Human Vaccines & Immunotherapeutics

Transcription

>> GOOD AFTERNOON. IT GIVES ME A GREAT DEAL OF PLEASURE TO INTRODUCE TO YOU JACQUES BANCHEREAU, SENIOR VICE PRESIDENT, CHIEF SCIENTIFIC OFFICER, AND HEAD INFLAMMATION AND VIROLOGY DISCOVERY TRANSLATIONAL AREAS OF HOFFMAN-LA ROCHE. DR. JACQUES BANCHEREAU TRAINED AS A PHARMACIST AT THE UNIVERSITY UNIVERSITY IN FRANCE. THEN UNDERTOOK TRAINING IN PARIS WHERE HE COMPLETED A Ph.D. IN BIOCHEMISTRY. HE SHARED IN THE RESEARCH UNIT IN FRANCE AND BEGAN HIS SCIENTIFIC CAREER FOCUSED ON CYTOKINES AND DENDRITIC CELL BIOLOGY. IN 1992, HIS GROUP WAS THE FIRST TO DISCOVER HOW TO GROW DENDRITIC CELLS AND REGARDLESS OF WHERE HE HAS BEEN SINCE THEN, HIS WORK HAS BEEN CRITICAL PART OF OUR INCREASINGLY DETAILED UNDERSTANDING OF THE FUNCTIONALITY AND DIVERSITY OF THIS GROUP OF RARE BUT SENTINEL CELLS IN THE IMMUNE SYSTEM. IMPORTANTLY, HOWEVER, SHOCK'S WORK HAS GONE BEYOND DISCOVERY RESEARCH. HE HAS ALSO BEEN ONE OF THE TRUE PIONEERS IN TRANSLATING BASIC IMMUNE DISCOVERIES TO THE CLINIC. IN 1996, HE FOUNDED AND SERVED AS THE DIRECTOR OF THE BAYLOR INSTITUTE FOR IMMUNOLOGY RESEARCH, ONE OF ONLY A FEW STATUTES FOCUSED ESSENTIALLY PRIMARILY ON HUMAN IMMUNOLOGY. HIS WORK SOLIDIFIED HIS LEADING ROLE IN THE CLINICAL ROLE OF DENDRITIC CELLS AND EXPANDED FROM THE TREATMENT OF CANCER TO AUTOIMMUNE DISEASE AND INFECTIOUS DISEASE. DR. SORBONI BANERJEE IS ONE OF ONLY A HANDFUL OF SCIENTISTS - JACQUES BANCHEREAU RECOGNIZED AS A SCIENTIST AND A TRANSLATIONAL RESEARCHER AND A WEALTH OF EXPERIENCE IN ACADEMIA AND THE PRIVATE SECTOR. IN THIS WAY, HE IS TRULY UNIQUE. HE IS THE RECIPIENT OF NUMEROUS AWARDS INCLUDING THE DANA AWARD FOR HUMAN IMMUNOLOGY RESEARCH GIVEN BY THE AAI IN 2009. THE TILING OF HIS TALK IS WELL DENDRITIC CELL SUB SETS UPON US TO ADDRESS THE CANCER AND AUTOIMMUNITY DISEASE. WELCOME. (APPLAUSE) >> THANK YOU VERY MUCH. IT'S ALWAYS A PLEASURE TO BE HERE. WHAT I'M GOING TO DO HERE TODAY IS TO TAKE YOU THROUGH CASEIS OF THE IMMUNE SYSTEM AND FOCUS ON DENDRITIC CELLS. THE FIRST 15 YEARS -- (INDISCERNIBLE) THE FOCUS IS ON DENDRITIC CELLS AND WE'LL GO FOR IT. AND I'M GOING TO REPORT THE WORK THAT WAS DONE IN THE PAST 10 YEARS WITH MY COLLEAGUES -- [READING] A LOT OF FUNDING FROM NIAID AND LOTS OF FUNDING FOR THE HIV WORK FROM DALLAS, WHICH IS A BIT UNUSUAL AND FROM THE NIH AND THE OTHER ORGANIZATIONS. YOU HAVE SEEN MANY OF THIS BEFORE. (INDISCERNIBLE) THEY HAVE DONE MOST OF THE WORK I'M GOING TO SHOW TO YOU. WHAT BROUGHT ME TO THIS, IS THE FIRM FINDING THAT THE COMBINATION OF -- WHAT WE CLONED WITH MY FRIEND, FROM ONE OF OUR CLONES, THAT THE CONDITION OF GMCSF -- (INDISCERNIBLE) AT THE TIME THAT THE DENDRITIC CELLS WERE NOT VERY MUCH IN FASHION. AND ACTUALLY, WE WERE SO IN THE WAY OF IT THAT WE HAD PUBLISHED IN 1990 THAT THIS COMBINATION WAS MAKING MICROPHAGES. BUT THEN WE REALIZED WHAT WE HAD WAS NOTHING MORE THAN MICROPHAGES AND THAT, FOR ME, NEARLY 20 YEARS -- (INDISCERNIBLE) THE MAN COMMITTED TO INNATE IMMUNITY, VIA DENDRITIC CELLS, HAS BEEN VERY VIGILANT. IT WAS HARD TO SEE HIM GO THREE DAYS BEFORE HE WAS AWARDED THE NOBEL PRIZE. BUT HE IS WITH US ALL THE TIME TELLING US WE DID A GOOD JOB. SO RALPH HAVE DEMONSTRATED THAT THE MASTER FUNCTION, IN IMAGE AND FORM, DENDRITIC TRAVEL FROM THE RIVERAISE INTO THE DRAINING LYMPHNODE WHERE THEY COMMIT INDUCTION OF TOLERANCE, THE ELIMINATION OF T-CELLS THAT -- (INDISCERNIBLE) SOME OF THIS MIGHT BECOME REGULATORY. NOW, IF MICROBE SHOWS UP AND IF EVERYTHING GOES WELL, THE MIKE ROBE CAN MAKE SENSE AND THE DENDRITIC CELLS GET ACTIVATED AND NOW IT'S A COMPLETELY DIFFERENT ANIMAL THAT YOU HAVE. THE DENDRITIC CELLS THAT COMMIT THE ACTIVATION OF ANTIGEN-SPECIFIC T-CELLS AND B-CELLS CONTRIBUTE TO ELIMINATION OF THE IMMUNE SYSTEM. THE REENTERS ADDED COMPLEXITY TO THE SYSTEM IN THE SENSE THAT THE ANTIGEN CAN GO INTO THE DRAINING LYMPHNODES AND CAPTURED BY DENDRITIC CELLS IN THE LYMPHNODES AND WHAT WE HAVE LEARNED IS THAT ALL THE DENDRITIC CELL SUBSETS HAVE DIFFERENT FUNCTIONS, NO LAB HAS CONTRIBUTED MORE TO THAT THAN -- (INDISCERNIBLE) SO I AM GOING TO BE SUMMARIZING THE WORK OF THIS GROUP OF PEOPLE BY LOOKING THE THREE ASPECTS OF DENDRITIC CELLS. I'M GOING TO TACKLE THE BIOLOGY AND TACKLE THE ROLLING PATHOLOGY AND HOPEFULLY I AM GOING TO TRY TO CONVINCE YOU THAT THERE IS A FUTURE IN MANIPULATING DENDRITIC CELLS OR TARGETING DENDRITIC CELLS FOR THERAPY. THE STORY WAS 40 YEARS AGO WHEN CHRISTOPHE HAD GROWN CD14 TO THE DENDRITIC CELLS, HE REALIZED THERE WERE TWO SUBSETS OF THE CELLS. ONE WAS CD ONE A AND ONE WAS CD14. THE DERMAL DENDRITIC CELLS IN THE DERMIS. WHAT CHRISTOPHER FOUND AT THAT TIME IS THAT THE CELLS, THE TWO CELL TYPES WOULD HAVE DIFFERENT FUNCTION. ONE OF THEM WOULD MAKE -- IL10 WAS A CYTOKINE CLONED A FEW YEARS BEFORE AND IT'S THIS POPULATION AND INTERESTINGLY THAT POPULATION WAS INTERESTING -- (INDISCERNIBLE) IN TWO PLASMA CELLS, ONLY THIS ONE. NOT THIS ONE. THIS ONE WAS FULL OF NONSPECIFIC -- BUT THESE CELLS WERE BETTER ACTIVATED T-CELLS. AT THAT TIME, T-CELLS WAS NOT MY CUP OF TEA. SO, THE PAPERS WERE FOCUSING ON THIS ASPECT OF B-CELLS. TO INJECT THE DENDRITIC CELLS INTO HUMAN BEING, WE WONDERED HOW WE COULD MAKE THESE DENDRITIC CELLS BETTER AT ACTIVATING CD8 T-CELLS AND THIS IS THE WORK OF -- (INDISCERNIBLE) IN WHERE WE TAKE DENDRITIC CELLS FROM THE SKIN IN THAT CASE, LANGERHANS CELLS, AND A PEPTIDE BINDS AND PUTS NAIVE T-CELLS ON TOP AND NINE DAYS LATER LOOK FOR THE ANTIGEN SPECIFIC T-CELLS USING THE IMAGE SEATED FROM IT. AND WHEN YOU SEE IF YOU TAKE THE NINE CELLS, YOU HAVE MUCH MORE OF THE ANTIGEN-SPECIFIC CD8 T-CELL IN THAT CASE IT'S A MARKED PEPTIDE, THEN WITH THE DC. NOW IT'S QUANTITY ENOUGH? IS THAT IMPORTANT? WELL, IF WE WERE TO LOOK AT A SURROGATE MARKER, THAT MEANS THE PEPTIDE PLUS T2 CELLS, THOSE ARE CELL LINES YOU PUSH WITH THE PEPTIDE HAVE YOU USED. YOU SEE THE T-CELLS THAT YOU ISOLATE FROM BOTH CAN KILL THESE CELLS. IS THAT A MARK? I'M NOT SURE. BECAUSE IF YOU DO THE REAL EXPERIMENT, IF YOU SEE WHETHER THESE T-CELLS CAN KILL TUMOR CELL, LIKE THIS ONE MELANOMA CELL, THERE IS NO KILLING WITH CD8 T-CELLS. THERE IS A BEAUTIFUL KILLING WHICH IS INDEPENDENT OF THE CONCENTRATION OF CELLS. SO, WHAT'S GOING TO? WHAT IS GOING TO IS THE CELLS ARE NOT THE SAME. THE CD8 T-CELLS YOU MAKE WITH HUMAN CELLS EXPRESS A LOT OF GUESSING -- (INDISCERNIBLE) THE CD8 T-CELLS YOU GREW WITH THE CD14 HAVE. (INDISCERNIBLE) AND NOW YOU UNDERSTAND WHY THIS CD8 T-CELLS DON'T KILL THOSE -- (INDISCERNIBLE) IS THERE ANY FUNCTION FOR THIS CD14? THIS IS WHERE WE WENT BACK TO OUR FIRST LOVE, THE B-CELLS. AND IN THAT CASE, WE LOOKED AT WHETHER THE DERMAL DC AND THE LANGER CELLS WOULD DIFFERENTIALLY ACTIVATE CD4 T-CELLS AND AFTER A WEEK, WE COULD SORT THE CELLS ACCORDING TO THE STATUS AND THEN TOGETHER WITH B-CELLS AND SOME APPROPRIATE ACTIVATORS AND MEASURE THE IMGLOBULIN. AND WHEN WE COULD FIND IS THAT THE CD4 DERMAL DC WOULD GENERATE T-CELLS THAT WOULD HELP B-CELLS IN THE REMARKABLE FASHION. THOSE ARE IMGOBLIN AND YOU HAVE A STRONG SWITCH. WHILE THIS IS MADE WITH LANGER CELLS WOULD NOT DO THE JOB. THE CELLS HERE STICK TO WHAT IS NOW CALLED TSH OR -- T-CELLS AND THEY MAKE A LOT OF IL21. NOW HOW DOES IT WORK? WELL, OF COURSE THE PAPERS TELL YOU MUCH MORE DETAILS. BUT IT WORKS IN THE SENSE THAT THE IL15 MADE BY THE LANGER CELLS JUST SHOWS THAT YOU DON'T MAKE IL15, SEEMS TO BE VERY IMPORTANT FOR PRIME MEANS CD8 T-CELLS. WHILE THE DC MAKE IL12 AND HAS DEMONSTRATED THE IMPORTANCE OF IL12 IN IMMUNITY. CURRENTLY WORKING WITH -- TO LOOK AT PATIENTS WITH IL12 DEFICIENCIES AND WE ARE EAGER TO HEAR THOSE RESULTS. NOW THIS INDICATES THAT THOSE DENDRITIC CELLS IN THE DERMIS SEEMS TO BE VERY GOOD, PUBLISHED 15 YOURS AGO AND THEY ARE VERY GOOD IN -- (INDISCERNIBLE) UNDER THE SIDE, THESE CELLS ARE VERY GOOD IN CD8 AS WELL AS CD4. SO MAYBE ONE DENDRITIC CELL IS MORE IMPORTANT FOR IMMUNITY AND THE OTHER IS MORE IMPORTANT FOR CELL IMMUNITY. NOW THE CAVEATS WE HAVE IS OUR FRIENDS IN THE FIELD OF DON'T SEEM TO REPRODUCE THIS FUNCTION OF LANGER CELLS AND WHETHER THIS IS DUE TO HUMAN IN-VITRO STUDIES OR WHETHER THIS IS DUE TO 60 MILLION YEARS OF DIFFERENT ADMISSION, REMAINS TO BE SEEN BUT CERTAINLY IN THE DESIGN OF THE VACCINE, WE TAKE VERY MUCH ATTENTION TO THIS FINDING. NOW I JUST WANT TO INTRODUCE YOU IN A MINUTE TO ONE OTHER DENDRITIC CELL TYPE, A PLASMA CELL WHICH LOOK LIKE PLASMA CELL AND MAKE A LOT OF TYPE 1IFN. WE FOUND A STRANGE CELL TYPE THAT LOOKED LIKE A PLASMA CELL BUT COULD BECOME DENDRITIC CELL UPON ACTIVATION. AND IT WAS DEMONSTRATED THIS THESE CELLS WERE THE CELLS MAKING A LOT OF -- (INDISCERNIBLE) IT WAS FOUND YEARS BEFORE. THIS IS GOING TO BE IMPORTANT FOR THE PROGRAM I'M GOING TALK TO YOU ABOUT IN A MINUTE. THE THING ABOUT THE PATHOLOGY, I WANT TO DISCUSS FIRST THE ROLE OF DENDRITIC CELLS IN CANCER AND IMMUNOPATHOLOGY. THE FIRST PAPER THAT WE PUBLISHED AFTER I MOVED FROM FRANCE TO TEXAS, THE PAPER ABOUT BREAST CANCER WHERE WE LOOKED AT THE PRESENCE OF DENDRITIC CELLS IN BREAST CANCER AND TO OUR SURPRISE, WITHIN THE CANCER TISSUE, WE COULD SEE, MAKE SURE DENDRITIC CELLS, OR RIGHT NEARBY WHERE THE CANCER WAS. AND NEAR THIS MAJOR DENDRITIC CELLS WERE CD4 T-CELLS AND IT HAS BEEN THERE FOR 10 YEARS AND INDICATIVE OF -- (INDISCERNIBLE) TO DEMONSTRATE THE IMPORTANCE OF THIS T-CELLS. AND I'M GOING SUMMARIZE THAT IN THREE SLIDES. FIRST, DEVELOP A HUMANIZED MOUSE MODEL AND THIS IS MOUSE INTO WHICH YOU PUT CD34 AND THOSE MOUSE HAVE DENDRITIC CELLS AND B-CELLS BUT IN THE INITIAL MODEL THERE WAS NO T-CELLS BUT THEY COULD BE TRANSFERRED FROM THE -- (INDISCERNIBLE) THAN WHAT WE ARE DOING TO GET THE CD34 CELLS. AND WHERE WOULD WE PUT THIS TO OUR HUMAN TUMOR CELL LINES THE ADDITION OF THE CD4 T-CELL RESULTS IN THE EXPANSION OF THE BREAST CANCER CELL. THAT SURPRISED US. AND WHAT SURPRISED US EVEN MORE IS THAT THE CD4 T-CELLS THAT WERE THERE WERE MAKING A LOT OF IL13. A BIT REMINISCENT OF THE WORK OF -- (INDISCERNIBLE) IF YOU WERE TO ADD AN ENTIRE 13 TO THESE ANIMALS, THE TUMOR WILL NOT GROW ANYMORE SUGGESTING THAT THE T-CELLS INDUCE THE GROWTH OF IL13. IT DID SHOW THAT THE BREAST TUMOR CELLS ARE SINGLE AND THE IL13 FROM TH2-LIKE CELLS WOULD INDUCE DENDRITIC CELLS TO BECOME A PATHOGEN AND THIS POSITIVE WOULD INDUCE NAIVE T-CELLS TO BECOME TH2. I COULD SHOW THERE WAS -- (INDISCERNIBLE) IN THE BREAST CANCER IN THAT IN ADDITION, THAT THE BREAST CANCER CELLS WOULD PRODUCE A LOT OF TSLP. BRINGING HER TO DO THE EXPERIMENT WHERE SHIELD INJECT TUMOR T-CELLS AND DENDRITIC CELLS BECAUSE THEN SHIELD SEE THE GROWTH. BUT WITH AN ANTIT-CELL ANTIBODY, THE GROWTH WOULDN'T BE THERE. SO THERE COULD BE A POTENTIAL IN THIS FIELD. NOW I DON'T THINK THIS MEDICAL KEELED WILL WORK BY THEMSELVES -- MOLECULE WOULD WORK BY THEMSELVES. BUT THEY MAY BE IMPORTANT. AWE ALL THAT BRINGS US TO -- (INDISCERNIBLE) WHERE THE BREAST CANCER MAKES TSLP, THE TSLP INDUCE, ACTIVATES THE DENDRITIC CELLS IN A FASHION THEY EXPRESS AT 40 LIGAND AND MAKES THE TH2-LIKE T-CELLS AND THAT PERMITS THE BREAST CANCER TO GROW INTO RESISTANT CHEMOTHERAPY. SO THIS IS A PATHWAY THAT MAY BE QUITE INTERESTING TO DISRUPT INTO IN THIS FIELD. NOW SIMILAR STUDY HAVE BEEN REPORTED BY A GROUP FROM SAN RAFAEL IN THE CONTEXT OF PANCREATIC CANCER. SO THERE IS REALLY A POTENTIAL TO LOOK AT SERIOUSLY THE CONTEXT OF DESIGNING DRUGS. THE PATHOLOGY I WOULD LIKE TO DISCUSS BRIEFLY WITH YOU IS AUTO IMMUNITY AND MOST SPECIFICALLY WE FOCUS ON ONE WHICH IS -- (INDISCERNIBLE) AS YOU KNOW SYSTEMATIC LUPUS IS A VERY CEASE DISEASE FOR WHICH ONLY ONE DRUG WAS MADE IN THE PAST 50 YEARS AND IT'S CALLED -- (INDISCERNIBLE) IT IS AN ANTIBATH, WHICH NOT VERY OFTEN USED. THE DISEASE IS PREVALENT IN WOMEN AND CAN BE LETHAL THROUGH THE PROBLEM OF -- (INDISCERNIBLE) A COMPLETELY UN-TOUCHED DISEASE. A BIT OF A PROBLEM. OR IT CAN BE ALSO VASCULITIS THAT CAN GIVE YOU THESE PICTURES. SO, WHEN VIRGINIA PAS EQUAL JOINS THE LABORATORY, SHE WAS A YOUNG -- AND SHE IS ALWAYS YOUNG -- AND SHE WAS DOING A LOT OF WORK IN THE AREA OF PLACENTA. AND SHE DECIDED TO START STUDYING THE PATIENT SHE WAS SEEING. AND AT THAT TIME THERE WAS PATIENTS SHE HAD, CHILDREN WITH THIS DISEASE AND WOULD KEEP HER IN THE WEEDS MOST OF THE TIME BECAUSE OF THE VASCULITIS PROBLEM. SO, WE STARTED LOOKING AT THAT IN VERY SIMPLE WAYS. WE STARTED LOOKING AT THE BLOOD OF THESE PATIENT AND IN THE SERUM OF THESE PATIENTS AND WE DID AN EXPERIMENT THAT PROBABLY WAS NOT A VERY POPULAR EXPERIMENT. WE JUST SAID, MAYBE THERE IS SOMETHING IN THE SERUM THAT DOES SOMETHING TO THE IMMUNE SYSTEM. JUST TAKING THE SERUM OF PATIENTS AND PUTTING THAT ON -- (INDISCERNIBLE) AND LOOKING IN MULTIPLE FASHION BY MORPHOLOGY FUNCTION EXPRESSION, HAS BEEN ABLE TO FIND A LOT OF THINGS IN LUPUS BUT ALSO AUTOIMMUNE DISEASE TOO AND ACTUALLY A VERY IMPORTANT THING IN THIS FIELD. HERE IT IS A PAPER THAT WAS PUBLISHED ABOUT 10 YEARS AGO AND EVEN MORE THAN 10 YEARS AGO, WHERE MONOCYTES FROM -- (INDISCERNIBLE) OF THE INSTITUTE WOULD WOULD BE CULTURED WITH THE AUTOLOGOUS SERUM AND NOT MUCH WOULD HAPPEN BUT THEN CULTURED WITH THE KID'S SERUM, YOU SEE THE CELLS AGGREGATE, CLUMPS HAPPENING AND THEN THOSE CLUMPS BEING MADE OF CELLS THAT WERE -- (INDISCERNIBLE) ITOSE CELLS HAD ALL THE CHARACTERISTICS OF DENDRITIC CELLS. SO, THE IDEA IS, WHAT IS HAPPENING? WHAT IS DOING THE JOB? WE HEARD THAT CD40 LIGAND WAS HIGH. WE HEARD A NUMBER OF THINGS, GNC WAS HIGH AND THOSE ANTAGONISTS WOULD NOT PREVENT THE GENERATION OF THESE CELLS. WHAT WOULD PREVENT THE GENERATION OF THESE CELLS IS AN ANTIBODY OF TYPE 1. AND THAT LED US TO THE CONCEPT THAT TYPE 1 INTERFERE ON WOULD BE A VERY IMPORTANT ELEMENT IN THE FIELD. WHERE YOU COULD SEE THAT EVENTUALLY MAYBE, IFN MADE BY PDC WOULD BE VERY IMPORTANT IN ACTIVATING AND THEN YOU WOULD HAVE THIS IMAGE, THIS IMMATURE DC PRESENTING TO AN ANTIGEN AND MAKING ACTIVATED T-CELLS RATHER THAN INDUCING A TOTAL AUTOGENIC SIGNAL. AND THE OTHER OPTION WAS THAT THE INTERFERON WOULD EXFROM THE CELL TYPE AND COULD BE -- (INDISCERNIBLE) IN ANY CASE, NUMEROUS COMPANIES MOVED INTO THIS FIELD AND GENERATED ANTITYPE 1 INTERFERON WITH THE SAME ANTIBODY SOMEWHERE. AND THERE IS A HOPE THAT BY BLOCKING THIS ACTIVATION, WE MAY RESULT IN DATA ON SLE. BUT EVEN AS REPORTED SOME DATA IN TERMS OF WHAT INTERFERON DOES, AT LEAST THE ONE THING IT DOES, IT DOES EXTINGUISH A SIGNATURE OF INTERFERON IN THE BLOOD. WHAT IS THIS? WHEN WE FOUND THAT THE SERUM WAS INDUCING THE ACTIVATION OF DENDRITIC CELLS IN AN INTERFERON DEPENDENT FASHION, WE WENT LOOKING AT WHETHER THERE WAS A LOT OF INTERFERON IN THE SERUM. AND THIS WAS DIFFICULT TO FIND. YOU COULD FINE IT SOMETIMES AND SOMETIMES YOU COULD NOT. AND NATURALLY, WE WERE IN THE EARLY 2000 THEN AND ACTUALLY IN THE EARLY 1980s, A NUMBER OF INVESTIGATORS HAD FOUND THAT. ACTUALLY THE ROLE OF INTERFERON WAS FIRST DESCRIBED HERE BY -- IN THE NEW ENGLAND PAPER IN 1979. HE WAS BROADER THAN THE -- (INDISCERNIBLE) BUT THE FINDING WAS THERE. SO, HOW COULD WE CONFIRM THAT THIS INTERFERON WAS INDEED HERE? THAT'S WHEN WE MADE ANOTHER SEIZE OF UNPOPULAR EXPERIMENTS AND AS WE FELT THAT DOING MACRO ARRAY OF THE PBMC WOULD GIVE US A CLUE. FORTUNATELY I WAS FUNDED BY A CONTRACT. AND IN THAT COMMITTED US TO SEE AN AMAZING INTERFERON. IT WAS REMARKABLE. WE HAD 30 PATIENTS HERE. 12 ARTHRITIS PATIENTS, NONCONTROL, THIS IS OF COURSE EACH ONE HERE. AND EACH ROLE IS ABOUT 700 GENES. OR GENE TRANSCRIPTS. AND THEN WHEN YOU SEE HERE IS MOST OF THE PATIENTS ARE -- (INDISCERNIBLE) IT SEEMS THAT THE CHILDREN, MORE THAN THE ADULTS, RESULT IN 70% OF THE ADULTS, AND -- (INDISCERNIBLE) DOING THE SAME WORK AT THE SAME TIME AS THE ADULTS AND WHAT SURPRISED US IS THIS, THAT WAS PARTICULARLY IMPORTANT IN THE PATIENTS WITH A VERY HIGH -- (INDISCERNIBLE) AND IT'S A SIGN OF GRANULAR PARESIS. SO WE WONDERED THAT AND IT TOOK ABOUT TEN YEARS TO UNDERSTAND THE IMPORTANCE OF THAT GRANULAR PARESIS SIGNATURE. THE FIRST THINGS THAT WE WENT IS LOOKING TO THE ATROPHY OF THESE PATIENTS AND BY ISOLATING THE NEUTROPHILS BY THESE PATIENTS AND COMPARING THAT FROM NEWT FILLS, WE COULD SAY THEY WOULD DIE FASTER AS MEASURED BY JUST RED AND BLUE. SO THEY ARE FAR LESS ROBUST THAN THE OTHER ONE. NOW, NEWT FILL ARE -- NUT ROW FILL ARE SOMETIME TOO NEGLECTED. WE DON'T HAVE THEM YOU GOING TO DIE. SO 10 IT IS SOMETHING IMPORTANT HERE. BUT THOSE CELLS TIE IN INTERESTING WAYS. NOW I DON'T KNOW WHETHER THIS IS A PROCESS OF -- (INDISCERNIBLE) BECAUSE THESE CELLS ACTUALLY MAKE THOSE NETS FOR NEUTROPHIL TRAPS JUST LIKE THE GRADUATORS IN THE ANCIENT ROAM WERE USING NETS TO GET TO THE OTHER GLADIATOR. AND THIS NETS IN ADDITION, ARE TOXIC. AND THEY PERMIT PROBABLY THE REMOVAL OF THIS BACTERIA THAT ARE INFECTING. BUT THE QUESTION IS, WOULD WE HAVE MORE NETS IN THE NEUTROPHIL OF LUPUS AND THE ANSWER IS YES. I SHOW YOU THE DATA. I SHOW YOU THIS PAPER WHICH IS IN -- (INDISCERNIBLE) AND THOSE CELLS, WE WONDERED WHETHER THIS NETS MADE BY NEUTROPHIL EXPOSED TO IMMUNE COMPLEXITY, IF THIS NET WOULD ACTIVATE THE CELLS THAT MAKE A LOT OF INTERFERON TO SEE IF WE COULD EXPLAIN THE WHOLE THING AND INDEED, I COULD FIND THAT CERTAINLY WHEN YOU ACKIVATE PDC WITH CPG, YOU CAN ACTIVATE THE CELLS AS EXPRESSION OF CD83. YOU SEE THEM THERE. BUT IF YOU WERE TO PUT THIS IN NETS, YOU WOULD HAVE MORE CLUMPS AND YOU HAD A VERY HIGH EXPRESSION OF CD83. AND VERY INTERESTINGLY, IS THIS NET VERY POWERFUL ACTIVATOR OF INTERFERON PRODUCTION BY PDC IF WHAT IS INTERESTING TO ME, WE DON'T HAVE AN VERY FOR THAT YET. YOU HAVE TWO, THE NETS THAT ACTIVATES A LITTLE BIT LIKE CPG. JUST A LITTLE BIT. AND YOU HAVE THE SUPER ACTIVATING NETS. THE ANSWER IS NOT YET. BUT THIS IS GOING TO BE INTERESTING. NOW THIS IS NOT TO SAY THAT THE PDC DERIVED INTERFERON IS ACTUALLY THE WHOLE CAUSE OF LUPUS. IT COULD BE OTHER INTERFERON AND THERE ARE SOME VERY INTERESTING FINDINGS, THERE ARE VARIOUS GROUPS IN THE PAST COUPLE OF YEARS TALKING ABOUT MUTATIONS IN THREATS AND MOLECULES LIKE THIS WHICH RESULTS IN THE SYNDROME OF WHICH ARE MUTATED -- (INDISCERNIBLE) AND TEXT IS A MOLECULE, A DNA THAT MAY DEGRADE THE DNA FRAGMENT MADE FROM ANDROGEN -- (INDISCERNIBLE) IT'S A VERY INTRIGUING SET OF NEW FINDINGS AND THAT PUZZLED US. BUT PLAY EXPLAIN DIFFERENT CAUSES FOR THIS DISEASE. NOW, DENDRITIC CELL AND THERAPY. I MEAN COMING FROM US IT WAS A KIND OF A STATEMENT, I WAS TIRED OF THE CUISINE THERE AND FELT LIKE I WANTED TO TRY NEW ADVENTURES. SO THERE IN DALLAS, WE WANTED TO USE THE DENDRITIC CELLS MADE IN-VITRO AND INJECT THEM INTO PATIENTS. AND WE HAD FOCUSED OUR EFFORT ON LATE-STAGE PATIENTS AND MELANOMA BECAUSE WE KNEW FROM ANTIGEN, FROM THE WORK OF ANOTHER INVESTIGATOR, STEVE ROSENBERG AND -- (INDISCERNIBLE) AND WE USED THOSE ANTIGEN AND TRIED TO VACCINATE PATIENTS. AND THIS WAS THE CONCEPT LED BY RALPH THAT IMMUNOLOGY AND VACCINE BASED ON DENDRITIC CELLS COULD HAVE THE POTENTIAL FOR THE THERAPY OF INFECTION, CANCER, ALLERGY, AUTO IMMUNITY AND TRANSPLANTATION AND WE HAVE BEEN WORKING IN THE DIRECTION SINCE. THIS IS THE POOR MAN'S PATH. THIS PATH OF TARGETING IS FOR THE RICH MAN. NOW I WILL EXPLAIN WHY. SO THIS WE CAN DO IN-VITRO AND -- (INDISCERNIBLE) YOU NEED A GMP FACILITY AND YOU CAN GET MONEY FOR GMP FACILITY. YOU NEED TO GET GMP CYTOKINE. AND BASICALLY ONE PART OF DENDRITIC, THIS IS SIMPLE. IT HAS TO BE GMP COMPLIANT. THAT EXPLAINS OUR MIGRATION. SO, LET'S START WITH THIS. I LOVE THIS. AND I LOVE THIS. BECAUSE YOU CAN MANIPULATE. AND ACTIVATE THEM IN DIFFERENT FASHION AND COMBINE THEM AND PUT DIFFERENT ANTIGENS AND INJECT THEM. WE KNOW THAT NOW. AND YOU CAN SEE HOW YOUR IMMUNE RESPONSE IS GOING. SO IF YOU PUT IT TOWARDS 7, 4, WHICHEVER ACTIVATOR GIVES YOU AND YOU CAN DO HUMAN BEINGS ALSO. SO SOMETHING THE MOUSE CANNOT -- YOU CAN DO IT IN THE MOUSE BUT IT NOT GOING TO TELL WHAT YOU IS GOING TO HAPPEN. SO THIS IS GOING TO BE EXTREMELY IMPORTANT FOR THE NEXT TIME. WHICH IS GOING TO BE THE PRODUCT IN A BOTTLE THAT YOU CAN SHIP EVERYWHERE IN THE WORLD AND MAKE AVAILABLE TO EVERYBODY. WHAT WE NEED TO DO IS NOT SUCH A SIMPLE TASK. WE DIDN'T KNOW KNOW WE HAD TO DO ALL THAT. WE NEED TO REDUCE HIGHER CTL. WE ARE HAPPY TO JUST HAVE SOME GAMMA INTERFERON PRODUCING CELLS FOR A LONG TIME. YOU KNOW IT WAS NOT ENOUGH. WE NEED TO HAVE LONG-TERM MEMORY, CD4 AND CD8 T-CELLS AND PROBABLY TO GET THOSE LONG-TERM CD8 CELLS, YOU NEED TO HAVE CD4 CELLS THAT HELP. AND THEN YOU WANT REGULATORY T-CELLS. SO WHEN I STARTED, VERY FEW THINGS I KNEW AND I PROBABLY WAS NOT THE ONLY ONE BUT WE TRIED AND VE HAVE INJECTED 150 PATIENTS WITH STAGE 4 MELANOMA WHEN YOU START STAGE 4 MELANOMA YOU START YOURSELF IN A DIFFICULT POSITION BECAUSE YOU HAVE PEOPLE WHO ARE IMMUNOSUPPRESSED. WHAT YOU ARE TRYING TO DO WHEN YOU VACCINATE THOSE PEOPLE YOU'RE TRYING TO TURN ON THE IMMUNE SYSTEM WHICH IS VERY EFFECTIVE. YOU COULD USE THE T-CELLS, WHICH AVOID THAT PRIMING OR ACTIVATION AND WE KNOW FROM THEIR WORK THAT THOSE T-CELLS CAN BE FABULOUS AND CAN PROTECT YOURSELF VERY WELL. IF YOU COULD DO IT STRAIGHT IN VIVO, THAT WOULD BE VERY -- BUT ANY WAY, USING DENDRITIC CELLS, WE COULD SEE SOME SPECTACULAR DATA. NOT MANY. BUT A VIEW. THAT IS VERY AMAZING. AND I CONTINUE IS A DISEASE SO IT'S NOT THE WORST OF ALL. BUT IT'S VERY INTERESTING THAT THIS LADY WENT TO SEE A LOT OF SURGEONS AND A LOT OF THINGS THAT -- (INDISCERNIBLE) WE HAD SPENT FOUR YEARS TRYING TO SHOW TO GET GOOD CD8 T-CELLS IN A CERTAIN WAY THAT WOULD PEMITT US TO GET GOOD CD8 T-CELLS AND WE ARE SEEMINGLY STRONG LIKE THREE PATIENTS EVENTUALLY, TWO OBJECTIVE AND ONE AFTERWARDS, HAD COMPLETE RESPONSE. WE ARE DOING BETTER YET. THIS LADY HAS BEEN WITHOUT TUMOR FOR FIVE YEARS. AND WITHOUT ANY TREATMENT. WHAT WAS HAPPENING WITH HER? WELL, FIRST IS WE DID SOME ANALYSIS OF HER CYTOKINE RESPONSE. THIS IS PEPTIDE FROM THE MARKED MOLECULE. YES FOR MARK. AND WE COULD SEE AFTER VACCINATION THAT THE CLUSTER WOULD BE POSITIVE BEFORE THERE WAS -- AND THEN WE COULD IDENTIFY TWO SPECIFIC PEPTIDES AND OUT OF THOSE PEPTIDES, WE COULD MAKE TETRAMERS AND WE COULD SEE THAT ONE OF THE PEPTIDE WAS RECEIVING VERY STRONG PROLIFERATION OF CD8 T-CELLS, THIS PEPTIDE AND WE COULD MEASURE THIS NUMBER OF T-CELLS IN THE BLOOD IN THESE PATIENT. AND BEFORE VACCINATION, THAT LADY HAD .01% AND AFTER VACCINATION, THE AIDS VACCINE, 1% AND AFTER 2.5 YEARS, WENT UP. AT 5 YEARS SHE STILL HAD 1% CELLS. AT 5 YEARS SHE HAD TWO LESIONS WHICH WERE REMOVED. AND UNFORTUNATELY THE TWO LESIONS -- (INDISCERNIBLE) THIS LADY UNFORTUNATELY IN 6-8 MONTHS PASSED AWAY IN SPITE OF HER CD8 T-CELLS. SO THERE WE HAVE SELECTED THE BEST ONE. WE ALWAYS TRIED TO PUT SEVERAL PEPTIDES IN OUR PATIENT. PEPTIDES WOULD NOT SELECT FOR PATIENT LOSING ONE ANTIGEN. BUT OF COURSE YOU LOSE YOUR ONE, YOU'RE IN TROUBLE. WE STILL HAVE PATIENTS THAT ARE LONG TIME AFTER. SO THAT PUT US ONE THING. YES, YOU CAN INDUCE VERY GOOD T-CELLS, NOT ALL THE TIME. AND ONE OF THE DISEASES IS BECAUSE OF THE PATIENT IS BEING SUPPRESSED SO YOU NEED TO DO BETTER JOB. SO MAYBE IT WOULD BE TO VACCINATE THEM BEFORE THEY ARE LATE STAGE 4. MAYBE STAGE 3 WOULD BE GOOD. AS AN ACADEMY DOING THE STAGE 3 TRIAL AND THE RANDOMIZED TRIAL, I NEEDED 120 PATIENTS AND THE THERE IS NO WAY. SO, WHAT DO YOU DO? YOU PURSUE IT IN A NONESSENTIAL WAY AND SAY MAYBE I CAN HAVE PATIENTS THAT ARE, HAVE A BETTER IMMUNE SYSTEM AND I CAN ADDRESS THE QUESTION. WHO HAS A BETTER IMMUNE SYSTEM? MAYBE PATIENTS WHO ARE UNDER HEART THERAPY AND DOING VERY WELL. SO WE WENT AND ENTIRELY FUNDED BY THE NRS, SOMETHING THAT WAS 35 YEARS AGO IS GOING TO BE PRESENTED BY MAYBE NEXT MONTH. IT'S 19 PATIENTS THAT WILL RECEIVE FOUR VACCINATION OF DENDRITIC CELLS WITH FOUR MELANOMA PEPTIDE. AND THIS PEPTIDE -- FOUR HIV PEPTIDE, SORRY. THOSE HIV PEPTIDE ARE FROM THREE ANTIGEN AND ABOUT BETWEEN 25-35 MERES AND THEY HAVE A TAIL. (INDISCERNIBLE) THIS IS THE PRODUCT. SO WE WOULD VACCINATE THOSE INDIVIDUALS AND THEN 12 WEEKS AFTER THE LAST VACCINE, WE WOULD INTERRUPT HEART THERAPY AND EVENTUALLY IT WAS 48 WEEKS. I'M JUST GOING TO SHOW YOU THE DATA FROM ONE PATIENT HERE. BUT THIS IS A KIND OF DATA THAT WAS VERY LOOKING FOR. THIS IS THE VACCINE, THE T-CELLS IN THE PATIENTS BEFORE VACCINATION. THOSE ARE CD4 T-CELLS IN THIS, AND THIS IS THE TNF. THIS IS INTERFERON. THIS IS THE MIX OF THE PEPTIDE WE HAVE USED. AND THEN THIS IS GUIDE 17, GUIDE 253. AND -- (INDISCERNIBLE). AND THIS IS AFTER VACCINATION. SO THESE PATIENTS HAS ABOUT FIVE% CD4 T-CELLS WHICH ARE SPECIFIC FOR THESE PEPTIDES -- 5%. YOU CAN SEE IN THE 17 AND 253 AND F116 IS IMMUNOGENIC. WE HAD THOSE. NOW THIS DENDRITIC CELL VACCINE IS MY MISTAKE, HAD NOT GOT A SINGLE CD40. BECAUSE WHEN WE HAD THE DCD40 LIGAND WAS FROM OUR DATA THAT I WASN'T HAPPY WITH. THESE PATIENTS HAVE OVERALL MOUNTED VERY GOOD CD4 RESPONSES BUT THE 8 RESPONSE NOT AS GOOD. THOSE DATA WILL BE PRESENTED IN GREATER DETAILS IN MOSS FROM NOW. BUT THIS DATA ARE VERY ENCOURAGING IN TERMS OF THE QUALITY OF T-CELLS THAT CAME OUT WITH THE VACCINES AND THAT REALLY BRINGS US TO THE NEXT. SO WHAT WOULD BE THE NEXT PHASE? WE REALLY THINK THE PARADIGM THAT HAS BEEN GIVEN BY RALPH STEIN MAN IN USING FUSION, WAS A VERY FASCINATING PARADIGM IN THE MOUSE AND WE ARE TRYING TO PRESENT AND RATHER THAN DOING THE MOLECULE THAT ARRIVED, STUDYING MOSTLY, WE WENT IN A RATHER INDUSTRIAL FASHION WITH VERY STRONG SUPPORT FROM NIAID AS WELL FOR THE HIV PROGRAM FROM FRANCE INTO MAKING MONOCLONAL ANTIBODIES AGAINST 10 DIFFERENT MOLECULES TRYING TO SEE WHETHER THE MOLECULE WAS IMPORTANT. AND UNFORTUNATELY, AS WE PREDICTED, IT SEEMS THAT EACH MOLECULE IS IMPORTANT. IT IS AS IF NOT ALL THE RECEPTOR -- FINALLY ALL THE MILLIONS OF YEARS SELECTING AND COUNTER SELECTING TO DO THE SAME THING. SO THAT WAS OBVIOUS. NOW THE PROBLEM IS, WHICH ONE IS GOING TO BE GOOD FOR WHAT? NOW IT WOULD REQUIRE THAT WE KNOW WHAT IMMUNE RESPONSE IS GOOD FOR WHAT DISEASE. SO WE HAVE STILL A LOT OF CONUNDRUMS, A LOT OF PROBLEMS TO FACE. SO IT CAN FEEL GOOD AND STILL WORK FOR YOU. SO, THIS IS A MOLECULE THAT WAS CLONING MY FORMER INSTITUTE IN FRANCE, THIS WAS TOO. IT TOOK ME BASICALLY 17 YEARS TO GET A -- (INDISCERNIBLE) I'M GOING TO SUMMARIZE IT FOR YOU. A LOT OF PEOPLE HAD A LOT OF EFFORTS AND IT'S NOT FINISHED. I'M GOING TO TAKE MY NEXT 50 YEARS TO PUT IT IN FOR LESS. SO WE HAVE MADE CONSTRUCTS AND THIS IS GERARD. HE HAS MADE MORE THAN 2000 CONSTRUCTS WITH THE SAME PEPTIDE THAT WE USED ON OUR WIN CRITIC CELLS THAT HE HAS ADDED TO A CD40 MOLECULE. AND IT SHOWS YOU THAT THIS IS NOT A SIMPLE THING. A SINGLE PEPTIDE LIKE THIS ONE, THE TIP HERE PREVENTS EXPRESSION OF THIS FUSION IN THE -- AND YOU NEVER KNOW WHY. YOU HAVE GOT TO DO BASICALLY A VERY TEDIOUS WORK TO FIND A COMBINATION WITH APPROPRIATE FLEXIBLE LINKERS THAT WOULD PERMIT THE EXPRESSION IN THE SYSTEM AND GERARD FOUND THAT. AND HE FOUND THAT THIS, WHEN T-CELLS ARE GENERATED IN RESPONSE TO THAT CD40, THE CD8 T-CELLS THAT YOU CAN ADD TO CD4 T-CELLS AND HIV, WOULD PREVENT THE EXPANSION OF THE HIV AND EVENTUALLY KILL CD4 T-CELLS THAT HAVE THE PEPTIDE. SO THAT'S A GOOD SOURCE TO THINK ABOUT. NOW, THIS WAS FOR CD40. WE WANTED TO STUDY OTHERS. WOULD OTHER MOLECULES BE BETTER THAN CD40? BECAUSE WE MADE A SERIES OF CONSTRUCTS LIKE THIS ONE WHICH IS A CONSTRUCT -- (INDISCERNIBLE) A BIG GRANT AND THIS IS -- (INDISCERNIBLE) LOCKS? GPR AND SEEMS TO BE EXPRESSED BY THE SAME SUBSET AND NOT EXPRESSED BY LIGAND CELLS BY THE WAY. BUT WHEN YOU TAKE THIS PIECES TOGETHER AND YOU PUT T-CELLS, WHAT YOU SEE IS HERE YOU HAVE SOME PROLIFERATION OF THE T-CELLS AS SHOWN. SO THESE TARGETED ANTIGENS SEEMS TO BE ALLOWING A MUCH MORE PROLIFERATION. NOW YOU TELL ME HOW YOU KNOW ANTIGEN SPECIFIC AND WE DID THOSE EXPERIMENTS AND IT'S THE WORK OF -- (INDISCERNIBLE) JUST PUBLISHED TWO WEEKS AGO. THAT WAS A LOT. ANTIGEN WHEN WE REACTIVATE THE T-CELLS, AND LOOK AT IL10, WE CAN SEE SPECIFIC T-CELLS HERE AND BOTH T-CELL WITH BOTH CONSTRUCTS. WHAT IS REALLY CURIOUS IS THAT IF WE LOOK AT IL10, WE ARE ALWAYS MUCH MORE IL10 EXPRESSED BY THE T-CELLS THAN WITH THE LOX AND WE ARE LESS INTERFERON. SO THIS IS AN INVERT. SO A LOT OF WORK WENT THROUGH. WE KNOW IT'S BECAUSE AS GPR IMDEUCES DENDRITIC CELLS TO MAKE IL10 AND THAT COULD BE DONE BOTH IN TERMS OF ACTIVATION OF A MEMORY RESPONSE HERE. WITH AHA. NOW THIS T-CELLS YOU WANT TO KNOW WHETHER THEY ARE SUPPRESSED SO WHAT WE DID, I SHOULD SAY, IS TO SORT THESE CELLS AND WHEN YOU MAKE THEM WITH ANTIDCSGPR, IT SHOWS THESE CELLS SUPPRESS A REACTION OR ANTIGEN-SPECIFIC REACTION WITH THOSE MEN WITH ANTILOX DO NOT SUPRESS. (INDISCERNIBLE) NOW THAT'S WHERE I WAS VERY EXCITED TO TAKE MY APPOINTMENT AUTO MOUNT SINAI AND WORK WITH THE GROUP UNLESS THE MOUSE HAS SOMETHING THAT IS VERY FAR AWAY FROM THIS. IT HAS 25% MODEL AT BEST. WHAT IS INTERESTING IS YOU ARE -- (INDISCERNIBLE) THEY ARE DIFFERENT MOLECULES. WE COULDN'T DO THE SAME EXPERIMENTS IN THE MOUSE UNLESS WE DID THE WHOLE SYSTEM. SO WE TIED TO DO THE MONKEYS. AND WITH THE MONKEYS IN PARIS, WE VACCINATED ANIMALS WITH FLU AND THEN WE GIVE THEM EITHER LOXHA ONE OR LOXPSA, OR DCAGPRAH1 OR -- AND THEN WE TOOK THE BLOOD OF THE ANIMALS AT VARIOUS TIME POINTS AFTER THE LAST VACCINATION WITH THE -- AND WHEN YOU CAN SEE HERE THE ANIMALS THAT WE HAD IN TERMS OF PSA HERE AND SUBSEQUENT POOLS OF PSA HERE, THEY CAN MAKE GOOD CD8 RESPONSE UP TO 3 WEEKS. WHILE THOSE THAT HAVE BEEN TREATED WITH GPRPSA HAVE MUCH LESS OF A RESPONSE AND CONVERSELY, THOSE THAT ARE TREATED WITH GPR HAVE AS WEEK 1, EARLIER, MOVED FAR MORE IL10 THAN THE ANIMALS THAT HAVE BEEN WITH THE LOX. SO IT SEEMS THAT WE HAVE IT. WHAT IS MISSING IN THIS EXPERIMENT IS, WOULD WE CURE A MONKEY FROM DIABETES? THIS IS SOMETHING WE ARE AIMING AT. I'LL SPEND A FEW MINUTES ABOUT MY NEW DRUG. AND IT HAS BEEN MOSTLY INDUCED BY THAT WE COULD GET GRANTS TO DO ALL THOSE CANDIDATE VACCINE FOR FLU, FOR HIV, FOR SERIES OF CANCER, FOR TB, FOR CV, FOR HPV, FOR DIABETES. THE PROBLEM WAS, HOW ARE WE GOING TO TEST THAT IN THE HUMAN BEING AND HERE WAS THE PROBLEM. THE 5 MILLION DOLLARS FOR EACH BATCH. SO WE WENT TO INDUSTRY TO TRY TO GET FUNDING AND MAKE A COLLABORATION. AND ONE OF MY FORMER COLLEAGUES, WAS WHOM I HAD MADE TRIAL WITH AN ADVENT FOR FLU VACCINE IN 1992. HE WAS THEN HE HAD BEEN GOING AND NOW THE HEAD OF THE RESEARCH AT ROCHE. AND HE WAS IN FRONT OF THE PROBLEM THAT BIG PHARMA GENERATE 32 MOLECULE PER YEAR AND MAKE 4,500. IN OTHER WORDS, THAT COULD -- WE DON'T NEED ANYONE TO DO OUR MOLECULES. (INDISCERNIBLE) THIS IS VERY, VERY HUMBLING. CHALLENGING AND FASCINATING. SO WHAT WAS THIS? WHAT IS THE ANSWER OF THE COMPANY? WELL? THEY NEEDED TO HAVE MORE SO TWO VERY LARGE RESEARCH CENTER, ONE IS RESEARCH AND DEVELOPMENT AND IS THE HEAD OF PO R AND WE REPORT TO HIM. WE WERE PARTNERS HERE AND COMPANIES THAT ARE HERE BUT WE HAVE LAWYER ESTABLISHED A LOT OF PARTNERSHIPS IN THIS ACADEMY. AND THEN EVENTUALLY, THE LATE STAGE, PHASE III AND MANUFACTURING ALL THAT IS A SINGLE ENTITY. SO THE IDEA IS TO KEEP A LOT OF INVASION HERE. WE CAN THE PROBLEM IS LACK OF BIOLOGICS. WE THINK IT'S A LACK OF MEDICINE, A LACK OF UNDERSTANDING DISEASES. WE DON'T NEED MORE TECHNOLOGY IN SOME WAY. WE THINK THE PROBLEM IS THAT. WE HAVE NOW 28,000 GENES. PROBABLY WE ARE ALL MAKING TARGETS AGAINST TWO OR THREE00. AND THERE ARE 26,000 AND NO CLUE WHAT THEY ARE DOING. SO I THINK IT'S GOING TO BE EXTREMELY IMPORTANT FOR OPERATION LIKE NIH AND OTHER INSTITUTIONS TO ALLOW THE KNOWLEDGE OF WHAT ARE ALL THESE GENES DOING? WHAT IS THEIR ROLE IN DISEASE? IT IS EXTREMELY IMPORTANT FOR US, WE GOING TO BE DEEPENING THE UNDERSTANDING OF DISEASE BIOLOGY AND THIS IS WHERE WE DO OUR WORK COLLABORATIONS. WE WANT TO ABSOLUTELY KNOW MUCH MORE HERE. IT IS A PROBLEM THAT WE HAVE. WE ARE NOW LOOKING AT THE SAME GENES, AS I SAID, BUT WE HAVE A LOT TO DO. WE HAVE A LOT OF HOPES. WE CAN HELP PATIENTS BY BEING OR DOING MORE PHYSIOLOGY. SO HOW DO I SEE WHERE WE ARE TODAY? I SEE THIS IS WHERE WE'RE. WE HAVE LIKE A ROCKET THE PHASE I, PHASE II, PHASE III, I SHOULD SAY THIS IS THIS PART OF THE COST. BUT I THINK THE PROBLEM IS WE DON'T HAVE A WIDE ENOUGH BASE TO CHOOSE FROM IT WOULD HAVE BEEN WONDERFUL TO ADD LIKE THE SHUTTLE THAT WOULD PERMIT TO GET YOU TO THE PATIENTS. SO IN OTHER WORDS, IF YOU MAKE A SECTION HERE, THIS IS WHERE WE ARE TODAY. SO WE ARE TRYING TO -- (INDISCERNIBLE) SOME ARE PECKS ARE GOOD AND -- (INDISCERNIBLE) AND WE DO MULTIPLY THE NUMBER SO WE HAVE A WIDER BASE, HOW TO USE AND WE GOING TO HAVE ONE OF THOSE OR TWO OF THESE AND THAT MEANS WE GOING TO BE ABOUT -- THE ONES WE KNOW MORE BIOLOGY AND WE UNDERSTAND MORE ABOUT THE DISEASE WE'LL BE ABLE TO PUT MORE RESOURCES AND WE WILL BE ABLE TO REALLY MAKE THE MEDICINE OF THE FUTURE. BIG PHARMA HAS BEEN VERY SUCCESSFUL. YOU HAVE ALL THE DRUGS THAT ARE WONDERFUL. YOU THEY COST ALMOST NOTHING BUT THERE ARE STILL A LOT OF DISEASES THAT NEED THE DRUGS, THAT NEED NEW MEDICINE, AND IT'S ONLY THROUGH THE PARTNERSHIPS BETWEEN THE ACADEMY AND INDUSTRY THAT WE ARE GOING TO ADDRESS THIS NEED. TO CONCLUDE, I LIKE TO SAY, THAT TAKING DENDRITIC CELLS INTO MEDICINE, IS AS OF RIGHT, I LIKE TO DEDICATE THIS TO RALPH WHO PASSED AWAY. THANK YOU VERY MUCH.