH WHAT WE WERE FINDING IN THE LABORATORY. THESE A VARIETY OF CELL LINES AND BLUE THE ABC, THE THREE OBVIOUSLY HAVING EFFECT HAVE BOTH MUTATION IN THE B CELL RECEPTOR. THE GCBs ARE NOT TOUCHED. SO THAT SEEMED TO LOOK LIKE HYPER ADDICTION TO B CELL. GENETICALLY WE ALSO KNEW THAT IF YOU SURVEY A LARGE NUMBER OF ABC TUMORS THERE ARE MORE THAT HAVE BECOME MUTATIONS THAN YOU WOULD PREDICT BY THE CHANCE. 10% OF THE ABC TUMORS HAD BOTH MUTATION. AND THEN A LITTLE BIT OF FUNCTIONAL EVIDENCE WAS THAT IF YOU INHIP THE MYD88 AND WEED OUT IN EVERY OTHER LANE IS AN INHIBITOR AND THERE'S LESS SIGNALING FROM THE RECEPTOR SOMEHOW. NOW IN ALL WALKS OF LIFE IN SCIENCE ALSO, SOMETIMES SEEING IS BELIEVING. WE LOVE THIS ASSAY THAT ALLOWS US TO SEE SIGNALING INSIDE CELLS. SO IT'S A VERY SIMPLE THING THAT ASKS WHETHER TWO PROTEINS ARE NEAR EACH OTHER YOU THINK ARE INVOLVED IN SIGNALING. YOU HAVE TO HAVE A DIFFERENT SPECIES ANTI-BODY TO EACH PRO TEEFNLT YOU THEN COME IN WIN A SECONDARY ANTI-SPECIES SPECIFIC ANTI-BODY THAT HAS ALL OF THE NUCLEO TIDES. SO HERE IS A APPROXIMATE ITALY GAS STATION. AND YOU MAY SEE IT'S LOOKING A LITTLE HARD THAT THERE ARE RED DOTS. THIS IS OBVIOUSLY THE BLUE NUCLEUS. THESE DOTS ARE NOT ON THE CELL MEMBRANE WITH A SELF-RESPECTING B CELL RECEPTOR OUGHT TO BE. AS A LITTLE CONTROL IF YOU KNOCK DOWN MYD99. A LOT OF CONTROLS THAT I'M NOT GOING TO SHOW YOU. SO HOW DO WITH UNDERSTAND THIS CYTO POLICIC. SO WE KNEW THIS. THIS IS FROM OUR CRISPR SCREENS. CLEARLY AND THIS WAS A NEW FINDING. WE DIDN'T KNOW THIS BEFORE WE DID THE CRISPR SCREENS. THIS IS IMPORTANT TO TUESDAY BECAUSE TLRIS NOT ON THE PLASMA MEMBRANE BUT RATHER A CYTEO PATHIC. AND OBVIOUSLY OUR THOUGHT THEN WAS MAYBE THIS IS WHERE THE B CELL RECEPTOR WERE. WE HAD SOME GENETIC EVIDENCE FROM OUR SCREENS FROM MYD99, SO THIS WHOLE PATHWAY AND ITS BIOGENESIS IS IMPORTANT IN THIGHS DOUBLE MUTANT LYMPHOMAS. IN THE SAME BRIGHT NOW TO SET THAT UP A LITTLE BIT, IT'S NOT A GREAT DISEASE. IT'S NOT A GREAT ANATOMICAL PLACE TO HAVE A RAPIDLY GROWING, AGGRESSIVE LYMPHOMA. I SHOWED YOU THE GENETIC RELATIONSHIP WITH ABC AS WELL. HERE'S A SURVIVAL WITH CHEMOTHERAPY. SO WE NEED A LOT OF HELP ON THIS DISEASE. SO WE DECIDED TO DO A PHASE ONE TRIAL OF A IBRUTINIB PLUS AN OPTIMIZED CHEMOTHERAPY. I'LL TELL YOU ABOUT CONTINUE A SECOND. WE WERE LOOKING FOR OVERALL RESPONSE RATE AND PROGRESSION-FREE SURVIVAL. SO WE DEVISED THIS SPECIAL RENLMENT THAT WE REALLY FAVOR WHERE IBRUTINIB IS GIVEN BY ITSELF FOR TWO WEEKS. PATIENTS CAN TOLERATE THIS AND THAT GIVES YOU THE ABILITY TO SEE THAT ACTIVITY OF THAT DRUG BY ITSELF WHEN YOU REALLY DON'T KNOW WHAT'S GOING TO KNOW PAUSE WE DO THE CHEM PAUSE WE WANT TO HELP THESE PATIENT. THE IDEA IS WE GIVE THE IBRUTINIB WITH THE CHEMOTHERAPY BUT BY DECREASING THE THRESHOLD MIGHT MAKE THESE TUMORS MORE SUSCEPTIBLE TO THE CHEMOTHERAPY. A LOT OF DATA BEHIND THAT. IN ALL OF HIS YEARS AND YEARS OF DRUG DEVELOPMENT IN LYMPHOMA CAME UP WITH AN OPTIMIZED REGIMENT COMPLETELY CHANGING SOME OF THE AGENTS THAT ARE NORMALLY GIVEN TO PATIENTS OF THIS TYPE TO OPTIMIZE FOR BRAIN PENETRATION AND I OF COURSE THAT WAS ALSO VERY IMPORTANT. SO FIRST A PATIENT. THIS WAS A 67-YEAR-OLD. SHE HAD A PRESENTATION WITH DIFFICULTY SPEAKING AND WALKING AND HAD A MASS. SHE HAD A GOOD RUN WITH CHEMOTHERAPY. A THREE YEAR COMPLETE RESPONSE. SHE HAD SOME RADIATION THERAPY AS WELL, AND THEN SHE HAD A RECURRENT DISEASE, INABILITY TO SPEAK AND THAT'S WHEN SHE CAME TO US. SO WITHIN ABOUT THE FIRST WEEK OR A FEW DAYS, SHE STARTED TALKING TO HER FAMILY. SO THAT WAS A MOMENT. AND THEN HERE IS HER TUMOR GOING AWAY PARTIALLY, A GOOD PARTIAL REMISSION. REMIND YOU THAT IT'S ONLY TWO WEEK OF THERAPY WITH THIS DRUG. SO HOW HAVE WE DONE? BY THE WAY, AND SHE'S STILL IN COMPLETE RESPONSE FOLLOWING THE CHEM PART TAKING NO TREATMENT TWO YEARS OUT. SO, SO FAR SO GOOD. THESE ARE EARLY DATA. WE'RE JUST AS CAUTIOUS AS WE CAN WITH EARLY DATA BUT THIS IS A REALLY GOOD RESPONSE RATE. SO HERE ARE 1 PATIENCE AND 17 OUT OF 18 SHOWED A DECREASE UP THEIR TUMOR, 16 OUT OF 18 MET OBJECTIVE PR RESPONSE RATE TO IBRUTINIB. SO A MUCH HIGHER RATE OF ARE SPONTANEOUS THAN WE HAD MEAN SEEN IN THE NODAL ARMY OF ABC LYMPHOMA. 87% WENT INTO A COMPLETE RESPONSE. HAD IMMEDIATE PROGRESSION, SURVIVAL AT THIS POINT OF 8.2 MONTHS. SO THAT'S HOPEFUL AND WE'RE NOW STARTING TO RAMP UP FOR A PHASE TWO TRIAL TO TAKE THIS FARTHER. IN THE LAST TWO MINUTE I WILL TELL YOU WHERE WE'RE GOING IN THE FUTURE REALLY QUICKLY AND LEAVE SOME TIME FOR QUESTIONS, IF THERE ARE ANY. SO OBVIOUSLY I MAY HAVE SHOWN YOU THAT THERE WERE ACTIVE RESPONSES, BUT LIKE UP ANY TARGETED THERAPY, YOU'VE ALL BEEN PAYING ATTENTION TO THESE WONDERFUL NEW DRUG THAT COME THROUGH FOR CANCERS OF THIS TYPE AND THE OTHER, AND AS SOON AS THEY ARE ANNOUNCED TO BE WONDERFUL, THE NEXT ANNOUNCEMENT SEASON WE'RE HAVING RELAPSE TO THESE TARGETED STORM SYSTEMS. SO THIS IS THE BEAST OF CANCER WE'RE TRYING TO DEFEAT. SO ONE WAY TO GET AROUND THIS IS TO WORK OUT MECHANISM BASED COMBINATION THERAPIES. AND I WANT TO EMPHASIZE THAT THESE ARE NOT IMPERIAL COMBINATIONS AS EARLIER DRUGS WERE DEVELOPING BECAUSE THAT WAS THE ONLY THING COULD YOU DO. DRUG COMBINATIONS FOR CHEMEE WORKED OUT FINE BUT THERE WERE NO FEWER MECHANISMS THOUGHT ABOUT THERE. THIS IS A BUSINESS SLIDE BUT I WANTED TO SHOW YOU IN ALL ITS GLORY OF WHAT WE THINK ABOUT AS THE INNER WORKINGS OF A CELL LINE AND CANCER IN GENERAL. SOME THINGS YOU'VE SEEN BEFORE, THE B CELL RECEPTOR BUT I'M ALSO SHOWING YOU THAT THESE LYMPHOMAS, AT LEAST IN OUR CELL LINE MODELS HAVE A MINIMUM OF FOUR DIFFERENT SURVIVAL PATHWAYS. THEY THE PATHWAY TRIGGERED DIRECT FREE FROM THE SIGNALING. AS ITS DOWN STREAM TARGET CYTOKIPS. THEN WE HAVE A VARIETY OF BCL2 FAMILY MEMBERS. BCL2 ITSELF EXPRESSED AT HIGH LEVELS, AND THEN CAUSES THE EXPRESSION ANOTHER SET OF SURVIVAL PATHWAWS. SO YOU LOOK AT THIS AND THEN YOU SAY YOU'VE BEEN FOOLISH, YOU'RE GOING TO TRY TO CONCUR THIS MESS OF SIGNALING WITH ONE AGENT TARGETING ONLY ONE OF THOSE FOUR SURVIVAL PATHWAYS. SO WE'VE BEEN GOING AT THIS ISSUE HARD AND THINKING THAT WE HAVE TO FIND RATIONALE COMBINATIONS THAT HIT THESE OTHER SURVIVAL PATHWAYS. ONE OF THEM WE'VE BEEN FORTUNATE TO WORK WITH, CRAIG THOMAS AND NCAS HE HAS A DRUG SCREENING PLATFORM WHERE YOU CAN DO THOUSANDS AND THOUSANDS OF DRUG INTERACTIONS, AND THAT'S BEEN VERY ILLUMINATED. OTHER TIMES WE'VE COME UP WITH THEM MAKING SOME EDUCATED GUESSES, BUT IN THE END HERE'S WHERE WE ARE. THERE ARE CLINICALLY AVAILABLE AGENTS ALL IN BLUE THAT ALL EARLY KILL OUR LYMPHOMA CELL LINES DIRECTLY AND MANY OF THEM SYNERGIZE VERY PROFOUNDLY WITH IBRUTINIB IN KILLING THESE ABC CELL LINES. SO WE HAVE NO SHORTAGE OF THINGS TO THINK ABOUT. THE PROBLEM IS SOMEWHAT DIFFERENT. SO JUST TO GIVE YOU BEFORE TELLING YOU THE PROBLEM, JUST SHOW YOU WE HAVE MOVED FORWARD WITH ONE OF THESE COMBINATIONS, IBRUTINIB. BY THE WAY, THERE WAS, YOU KNOW, DEFINITELY NOT AS HARD AS AN ACT OF CONGRESS PERHAPS, BUT IT WAS DIFFICULT TO GET TOO DIFFERENT DRUG COMPANIES TO WORK TOGETHER ON A COMBINATION TRIAL, AND WE SHOWED HIM THE SCIENCE OVER AND OVER AND OVER AGAIN AND THEY FINALLY BOUGHT IT. THEY FINALLY BOUGHT INTO THE SCIENCE MADE SENSE AND ALLOWED US AND SPONSORD THIS TRIAL. AND ONE OF THE BITS OF SCIENCE WAS WHEN WE DID A ZENAGRAPH MODEL AND USED NOT A FULLY ACTIVE BOTH OF, WE COULD CLEARLY SEE THAT THE TWO TOGETHER WERE QUITE SYNERGISTIC IN CONTROLLING TUMORS. AND SO THIS STUDY IS ONGOING SO I HAVE NO REAL RESULTS BUT AN ANECDOTE THAT WE'VE SEEN A LOT OF RESPONSES. THIS IS A PERSON WITH A RECURRENT RELAPSE. IT DOESN'T LOOK QUITE SO NASTY, BUT THERE, BUT IT'S A BAD ONE. THIS WAS A RECURRENT DISEASE, AND THIS CAN KILL YOU. IT'S GONE NOW. THESE ARE JUST DISCOLORATIONS IN THE SKIN. SO WE WILL READ OUT THE FINAL RESULTS OF THIS TRIAL LATE OR MIDDLE THIS YEAR. SO WE'LL SEE. WE KNOW IT'S AN ACTIVE COMBINATION AND EQUALLY IMPORTANT IN TARGETED COMBINATION THERAPY, SAFELY ADMINISTERED. SO THIS IS IMPORTANT. YOU CAN DO SOME -- DO A NUMBER TO PATIENTS IF YOU AREN'T CAREFUL BY MIXING THESE INAPPROPRIATELY. SO WHERE WE THINK THIS PROCESS IS GOING AND I DON'T THINK EVERYBODY IN CANCER THINKS EXACTLY THIS WAY BUT IT'S WHAT SEEMS OBVIOUS TO ME IS THAT EVER CANCER I BELIEVE HAS MULTIPLE SURVIVAL PATHWAYS. TONIGHT DOESN'T NEED JUST ONE. IT PROBABLY NEEDED DIFFERENT ONES AT DIFFERENT STODGES OF TUMOR EVOLUTION. IF WE NOTICE EACH PATHWAY HAS SEVERAL NODE IN IT THAT CAN BE TARGETED WITH DIFFERENT AVAILABLE DRUGS, SO THERE'S FOUR DRUGS IT. I HAVEN'T TOLD YOU HUTCH ABOUT THE RESISTANCE OF MECHANISMS THAT COME UP. LET'S JUST SAY THERE'S ONE RESISTANCE MECHANISM AND IT HAS TWO NODE, THERE'S TWO MORE DRUGS YOU HAVE TO CONSIDER. THE EIGHT DIFFERENT CLINICAL TRIALS THAT WOULD MIX AND MATCH THE DRUGS SHOWN ON HERE TO OVERCOME ALL OF THESE MECHANISMS SO THAT'S NOT GOING TO WORK. THERE ARE TOO FEW PATIENTS GOING ON TO CLINICAL TRIAL AND I DON'T HAVE ENOUGH PATIENCE TO USE A DIFFERENT FORM OF THAT. IT'S TOO SLOW, SO I THINK THIS IS A GREAT OPPORTUNITY FOR SCIENTIST TO THINK AND TO ADD VALUE FOR CLINICAL WORK WHERE WE HAVE TO NO, MA'AM FATE THE BEST TRIALS, MECHANISM THAT WE UNDERSTAND AND HOPEFULLY PRE DICK THAT THEY WILL ALSO BE SAFE AND TRY A FEWER NUMBER OF THOSE. SO I'M GOING TO STOP HERE. WE HAVE ONE MORE ACKNOWLEDGMENTS AFTER THE TRADITIONAL ACKNOWLEDGMENTS. THE TRADITIONAL ACTION ANONYMITIES ARE THAT JIM RUNNING OUR LABS DESERVES A LOT OF CREDIT. RIPE WORK IS A STAFF SCIENTIST IN THE LAB. ALL OF OUR STRUCTURAL GENOMEICS HAS BEEN TO KNOW BY ROLAND SMITH. THE IRF4 WORK, I DIDN'T TELL YOU ABOUT IRF4 BUT THAT WAS THE WORK OF A POST DOC WITH MY LONG TIME 0 YEAR ANNIVERSARY STAFF SIGN ACTIVITY AND COLLABORATORS IN THE LABORATORY OF PATHOLOGY. I MENTIONED CRAIG THOMAS. SO FOR FUN I WOULD TELL YOU WHAT MY MENTORS ARE. WHEN I GOT STARTED THE WORD MENTOR HAD NOT ENTERED THE LEXICON OF SCIENCE. YOU KIND OF JUST DID YOUR WORK AND LEARNED BY YOUR ENVIRONMENT BUT NOBODY SAID SORT OF LOU, HERE'S WHAT YOU SHOULD TO BUT THEY SORT OF HINTED AT WHAT I SHOULD TO AND I WAS ATUNE. HERE WAS MY PHD ADVISER, HE WAS THE APIT KNEE OF A LABORATORY SCIENTIST IMMUNOLOGIST AND HERE WAS HIS THOUGHT FOR ME. HE HONESTLY WITH SAY THIS TO ME. HE WOULD SAY YOU HAVE TO COME INTO THE LAB AND NOT THINK ABOUT MAKING A SINGLE DISCOVERY, JUST ENJOY THE PROCESS OF DOING EXPERIMENTS AND I THINK THAT'S SO IMPORTANT. IT'S A REAL CHILL JOB IN THAT SENSE. YOU JUST COME IN, RUN YOUR OWN LAB AND YOUR OWN EXPERIMENTS AND MAKE YOUR OWN WORK FOR YOURSELF, AND IT'S A REALLY LOVELY WAY TO THINK ABOUT YOUR CAREER IN SCIENCE. I HAD ANOTHER MENTOR AT PENN, AND THAT WAS MARTIN AND VERY INFLUENTIAL ON ME IN A QUITE DIFFERENT WAY. SO HIS APPROACH TO ME WAS TO GET WITHIN TWO INCHES OF MY FACE AND SAY THAT'S THE STUPIDDIST THING I'VE EVER HEARD, AND THIS WAS VERY FORMA ACTIVE. BUT -- IT WAS JUST FANTASTIC BECAUSE THEN I'D SAY, IN AND OUT NO, AND I START TO STRUGGLE AND ANSWER HIM BACK AND THAT WAS REALLY REALLY IMPORTANT. AND SORT OF TOUGHENED ME PUP A LITTLE BIT, SHALL WE SAY, AS A SCIENTIST WHICH IS VERY IMPORTANT. REALLY IMPORTANT IN MY LIFE, THE MOST FORMA ITIVE MOMENTS WAS BEING A POST DOC IN DAVID BALTIMORE'S LAB. IT'S VERY HARD TO EXPRESS HOW HE INFLUENCES ME SO PROFOUNDLY H BUT I THOUGHT THIS MIGHT GET IT. SO WHAT HE WOULD SAY FROM TIME TO TIME SPARINGLY WOULD BE THAT'S AMUSING, AND THIS WAS THE HIGHEST FORM OF PRAISE. YOU DID NOT BORE ME. YOU DID NOT WASTE MY TIME. THIS IS WORTH CONSIDERING. YOU ARE WORTH CONSIDERING AS A PERSON AND YOUR EXPERIMENT IS WORTH CONSIDERING. SO THIS JUST SET FOR AN AN INCREDIBLE PLEA HIGH STANDARD FOR WHAT YOU WERE SUPPOSED TO ACHIEVE IN SUNNIES, AND SO I'VE KEPT THAT WITH ME EVER SINCE. SO THEN SITTING IN THE FRONT ROW IS ANOTHER SCHEMELY IMPORTANT MENTOR OF MINE WHO RECRUITED ME HERE. I DON'T HAVE TIME TO SAY THE FATEFUL WAY THAT ALL HAPPENED IN A BEAUTIFUL ISLAND IN THE MEDITERRANEAN BUT THAT'S ANOTHER STORY. SO INFLUENTIAL IN SO MANY WAYS, BUT I'LL HAVE TO EXPLAIN THIS ONE. I'D LIKE YOU TO ATTEND CLINICAL ROUND. OKAY. YOU SAID MANY GOOD THINGS. THIS WAS IMPORTANT WHEN YOU THINK BACK ON IT BECAUSE IN FACT HE HAD FRIDAY ROUND THAT WERE JUST STANDARD WHAT YOU'D GET IN MEDICAL SCHOOLS. WE'RE SEEING THE PATIENT ON THE WARD AND WHAT HAPPENED IN THE PAST YEAR. I WAS RUNNING ABOUT AS FAST AS I COULD AWAY FROM CLINICAL MEDICINE. BUT YOU KNOW I SAID, WELL, HE'S MY POSITIVE. I'LL COME ON FRIDAY AND SOLDIER ON. BUT IT DID IMPEW IN ME THIS IMPORTANCE THAT ESTLEDZ IN HIS RESEARCH THAT I NOW FEEL VERY STRONGLY TO HAVE THIS RELATIONSHIP BETWEEN WHAT YOU TO IN THE LABORATORY AND WHETHER YOU CAN HELP PATIENT, SO THAT I CREDIT TOM FOR. ANOTHER FAMOUS FACE, YOU'RE ALL FAMILIAR WITH OUR FRIEND RICK. HE WAS REALLY HELPFUL IN JUMP STARTING MY CAREER IN GEE NO, MA'AMICS. AND HE JUST BECAME THE NCI DIRECTOR WHEN I WAS RAMPING UP. WHEN WE WERE TOGETHER HE SAID LOU, YOU'RE JUST NOT THINKING BIG ENOUGH. DID THAT SOUND LIKE RICK? WHAT MEANT BY THIS IS WE FOUND EARLY GOOD RESULTS AND WHAT MEANT TO SAY IS WE'RE GOING TO GET EVERYBODY IN THE WHOLE WORLD TOGETHER IN ONE ROLL THAT STUDY LUMP HIMS AND WE'RE GOING TO PROFILE ALL OF THEM AND IT'S GOING TO BE GREAT. SO THIS WAS RICK TO A T, AND I HAVE EMBRACED THAT KIND OF GUNG HOE MENTALITY. THAT'S VERY, VERY IMPORTANT I THINK FOR SUCCESS. AND THEN MY FINAL MENTOR THAT I'LL CALL OUT SPECIFICALLY IS HAROLD. THE NEXT IMPORTANT NCI DIRECTOR FOR ME IN MANY WAYS HAD A LOT OF THIS DAVID BALTIMORE TYPE OF MAKING YOU WANT TO UP YOUR GAME TO THE HIGHEST POSSIBLE LEVEL. THAT WAS VERY IMPORTANT. BUT HERE WAS HIS SPECIAL THING. HE SAID, LOU, I MAY NEED A LITTLE HELP FROM YOU. AND THIS WAS A VERY LITTLE HELP FROM YOU. THAT WAS HIS WAY OF SAYING I WANT YOU TO DO HIS OTHER BIG JOB FOR ME AND DON'T STOP WORKING IN YOUR LAB EITHER. THIS IS WHAT THAT VERY NAIVE PHRASE MEANT, AND I ACTUALLY AN VERY GRATEFUL THAT HE GAVE ME THE OPPORTUNITY, AND I HAVEN'T TALKED ABOUT THIS TODAY TO -- YOU TAKE OUR BUDGET IN THE INTER ARE MURAL PROGRAM AND HAD A ZERO OR TWO, THAT IS WHAT OUR BUDGET ARE ON THE OTHER SIDE OF WHAT WE DO, AND THAT'S REALLY FUN TO THINK ABOUT. IT'S A DIFFERENT MODE OF THINKING THAN WE DO IN THE LABORATORY BUT IT HAS ITS OWN REWARD. SO THANK YOU VERY MUCH. [ APPLAUSE ] >>> THANKS. I WOULD WARRANT THERE ARE A NUMBER OF PEOPLE ON THIS SLIDE AND LOTS OF PEOPLE INFLUENCED IN A SIMILAR WAY. SO YOU'LL TAKE QUESTIONS, I GUESS? YES. >> YEAH, I OVER-SOLD THAT A BIT, SO IT'S PRETTY DARN SAFE AS CANCER DRUGS GO. SO THE SURPRISE THOUGH IS THERE'S NO FUNCTION, THE NORMAL B CELL NUMBERS ARE UNTOUCHED, JUST DOWN A LITTLE. AND IN MOST PATIENTS THERE'S NOT A HEIGHTENED SUS SENTABILITY TO INFECTION. WHAT WE HAVE FOUND RECENTLY THOUGH IS THAT IF YOU HAVE PROBABLY OTHER IMMUNE SUPPRESSANTS ON BOARD SUCH AS STEROIDS, THEN YOU CAN GET IN TROUBLE WITH B2 K. WE HAVE FORGD AT NIAD TO SHOW THE FUNCTION IN IMMUNE CELLS MOST LIKELY IS IMPORTANT FOR CONTROLLING SONGS -- CERTAIN FUNGAI. THOUSANDS OF THEM ARE TAKING IBRUTINIB WITHOUT ANY SIDE-EFFECTS. THAT'S A TRUE STATEMENT AND THAT'S WHY THIS IS A SPECIAL KIND OF DRUG. >> THAT LEADS ME TO MY SECOND QUESTION. >> RIGHT. THAT'S EXACTLY IT. I DIDN'T GET AT IT VERY DEEPLY BUT WE'RE MUCKING WITH ESSENTIAL PATHWAYS, IN OUR CASE IMMUNE CELLS, BUT EVEN MORE GENERALLY WITH OTHER CANCER THERAPIES, AND IF YOU HIT TWO THINGS THE WRONG WAY, THERE'S GOING TO BE SOME NORMAL CELL IN THE BODY THAT WON'T LIKE THAT MUCH. SO IT'S REALLY ALL ABOUT THERAPEUTIC WINDOW AND WHAT YOU CAN GET AWAY WITH. AND I WON'T REGALE YOU WITH SOME REALLY REALLY BAD OUTCOMES IN CLINICAL TRIALS WHERE PEOPLE HAVE HAD TWO DIFFERENT TARGET AGENTS AT THE SAME TIME. SO WE ARE WELL AWARE OF THAT. BUT, AS YOU MENTIONED, WE'RE DOING A TRAIL AND IT DOES NOT APPEAR THAT WE ARE, YOU KNOW, CREATING HAVOC. IT'S TOLERATED. MENT TO FOLLOW-UP ON THAT, THERE IS EVIDENCE IN THE LITERATURE EFFECT IMMUNE CELLS OTHER THAN B CELLS. SO MY QUESTION IS CAN YOU COMMENT ON THESE EFFECTS AND ALSO THE POTENTIAL FOR COMBINATION THERAPY WITH SMALL MOLECULES WITH IMMUNO THERAPIES. >> GREAT QUESTION. I THINK THAT'S AN OUTSTANDING THOUGHT THAT THERE WOULD BE A SYNERGY BETWEEN IMMUNE THERAPIES AND TARGETED THERAPIES FOR THE MALIGNANT CELL. IN FACT, IN OUR STUDY I SHOWED YOU ON THE PHASE TO STUDY. WHEN THE PATIENTS WERE HERE AT THE CLINICAL CENTER, WE WERE ABLE TO GET BIOPSIES ON TREATMENT. AND THE SIGNATURE BY GENE EXPRESSION PROFILING THAT SHOWED UP WAS T-CELLS IN THE RESPONDING LYMPH NODE. NOT IN THE ONES THAT DIDN'T RESPOND. ANECDOTAL, NEED TO FOLLOW-UP BUT IT'S ALONG THE LINES THAT YOU'RE MENTIONING. OVER HERE FIRST, AND THEN LARRY. >> VERY BRIEFLY. THERE WAS AN INTERMEDIATE STEP, THOSE OF US WHO TRAINED IN THE '80s REMEMBER THE DAYS. AND YOU ESSENTIALLY CHOSE, THE WORKING FORM NATION WHICH NOBODY UNDERSTAND WHAT IT MET. THIS HAS ENABLED PEOPLE TO DO TUMOR OF UNDER KNOWN ORIGIN. AND BELIEVE IT OR NOT IN THE LITERATURE THOSE USED TO BE VERY BIG TOPIC. APPARENTLY THEY ARE NO LONGER IMPORTANT NOW THAT YOU HAVE GENETIC AND YOU CAN SAY THIS IS FROM THAT TUMOR. >> RIGHT, SO I THINK THAT THE IMPORTANT POINT THAT I TAKE FROM YOUR QUESTION IS PATH OLE JUST SHOULD EMBRACE THESE NEW TECHNOLOGIES AND THEY HAVE ALWAYS EMBRACED TESTIMONIES. THEY EMBRACED THIS EARLY MOLECULAR STUDY AS YOU MENTIONED. IT'S A MOLECULAR TEST OF THE TUMORS. WE'RE JUST DOING TEST OF HUNDRED OF THOUSANDS OF GENES SOMETIMES. THE SCIENCE OF DIAGNOSISSING DISEASE HAS TRADITION HEE BEEN IN THE LABORATORY OF PATHOLOGY OR IN THE HAND OF PATHOLOGISTS. IF PATHOLOGIST WANT TO STAY PART OF THE SOLUTION IN PRECISION MEDICINE, THEY'VE GOT TO EMBRACE THESE TECHNIQUES I THINK. >>> THANKS, LOU. DO YOU HAVE DIRECTLY THERE. LIKEWISE, WE NOW RECRUITED AND JASON'S SISTER SHOWED THERE WAS A SEPARATE PATHWAY INVOLVING THE S1 PR RECEPTOR THAT IS A NEGATIVE INFLUENCE AND THAT'S WE CURRENTLY DELETED. BUT THEN ON THE OTHER HAND YOU'VE GOT BCL2 TRANCESLOCATED IN 45% OF THE CASES.