OKAY. I WANT TO START WITH A COUPLE CORRECTIONS. I'VE GONE BACK AND LISTENED TO THE FIRST TWO SESSIONS, REALIZED THAT I MADE MISTAKES ALL THE TIME. SOME ARE TRIVIAL. SO FOR EXAMPLE, A PAPER CAME OUT 1969, NOT 1967. IT WAS, OF COURSE, OUR COMMITTEES, NOT SACRA DAYS THAT JUMPED OUT OF THE BATH AND RAN AROUND. SOME NOT SO TRIVIAL. FOR EXAMPLE, IN GOING THROUGH COSTIMULATERS, I SAID THAT CD40 LIGAND WAS A STRONG COSTIMULATER OF T CELLS. THAT'S INCORRECT. THERE IS ONE PAPER WHICH IS MISSING A VERY IMPORTANT CONTROL. WHICH SUGGESTS THAT CD40 LIGAND IS NECESSARY DURING T CELL DEVELOPMENT AND THAT IT SIGNALS INTO C TELLS. BUT MOST OF THE EVIDENCE IS THAT CD40 LIGAND IS USED BY T CELLS TO BIND TO EDUCATE THE CELL THAT HAS CD40. IT'S NOT SO MUCH IT'S A STRONG CO-STIMULATER BOO ITSELF. IT'S USED TO SUPER ACTIVATE OR LICENSE ENERGY PRESENTING CELLS. IN A WAY, IT'S NOT THE CL40 LIGAND ITSELF. THAT WAS AN IMPORTANT ONE TO FIX. TODAY IS TUMORS. LAST WEEK WE DID FETUSES AND SURGICAL TRANSPLANTS. AND THE CONCLUSION THERE WAS THAT EVEN THOUGH THE FETUS IS FOREIGN, IT'S NOT REJECTED BECAUSE IT DOESN'T LOOK DANGEROUS. IF IT'S DOING ITS NORMAL DEVELOPMENT. AND THAT SURGICAL TRANSPLANTS ARE REJECTED BECAUSE THEY LOOK DANGEROUS. BECAUSE OF THE DAMAGE DONE BY THE SURGERY, OR THE REPROFUSION INJURY. OR EVEN SOMETIMES THE DISEASE THAT KILLED OFF THE FIRST GRAPH. SO IF FETUSES AREN'T REJECTED BECAUSE THEY DON'T LOOK DANGEROUS AND TRANSPLANTS ARE REJECTED BECAUSE THEY LOOK„i DANGEROUS AND FOREIGN, WHY AREN'T TUMORS REJECTED? WE KNOW THERE ARE TUMORS THAT EXPRESS FOREIGN ANTIGENS. VIRALLY ENCODED OR MUTATED PROTEINS OR MOLECULES THAT WERE UP REALLY EARLY IN FETAL DEVELOPMENT LONG BEFORE THE IMMUNE SYSTEM ARRIVED AND GET TURNED OFF. SO EARLY FETAL ANTIGENS. OR THEY SOMETIMES EXPRESS MUCH HIGHER QUANTITIES OF SELF-ANTIGENS THAT THE NORMAL TISSUE. SO THESE OUGHT TO BE REJECTED. YET THEY'RE NOT. AND WHENIVERAM SUGGESTED THIS WAS A SELF-MODEL I PATTEDŤ— HIM ON THE SAID AND TUMORS ARE IMMUNOSUPPRESSIVE. A LOT OF PEOPLE STILL SAY THAT. THERE IS THE MILO DERIVED SUPPRESSER CELLS IN TUMORS, THE T. REGULATORY CELLS IN TUMORS, SO ON. TUMORS ARE IMMUNOSUPPRESSANT. BUT WE KNOW THE IMMUNE SYSTEM CAN GET RID OF TUMORS. WHY DOESN'T IT? FORA WHILE, IT WAS THOUGHT THAT IT DOES GET RID OF TUMORS, MOST OF THEN. THE IDEA -- WHEN I WAS A GRADUATE STUDENT IN THE 70s, WAS THAT WE GET A TUMOR EVERY 3 MINUTES OR SO. THE IMMUNE SYSTEM GETS RID OF THEM. WHEN WE GET A TUMOR, WHEN A TUMOR GROWS OUT IT'S BECAUSE THE IMMUNE SYSTEM COULDN'T GET RID OF IT. THAT WAS A THEORY UNTIL ABOUT„i THE LATExD 70s WHEN THE NUDE MOUSE WAS DISCOVERED. NO T. CELLS, THOUGH THYMOUS.vOm NUDE MICE HAVE A FEWŤ—–r T CELLS FROM THEIR MOTHERS. FOR THOSE THAT WORK WITH NEWS BE CAREFUL. NUDE MICE IN MOST„i COLONIES ARE BRED FROM HETEROZYGOUS MOOD MOTHERS. THAT'S BECAUSE NUDE MICE HAVE NO HAIR, AND THEY'RE NOT VERY GOOD AT KEEPING TEMPERATURE CONTROL. AND SO THEY HAVE TROUBLE DURING PREGNANCY. THE WAY PEOPLEi] BREEDxD NUDE MICE. THEY HAVE HETEROZYGOUS MOTHERS WHICH HAVE HAIR, AND HOMOZYGOUS FATHERS. LEAF THE LITTER IS NUDE, HALF IS HAIRY. WELL, DEPENDING ON WHAT COLONY, AND HOW THEY'RE BREAD, NUDE MICE HAVE T CELLS FROM THEIR MOTHERS. BE CAREFUL. FOR A WHILE PEOPLE THOUGHT NUDE MICE HAD T CELLS FROM [INDISCERNIBLE]. ACTUALLY IT'S FROM THEIR MOTHERS. ANYWAY, NUDE MICE, 50% DON'T HAVE T. CELLS FROM THEIR MOTHERS AND DONALD HAVE A HIGHER INCIDENT OF TUMORS THAT NORMAL MICE. THE IDEA THAT THE IMMUNE SYSTEM IS CONSTANTLY SURVEYING -- LOOKING FOR TUMORS KIND OF DIED. AND THEN THE RAG MOUSE AND SKID MOUSE WERE DISCOVERED AND THEY DON'T HAVE MANY MORE TUMORS THAN NORMAL MICE EITHER. THERE HAS BEEN A RESURGENCE OF THE IDEA OF IMMUNO SURVEILLANCE. AND THERE IS SOME EVIDENCE THAT IF YOU TAKE T CELL DEFICIENT MOUSE AND DIFFERENT IT LIKE MCA UNDER THExD SKIN -- BY THEMSELVES DON'T HAVE MORE TUMORS THAN NORMAL MICE BUT IF YOU GIVE THEM TUMOR INDUCING AGENTS, THEY WILL GET MORE TUMORS THAN NORMAL MICE. I DON'T THINK THAT'S VERY GOOD EVIDENCE FOR IMMUNOSURVEILLANCE BUT THERE I GO. IT HAS [INDISCERNIBLE] THE FIELD. SO WHY DO I THINK THE TUMORS ON THE WHOLE DON'T GET REJECTED. >> SO FIRST, WE NOŤ— LONGER THINK YOU GET A TUMOR EVERY 3xD MINUTES. WE THINK TUMOR GENESIS IS RARE. BECAUSE OFxD GENES LIKE P53lp ANDlpxD SO ON. THAT MONITOR CELLS, TELL THEM TO DIE BETWEEN THEY DO BAD THINGS. – DON'T THINK THE IMMUNE SYSTEM GENERAL IS GOING TO RESPOND TO IT. THE REASON IT'S NOT IN GEN GOING TO%q– RESPONDt( TO IT, TUMORS DON'T TOOK DAMAGE YAZIDI. WHAT'S WRONG -- DANGER I CAN'T SAY. WHAT'S WRONG WITH A TUMOR? WHAT'S WRONG, IT HAS LOST GROWTH CONTROL. SO IT'S DIVIDING WHEN IT SHOULDN'T. RIGHT? MAKING A BUNCH OF CELLS. NOT LOOKING DANGEROUS, AT LEAST IN THEq BEGINNING. IT'S SIMPLY A CELL THAT HAS LOST GROWTH CONTROL. DIVIDING. OR MULTIPLING. I REMEMBER THE DAY THAT I DISCOVERED THE DECISSION AND MULTIIFICATION IN BIOLOGY ARE THE SAME. AND SUPPOSE THIS IS A TUMOR THAT WAS EXPRESSING TUMOR ANTIGENS. IN MHC. CALL THEM T ANTIGENS. SUPPOSE YOU HAD A T CELL THAT COULD SEE THAT. THIS IS A VIRAL ANTIGEN, MUTATED ANTIGEN, EARLY EMBRYONIC ANTIGEN. WHAT'S GOING TO HAPPEN TO THAT T CELL? SOMEBODY TELL ME. IT WILL GET SIGNAL ONE. AND -- >> [INAUDIBLE] >> NOT SIGNAL TWO. AND? >> [INAUDIBLE] >> DIE. RIGHT? SIGNAL ONE. GO AHEAD.A5„i >> [INAUDIBLE]NB >> IF YOU'RE GOING–r TO TALK FOR A LONG TIME YOU HAVE TO GO TO THE MICROPHONE. IF IT'S A QUICK QUESTION I CAN REPEAT YOU CAN JUST SAY IT. >> I SAID I WAS THINKING ABOUT THE FOREIGN ANTIGEN, AND LENGTHING THAT TO THE TOLERANCE WE TALKED ABOUT LAST WEEK. YOU JUST SAID A FEW MINUTES AGO THAT TUMOR EXPRESSED HIGH AMOUNT OFŤ— ANTIGEN DOES THE DOSE PLAY A ROLE, ANTIGEN DOSE, PLAY A ROLE IN [INDISCERNIBLE] >> GOODNB QUESTION. >> MOST TUMORS WILL HAVE THE [INDISCERNIBLE]. >> THAT'S MORE THAN ONE QUESTION. DOES THE DOSE OF ANTIGEN MANAGE TO TOLERANCE? THERE ARE THEE WRITICAL REASONS FOR SAYING YES. SOf‡ THIS8– IS ORIGINALLYxD„ixD THOUGHT ABOUT BY MEL,lp CONE, I„%3„ STILLŤ— THINK i- TOLERANCE IN THEf‡xD THYMUS. 2t$IS IS WHATxD HE'c SAID.„i IF --„i SO FIRST, YOU HAVE T CELLS OF INVESTIGATOR AFFINITY. [TECHNICAL DIFFICULTIES] [TECHNICAL DIFFICULTIES]. THEN THERE ARE BE A SET OF T CELLS THAT YOU HAVE NOT TOLLS ARED THAT COULD BE ACTIVATED. SO HE ARGUED THAT YOU WANT THE SAME TOLERANCE AS FOR ACTIVATION. NOW, CHARLIE HAD A PAPER -- BY THE WAY, BEFORE CHARLIE GOT INTO TRRs HE DID A LOT OF EXPERIMENTS. SLOPPY EXPERIMENTER. BUT HE DID HAVE A PAPER SHOWING THAT -- >> [INAUDIBLE] >> PATTERN RECOGNITION RECEPTOR. WHAT IS PRR. PATTERN RECOGNITION RECEPTOR. INVENTED BY CHARLES. BRILLIANT. HE HAD A PAPER SHOWING TOLERANT INDUCTION IN THE THYMUS MIGHT REQUIRE A THRESHOLD ABOUT 1,000 FOLD LOWER THAN ACTIVATION IN THE PERIPHERY. I DON'T KNOW THAT I THAT WAS EVER REPEATED BY SOMEBODY ELSE. MAYBE IT WAS. IF SOMEBODY KNOWS ABOUT THAT, LET ME KNOW. BUT THEORETICALLY ARGUE IT SHOULD BE THE SAME. SO IF YOU'RE TOLERANT IN THE THYMUS, OF A PARTICULAR CONCENTRATION OF SOMETHING -- WE'RE GOING TO COME PACK TO THAT DURING AUTO IMMUNITY. AND YOU HAVE A CELL THAT EXPRESSES A LOT MORE, YOU WILL HAVE SOME LOWER AVIDITY T CELLS THAT HAVE ESCAPED THE THYMUS. IF THAT PERIPHERY IS HEALTHY, WHAT WILL HAPPEN? SIGNAL ONE WITHOUTxDrSIGNAL TWO AND TWO.Ť— THAT'SŤ— A REAL SIMPLE. WEt( TALKED ABOUT AND LONG BEFORE THE„i DISCOVERY OF THESE MOLS, THAT THEY'RE’R„–r–r„ix =z THEY'RE ALSOś SO ON.jFŤ—t(„i„iŤ— TśSOzs"% WRONG. –wsH‡HExD HEAD'S UP.r% SIGNAL WITHIN IS r AxDw3 CELL T O–r–r BECOME THAT„i„i ALLOWSr SENSITIVE TOjFt( A WHOLExD–r PUNCHxD OFjF COSI9 AND [TECHNICALt( DIFFICULTIES] SO THAT EXPLANATION DOESN'T WORK. HERE IS WHAT DID WORK. THAT IS, WHEN YOU PUT CELLS IN CULTURE THEY'RE ON PLASTIC. AND YOU STIMULATE THEM WITH ANTI-CD3, ON PLASTIC. THERE ARE NO COHINTRY MOLECULES THERE. THEY'RE NORMAL TISSUES, THEY'RE NOT THERE IN THAT DISH. SO YOU HAVE YOUR HEAD'S UP SIGNAL AND YOU TURN IT ON. BECAUSE YOU DON'T HAVE THE COINHIBITORY MOLECULES ON THE DISH. BUT YOU DO HAVE COINHIBITORY MOLECULES ON THE TISSUE. SO IT'S THAT BALANCE. >> [INAUDIBLE] >> YOU COULD EXPRESS ABSOLUTELY TEST THAT EXPERIMENTALLY. HAS SOMEBODY DONE THAT? LET ME REPEAT THAT SO THE VIDEO PEOPLE CAN HEAR. SO YOU OUGHT TO BE ABLE TO TEST THAT BY PUTTING COINHIBITORY MOLECULES ON THE DISH. THAT'S BEEN DONE? >> I WOULD HAVE TO LOOK [INAUDIBLE] >> YOU'D TO HAVE LOOK FOR PAPERS. WELL, LOOK FOR THEM. I KEEP ASKING PEOPLE TO SEND ME THOSE PAPERS. HOWARD YOUNG SENT ME ONE. I FORGOT TO SEND IT TO YOU. I WILL SEND THAT TO YOU. >> [INAUDIBLE] >> THE QUESTION IS, THIS IS A SLOPPED WILL SOLID TUMOR. IS IT DIFFERENT IF THE TUMOR WERE A B CELL OR ANTIGEN PRESENTING CELL? THE ANSWER IS YES AND NO. SO THERE ARE, AS FAR AS I KNOW, NO TUMORS OFF FUNCTIONAL DENDRITIC CELL. THERE ARE TUMORS IN DOGS AND I THINK THAT THEY ARE [INDISCERNIBLE] TUMORS, TWO TYPES. THERE IS ONE IN BERNIE'S MOUNTAIN DOGS, WHICH KILLS THEM. AND THERE IS ONE THAT'S PREVALENT IN BOXERS, I THINK IT'S BOXERS, WHICH HAS A COMPLETELY DIFFERENT BROKINGNOSIS. WHAT HAPPENS IN THE BOXER, AND I KNOW OFF ONE SHELTIE ALL RIGHT THAT HAD IT, AS WELL. YOU GET A CUTANEOUS TUMOR. IT GROWS. AND THEN IT NECROSIS AND DISAPPEARS. YOU GET ANOTHER ONE, SAME THING. ANOTHER ONE, SAME THING. FINALLY YOU DON'T GET THEM ANYMORE. THERE WAS A GUY IN CAMBRIDGE, ENGLAND, A VET DOING A Ph.D. OR POSTDOC. I DON'T KNOW THAT HE EVER PUBLISHED. BUT I HEARD HIM GIVE A TALK WHERE HE ANALYZED THE DIFFERENCE IN FUNCTION OF THOSE TWO KINDS OF TUMORS. AND THE BERNIE'S MOUNTAIN DOG TUMOR IS A VERY, VERY EARLY DENDRITIC CELL TUMOR, DOES NOT ACT AS APC. AND THE OTHER ONE, THE BOXER ONE, CAN ACT AS AN APC. SO HERE IS WHAT I THINK IS HAPPENING. YOU'VE GOT THIS TUMOR GROWING IN SKIN. IT'S AN UNACTIVATED DENDRITIC CELL. THE DOG GETS A FLEA BITE OR PLAYING WITH A LITTER MATE. THE CELLS GET ACTIVATED. NOW THEY PRESENT THEIR OWN TUMOR ANTIGENS, THEY GET AN IMMUNE RESPONSE AND GO AWAY. IN BERNIE'S MOUNTAIN DOG, EVEN IF THEY GET ACTIVATED -- I DON'T EVEN KNOW THIS THEY CAN. THEY DON'T ACTIVATE -- B CELL TUMOR IS INTERESTING. I DON'T KNOW IF I SAID IT YET. I'LL SAY IT AGAIN. I COINED THE TERM PROFESSIONAL APC. WHICH MEANS I GET TO DEFINE IT. RIGHT? OKAY. A PROFESSIONAL APC IS AN APC THAT CAN TURN ON A NAIVE T CELL. A SEMI PROFESSIONAL IS AN APC THAT CAN TURN ON NAIVE -- SORRY, MEMORY T CELL. B CELLS ARE SEMI PROFESSION. IF THEY PRESENT TO A TRULY NAIVE C CELL, IF THEYDUCE TOLERANCE. WE FIRST SHOWED THAT, OTHER PEOPLE HAVE REPEATED THAT. IT'S HARD TO DO BECAUSE YOU REALLY NEED A POPULATION OF TRULY NAIVE T CELLS. IF THEY PRESENT TO A MEMORY CELL, ARREST GOING MEMORY CELL, THEY INDUCE ACTIVATION. THIS ARE THEORETICAL REASONS WHY THAT SHOULD BE. THOSE ARE THE DATA. A B CELL IS A SEMI PROFESSION. DENDRITIC IS PROFESSIONAL. [INDISCERNIBLE] I HAVE NO REASON FOR THINKING THAT A MACROPHAGE SHOULD NOT BE A PROFESSION. UNLIKE A B CELL. SO IF IT'S A B CELL TUMOR, AND THE CELLS THAT CAN SEE IT ARE KNEE EVE, THEY WILL BE TOLLS ARED. IF IT'S A B CELL TUMOR AND THE CELLS THAT CAN SEE IT HAVE BEEN TURNED ON BY SOME CROSS REACTIVE ENVIRONMENTAL ANTIGEN, OR MAYBE THE VIRUS THAT IS CAUSING THE TUMOR, RIGHT, EPD FOR EXAMPLE, THEN THE B CELL, IF IT'S AN APC, IF THAT TUMOR CAN UPREGULATE, SHOULD BE ABLE TO TURN ON THE T CELL. WHAT PREDICTION MIGHT BE THAT B CELL TUMORS ARE NOT GOOD AT COSTIMULATING. THAT ISN'T ENTIRELY TRUE, BECAUSE EBV CELL LINES CAN BE MADE THAT ARE GREAT AT LEAST COSTIMULATING T CELL CLONES, WHICH ARE MEMORY CELLS. I DON'T THINK IT MAT ERS WHETHER THE TUMOR IS A SOLID TUMOR OR LIQUID TUMOR. IF IT'S NOT COSTIMULATING, IT'S NOT GOING TO TURN ON AND IMMUNE RESPONSE. AGAIN, THE MERE PRESENCE OF ANTIGEN IS NOT ENOUGH TO TURN ON AN IMMUNE RESPONSE. THIS TUMOR IS GROWING. WHILE IT'S GROWING, IF T CELLS ARE ALLOWED TRY THERE, IT'S INDUCING TOLERANCE. NOW, EVENTUALLY, IF IT'S A SOLID TUMOR, AND IT GETS BEG ENOUGH, AND IF IT'S POORLY VASCULARIZED, IT'S GOING TO START STARVING IN THE MIDDLE. NOW, STARVATION DEATH IS ALSO PROGRAMMED CELL DEATH. EVEN THAT ISN'T GOING TO TURN ON AN IMMUNE RESPONSE. UNTIL YOU GET SO MUCH DEATH IN THE MIDDLE OF THIS TUMOR THAT YOU OVERLOAD THE SCAVENGERING CAPACITY. WHEN THAT HAPPENS, THE CELLS STILL DIE BUT SOME OF THEM WON'T GET SCAVENGED. WHEN THEY DON'T, THEY GO INTO SECONDARY NECROSIS. AND THEY'LL RELEASE ALARM SIGNALS AND YOU MIGHT GET AN IMMUNE RESPONSE. RIGHT? IF THERE ARE PROFESSIONAL APC'S IN THIS TUMOR THAT CAN PICK UP THE ANTIGENS. AND IF THERE ARE STILL SOME T CELLS THAT CAN SEE IT. ALL RIGHT? SO BY THE TIME A TUMOR GETS TO THAT STAGE, THERE MIGHT BE 3C OF T CELLS LEFT. THAT CAN SEE THAT TUMOR. WHAT'S GOING TO HAPPEN, ASSUMING THAT YOU'VE GOT PROFESSIONAL APC'S IN THERE, YOU HAVE ENOUGH DEATH TO CAUSE ALARM SIGNALS. YOU OVERLOAD THE CAVENAGING, YOU ACTIVATE A LOCAL APC. DOES ANYBODY HAVE ONE OF THESE? I'M GOING TO RUN OUT, LOOKS LIKE. ALL RIGHT. I'LL TRY TO USE IT JUDICIALLY. THAT APC IS GOING TO GO TO A LOCAL -- LYMPH NODE. WHERE IT PRESENTS ANTIGEN. TUMOR ANTIGEN. ANYBODY HAVE A SHARPY? THANK YOU VERY MUCH. WONDERFUL. L HERE YOU HAVE AN ACTIVATED APC PRESENTING TIMER ANTIGEN. AND 3T CELLS THAT CAN SEE IT. LET'S SAY ONE COMES IN, LETS SIGNAL ONE, COSTIMULATED. MAKES A SMALL ARMY. OF T CELLS WITH SPECIFICITY. THEY'RE GOING OUT INTO THE PERIPHERY. AND IF THIS HAS HAPPENED, THE ENDOTHELIUM, BECAUSE OF THE DEATH GOING ON, IS GOING TO BE ACTIVATED. AND THOSE T CELLS, SOME, WILL FIND A TUMOR. NOW, HOW MANY CELLS CAN A KILLER CELL KILL? ANYBODY KNOW? ESTIMATES ARE 3-30 TARGETS BEFORE IT NEEDS TO BE RELEADED. ALL RIGHT? SO YOU LOAD THE GUN. SHOOT YOUR BULLETS, THEY BE YOU HAVE TO GET RELOADED, REACTIVATED. IT'S NOT AN EASY QUESTION TO ANSWER. THOSE ARE THE ESTIMATES. SO LET'S SAY YOUR THREE REMAINING T CELLS HAVE EACH MADE TEN. AND THEY GO OUT AND KILL TUMOR CELLS. EACH KILLS 3-30. YOU HAVE TEN TIMES 30. SO YOU'VE KILLED 300 TUMOR CELLS. NOW YOU NEED TO REACTIVATE THOSE T CELLS. THAT TAKES SOME TIME TO HAVE TO GO BACK INTO THE DRAINING NOTICED, THEY HAVE TO FIND THAT APC, WHAT'S THE TUMOR DOING IN THE MEANTIME? GROWING! MAKING MILLIONS MORE CELLS. RIGHT? YOU'VE LOST THE RACE. SO STEVE ROSENBURG, AMERICA'S MR. CANCER, HAD A BRILLIANT IDEA. AND THAT WAS IF YOU HAVE A TUMOR THAT HAS TUMOR INFILTRATING LYMPHOCYTES IN IT, PRESUMABLY BEEN ACTIVATED BY THIS PROCESS, BUT THERE AREN'T ENOUGH OF THEM, PULL THEM OUT OF THE TUMOR, GROW THEM UP IN BATH TUBS FULL OF IL-2, AND STICK THEM BACK IN. AND HE DID THAT! AND WHEN I FIRST HEARD HIM TALK, HE HAD A SET OF SLIDES WHICH I WILL NEVER FORGET. HE HAD A PATIENT WITH A MELANOMA METASTASIS IN THE LUNG, THE SIZE OF A SOFT BALL. FOR THOSE FROM FOREIGN COUNTRIES, THAT'S A BASEBALL THAT IS USED BY WOMEN WHO PLAY BASEBALL. CALLED A SOFT BALL, NOT AS HARD AS A BASEBALL. BIGGER. EASIER TO HIT. PEOPLE THINK WOMEN AREN'T ATHLETES, RIGHT? SO THEY GIVE THEM BIG BALLS TO HIT. ANYWAY, SOFT BALL. [LAUGHTER] HE GAVE THIS PERSON [INDISCERNIBLE] AND THE TUMOR WENT DOWN THE SIZE OF A BASEBALL. SEE GAVE THEM TILLS, THE TUMOR WENT DOWN TO THE GOLF BALL SIZE. THEN HE STOPPED. AND THE TUMOR GREW OUT AND KILLED THE PATIENT. NOW, WHAT WAS WRONG WITH THAT THERAPY? SOMEBODY? HE STOPPED! NOW, WHAT YOU THINK INFLUENCING WHAT YOU DO. AND IF YOU'RE STUCK IN THE OLD SELF-NON SELF-MODEL, THEN YOU THINK THAT THE MERE PRESENCE OF ANTIGEN IS ENOUGH TO MAINTAIN AN IMMUNE RESPONSE. ONCE YOU GET GET THAT IMMUNE RESPONSE GOING, THE PLEASANCE OF THE ANTIGEN SHOULD MAINTAIN IT. AND SO YOU THINK THAT BY GETTING THAT IMMUNE RESPONSE GOING, YOU CAN CLEAR THE TUMOR. BUT IT'S NOT TRUE. THE MERE PRESENCE OF ANTIGEN ISN'T SUFFICIENT TO MAINTAIN AN IMMUNE RESPONSE. YOU NEED COSOMETIMUATION. YOU NEED ACTIVATED APC OF C. FOR THE SECONDARY, YOU DON'T NEED PROFESSIONAL APCs, YOU CAN DO IT WITH SEMI PROFESSIONALS, BUT YOU NEED COSTIMULATORY APCs. NOW, THE USE OF TILLS IS NOT THE ONLY PLACE IN TUMOR THERAPY WHERE WHAT YOU THINK INFLUENCES WHAT YOU DO, IT'S ALSO TRUE FOR MANY PEOPLE WHO WORK WITH TUMOR VACCINE. THEY'RE IN WHAT I CALL VACCINE MODE. >> [INAUDIBLE] >> THE QUESTION S HE'S SURPRISED THAT ROSENBURG FOLLOWED THAT LOGIC. WHAT HE WAS PLAYING WAS A NUMBERS GAME, RIGHT? EXPANDING THE T CELLS THAT COULD SEE THE ANTIGEN. ABSOLUTELY RIGHT. AND IF HE'D HAD -- IF IT WAS A REALLY SMALL TUMOR, HE PUT IN ENOUGH T CELLS TO GET RID OF THE LAST TUMOR CELL. GREAT. EVEN THE SECOND SET OF T CELLS IS NOT ENOUGH. TO GET RID OF THE LAST TUMOR CELL. THEN YOU NEED TO BOOST THEM BECAUSE WHAT'S GOING TO HAPPEN, THEY'RE ACTIVATED, GOING TO KILL TUMOR CELLS AND GO INTO ARRESTING MEMORY STAGE. SO YOU HAVE THE NUMBERS. OKAY? NOW, IT'S ALWAYS TRUE THAT THEY HAVE FOUND -- THOSE PEOPLE HAVE LEARNED AND AMAZING AMOUNT OF STUFF ABOUT HOW TO USE THE IMMUNE SYSTEM TO KILL TUMORS, ONE OF THE THINGS THEY'VE DISCOVERED, IT'S NOT A GOOD IDEA TO USE OLD T CELLS. T CELLS THAT YOU PUT IN CULTURE FOR A LONG TIME, DIVIDED A LOT. YOU HAVE YOUNGER T CELLS, LONGER AT THE LAMERS. BUT MY GUEST IS IF THEY COULD BOOST THOSE T CELLS THEY COULD CLEAR THAT BASE SET. GOLF BALL, OKAY? THE NUMBERS ARE THERE. THEY CAN PULL THEM OUT OF SOMEBODY'S ARM AND SEE THEM WITH TETRAMERS, THEY CAN PUT THEM EARN CULTURE AND RESTIMULATE THEM AND SHOW THEY MAKE GAM RELATION -- INTERFERON. YOU NEED TO KEEP BOOSTING THEM. SO FAX MODE DOESN'T WORK HERE. WHAT DO I NEED BY VACCINE MODE? VACCINE, ONE SHOT, TWO SHOTS, THIS IS A TYPICAL THING YOU DO WITH A VACCINE. PRIME, BOOST. THAT WORKS FOR AN INFECTION. BECAUSE YOU PRIME, YOU EXPAND THE NUMBER OF T CELLS, YOU BOOST, EXPAND THEM AGAIN. THAT'S AS GOOD AS YOU'RE GOING TO GET. NO SENSE BOOSTING MORE. THEY GO INTO ARRESTING MEMORY STAGE. WHEN THE PATHOGEN COMES BACK, IT DOES THE DAMAGE THAT ACTIVATES THE APCs, THAT NOW REACTIVATES THOSE MEMORY CELLS. BUT KILLING A TUMOR, KILL ERS KILLING A TUMOR, UNLESS THEY'RE KILLING A LOT OF IT AND OVERLOADING THE LOCAL CAVENAGING CAPACITY IS NOT GOING TO MAINTAIN THE RESPONSE. KILLERS KILL BE REDUCING AS OPPOSED TO IN THEIR -- APOPTOSIS IN THEIR TARGETS. IF YOU HAVE A SMALL NO. AND YOU KILL, THEY GET APTOWSED, SCANAGED. >> THE QUESTION IS YOU WOULD PREKICK A SURGICAL RESECTION, NOT FOR THE PURPOSE OF CLEARING THE BUT FOR THE PURPOSE OF CAUSING DAMAGE, WOULD CAUSE THE TUMOR TO GO AWAY OR AT LEAST TO GET AN IMMUNE RESPONSE. SURE. BUT IN ORDER TO DO THAT, YOU HAVE TO NOT CLEAR THE TUMOR. RIGHT? SO MOST ONCOSURGEONS TRY TO GET ALL OF IT. THEY'RE GOING TO CAUSE SOME DAMAGE. ABSOLUTELY. THEY'RE GOING TO ACTIVATE LOCAL APCs. BUT THERE IS NO TUMOR ANTIGEN LEFT! SO THERE ARE TIMES WHEN THEY CAN'T GET RID OF THE WHOLE TUMOR? WHAT HAPPENS THEN. PREDICTION. FIRST I WAS TOLD JUST TWO WEEKS AGO, CAN'T REMEMBER WHERE I WAS TALKING ABOUT TUMORS, BY A SURGEON THAT IF YOU GO BACK IN THE LITERATURE, YOU FIND THAT DIRTY SURGERY, MEANING WHERE THEY DON'T GET THE WHOLE TUMOR, GIVES YOU SOMETIMES A BETTER PROGNOSIS THAN CLEAN SURGERY. SO I WOULD SAY THAT'S BECAUSE THE TUMOR ANTIGENS ARE THERE AND AFTER GETTING PRESENTED BY THE APC. BUT BY ITSELF, THAT'S ONLY A PRIME. RIGHT? IF YOU WANT TO GET RID OF THE LAST TUMOR CELL, YOU HAVE TO KEEP BOOSTING. WHEN YOU CUT THAT TUMOR, AND YOU LEAVE TUMOR ANTIGENS, IF THERE IS STILL T CELLS THAT CAN SEE IT, YOU WILL GET A RESPONSE. IT WILL COME UP, PEEK AT DAY 7, AND BE GONE BY DAY 14. OR DAY 30. REMEMBER THE LIFE OF A DENDRITIC CELLS, 3-21 DAYS. YOU ACTIVATE THEM, EXPRESSING TUMOR ANTIGENS, NOT EXPRESSING BUT PRESENTING. THEY'RE DEAD IN 21 DAYS. FEW DAYS AFTER THAT, YOUR LAST T CELL THAT NEEDS TO BE RESTIMULATED WON'T BE. IT'S GOING INTO A MEMORY STAGE. YOU NEED TO KEEP BOOSTING. SO THERE WAS A PAPER THAT I SENT OUT FOR YOU ALL TO READ. SHOWING THAT IF YOU DO DAMAGE IN A TUMOR, YOU CAN -- ACTUALLY WE DON'T KNOW IF IT WAS AN IMMUNE LEE SPONS. IF YOU DO REPEATED DAMAGE IN A TUMOR, YOU CAN OFTEN CLEAR THEM. WHO DID THAT? COLEY. BACK IN THE 1890s WHEN WE DIDN'T KNOW SQUAT ABOUT THE IMMUNE SYSTEM, BILL COLEY WAS INJECTING A NASTY MIX OF BACTERIAL TOXINS INTO TUMORS. NOW, HE HAD A VERY NICE PAPER IN 1898, WHICH FELL ACROSS LONG BEFORE WE COULD FIND PAPERS ONLINE. IN THE BOWELS OF THE NIH LIBRARY FOLLOWING REFERENCES BACK. I CAME TO THIS PAPER IN 1898. HE WAS INJECTING TOXINS. SO THE STORY OF COLEY IS INTERESTING. HE WAS A SURGEON. IN NEW YORK. AND HE RAN INTO THE RIGHT CIRCLES, FRIENDS WITH THE ROCKEFELLERS, ONE OF THE KIDS HAD A FIANCE WHO FOOT A TUMOR. AND COLEY IS A SURGEON. HE SAYS NO PROBLEM, I'LL CUT IT OUT. HE CUT IT OUT. AND IT RECURRED. AND SHE DIED ANYWAY. SO HE GOT REALLY INTERESTED IN TUMORS PAUSE OF THIS. THIS IS A SURGICAL FAILURE. AND HE STARTED LOOKING AT HOW TO CURE TUMORS. HE HAD A PATIENT WHO HAD A SARCOMA ON THE NECK THAT GOT AN INFECTION WITH A BACTERIUM CALLED ARSYPHILIS. AIR SYPHILIS IS A NASTY BUG. AND THE TUMOR WENT AWAY. IT WAS A LARGE TUMOR ANTIGEN, WENT AWAY. SO HE STARTED INJECTING TUMORS WITH THIS. AND UNFORTUNATELY, HE KILLED AS MANY PEOPLE AND HE CURED. SO HE DECIDED THAT WAS NOT A GOOD THING TO DO. WHAT HE STARTED DOING INSTEAD WAS MAKING A MIX OF THE TOXIN FROM AIR SYPHILIS AND FROM ANOTHER BUG WHO'S NAME I CAN'T REMEMBER, BUT IT'S IN THE PAPER -- SORRY? BASILAS. OF SOME KIND. IN A MIXER WAS ABLE TO MAKE TUMORS GO AWAY. HE DIDN'T CURE EVERYBODY. HE DID ABOUT 30% OF HIS PATIENTS THAT HAD SACOMAS. ONE COULD GUESS THAT THE ONES HE DIDN'T CURE WERE THE ONES WHERE HE COULD GET RID OF THE TUMOR HE COULD INJECT INTO, BUT THERE WOULD BE METABOLISM IN OTHER PLACES THAT HE COULDN'T GET TO. NOW, WHAT WAS -- METASTASES IN OTHER PLACES. A, HE WAS CAUSING DAMAGE TO THE TUMOR. B, HE WAS DOING IT REPEATEDLY. AND -- WELL, NO. HE WAS CAUSING -- HE WAS -- TWO THINGS. HE WAS LOCALLY CAUSING DAMAGE AND HE WAS DOING IT REPEATEDLY. NOW, WHAT'S IMPORTANT ABOUT LOCAL CAUSING DAMAGE? A, YOU TURN ON THE IMMUNE RESPONSE. RIGHT? THE DENDRITIC CELLS PICK UP TUMOR ANTIGENS AND PRESENT THEM. BY CAUSING DAMAGE IN THE TUMOR YOU ACT EVALUATE THE LOCAL ENDOTHELIUM IN THE TUMOR. WHEN THE IMMUNE SYSTEM GETS TURNED ON THE LYMPHOCYTES CAN GET TO IT. >> [INAUDIBLE] >> HE DID. ALL RIGHT. SO DIDN'T HE POINT OUT IN THE PAPER HE ALSO DID INJECTIONS REMOTELY? AND HE DID. AND THERE ARE PEOPLE TODAY STILL DOING THAT. THERE IS A COMPANY IN CANADA, DON IS THE HEAD OF THAT THAT MAKES A TOXIN, COLEY'S FLUID. TOXIN ISN'T A NICE WORD. AND THEY INJECT REMOTELY. THEY INJECT TO THE POINT OF GETTING FEVER. SO FOR THEM IT'S VERY IMPORTANT TO GET FEVER. NOW, FEVER IS SOMETHING AT LEAST IN EXPERIMENTAL CULTURES, THAT WILL ACTIVATED DENDRITIC CELLS. BY CAUSING SYSTEMATIC FEVER, YOU'RE NOT ONLY GOES TO ACTIVATE SYSTEMATIC DENDRITIC CELLS. YOU ALSO ACTIVATE THE ONES IN THE TUMOR. IN MY OPINION IT'S A LOT BETTER TO DO IT IN THE TUMOR. >> I WAS KIND OF WONDERING, WAS THIS LIKE THE FIRST CHEMOTHERAPY? >> I COULD YOU WOULD CALL IT CHEMOTHERAPY. >> BEFORE X-RAYS? HE DOESN'T MENTION AN X-RAY AT ALL IN THE PAPER. >> DOES ANYBODY KNOW WHEN X-RAYS WERE INVENTED? 1930s? 1905? BEFORE X-RAY. >> SO I MEAN I AGREE WITH HA -- >> I CAN'T HEAR YOU. >> HE SHOWED -- HE MADE AN ARGUMENT FOR A SYSTEMATIC EFFECT THAT YOU COULD INJECT REMOTELY AND HAVE ACTION EVEN ON THE -- >> IF HE GOT FEVER. NOW, THERE IS A PAPER IN DOG WHERE THEY USED BCG. IT'S ACTUALLY A VARIANT OF BOVENTUBERCULOSIS. -- BOVINE TUBERCULOSIS. USED IN BLADDER CANCERS. THEY ROLL THE PERSON GO IT GETS ALL OVER THE BLADDER. THERE IS A VENEARIAL TUMOR IN DOGS THAT -- THE INCIDENT IS GOING DOWN. DOGS DON'T MATE AS MUCH AS THEY USED TO IN THE PAST. THEY'RE ON LEASH AND NEUTERED. BUT IT'S A VENEARIAL TUMOR WHERE THE TUMOR IS TRANSMITTED SEXUALLY. GOT A VIRUS THAT'S TRANSMITTED. IT'S THE TUMOR. THAT TOMBINGER ALWAYS HAS THE SAME IMAGE C TYPE NO MATTER WHAT DOG YOU FIND IT IN. SO EVEN THOUGHTS AALLOGENIC, EXPRESSES MHC, IT'S TRANSMITTED CAPITALLY AND IT GROWS. THERE WAS A PAPER USING THE TUMOR WHERE THEY GOT DOGS THAT HAD THE TUMOR. THEY INJECTED INTO THE TUMOR OR ON THE OTHER SIDE OF THE DOG. THEY FOUND IT WAS MOST SUCCESSFUL IF THEY INJECTED IT INTO THE TUMOR. SO I THINK THERE ARE TWO REASONS FOR THAT. ONE YOU GET ACTIVATED APC THAT PRESENTS TUMOR ANDGENS, TWO, YOU ACTIVATE THE LOCAL ENDOTHELIAL CELLS. GO AHEAD. >> [INAUDIBLE]. >> I'M SAYING COLEASE PAPERS, TWO COINS CREES WITH CREATING THE DANGER. YOU DON'T ACTUALLY NEED THE SURGERY BECAUSE NOW THERE IS EVIDENCE THAT [INDISCERNIBLE]. ACTIVATES THE IMMUNE SYSTEM. LOTS OF PAPER OUT THERE WITH THAT. >> WAIT. HOW DO YOU THINK RADIATION DOES THAT? >> BECAUSE YOU CAN LEGITIMIZE ACTIVATION MARKERS. >> HOW DOES RADIATION -- >> BECAUSE RADIATION IS CREATING THE DANGER KILLING CELLS THAT AUTOMATICALLY ACT CONTRACT THE SYSTEM BY KILLING THE CELLS. >> MOST RADIATION CAUSES APPOTIC DEATH. I THINK RADIATION WORKS WHEN YOU KILL SO MANY CELLS YOU OVERLOAD THE SCAVENGING CAPACITY. I THINK PROTEIN THERAPY -- PROTON THERAPY. >> SO I THINK THE REASON THAT IN THE SENSE YOU NEED TO CREATE A DANGER AND THE FACT THAT YOU CAN INJECT THE TOXIN REMOTELY AND GET RESPONSE -- MOST OF THE [INDISCERNIBLE]. SO THEY CAN GO EVERYWHERE. AND THEY CAN BIND THE CELLS. AND THAT'S HOW SOME OF THE IDEAS BEHIND THE ONCOLOGY [INDISCERNIBLE] FOR TUMORS WORK. MOST TUMOR OR MOST VIRUS IS LIKE POLIO VIRUS. TREATING THE BLASTOMA, BECAUSE THEY CAN USE THAT INJECTED REMOTELY. IT FIND THE -- BECAUSE MOST -- YOU KNOW, EXPRESS THE [INDISCERNIBLE] RECEPTOR. SO YOU CAN -- AND GIVING THAT VIRUS, YOU KILL THE GLIOBLASTOMA. SO ALSO WORKS IN THE SENSE THAT YOU DO HAVE MOST TOXINS OR MOST VIRUSES WILL HAVE A RECEPTOR THAT EVEN IF YOU GIVE IT REMOTELY, IT MAY FIND THE TARGET. AWAY FROM THE INJECTION SITE. >> ACCEPT THAT AT LEAST IN THE COLEY'S CASE, AND ALSO THE CANADIAN MODERN VERSION OF THAT, IF I DON'T GET FEVER YOU DON'T GET A VERY GOOD RESPONSE. EVEN THOUGH THE TOXIN MAY BE GOING TO LOSS OF TISSUES -- THAT'S NOT A TOXIN YOU WANT TO USE. WHEN YOU GET ENOUGH ON THE TUMOR TO KILL THE TUMOR YOU'VE KILLED EVERYTHING ELSE. >> [INAUDIBLE] >> IT DOESN'T MEAN THE TOXIN IS BINDING TO THE TUMOR CELLS, NECESSARILY. THAT'S NOT SOMETHING YOU WANT TO DO UNLESS YOU CAN GET IT INTO THE TUMOR. IF YOU GET IT INTO THE TUMOR, USING A KNOWN SPECIFIC TOXIN IS FINE. SO YOU SAID SOMETHING ELSE REALLY IMPORTANT. RADIATION -- SO PEOPLE KNOW NOW FROM MOUTH STUDIES, THAT ONE OF THE WAYS IN WHICH RADIATION WORKS ON TUMORS IS THAT IT ACTIVATES THE IMMUNE SYSTEM. IF YOU DON'T HAVE AN ACTIVE IMMUNE SYSTEM, RADIATION ISN'T SO GOOD. YOU NEED TO ACTIVATE THE IMMUNE SYSTEM TO HAVE RADIATION BE REALLY EFFECTIVE. SO THAT BRINGS US TO ANOTHER PAPER WE READ, WHAT ASPECT OF THE IMMUNE SYSTEM DO YOU NEED TO ACTIVATE IN ORDER TO GET AN EFFECTIVE ANTI-TUMOR IMMUNE RESPONSE? SO MOST PEOPLE WORK ON TRYING TO ACTIVATE [INDISCERNIBLE] T. CELLS. WE HAD A PAPER TO READ THAT SAID THAT THEY DON'T WORK ALONE. ANYBODY READ THAT PAPER? ANYBODY WANT TO TELL ME ABOUT IT? NO? [INAUDIBLE] >> I'M SORRY? >> [INAUDIBLE] >> I CAN'T HEAR YOU. >> [INAUDIBLE] >> IT WAS ONE WHERE THEY SHOWED THEY NEED CD4 HELP. DON'T DO IT FROM YOUR SEAT. >> [INAUDIBLE] >> NO. WHO WANTS TO TELL ME ABOUT THE PAPER SHOWING THAT YOU NEED CD4 HELP? OKAY. >> I GUESS WHAT THEY DID THERE IS THEY -- I HAVE QUESTIONS ABOUT THAT PAPER. >> I HAD LOTS OF QUESTIONS ABOUT THE PAPER, TOO. >> THEY PUT THE BETA [INDISCERNIBLE] IN THE -- IN TUMORS. AND -- >> WHY DID THEY PUT IT IN THE TUMORS? >> BECAUSE IT ELICITS NORMALLY A PRETTY GOOD IMMUNE RESPONSE. >> NO. >> OKAY? >> NO. SO THE REASON -- THEY HAVE A TUMOR. THEY -- WHAT IS BETA GAL FROM WHERE DOES IT COME FROM? BACTERIA. IT'S A VERY FOREIGN MOLECULE. WHAT THEY WERE DOING HERE IS CREATE AN EXPERIMENTAL TUMOR ANTIGEN. AN ANTIGEN TO WHICH THE IMMUNE SYSTEM OUGHT TO RESPOND, STRONGLY. GO ON. >> OKAY. AND -- AND IT'S GROWING. >> THEY MADE BETA GALACTIC CITAS RESPONDING, REACTIVE CD4 T CELLS. >> HOW DID THEY DO THAT? >> BY SELECTING FOR CLONES THAT EXPRESSED IL-2. >> HOW DID THEY ACTIVATE THEM? >> HOW DID THEY ACTIVATE THEM? >> HOW DID THEY ACTIVATE -- SO THEY HAVE A MOUSE WITH A BUNCH OF CD4 T CELLS. THE TUMOR ITSELF ISN'T GOING TO DO IT. HOW DID THEY? ANYBODY? INJECT THEM WITH THE ANTIGEN? NO. BY ITSELF THAT WOULDN'T GIVE YOU AN IMMUNE RESPONSE. THEY MADE A VIRUS EXPRESSING BETA GAL. THEY IMMUNIZED THE MICE AND THEN THEY GET CD4 CELLS. THEN WHAT. >> OKAY. SO I MEAN MY ORIGINAL STATEMENT, I THOUGHT -- I WAS CONFUSED ABOUT THIS. SO THE BETA GAL IN THE VIRUS INDUCES A GOOD IMMUNE RESPONSE, NOT IN THE TOMB. SO IT'S IMMUNOGENETIC. >> IMMUNOGENIC IN THE VIRUS. >> RIGHT. AND SO THEY -- SO THEN THEY DID SOME STUDIES WHERE THEY CLAIMED, I GUESS, THAT THEY DELETED ALL THE CD8 POSITIVE T CELLS. >> HANG ON. START WITH -- DO THE CD8s GET RID OF THE TUMOR WITHOUT THE COWED 4s? >> NO. >> THAT WAS THE MOST IMPORTANT PART OF THE PAPER. IF THEY PUT IN THESE DOCUMENTER SPECIFIC CD4S, THE MOUSE DOES NOT CLEAR THE TUMOR. CD8s BY THEMSELVES DON'T DO THE JOB. THEY NEED HELP. SECOND POINT. GO AHEAD. >> SO THEN AT SOME POINT THEY SAID THEY DELETED ALL THE CD8 POSITIVE T CELLS. AND SHOWED THAT THEY COULDN'T CLEAR THE TUMOR THAT WAY. THEY DIDN'T REALLY SAY HOW THEY DELETED ALL THE CD8 POSITIVE T CELLS IN THE PAPER. >> THEY MADE A SECOND POINT IN THE PAPER THAT THEY DIDN'T REALLY SHOW, THAT IS, THAT THE CD4s DON'T DO IT BY THEMSELVES. THE WAY THEY DID THAT, PUT THE CD4 CELLS INTO MICE, CLASS ONE NEGATIVE. MICE DON'T HAVE CD8s, SO THEY PUT ACTIVATED ANTI-TUMORS INTO A MOUSE THAT DOESN'T HAVE CD8. AND THEY DON'T CLEAR THE TUMOR. FROM THAT EXPERIMENT, THEY CONCLUDED THAT THE CD4s BY THEMSELVES CAN'T DO IT. NOW, I DON'T AGREE WITH THAT. THE THING ABOUT CLASS ONE NEGATIVE MICE IS THEY CAN REJECT CLASS ONE POSITIVE CELLS USING NK CELLS. AND OTHER WAYS. SO WHEN YOU PUT CD4T CELLS INTO A CLASS 4 NEGATIVE MOUSE I DON'T NOTICED IF YOU NEED CD8s OR THE CD4s GOT REJECTED. THEY DIDN'T LOOK FOR THAT. THAT WAS A PROBLEM WITH THAT PAPER. BUT THE IMPORTANT PART ABOUT THAT PAPER THAT WASN'T PROBLEMATIC IS THAT IN THE ABSENCE OF CD4s, THE 8s DIDN'T WORK. SO PEOPLE WHO ARE MAKING EVACUATIONS FOR TUMORS -- EVACUATIONS FOR TUMORS USING SPECIFIC PEPTIDES THAT CAN BE SEEN BY CD8s NEED TO READ THIS PAPER. CD8 SAID BY THEMSELVES WITHOUT HELP ARE NOT GOING TO DO IT. SO HOW DOES A CD4 T CELL HELP A CD12348. >> [INAUDIBLE]. >> THAT'S THE RIDGE PAPER. HE'S GIVE ENOUGH IL-2 TO GET VASCULAR LEAKAGE. THAT WILL ALLOW CELLS TO GO INTO THE TUMOR. >> [INAUDIBLE] >> SO CD4S HELP CD8S BY WHAT WE CALL CONDITIONING -- THE TERM WAS INVENTED LICENSING. SO WHAT HAPPENS? THIS ARE TWO WAYS, WE STARTED THIS PAPER. TWO-WAYS. SO YOU HAVE AN APC, WHAT WAS ALREADY KNOWN IS THAT THE CD4 AND CD8 NEED DO SEE ANTIGEN ON THE SAME APC. THEY DON'T HAVE TO SEE THE SAME ANTIGEN. BUT THEY NEED TO SEE THE ANTIGEN ON THE SAME APC. SO THERE WERE 2 POSSIBILITIES FOR THAT REQUIREMENT. ONE, IF THIS IS THE CD4 T CELL, AND THIS IS THE CD8 T CELL, ONE POSSIBILITY IS THAT THE CD4 MAKES IL-2. THAT THAT GOES OVER TO THE CD8. ANOTHER POSSIBILITY WHICH WAS FIRST SUGGESTED BY KEVIN, REMEMBER KEVIN, THE ONE THAT INVENTED COSTIMULATION? AND CUNNINGHAM? IS THAT THE CD4 DOES SOMETHING TO THE APC, WHICH NOW ALLOWS IT TO TURN ON THE CD8. LONG STORY SHORT, THIS IS THE PROCESS, NOT THIS ONE. IN THE RIDGE PAPER, THAT WAS ONE OF THREE PAPERS FROM 3 LABS, SHOWING THE CD8 OR ANTI-TRANSPLANT NEEDED HELP. ONE OF THE THINGS IMPORTANT ABOUT THIS PAPER AND NOT USUALLY PICKED UP IS THAT THESE WERE MEMORY CD8s. NOT NAIVE CD8s. AND WHAT IT SAYS IS THAT EVEN THE MEMORY CELL NEEDS HELP. SO WHEN YOU PUT IN KILLS -- TILLS, AND PURIFY CD8 YOU NEED TO GIVE THEM SOME HELP. WHEN YOU BOOST THEM, YOU NEED TO GIVE THEM SOME HELP. CD8s BY THEMSELVES WON'T DO THE JOB. >> [INAUDIBLE] >> SO I DON'T THINK THERE IS A DIFFERENCE BETWEEN LAUGHERTY'S MODEL AND RIDGE. SO BOTH OF THEM -- I MEAN LAUGHERTY'S WAS THEORETICAL, JOHN RIDGE'S WAS THE DATA. HE WAS A TECHNICIAN, THE FIRST AUTHOR OF THE SCIENCE PAPER -- SCIENCE OR NATURE. TOOK HIM 4 YEARS TO DO THIS. THEY DON'T HAVE TO BE THERE AT THE SAME TIME. THAT'S WHAT IS REALLY IMPORTANT ABOUT THIS. THE CD4 LICENSING THE APC. YOU CAN NOW GET RID OF THE CD4S, THE APC WILL BE ABLE TO TURN ON THE CD8. WHAT'S IMPORTANT ABOUT THAT DISJUNCTION IN TIME IS THAT THE CD4 AGAINST ONE ANTIGEN AND CD8 AGAINST ONE ANTIGEN ARE BOTH RARE CELLS. THE CHANCES THAT THEY'LL MAKE THE APC PRESENTING THAT ANTIGEN AS THEY GO THROUGH THE LYMPH NODES, AT THE SAME TIME, IS REALLY LOW! EVEN WITH THIS DISCONNECT OF TIME. IT'S AMAZING. THAT THEY MEET THE SAME APC. NOW, RON'S GROUP HAD MORE DATA ON THIS BUT I ALREADY GAVE YOU CD8 PAPERS, SO I FIGURED -- I COULD HAVE GIVEN YOU 50. THEY SHOWED THAT WHEN THE 4 ARE YOU TURNS ON THIS APC, THE APC SOME HOW ACTUALLY CALLS TO IT THE CD8S. IT STARTS MAKING SOME KIND OF CHEMO KIND THAT DRAWS CD8S TO IT. WHEN THE CD8S GO THROUGH A LYMPH NODE, THOSE ARE THE APC'S THEY'RE MOST OFTEN GOING TO LOOK AT. OKAY? SO IF YOU WANT TO MAKE A GOOD TUMOR VACCINE, YOU NEED A EVACUATION THAT TURNS ON 4RISHS CELLS AND CD8 CELLS. THERE IS ALSO EVIDENCE THAT CD4S CAN DO IT BY THEMSELVES. >> [INAUDIBLE] HOW LONG IS THE LICENSING STABLE? I WOULD GUESS FOR THE LIFE OF THE DENDRITIC CELL. WE HAVEN'T DONE THAT EXPERIMENT. I DON'T KNOW THAT -- I'M TRYING TO THINK OF HOW YOU WOULD DO THAT EXPERIMENT. IN VITRO, A LOT OF THIS IS IN VITRO. SOME IN VIVO AS WELL. THE CULTURE CONDITIONS ARE NEVER GOING TO BE THE SAME AS IN VIVO. I SUPPOSE YOU COULD TAKE MALE DENDRITIC CELLS, EXINTERPRETSING HY. EITHER ALLOW THEM TO INTERACT WITH THE CD4 T CELL OR NOT AND INJECT THEM INTO A MOUSE THAT HAS NO CD4 T CELLS. AND THEN AT VARIOUS TIMES YOU COULD ADD KNEE HE HAVE BEEN CD8 AND ASK IF THEY GET ACTIVATED. NOT EASY BUT YOU COULD DO IT. I DON'T THINK ANYBODY HAS DONE IT. SO YOU'RE MAKING AN AIN'T TUMOR VACCINE, YOU HAVE TO COUNTRY ON CD4S, IS THERE EVIDENCE 4s CAN DO IT. I KNOW PEREZ, ANOTHER PAPER I COULD HAVE GIVEN YOU TO READ. I KNOW SYNRESEARCHER HERE AT THE -- IS A RESEARCHER AT THE NIH. NOT ONLY A GREAT ANTI-TUMOR RESEARCHER, ALSO -- I DON'T KNOW, [INDISCERNIBLE] IN TAEKWONDO. SHE REPRESENTED THE U.S. IN SOME TOURNAMENTS IN KOREA, AN AMAZING WOMANING. ANYWAY, SHE SHOWED THAT CD4 T CELLS, CALLED MARYLAND, SHE USED CD8 T CELLS. [INDISCERNIBLE] A WORLD WAR I SPA. AN ANTIMALE KILLER. [INDISCERNIBLE]. AND SHE SHOWED FOR 6 DIFFERENT TUMORS, FROM DIFFERENT TURNS, THAT WERE CARING HY, ALL RIGHT, SO MALE TUMORS, THAT THE CD4T CELLS ALONE COULD CAUSE TUMOR REJECTION. TOOK HER FOUR YEARS TO GET THAT PAPER PUBLISHED. SHE WENT DOWN THE LIST. NATURE AND NATURE MEDICINE, IT WAS FINALLY PUBLISHED I THINK IN CIRCULATION RESEARCH. NOBODY WANTED TO HEAR THIS. AND THEN A FEW YEARS LATER, JIM NELSON'S LAB AND NICK LAB HAD TWO PAPERS BACK TO BACK IN THE JOURNAL OF EXPERIMENTAL MEDICINE SAYING EXACTLY THE SAME THING. SO IT'S 3 DIFFERENT LABS SHOWING THAT YOU CAN CLEAR A TUMOR IN THE ABSENCE OF CD8 CELLS IF YOU HAVE GOOD CD4S. SO RIGHT NOW, I THINK THE TUMOR ERADICATION FIELD IS RATHER FOCUSED ON CD8S. BUT I THINK THEY NEED TO START FOCUSING ON CD4S AS WELL. A FEW PEOPLE ARE. A FEW FOCUSING ON CD4s. SO IF YOU DO DAMAGE TO A TUMOR, SUFFICIENTLY OFTEN ENOUGH, YOU CAN SOMETIMES GET RID OF IT. YOU CAN USUALLY GET RID OF IT. NOT NECESSARILY THE METASTASES. SOMETIMES YOU CAN TURN OFF METASTASES AS WELL AS. THE IMMUNE RESPONSE CAN DO THAT. HOWEVER, IF THE METASTASES IS HAPPY, MEANING IT'S ENDOTHELIUM IS NOT ACTIVATED, THEN EVEN THE ACTIVATED T CELLS MIGHT GO RIGHT ON BY. I KEEP PUSHING THIS. YOU NEED ACTIVATED ENDOTHELIUM, SO THE T CELLS WILL SLOW DOWN, ROLL, STOP, GO INTO THE LOCAL TISSUE. SO YOU NEED TO DO SOMETHING TO THE TUMOR. SO VACCINATING SOMEBODY IN THE ARM WHEN THEY'VE GOT A TUMOR SOMEWHERE ELSE MAY NOT WORK VERY WELL UNLESS YOU ALSO DO SOMETHING TO THE TUMOR. SO YOU NEED DAMAGE TO START THE IMMUNE RESPONSE, DAMAGE TO MAINTAIN THE IMMUNE RESPONSE, AND DAMAGE TO BRING THE IMMUNE RESPONSE TO THE TUMOR. INTHE TUMOR IS DYING A LOT, BIG SOLID TUMORERING, OVERLOADING THE SCAVENGENING CAPACITY, YOU HAVE ENOUGH DAMAGE AND YOU DON'T HAVE TO DO IT. IF IT'S TINY METED METIN -- METASTASES IN THE LUNG YOU MIGHT WANT TO GIVE SOMEBODY AN INHALER WITH SOMETHING NASTY. THIS IS A VERY GOOD EXAMPLE OF THAT IN ANOTHER PAPER I THOUGHT ABOUT GIVING YOU TO READ. WHICH IS NOT ABOUT TUMORS, BUT SHOWS YOU NEED TO HAVE DAMAGE IN THE TISSUE TO GET AN IMMUNE RESPONSE TO GET RID OF THE TISSUE. THAT IS A PAPER BY THE GROUP IN HIDALBURG WHERE THEY HAVE, AGAIN, TCR TRANSGENIC T CELL. IT'S T CELL RECEPTOR IS AGAINST H2KB, TIN HOUSE, A MAJOR CLASS ONE ANTIGEN. A REALLY GOOD TARGET FOR CD8 KILLERS. AND THEY ALSO HAVE ANOTHER MOUSE WHICH EXPRESSES -- I BET THEY HAVE SEVERAL, EXPRESSES KB. AND THEY HAVE SEVERAL MICE THAT EXPRESS KB. THEY HAVE ONE THAT EXPRESSES IT ONLY ON THE TIP OF THE TONGUE. THEY HAVE ONE THAT EXPRESSES IT IN THE SKIN. ONE THAT EXPRESSES IT EVERYWHERE. ONE THAT EXPRESSES IT IN THE LIVER. SO WHAT THEY DID WITH THE ONE IN THE LIVER IS INTERESTING. THEY ACTIVATE THESE GUYS. SO THEY NOW HAVE A POPULATION OF ACTIVATED CD8 T CELLS. AND THEY INFUSE THEM INTO THE MOUSE THAT EXPRESSES KB. ALL RIGHT? A LOT OF THEM. THESE ARE ACTIVATED. IF THEY TEST THEM IN CULTURE THEY KILL. CAN ANYBODY PREDICT WHAT HAPPENS TO THE LIVER? IT'S THE TARGET. WHO SAYS IT GETS REJECTED? WHO SAYS IT DOESN'T? SORRY? >> [INAUDIBLE] >> DOES THE LIVER -- SO THE LIVER IS CARING THE TARGET FOR THESE ACTIVATED CD8S. DOES IT GET REJECTED? >> [INAUDIBLE]. >> NOPE. NOPE. PERFECTLY FINE. IT IS TOTALLY PERFECTLY FINE. UNLESS THEY GIVE THAT MOUSE A VIRUS WHICH IS LIVER TROPIC. OR THEY GIVE IT A REALLY SMALL DOSE OF CARBON TETRO CHLORIDE. IT HURTS THE LIVER, CAN DESTROY THE LIVER. THEY GIVE A REALLY, REALLY SUBTLE, LETHAL DOSE AND CD8S, NOW IT WIPES OUT THE LIVER. SO SIMPLY ACTIVATING THE CELL IS NOT ENOUGH. YOU NEED TO DO SOMETHING TO THE TISSUE OR IF IT'S A TUMOR, YOU NEED TO DO SOMETHING TO THE TUMOR. OKAY. SO THERE ARE PEOPLE WHO HAVE UNDERSTOOD THAT YOU NEED TO KEEP THIS IMMUNE RESPONSE GOING. THIS IS NOT JUST THEORETICAL ANYMORE. WE HAVE TWO PAPERS THAT WE READ ASIDE FROM COLEY. WHERE THE AUTHOR SAID IT WAS IMPORTANT TO JUST KEEP BOOSTING THAT IMMUNE RESPONSE. ONE OF THEM WAS THE PAPER BY BEN DANDY. ANYONE WANT TO TELL ME ABOUT HIM? YOU'VE ALL BEEN BURNED. NO ONANTS TO GET TO THE MICROPHONE. YOU'VE DONE ONE. >> I'VE DONE ONE. >> YOU'VE DONE ONE. QUICK. >> HE BASICALLY HAD 33 PATIENTS, AND THEY ALL EXPERIENCED THEIR FIRST THREE LAPS OF LYMPHOMA, AND HE USED TO RESCUE [INDISCERNIBLE] TO ISOLATE THE PATIENT IN TUMOR SPECIFIC ANTIGENS FROM TUMORS. >> WHICH IS? DOES ANYBODY KNOW WHAT KIND OF ANTIGEN LYMPHOMA HAS A LOT OF? >> IT'S A B CELL THAT MAKES ANTIBODY. SO HE ISOLATED THE ANTIBODY THAT EACH INDIVIDUAL TUMOR WAS MAKING THIS IS PATIENT SPECIFIC THERAPY. >> SO HE ISOLATED PROTEINS, COUPLED THEM TO THE KEY HOLE [INDISCERNIBLE], AND INJECTED IT SUBQ WITH ADJUVANT. HE DID THIS FOUR INJECTIONS, ONCE A MONTH. THEN ONE BOOST TWO MONTHS LATER, FIVE MORE BOOSTS EVERY THREE MONTHS. AND 80% OF THE PATIENTS SHOWED A VACCINE INDUCED RESPONSE. TWO-THIRDS OF THESE SHOWED A RESPONSE THAT SLOWLY DECLINED WITH SUBSEQUENT VACCINES. >> WHAT HAPPENED TO THE TUMORS? >> BASICALLY, THEY GOT NO RELAPSES DURING THE VACCINE PERIOD. SO BASICALLY, THEY HAD REGRESSION. AND CERTAINLY, I GUESS THE QUESTION AT THE END OF THE PAPER IS DID THE PATIENTS DIE WHEN THEY STOPPED THE TRIAL. >> WELL, NO. SOME OF THEM. IF YOU'RE DOING A PERSONALIZED VACCINE, IT'S HARD TO KNOW WHAT TO USE AS A CONTROL. EVERY VACCINE IS DIFFERENT. EVERY PERSON'S VACCINE WASTH OWN ANTIBODY THAT THAT TUMOR WAS MAKING. SO WHAT THEY INVENTED, THE IDEA OF USING EACH PATIENT AS THEIR OWN CONTROL. SO THIS IS ACTUALLY THE USE OF A VACCINE WHICH HAS BEEN AROUND FOR A WHILE, THIS VACCINE WAS INVENTED BY A GUY NAMED RON LEVI AND STANFORD, AND THEY TAKE THE TUMOR, THE LYMPHOMA, THEY UBER DIES IT, THEY GET HYBRIDS THAT MAKE THE ANTIBODY. THEY STICK IT TO KLH, ADJUVANT AND INJECT IT. AND THEIR FIRST PROTOCOL WAS FIVE INJECTIONS. AND THEIRIFIES ONE TRIAL WAS ASTONISHING. THEY HAD, I THINK, IT WAS NINE PATIENTS. YOU GOT TO REALIZE THAT PHASE ONE IS A SAFETY TRIAL. YOU HAVE PEOPLE WHO ARE GOING TO DIE. GIVEN THEIR BODIES TO SCIENCE. AND YOU'RE ASKING THE QUESTION ARE YOU GOING TO KILL THEM FASTER THAN THEY WOULD DIE ANYWAY? AND OUT OF THE 9, I THINK 7 WENT INTO REMISSION. THAT'S AMAZING. FOR PHASE 1. HOWEVER, FIVE INJECTIONS. RIGHT? SOME OF THOSE PEOPLE, THEN, LATER RELAPSED. SO ROD LEVI HAD A POST-DOC, ANOTHER FAMOUS ONCOLOGIST. HE HAD A POST-DOC NAMED [INDISCERNIBLE]. AND HE DECIDED TO TRY USING THE SAME VACCINE AND JUST CONTINUING TO BOOST. SO THEY TREATED 25 PEOPLE. 20 OF THEM RESPONDED. 5 DIDN'T. NOW, FROM EARLIER PAPERS FROM THAT LAB AND THE GREAT GRANDFATHER, HEAVI'S LAB, WHAT THEY LEARNED IS THAT IF SOMEBODY STILL HAS MINIMUM RESIDUAL DISEASE, THEY PROBABLY WON'T RESPOND. THAT'S BECAUSE THESE ARE NOT PROFESSIONAL APCs, THESE ARE B CELLS EXPRESSING ANTIGEN. AND YOU HAVE A LOT OF B CELLS EXPRESSING THIS ANTIGEN. IN MY OPINION THEY INDUCE TOLL DOLLRANCE. YOU NEED A PERSON TREATED AND NO LONGER HAS RESIDUAL DISEASE. SO THEY TREATED 25 PEOPLE, 20 RESPONDED. OF THE, 218 HAD NOT RELAPSED BY -- OF THE 20, 18 HAD NOT RELAPSED. IN LYMPHOMAS, IF YOU TREAT SOMEBODY, AND THEY RELAPSE, THEY'RE GOING TO RELAPSE AGAIN QUICKER. AND THE REASON IS, THE REASON IS THEY HAVE A FEW CELLS RESISTANT TO THE CHEMOTHERAPY . ANY MUTATIONS MAKES THEM MORE RESISTANCE WILL GROW OUT. WHAT HAPPENS DO LYMPHOMA PATIENTS, THEY RELAPSE, AND THEN AGAIN, AND THEN AGAIN, AND THEN AGAINST SOON YOU CAN'T TREAT THEM ANYMORE. SO WHAT THEY FOUND WAS THAT 18 OUT HAVE 20 WHO RESPONDED HAD NOT RELAPSED BY TWICE THE AMOUNT OF TIME AT LEAST THAT THEY HAD RELAPSED THE FIRST TIME. AND BY TWICE THE AVERAGE RELAPSE TIME. NOBODY RELAPSED WHILE THEY WERE STILL GIVING THE VACCINE, WHICH WAS 2 YEARS. ONE GUY DIED AT 2-AND-A-HALF. HE RELAPSED. AND THAT IS AS FAR AS I KNOW ABOUT HOW FAR THAT PAPER WENT. I WAS GOING TO TRY TO GET AHOLD OF THEM AND SEE HOW THOSE PEOPLE ARE DOING NOW BUT I DIDN'T. MAYBE I'LL DO THAT FOR NEXT WEEK, SEE HOW THE PEOPLE ARE STILL DOING. SO 80% RESPONSE. AND IF YOU LOOK AT THE PAPER, MOST OFF THOSE PEOPLE ARE AT FIVE YEARS. THAT'S PRETTY GOOD. >> BUT THEY'RE NOT BEING VACCINATED ANYMORE. >> NO. ONE GUY DIED. AT 2-AND-A-HALF. SO WHAT IT SAYS IS IF YOU CAN KEEP VACCINATING LONG ENOUGH -- NOW, THIS TUMOR DOES NOT SO MUCH OF AN ACCESS PROBLEM. IT'S A LIMPOMY EYE. IN LYMPH NODES AND MACES LIKE THAT WHERE THE IMMUNE SYSTEM GETS TO ANY WAY. IF THIS WERE A SOLID TUMOR AND YOU WERE VACCINATING AND NEEDED TO BOOST AND BOOST YOU WOULD NEED TO BE DOING SOMETHING TO THE TUMOR. THAT WAS ONE WAY OF KEEPING THE IMMUNE RESPONSE GOING, WHICH IS KEEP BOOSTING. ANOTHER WAY THAT PEOPLE TRIED WAS TO LINK THE T CELL RECEPTOR TO AN INTERNAL PIECE OF A RECEPTOR FOR COSTIMULATION. SO THIS IS THE [INDISCERNIBLE] PAPER. RIGHT, WHAT DID THEY DO IS THIS THEY MAKE T CELLS, GET T CELLS FROM THE PERSON WHO HAS A TUMOR, IN THIS CASE, A LEUKEMIA. ALSO A B CELL TUMOR. BUT UNLIKE A LYMPHOMA, LEUKEMIAS ARE WHAT THEY CALL WET TUMORS, LYMPHOMAS ARE QUITE SOLID. AGAINST A B CELL MAKING ANTIBODY, THEY DIDN'T TARGET THE ANTIBODY. WHAT THEY TARGETED WAS A MOLECULE CALLED CD19, WHICH IS ON THE SURFACE OF JUST ABOUT ALL B CELLS. WHAT THEY'RE GOING TO DO WITH PEOPLE THAT HAVE A LEUKEMIA IS SIMPLERY WIPE OUT THEIR B CELLS. THEY'RE NORMAL B CELLS AND LEUKEMIA B CELLS. UNLIKE THE VACCINE WHICH IS TARGETED JUST TO THE TUMOR B CELL. WHAT DO THEY DO? THEY MAKE A T CELL. THAT HAS AN ANTIBODY AGAINST CD 19. SO ONE OF THE WAYS TUMOR ESCAPE THE IMMUNE SYSTEM, THEY LOSE MHC. WE KNOW THAT KILLER CELLS NEED TO BE PEP SIDES IN MHC. SO ANY TOMB THAT ARE MUTATES THAT LOSES THE MHC CAN NO LONGER BE KILLED WE A CTL. CAN BE KILLED BY NK CELLS BUT NOT A CDL. SO THEY MADE AN ANTIBODY AGAINST CD19. THIS IS SPECIFIC FOR CK19. AND THEY ATTACH IT TO A CD8, HINGE, AND THEN ATTACH IT TO A TRANSMEMBRANE REGION OF CD28. CD8. TYPE MEMBRANE. ANYBODY KNOW WHAT CD28 IS. A RECEPTOR FOR COSTIMULATION ON T CELLS. INTERNALLY, THEY ARATTACK IT TO AN INTERNAL ACTIVATING REGION OF CD28. I CAN'T REMEMBER WHICH DIRECTION THEY DID THIS. AND TO CD137. ALSO KNOWN AS 41BB. WHICH IS A RECEPTOR FOR ANOTHER COSTIMULATERY MOLECULE. SO TWO RECEPTORS FOR COSTIMULATION. THE CD28 TRANCES MEMBRANE, CD ALPHA AND CD19. WHAT THAT MEANS, WHEN THIS BINDS AND THE ANTIBODIES PATCH THROUGH -- BECAUSE OF THE BINDING IT WILL BRING THESE TOGETHER. AND IT'S GOING TO ACTIVATE NOT ONLY THIS COSTIMULATORY RECEPTOR BUT ALSO THIS. SO WHAT THEY'VE DONE HERE IS THEY'VE REMOVED THE NEED FOR COSTIMULATION ON THE TARGET CELL. THE SIMPLE BINDING OF THAT RECEPTOR TO THE TUMOR SHOULD BE SUFFICIENT TO KEEP REACTIVATING THAT T CELL. SO THAT WAS THEIR WAY OF KEEPING THE IMMUNE RESPONSE GOING. THEY KNOW THAT YOU HAVE TO KEEP IT GOING. SO WHAT HAPPENED? THEY HAVE PEOPLE THAT HAVE THIS TUMOR. THEY INFUSE THEM WITH A T CELL. THE PAPER HAD 14 PATIENTS. WHAT HAPPENED TO THEM? [INAUDIBLE] >> SORRY? >> [INAUDIBLE] >> FOR THE PAPER IT WAS 4. 4 HAD A COMPLETE RESPONSE. CD8 OF THOSE 14 RESPONDED. 4 HAD A COMPLETE RESPONSE. MEANING THEY GOT RID OF THEIR TUMOR. >> ABOUT A FOURTH OF THEM DID. >> 4. 4 OUT OF S ONE. >> 1/4 OF THE PATIENTS. 4 OUT OF 14. LESS THAN A THIRD, MORE THAN A FOURTH. WHATEVER THAT IS. 29%. CLEARED THE TUMOR. NOW, THEY NOTICED SOMETHING ABOUT THE ONES THAT DIDN'T. THAT IS, THAT THE T CELLS DIDN'T PERSIST. THEY HAVE A FIGURE EACH ONE OF THESE AS A PATIENT. WHATEVER. AND THEY LOOKED AT THE EXTENSION AND PERSISTENCE OF THOSE CAR T CELLS. AND THEY FOUND THAT ON THE WHOLE -- I CAN'T REMEMBER EXACTLY HOW IT WENT. THE COMPLETE RESPONDERS HAD T CELLS THAT PERSISTED. THERE WAS ALSO ONE PARTIAL RESPONDER THAT HAD T CELLS THAT PERSISTED. BUT EVERYBODY ELSE, WHETHER IT WAS A PARTIAL RESPONDER NON RESPONDER, THE T CELLS WENT UP MAY BE A LITTLE, MAYBE A LOT BUT THEY DISAPPEARED. FOR SOME REASON, THE CD28 OR CD137 WAS NOT WORKING IN SOME PEOPLE. IT WORKED IN FIVE OUT OF 14. IN FOUR OF THOSE FIVE IT HELPED TO CLEAR THE TUMOR. IN THE OTHER ONE, THEY GOT A PARTIAL RESPONSE. NOW, I DON'T KNOW WHY THIS WOULD BE. AND THEY DON'T KNOW, EITHER. THEY LOOKED DAHL KIND OF CHARACTERISTICS FROM THOSE PEOPLE TO TRY TO FIGURE OUT WHY THE T CELLS PERSISTED IN SOME AND NOT OTHERS. THEY COULDN'T FIND ANYTHING. BUT IN READING UP ON CD137, I DISCOVERED SOMETHING THAT MAY BE A HINT. AND THAT IS, THAT THERE IS A GUY NAMED KWAN, SHOWED THAT IF HE MADE CD137 NEGATIVE MICE, THAT WOULD BE 6 -- BLOCK AND H2B, OR C. [INDISCERNIBLE] THEY'RE DIFFERENCE IN A LOT OF WAYS, VERY DIFFERENT MICE. THE CD137 NEGATIVE B6s HAD UPREGULATION OF INFLAMMATORY. THE 137 NEGATIVE Cs HAD A DOWN REGULATION OF INFLAMMATION. THE SAME MOLECULE IN DIFFERENT ENVIRONMENTS CAN BE HALF DIFFERENTLY. IN SOME CASES IT CAN UPREGULATE T REGULARS, IN SOME EFFECTERS. THE LIGAND IS ON APCs. THE LIGAND IS ALSO ON NORMAL TISSUES. DEPENDING WHICH TISSUE IT CAN CAUSE A DIFFERENT RESPONSE. DEPENDING ON WHAT LEVEL IT'S AT, IT CAN CAUSE A DIFFERENT RESPONSE. THE WAY IT SEEMS THAT WORKS IS THAT THE 41BB AND LIGRAND ARE POTH ON THE MEMBRANE. AND THEY CAUSE EACH OTHER TO DOWNREGULATE. SO IF YOU NOW HAVE ANOTHER CELL WHICH HAS THE LIGAND, AT LOW LEVELS, YOU STILL HAVE A LOT OF DOWNREGULATION. IF IT HAS IT AT HIGH LEVELS, NOW IT HOLDS IT TO THE SURFACE. SO THAT'S ONE WAY IN WHICH IT COULD BE POSSIBLE TO TITRATE THE SIGNAL. I DON'T KNOW THAT THAT'S IT BUT ONE THING THAT JUNE AND HIS LAB MIGHT WANT TO DO IS SEE WHAT'S DIFFERENT BETWEEN B6 AND SEE IF THAT IS ALSO THE DIFFERENCE BETWEEN THE PATIENTS THAT RESPOND TO THIS CAR AND -- WELL, WHERE THEY CAN PERSIST AND THE ONES WHERE IT CAN'T PERSIST. >> I HAD A QUESTION, DIDN'T -- >> WE HAVE 7 MINUTES LEFT. >> ALL RIGHT. DIDN'T THEY USE A LINTY VIRUS TO EFFECT THE T CELLS. IS IT POSSIBLE IT'S IN SOME OF THE PATIENTS THAT THEY -- THEIR T CELLS WERE NOT AS TOLERANT OF THE VIRUS? >> I DON'T KNOW -- IT'S THE SAME -- I DON'T KNOW. POSSIBLE. >> JUST -- >> I DON'T KNOW HOW MUCH OF THAT VIRUS IS LEFT IN THE T CELLS OR EXPRESSED. >> BECAUSE LIKE -- >> YOU CAN IMAGINE THAT SOME VIRAL ANTIGEN -- IT'S A VIRAL VECTOR. I DON'T KNOW HOW MUCH VIRUS IS LEFT AND EXPRESSED. IF THERE IS SOMETHING EXPRESSED YOU CAN IMAGINE THAT SOME PEOPLE REJECT THOSE T CELLS. IT'S POSSIBLE. ABSOLUTELY POSSIBLE. >> I DON'T KNOW THAT. >> INSIDE. >> THEY HAVE ETAKEN THE VEERS OUT. WE KNOW LONGER HAVE THAT. SO THEY HAVE OTAKEN THE VIRUS OUT. >> [INAUDIBLE]. >> NO MORE ANTIVIRAL RESPONSE. BUT THE T CELLS DON'T WORK AS WELL EITHER. >> YOU NEED TO GO TO THE MICROPHONE. >> I'M DONE. >> SPEAKING OF DETROITO KINDS, WE HAVE FIVE MINUTES. I DON'T KNOW WHY THIS WENT SO LONG. WE HAVE FIVE MINUTES. UNLESS YOU WANT TO STAY. BUT YOU CAN'T STAY LONG BECAUSE THOSE PEOPLE HAVE TO GO HOME. THE OTHER THING PEOPLE HAVE DONE, RATHER THAN TRYING TO MAINTAIN TWO CELLS BY GIVING T CELLS OR BY BOOSTING, IS TO TRY AND UPREGULATE THE NATIONAL ACTIVITY OF THE FEW T CELLS THERE ALREADY TRYING TO GET RID OF THE TUMOR. RIGHT? AND THEY DO THAT BY WHAT THEY CALL CHECK POINT BLOCKADE. SO REMEMBER THOSE COINHIBITORY MOLECULES? WHICH ONE DID WE READ ABOUT? >> TD1. >> PD1. PD IS A MOLECULE, IF YOU STIMULATE IT, THE CELL GOES INTO APOPTOSIS. OR AT LEAST TIMES. SO THEY WANTED TO BLOCK THAT. TO SEE IF THE NORMAL APTOTIC SIGNALS GIVEN BY COINHIBITORY MOLECULES COULD -- IF YOU BLOCK THOSE, COULD I NOW ALLOW THE PERSON'S OWN NATIVE T CELLS TO EXPAND AND GET RID OF THE TUMOR. >> AND THE ANSWER IS YES, IN SOME CASES. RIGHT? SO THEY HAD 33 PATIENTS. I CAN'T REMEMBER EXACTLY NOW HOW MANY RESPONDED. I THINK IT WAS -- THEY HAD 33 PATIENTS TO START. THEY TREATED 25. I THINK IT'S GOING TO BE LIKE -- 18 OR SO RESPONDED. THEY HAD IN THIS CASE, CD8 COMPLETE RESPONSES. SO CD8 OF THOSE PEOPLE -- SO CD8 OF THOSE PEOPLE CLEARED THEIR TIMERS. -- EIGHT OF THOSE PEOPLE. SO EVERYBODY IS DOING WITHOUT THE SAME WITH THESE VARIOUS TREATMENTS. ONE OF THE DIFFERENCES IS THAT SOME OF THEM HAVE WORSE SIDE EFFECTS THAN OTHERS. SO PEOPLE WHO GET CHECK POINT BLOCKADE, THERE IS ACTUALLY A PAPER ABOUT ALL THE ADVERSE SIDE EFFECTS OF CHECK POINT BLOCKADE TESTS. THEY GET LITTLE UNDER HALF GET SKIN RASHES. THEY GET DIARRHEA. SOME OF THEM LOSE THEIR THYROIDS. SOME OF THEM, THE THYROIDS RETURN FUNCTION, SOME DON'T. IT'S PERMANENT. YOU'RE BLOCKING THE ACT OF THE COINHIBITORS DO WORK. AUTOIMMUNE PROBLEMS ARE SHOWING UP. IN MICE, YOU CAN KILL MICE WITH CHECK POINT BLOCKADES IF THE MICE ARE AUTOIMMUNE PRONE. SO RIGHT NOW, PATIENTS THAT HAVE AUTOIMMUNE DISEASES ARE ON THE WHOLE NOT IN THESE TRIALS. SO IF YOU HAVE AN AUTOIMMUNE DISEASE AND YOU GET A TUMOR, YOU'RE OUT OF LUCK. SOMETHING LIKE VAN DANDY, WHERE THEY'RE MAKING A VACCINE THAT TARGETS THE TOMB IRRELEVANT, THEY DON'T HAVE THAT. -- TUMOR, THEY DON'T HAVE THAT SIDE EFFECT. OKAY. WHAT ARE THE TAKE HOME MESSAGES, YOU NEED TO TURN ON AN IMMUNE RESPONSE AND MAINTAIN IT. UNTIL THE LAST IS GONE. YOU NEED TO DO SOMETHING TO THE TUMOR IF IT'S NOT LYMPHOID. YOU NEED TO DO SOMETHING TO THE TUMOR TO GET THE IMMUNE RESPONSE TO GO THERE. THE ONE THING YOU HAVEN'T DISCUSSED, YOU HAVE TO ASSURE YOUR IMMUNE RESPONSE IS OF THE RIGHT CLASS. AND WE'LL TALK ABOUT THAT WHEN YOU DO CLASS. WHICH IS NEXT WEEK. ALL RIGHT. IN THE FEW MINUTES LEFT ARE THERE NEW ANY OTHER QUESTIONS? >> [INAUDIBLE] >> WHY DO MHC1 DEFICIENT MICE REJECT POSITIVE CELLS? >> [INAUDIBLE] >> WHY DO THEY REJECT CD4S? THEY'RE GOING TO REJECT ALL KINDS OF CELLS THAT COME IN. SO PEOPLE USED TO THINK THEY WON'T REJECT ANYTHING. THEY DON'T HAVE A LOT OF CD8 CELLS. HOWEVER, THERE IS EVIDENCE FROM OUR LAB AND OTHERS THAT CD4S CAN REJECT TISSUES. SO THEY DO HAVE CD4 T CELLS. THEY ALSO HAVE HAVE NKT CELLS. THEYTHEYTHEYTHAT'S ALL I KNOW. >> [INAUDIBLE] >> HOW DOES CD4 T CELLS KILL A TUMOR? THAT I KNOW IS SECOND PAPER, WHICH IS ALSO TRYING TO PUBLISH FOR FOUR YEARS, AND NOBODY WANTS TO HEAR IT. SO QUICKLY, THE TAKE HOME MESSAGE, IS THAT IT CHANGES THE PHENOTYPES, THE CD4s CHANGE THE PHENOTYPE OF THE TUMOR INFILTRATING MARC PHAGES. -- MACROPHAGES. THAT'S ALL I'M GOING TO TELL YOU. SOMEBODY ACCEPT THIS PAPER. NOBODY WANTS IT. THE REVIEWERS DON'T -- THE EDITORS DON'T EVEN SEND IT FOR REVIEW SOMETIMES. BECAUSE IT'S BEEN DONE IN IMMUNODEFICIENT MICE. NOW, I KNOW HIS ARGUMENT, AND MINE TOO. IF YOU WANT TO SHOW A CD4 CLEARS A TUMOR IN THE ABSENCE OF CD8, YOU HAVE TO DO IT IN DEABSENCE OF CD8. YOU CAN'T DO IT IN NORMAL MICE. BECAUSE IF YOU DO IT IN NORMAL MICE, EACH WILL TELL YOU IT'S THE CD8s. >> SO -- WHAT DO YOU DO? YOU DO IT IN THE WAY, THE ONLY WAY YOU CAN DO IT AND THEN THEY TELL YOU THAT'S NOT A PHYSIOLOGICAL SYSTEM. I'M REALLY SORRY. I DON'T KNOW WHAT TO DO ABOUT THAT. >> [INAUDIBLE] >> IT'S THE SAME. >> [INAUDIBLE] >> YEAH. AND BY THE WAY, WE TRIED DEPLETING -- WHAT HE SAID. YOU HAVE TO PROVE YOU DEPLETED THE LAST CD8. BY THE WAY, IT'S HARD TO DO. WHEN WE TRIED DEPLETING CD4 WE TOOK THE MICE. WE DEPLETED THE CELLS USING 2 ANTIBODIED AND WE WAITED. AND THEY COME BACK. IN THE ABSENCE OF A THYMUS. NOW, THERE ARE [INDISCERNIBLE] COLONIAL AND HERE IS WHAT I THINK IS GOING ON THERE. THE DEATH IS PROBABLY ABOUT ADDC. AND AT THE TIME YOU DEPLETE THEM THERE WILL BE SOME T CELLS THAT ARE IN CENTERS. AND I DON'T THINK THEY'RE IN K CELLS IN CENTERS, SO THOSE T CELLS ARE PROTECTED. IT'S REALLY TOUGH TO COMPLETELY DEPLETE. >> THIS GOES BACK TO THE BEGINNING WITH THE -- >> COLEY? >> GREAT. >> HOW DID YOU KNOW? SO ONE PREDICTION WOULD BE THAT IF FEVERS CAN INDUCE THE WHOLE SALE ACTIVATION OF CELLS AND THAT'S WHAT'S RESPONSIBLE FOR THE EFFECT, YOU EXPECT PEOPLE OF CHRONIC ILLNESSES TO BE PRONE TO AUTOIMMUNITY TO SPONTANEOUS ABORTION, THINGS LIKE THAT. ARE YOU AWARE OF ANY CLINICAL DATA? >> THAT IS REALLY INTERESTING. >> OR PEOPLE WITH MALARIA. >> -- THIS IS A GUY THAT DOES NOT KNOWLEDGE IN A BOX. YES. -- NOT THINK IN A BOX. EVERY SINGLE NORMAL PREGNANCY IS ASSOCIATED WITH FEVER. OKAY. >> [INAUDIBLE] >> AT THE TIME OF DELIVERY YOU HAVE FEVER. THAT REMINDS HE OF IT OTHER OF COURSE I FORGOT TO SAY. SO SEVERAL PEOPLE HAVE WRITTEN ABOUT RH DISEASE. IF THE MODEL SAYS YOU DON'T REJECT FETUSES BECAUSE THEY DON'T LOOK DANGEROUS, WHY DO WOMEN RESPOND TO RH? AND THIS ONE IS INTERESTING. WOMEN GET PRIMED AT BIRTH. BIRTH IS DANGEROUS. YOU HAVE RIPPING, BLEEDING, SURGEONS WITH KNIVES. AND THE MEDICAL PROFITS KNOWS THIS. THEY KNOW THEY GET PRIMED AT BIRTH. IF THEY HAVE AN RH NEGATIVE WOMAN CARING AN RH POSITIVE CHILD, THEY GIVE HER ANTIBODY RIGHT AROUND BIRTH TO COVER UP THOSE ANTIGENS SO THAT SHE DOESN'T RESPOND. IT'S NOT THE PREGNANCY. IT'S BIRTH. SO IF THIS IS FEVER AT BIRTH, GREAT. YOU KNOW YOU'VE GOT A LOT OF STUFF HAPPENING. YOU WANT TO TURN ON YOUR IMMUNE SYSTEM TO GET RID OF INFECTIONS, A PLAY SENTA TO GET RID OF. -- PLACENTA TO GET RID OF THAT YOU MAY NOT GET RID OF IMMEDIATELY. I'M NOT SURPRISED. ANY OTHER QUESTIONS? OKAY. NEXT WEEK, HOW DO WE REGULATE