WE'LL START WITH REVIEW OF MINUTES BY DR.S CANNON AND WOOLEY. >> CANNON, I THOUGHT THEY WERE FINE. >> THE DISCUSSIONS OF THE PROTOCOLS LOOKED TO REPRESENT OUR DISCUSSION. TOWARD THE END WHERE WE HAD THE BIOSAFETY DISCUSSION, THERE WAS A LITTLE BIT OF THE DISCUSSION THAT I FELT STILL NEEDED TO BE CAPTURED STARTING ON ABOUT PAGE 291 OF THE TRANSCRIPT. THERE WERE SOME COMMENTS BY DR. FOST AND THEN DR. CANNON AND RIGHT AFTER THAT, I MADE A COUPLE OF COMMENTS AND ASKED THEM QUESTIONS THAT LED INTO A VERY GOOD DISCUSSION ON THAT BIOBUBBLE WITH THE SUITS AND THE ISSUES SURROUNDING THAT WHICH WAS THE WHOLE REASON WHY WE WANTED TO GO TO OPEN CAGING TO AVOID THAT BIOBUBBLE. IT WAS ABOUT 17 PAGES OF DISCUSSION THERE. IN THE MINUTES IT WAS LISTED AS PUBLIC COMMENT BUT IT WASN'T PUBLIC COMMENT AT THAT POINT, IT WAS STILL RAC DISCUSSION. SO THERE WAS SOME DISCUSSION THAT WAS MISSED AND SOME DISCUSSION THAT WAS DOWN IN THE PUBLIC COMMENT PORTION OF THE MINUTES THAT PROBABLY WAS STILL RAC DISCUSSION. MY RECOLLECTION WAS THERE WAS NOT MUCH PUBLIC DISCUSSION. I THINK AT THE END YOU ASKED WERE THERE OTHER COMMENTS AND I DON'T THINK THERE WERE FROM THE PUBLIC. SO THOSE FEW CHANGES I WOULD RECOMMEND, OTHERWISE EVERYTHING LOOKED TO BE IN ORDER. >> JUST UPDATE THE COMMITTEE ON THE STATUS OF THIS DISCUSSION? FOR THOSE WHO WEREN'T HERE WE HAD A DISCUSSION AFTER HOUSING OF NON-HUMAN PRIMATES. >> RIGHT. RIGHT NOW THEY'RE GOING TO DO PROBABLY A PHASED IMPLEMENTATION OF THAT, WHERE WE CAN DO SOME CHANGES AFTER CONSULTATION THOSE CONSIDERED A MINOR ACTION AND THEN MOVE FORWARD TO ALLOW US TO IMPLEMENT THOSE RECOMMENDATIONS. >> LET'S START OFF BY HAVING INTRODUCE OURSELVES AGAIN. >> DR. DONAHUE. >> MY NAME IS KEVIN DON KNEW, DIRECTOR OF ELECTROPHYSIOLOGY RESEARCH UNIVERSITY OF MASS MARKS MY RESEARCH INTERESTS ARE CARDIAC ARRHYTHMIAS, MECHANISM OF ARRHYTHMIAS AND GENERAL THERAPY FOR ARRHYTHMIAS. >> I'M SAWATI CHAT GEE, I WORK WORK -- CHATTERJEE, I WORK -- >> JOE PILEWSKI, UNIVERSITY OF PITTSBURGH. INTEGRITY AND HOST DEFENSE. >> I'M HOWARD KAUFFMAN, I'M AT THE RUTGERS CANCER INSTITUTE NEWIER SIX MY INTEREST IS TUMOR KNEWMOLOGY AND ONCOLYTIC VIRUSES FOR MELANOMA. >> I'M MICHAEL ATKINS MEDICAL ONCOLOGIST AND DEPUTY DIRECTOR GEORGE LOMBARDI CANCER CENTER IN WASHINGTON D.C., INTERESTED IN IMMUNOTHERAPY MELANOMA AND KIDNEY CANCER. >> I'M LORI (INAUDIBLE) I TEACH AT NORTHWESTERN UNIVERSITY DEPARTMENT OF (INAUDIBLE) BUY ETHICS I'M INTERESTED IN BIOETHICAL ISSUES AN EMERGING RESEARCH. >> I'M DON DAWN WOOLEY, SCHOOL OF MEDICINE I STUDY HIV VIRAL VECTOR AN CERTIFIED BIOSAFETY PROFESSIONAL ALSO. >> REBEDA DRESSER, WASHINGTON UNIVERSITY BIOETHICS LAW RESEARCH ETHICS. >> DODGE KOHN AT UCLA T I STUDY GENE THERAPY WITH HEMATOPOIETIC STEM CELLS. >> P HAMMARSKJOLD, ASSOCIATE DIRECTOR AT THE RETRO VIRUS RESEARCH UNIVERSITY OF VIRGINIA AND I AM INTERESTED IN MOLECULAR BIOLOGY AND GENETICS OF VIRUSES AND VECTORS INCLUDING HIV I'M ALSO INTERESTED IN RNA BIOLOGY >> I'M PAULA CANNON, UNIVERSITY OF SOUTHERN CALIFORNIA, I'M INTERESTED IN JEAN THERAPY USING HEMATOPOIETIC STEM CELLS AND HIV. >> HANS KIEM, UNIVERSITY OF WASHINGTON FRED HUTCHINSON CANCER RESEARCH CENTER CLINICAL INTERESTS STEM CELL TRANSPLANTATION AND RESEARCH STEM CELL GENE THERAPY. >> PATRICK HERRING STONY BROOK UNIVERSITY WE STUDY ADENOVIRUS INFECTION AND ADENOVIRUS VECTORS. >> RICH WHITLEY, I'M INFECTIOUS DISEASE DIVISION UNIVERSITY OF ALABAMA BIRMINGHAM AND I'M INTERESTED IN USING HERPES PLEX TO TREATS GLIOBLASTOMA MULTI-FORM. >> SCOTT ANTONIO, MOFFET CANCER CENTER MEDICAL ONCOLOGIST FOCUS ON LUNG CANCER. >> LAYMY ROSS, UNIVERSITY OF CHICAGO GENERAL PEDIATRICIAN AND ASSOCIATE DIRECTOR OF MCCLAIN CENTER FOR CLINICAL MEDICAL HEALTHICS, RESEARCH AREA IS GENETICS. >> DENISE GAVIN FDA. >> RAC MEMBERS ON THE PHONE? (OFF MIC) >> OKAY. WE'LL MOVE WITH THE FIRST PRESENTATION. AND IT IS PROTOCOL NUMBER 14061319 PHASE 1 STUDY OF CHIMERIC ANTIGEN RECEPTOR MODIFIED T-CELLS TARGETING NKG 2D LIGAND PATIENTS WITH ACUTE MYELOID LEUKEMIA, ADVANCED MYODISPLASTIC SYNDROME AND MULTIPLE MYELOMA. PRESENTING WILL BE DR. BAUMEISTER, AN INSTRUCTOR AT HARVARD MEDICAL SCHOOL AND HEMATOLOGIST ONCOLOGIST AT BOSTON CHILDREN'S HOSPITAL AND DANA-FARBER CANCER INSTITUTE. HIS SPECIALISTS INCLUDE HEMATOLOGIC MALIGNANCIES AND HEMATOPOIETIC TRANSPLANT. ALSO DR. SYNCMAN, PROFESSOR MICROBIOLOGY, IMMUNOLOGY, HIS INTERESTS ARE NK CELL RECOGNITION MECHANISMS AS PART OF IMMUNE DEFENSE AGAINST CANCER INFECTION AND HOW NK CELLS AND T-CELLS EFFECTOR MECHANISMS AFFECT THE TUMOR MICROENVIRONMENT. I BELIEVE ALSO ON THE PHONE IS DR. DRENOFF, ARE YOU ON THE PHONE? HE MAYBE JOINING US. DR. DRENOFF PROFESSOR DEPARTMENT OF MEDICINE DIRECTOR OF HUMAN GENE LABORATORY TRANSFER CORE AND CO-LEADER AT THE DANA-FARBER CANCER INSTITUTE. DR. BAUMEISTER, GO AHEAD. >> GOOD MORNING. THANK YOU, VERY MUCH FOR THE OPPORTUNITY TO DISCUSS OUR PROTOCOL HERE. AND FOR THE VARIOUS REVIEW COMMENTS WE HAVE RECEIVED. AS MENTIONED, SENIOR CO-PI ON THIS STUDY WILL BE (INAUDIBLE) WHO WILL HOPEFULLY JOIN US SHORTLY BY PHONE. AND I WOULD ALSO LIKE TO KNOW THAT THERE ARE SEVERAL EXPERIENCED CO-PIs FROM THE STEM CELL TRANSPLANT DEPARTMENT AS WELL AS THE AML AND MULTIPLE MYELOMA DISEASE SPECIFIC CENTERS AT THE DANA-FARBER AS WELL AS CELL MANUFACTURING CORE. THE STUDY IS SPONSORED BY (INAUDIBLE) MEDICAL -- AND (INAUDIBLE) IS ALSO WITH US THIS MORNING CELDARA CHEMICAL AND THE PRE-CLINICAL INVESTIGATION AND YOU SEE HIS UI STATEMENT HERE. FOR THE AGENDA, I WOULD LIKE TO GIVE AN OVERVIEW OF THE CAR T-CELLS WHICH ARE NKG 2D CELLS AND NKG 2D LIGANDS AND BACKGROUND OF THE BIOLOGY OF THIS, I WOULD LIKE TO INTRODUCE YOU TO THE PRE-CLINICAL STUDIES SUPPORTING THIS THERAPEUTIC APPROACH AND GIVE AN OVERVIEW OF THE PHASE 1 TRIAL DESIGN. WITH PARTICULAR FOCUS ON THE MONITORING AND MANAGEMENT OF POTENTIAL SIDE EFFECTS AND THEN POINT OUT A FEW KEY FEATURES OF THE CONSENT. I'M SHOWING MOST IN THIS AUDIENCE ARE FAMILIAR WITH SHARE CONCEPT OF ANTIGEN RECEPTOR OR CAR T-CELLS BUT JUST TO REVIEW BRIEFLY THAT THE CLASSIC CAR T-CELL CONSTRUCT CONSISTS OF A COMPONENT OF AN ANTIBODY SINGLE CHAIN FRAGMENT VARIABLE REGION, CDC DATA CHAIN OF T-CELL RECEPTOR. THAT IS FIRST GENERATION CAR AND T-CELL AS MANY OF THE CARS THAT ARE NOW CLINICAL TRIALS, ALSO INCORPORATE AN ADDITIONAL CO-STIMULATORY DOMAIN SUCH AS THE CD 28 OR 41BB DOMAIN, FOR FOR ADDITIONAL CO-STIMULATORY SIGNAL IN THE T-CELLS. THE OVERALL CONCEPT OF CAR T-CELL THERAPY IS THAT PATIENT'S T-CELLS ARE MODIFIED TO EXPRESS CHIMERIC RESTORE AND THAT THE RECEPTOR RECOGNIZES A LIGAND OR MULTIPLE LIGANDS ON TUMOR CELLS, AND SUCH T-CELL CAN BE REDIRECTED TO RECOGNIZE THESE LIGANDS AND TO THEN KILL THE TUMOR CELLS. THE CMCS 1 CAR TARGETS NK 2D LIGANDS, IT IS A BIT DIFFERENT FROM THE CLASSIC T-CELL CONSTRUCT IN THAT IT USE AS FULL LENGTH ACTIVATING IMMUNE RECEPTOR NATURALLY OCCURS IN HUMANS, CD8 T-CELLS GAP MALL DELTA CELLS, NK CELLS AND SMALL PERCENTAGE OF CD4 CELLS. THIS INSTANCE THE FULL LENGTH RECEPTOR IS COUPLED TO THE CD 3 BETA CHAIN AND ALLOWS SIGNALING THROUGH THE BETA CHAIN AND I SHOULD NOTE THAT NKG 2D DOES NOT HAVE A SIGNALING DOMAIN OF ITS OWN BUT REQUIRES ASSEMBLY WITH ADAPTIVE MOLECULE DAP 10 FOR SURFACE EXPRESSION AND SIGNALING SO THAT YOU WOULD EXPRESSION THAT THE CMCS 1 CAR ALSO IS ABLE TO SIGNAL THROUGH DAP 10. TESTIFY MOUSE EXPRESSES SHORT ISOFORM THAT ALLOWS ASSEMBLY OF STAT 12 BUT THAT IS NOT THE CASE IN HUMANS. SO WHAT DOES THE CSCS 1 CAR RECOGNIZE? IT RECOGNIZES ALL THE NKG 2D BUY LIGANDS THAT THE NATURAL RECEPTOR OF NKG 2D RECOGNIZES, NAMELY MIC A, B AND THE US 16S 1 THROUGH 6. WHAT IS UNIQUE ABOUT THIS TARGET IS THAT NKG 2D LIGANDS ARE NOT EXPRESSEDD ON HEALTHY CELLS BUT THAT CELLS ARE ABLE TO UP-REGULATE LIGANDS IN RESPONSE TO DNA DAMAGE OR CELLULAR DAMAGE SUCH AS DURING INFECTION AND IMPORTANTLY DURING MALIGNANT TRANSFORMATION. SO THIS IS PART OF AN EVOLUTIONARY CONSERVED SYSTEM ALLOW CELLS TO SIGNAL TO THE IMMUNE SYSTEM THAT THERE HAS BEEN A DEFECT IN THE CELLS AND THEY NEED TO BE ELIMINATED. I SHOULD NOTE THERE IS A REPORT OF A LIGAND EXPRESSION IN THE GUT EPITHELIUM THIS, THOUGH CLARIFIED THIS IS LOCATED INTRACELLULARLY. FURTHER THERE'S REPORTS OF EXPRESSION OF LIGANDS IN THE RESTRICTED AREA OF MEDULLA OF THE THYMUS WHERE IT'S THOUGHT TO HELP CD8 COMPLETE THEIR DEVELOPMENTAL PROGRAM UP REGULATE NKG 2D ON THE SURFACE. STRIKINGLY NKG 2D LIGANDS ARE EXPRESS AID CROSS A BROAD RANGE OF DIFFERENT CANCERS BOTH SOLID TUMORS AS WELL AS HEMATOLOGIC MALIGNANCIES INCLUDING AML AND MULTIPLE MYELOMA WHICH THIS TRIAL FOCUSES ON. TO SHOW YOU SOME OF THE PRE-CLINICAL DATA TO SUPPORT THIS THERAPEUTIC STRATEGY, THIS IS A MOUSE MODEL OF MULTIPLE MYELOMA. IN WHICH MICE ARE RECEIVING A MOUSE NKG 2D CAR TRANSCAUSED T-CELL FOR CONTROL T-CELLS THAT HAVE BEEN TRANSDUCED WITH WILD TYPE AND NKG 2D WOULD THE CHIMERIC CONSTRUCT. YOU CAN SEE ON THE LEFT THAT ESTABLISH MULTIPLE MYELOMA IN MICE WHEN THESE MICE RECEIVE NKG 2D CAR T-CELLS ON THE LEFT SIGNAL INFUSION THIS LEADS TO SIGNIFICANT SURVIVAL ADVANTAGE ON THE RIGHT IF ANIMALS RECEIVE TWO INJECTIONS OF NKG 2D CELLS ALL THE MICE SURVIVE. IMPORTANTLY, ALTHOUGH NKG 2D CAR T-CELLS THEMSELVES IN THE MOUSE MODEL DO NOT PERSIST VERY LONG THEY INDUCE HOST IMMUNITY IN THE TUMOR AND IMMUNOLOGIC MEMORY. SO WHAT YOU CAN SEE ON THE LEFT IS SPLENCYTES FROM SURVIVING MICE WHO HAD BEEN TREATED WITH NKG 2D CAR T-CELLS ISOLATEED FROM THE MICE AND THEN CULTURED ISOLATED WITH LIGAND NEGATIVE TUMOR CELLS OR IRRELEVANT TUMOR CELL LINE THAT DOES EXPRESS LIGANDSES LYMPHOMA CELL LINE DO NOT RESPOND WITH DIFFERENT GAMMA PRODUCTIONS. HOWEVER WHEN THEY RECOGNIZE ANTIGENS ON THE MULTIPLE MYELOMA IN VITRO THEY DO PRODUCE HIGH LEVELS OF INTERFERON GAMMA. THEN ON THE RIGHT IN VIVO EXPERIMENT WHEN NAIVE OR SURVIVING MICE ARE CHALLENGED WITH A DIFFERENT TUMOR CELL IN THIS CASE LYMPHOMA THAT EXPRESSES LIGANDS THEY DO POORLY AS DO THE MICE CHALLENGED WITH MULTIPLE MYELOMA. IF SURVIVING MICE ARE CHALLENGED WITH MULTIPLE MYELOMA THEY ARE ABLE TO REJECT AND ALL SURVIVE. INDICATING THE THERAPY HAS PROMPTED HOST IMMUNITY AND IMMUNOLOGICAL MEMORY. AGAINST OTHER ANTIGENS NOT JUST THE NK 2D LIGANDS, CHARLES WALTMAN HAS SHOWN EFFICACY IN PRE-CLINICAL MODEL ACROSS MULTIPLE DIFFERENT TUMOR MODELS HERE TO SHOW YOU THAT THIS ALSO WORKS IN LYMPHOMA, AGAIN ON THE LEFT SIGNAL INFUSION, AND ON THE RIGHT ANIMALS RECEIVED CRE INJECTION OF NK 2D CAR T-CELLS. WHAT ARE IMPORTANT COMMENTS WE RECEIVED DURING THE RAC REVIEW WAS LEGITIMATE CONCERN THAT SINCE NKG 2D LIGANDS ARE INDUCE IBLE, THE CONCERN NEE THEY MIGHT BE INDUCED ON HEALTHY TISSUES IN THE COURSE OF THIS THERAPY OR SIGNIFICANT INFORMATION IN THE HOST AND WHETHER THERE WOULD BE OTHER ANIMAL MODELS THAT COULD ELUCIDATE THIS FURTHER IN THE PRE-CLINICAL SPACE SO IN THIS REGARD IT'S VERY IMPORTANT TO NOTE THAT THERE'S REALLY DISTINCT DIFFERENCES BETWEEN THE HUMAN NKG 2D LIGANDS SHOWN HERE AND THEN NKG 2D LIGANDS IN THE MOUSE OR MONKEY MODEL. SO THAT WE WOULD NOT EXPECT THAT XENOGRAPH MODELS WOULD APPROPRIATELY ADDRESS THE POTENTIAL FOR AUTOIMMUNE TOXICITIES OR UP REGULATION OF LIGANDS IN THE COURSE OF CYTOKINE RELEASE SYNDROME. THE ANIMAL MODEL UTILIZING THE MOUSE LIGANDS SAN ADEQUATE MODEL TO ASSESS THIS AND IT'S IMPORTANT TO NOTE IN THE PRE-CLINICAL STUDY THERE HAS BEEN NO AUTOIMMUNE TOXICITIES IN PARTICULAR NO GUT TOXICITIES OBSERVED AT THE PHARMACO LOGICALLY EFFECTIVE DOSE THERE SNOW ELEVATION OF CYTOKINE LEVEL BUS WHEN HIGH DOSES OF NKG 2D CAR T-CELLS ARE GIVEN IN THE MOUSE SIMILAR TO HUMAN WHAT HAS BEEN SEEN IN TRIALS WITH CYTOKINE RELEASE SYNDROME, THOSE MICE HAVE AN ELEVATION OF INFLAMMATORY CYTOKINES BUT I THINK IT'S IMPORTANT TO STRESS THAT EVEN IN THAT SCENARIO, THERE WAS NO AUTOIMMUNE TOXICITY OR INFLAMMATORY RESPONSES OBSERVED. HOW DOES THIS WORK FOR THE PATIENT? T-CELLS ARE ISOLATEED FROM THE PATIENT AND THEN ACTIVATED AND EXPANDED IN VITRO AND GENETICALLY MODIFIED TO EXPRESSION THE CAR CONSTRUCT. SHOWN HERE ON THE RIGHT. AND THEN T-CELLS ARE ADMINISTERED BACK TO THE PATIENT VIA SINGLE IP INFUSION AND EXPECTED TO RECOGNIZE AND ELIMINATE LIGAND BEARING TUMOR CELLS. SO THIS IS TO SHOW YOU THE HUMAN, CNCS 1 CAR CONSTRUCT CONSISTING OF FULL LENGTH NKG 2D MOLECULE COUPLED TO THE CD 3 BETA CHAIN. AS I MENTIONED, SPECIAL REQUIRES ASSEMBLY WITH DAP 10. THIS IS CLONED INTO THE LEUKEMIA VIRUS BASED ONCO RETROVIRAL VECTOR, A VERY ESTABLISHED VECTOR USED IN OTHER CAR T-CELL TRIALS. FOR CLINICAL GRADE PRODUCTION OF VIRUS, PACKAGING CELL LINE PG 13 WAS USED, LEUKEMIA VIRUS PSEUDO TYPE AND HAS BEEN USED IN OTHER CAR T-CELL STUDIES SAFELY. TO SHOW YOU A BIT OF DATA OF HUMAN CAR IN VITRO, IT IS EFFECTIVE AND SPECIFIC AGAINST HUMAN TUMOR CELL LINES IN VITRO. I APOLOGIZE THE LEGEND ON TOP ONLY SHOWS ONE DONOR, THIS IS EXPERIMENT DONE FROM TWO DONORS DONOR 115 AND 119 WHERE T-CELLS ARE EAT PEARL NOT TRANSDUCED OR TRANSDUTIESED WITH THE CMCS 1 CAR CONSTRUCT. YOU CAN SEE WHEN T-CELLS ARE CULTURE AID LOAN DON'T PRODUCE INTERFERON GAMMA BUT WHEN EXPOSED TO LIGAND BEARING TUMOR CELL LINES HERE 866 LINE CMCS 1 CAR TRANSDUCED T-CELLS PRODUCE HIGH LEVELS INTERFERON GAMMA WHERE THE MOCK DO NOT. IMPORTANTLY WHEN CAR T-CELLS ARE CULTURED WITH AUTOLOGOUS PBMC OR FRESH OR FROZEN BONE MARROW I THEY DON'T RESPOND TO HEALTHY TISSUES IN VITRO. THE EFFECT IS SPECIFIC BECAUSE WHEN BLOCKING ANTIBODY IS ADDED TO CULTURE AND BLOCKING ANTIBODY TO NKG 2D THIS ABROGATE IT IS EFFECT WHEREAS CONTROL IGG ABOUT DO BODY DOES NOT. -- ANTIBODY DOES NO. CXFC WHAT ARE THE OBJECTIVES OF THE PHASE 1 TRIAL? THE PRIMARY OBJECTIVE TO DETERMINE SAFETY AND FEASIBILITY OF IV ADMINISTRATION OF CMCS 1 T-CELLS IN PATIENTS WITH AML MDS AND MULTIPLE MYELOMA WHO HAVE NO STANDARD TREATMENT OPTIONS AND REFRACTORY DISEASE WITH POOR PROGNOSIS. THE SECONDARY OBJECTIVE ARE ONE CLINICAL TO ASSESS THE PROGRESSION FREE SURVIVAL, AND THE TUMOR EFFECT BY STANDARD CRITERIA FOR EACH TUMOR TYPE. AND THEN IMPORTANTLY, CORRELATIVE IMMUNOBIOLOGY STUDIES TO REALLY ELUCIDATE THE FUNCTION AND IMMUNOGENICITY OF THESE CELLS IN VIVO AND EFFECT ON THE HOST IMMUNE SYSTEM. AS I MENTIONED, IT WAS BROUGHT UP IN THE RAC REVIEW AND SOMETHING WE HAVE BEEN THINKING CAREFULLY FOR A LONG TIME, CERTAINLY WITH CAR T-CELLS IN GENERAL HAS POTENTIAL FOR STRIKING THERAPEUTIC BENEFIT BUT ALSO SIGNIFICANT TOXICITIES AND SINCE THIS IS FIRST IN HUMAN TRIAL DIRECTED AGAINST LIGANDS THAT CAN BE EXPRESSED INDUCEBLY, WE HAVE REALLY DESIGNED THE STUDY WITH OUT MOST CAUTION AND INCLUDED SAFE GUARDS AND MONITOR TEAGUETURE TO ENSURE TO THE BEST OF OUR ABILITY THE SAFETY OF THE SUBJECTS. P SO I WANT TO HIGHLIGHT A FEW OF THOSE, ONE IS THAT WE'RE STARTING AT VERY LOWING DOSE, THAT OTHER TRIALS HAS BEEN USED FOR KILO GRAM OR ADMINISTERED MULTIPLE DOSE BUS THIS IS A LOW FLAT SINGLE STARTING DOSE THAT WILL BE ADMINISTERED. THERE IS ACTUALLY A REPORT THAT CERTAIN CHEMOTHERAPEUTIC AGENTS USED IN THESE DISEASES CAN UP REGULATE LIGANDS ON TUMOR CELLS, WHILE NO UP REGULATION OF HEALTHY TISSUES ON HEALTHY TISSUES HAS BEEN REPORTED. BUT WE DON'T THINK THAT THIS IS SUFFICIENTLY CHARACTERIZED IN A HUMAN TO JUSTIFY PATIENTS GET CHEMOTHERAPY AND SO WE IN FACT PATIENTS ARE NOT ALLOWED TO RECEIVE CHEMOTHERAPY OR RADIATION THERAPY THREE WEEKS PRIOR TO INFUSION TO REALLY MINIMIZE THE RISK FOR NKG 2D LIGAND EXPRESSION ON HEALTHY TISSUES. ALONG THE SAME LINE WE WAS INCLUDED STRINGENT EXCLUSION CRITERIA, AND ARE EXCLUDING ANY PATIENT WITH ACTIVE INFECTION, OR AUTOIMMUNE DISEASES OR PATIENTS WHO HAVE UNDERGONE MAJOR SURGETRY PAST FOUR WEEKS. ALL PATIENTS HAVE SCREENING VISIT ON THE DAY OF INFUSION TO MAKE SURE THERE'S NO ENDOCRINE NEXT THAT HAS OCCURRED. PATIENTS WILL BE CLOSELY FOLLOWING INFUSION, CLOSE OUTPATIENT FOLLOW-UP AS RECOMMENDED BY THE FDA DURING THE IND APPROVAL PROCESS. THE FDA ALSO RECOMMENDED AND WE INCLUDED THIS IN THE PROTOCOL THAT ANY PATIENT WAS CONCERNED FOR INVOLVING CYTOKINE RELEASE TOXICITIES WILL BE ADMITTED TO THE HOSPITAL FOR FURTHER MOBTORRING. AND WE HAVE INCLUDED VERY SPECIFIC ALGORITHMS FOR MANAGING AND RECOGNIZING CRS EARLY AS WELL AS POTENTIAL GI TOXICITIES. FURTHERMORE PARTICIPANTS WILL BE STAGGERED SUCH THAT THE SECOND PATIENT ON EACH DOSE COHORT CANNOT BE ENROLLED UNTIL 30 DAYS AFTER THE FIRST PATIENT IN THAT COHORT TO REALLY ENSURE THAT WE HAVE APPROPRIATE TIME WINDOW DURING WHICH PATIENTS CAN BE OBSERVED IF ANY SIGNIFICANT TOXICITIES WERE TO OCCUR. I APOLOGIZE IF THAT WAS NOT INCLUDED IN THE PROTOCOL VERSION YOU RECEIVED BUT THE STUDY WILL BE MONITORED BY THE NHLBI SAFETY -- DATA SAFETY MONITORING BOARD, AN INDEPENDENT DATA SAFETY MONITORING BOARD WITH NO CONNECTION TOP THE DANA-FARBER OR MEDICAL WHATSOEVER. SO PREVIOUS SLIDES, BRIEFLY THE PHASE 1 ELIGIBILITY IS HISTOLOGICALLY CONFIRMED AML OR NDS THAT IS NOT IN REMISSION AND PUBLISHED THERE ARE NO REASONABLE STANDARD TREATMENT OPTIONS AS WELL AS RELAPSE OR RELAPSE REFRACTORY MULTIPLE MYELOMA WITH PROGRESSIVE DISEASE SO REALLY PATIENT WHOSE HAVE A VERY TERRIBLE PROGNOSIS. AS I MENTIONED, WE HAVE EMPLOYED VERY SPECIFIC EXCLUSION CRITERIA TO MINIMIZE RISK OF LIGAND TO UP REGULATION AS WELL AS ANY AUTOIMMUNE DISEASE WHICH LIGANDS MAYBE EXPRESSED. THEN CAREFULLY INCLUDED THAT PATIENT VERSUS A FOCUSED NEUROLOGICAL EXAM AND IF THERE'S ANY CONCERN FOR CNS INVOLVEMENT OF DISEASE THEY HAVE TO UNDERGO IMAGING. PRIOR ALLOGENEIC STEM CELL TRANSPLANT, GENE THERAPY ALSO EXCLUDED. SO TO GIVE YOU AN OVERVIEW OF THE PHASE 1 TRIAL DESIGN, THIS WILL BE HA DOSE ESCALATION STUDY WITH FOUR DOSE COHORTS AND THAT PATIENTS WILL BE INVOLVED SEQUENTIALLY STARTING AT THE VERY LOW SINGLE FLAT INFUSION OF 1 TIMES TEN TO THE 6 CELLS ON DAY ZERO AND THEN OUR ESCALATING AND HALF AS RECOMMENDED BY THE FDA. AND THEN THERE WILL BE A DISEASE SPECIFIC DOSE EXPANSION COHORT AT NTD WITH 6 PATIENTS IN EACH COHORT THERE. AS YOU CAN SEE, PATIENTS WILL BE FOLLOWED VERY CLOSELY ESPECIALLY INITIALLY, THIS WAS A REQUEST BY THE FDA AS WELL, AND SUBSEQUENT AT FOLLOWING TIME POINTS AND 15 YEAR SAFETY FOLLOW-UP GIVEN THE GENE TRANSFER INVOLVED. DURING THE REVIEW THERE WAS A QUESTION ABOUT NUMBER OF PARTICIPANTS ENROLLED ON THIS PROTOCOL, SO I WANTED TO BRIEFLY GET INTO DESIGN, THREE PLUS THREE DESIGN MEANING THREE PATIENTS WILL BE INVOLVED AT DOSE LEVEL AND IF THERE'S NO DLT SUBS DENT PATIENTS ARE INVOLVED AT HIGHER DOSE LEVEL 30 DAY WINDOW BETWEEN FIRST AND SECOND PATIENT AND NEXT DOSE LEVEL. AND IF THERE'S DLT ADDITIONAL THREE PATIENTS WILL BE ENROLLED AT THAT LEVEL AND PROCEED ACCORDING TO THE GRAPH ON THE RIGHT. SO DEPENDING HOW MANY DLT THERE WILL BE OBSERVED DOSE ESCALATION N ALL FOUR DOSE COHORTS INCLUDE 12 TO 24 PATIENTS AND EXPANSION COHORTS INCLUDE SIX PATIENTS EACH, 24 TO 36 PARTICIPANTS, WE CERTAINLY CAN VERIFY MORE IN THE PROTOCOL. I SHOULD ALSO NOTE THAT ALTHOUGH NKG 2D LIGANDS ARE EXPRESSED IN SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES FOR THIS TRIAL WE CHOSE HEMATOLOGIC MALIGNANCIES BOTH AML AND MULTIPLE MYELOMA AND THE DIFFERENT TOXICITY PROFILE AS WELL, WE SPECIFIED IN THE PROTOCOL THAT PER GROUP OF THREE PATIENTS AT LEAST ONE WOULD HAVE TO HAVE AML OR NDS AND THE OTHER HAS TO HAVE MULTIPLE MYELOMA OBVIOUSLY A ONE TO ONE RAN RNA DOCUMENTIZATION IS IDEA, THAT DESIGN NOT DOABLE. BUT WE FEEL THAT BY ENSURING EACH DOSE LEVEL HAS EACH DISEASE REPRESENTED, THAT SHOULD CAPTURE DIFFERENCE FINANCE TOXICITIES AND PROVIDE FOR DOSE EXPANSION COHORTS THAT CAN FURTHER CLARIFY THE TOXICITY PROFILE POTENTIALLY IN THAT SPECIFIC DISEASE. HERE IS JUST TO SHOW YOU AGAIN SPECIFIC ALGORITHMS THAT NO CUSS ON EARLY RECOGNITION AND MANAGEMENT OF CYTOKINE RELEASE P SYNDROME. AS I MENTION LIGAND EXPRESSION RELEASE INTRACELLULAR AND GUT EPITHELIUM, NEVERTHELESS WE WILL HAVE PARTICULAR FOCUS ON THAT TOXICITY AND HAVE INCLUDED GUIDELINES HOW THAT MIGHT BE DIAGNOSTICALLY WORKED UP AND TREATED. I WANT TO HIGHLIGHT A FEW KEY POINTS OF THE CONSENT WHICH CERTAINLY INCLUDES THERE'S A RISK FOR CYTOKINE RELEASE SYNDROME AND THIS IS POTENTIALLY LIFE THREATENING OR FATAL AND MAYBE IRREVERSIBLE BECAUSE OF POTENTIAL LOW LEVEL EXPRESSION OF LIGANDS IN THE GUT WE ALSO WANT TO MAKE SURE PARTICIPANTS ARE AWARE WE HAVE PARTICULAR FOCUS ON THAT AND THAT IN GENERAL CERTAINLY CONCERN IT WILL HAVE TO BE SHOWN IF THERE'S ANY AUTOIMMUNE EFFECT OF THIS THERAPY THOUGH NO PRE-CLINICAL ANIMAL MODEL DOESN'T SUGGEST THAT. CERTAINLY WITH ANY GENE TRANSFER WE POINT OUT THE RISK FOR INSERTIONAL ONCOGENESIS AND RISK REPLICATION COMPETENT RETRO VIRUS AND I THINK ANOTHER IMPORTANT COMMENT FOR RAC REVIEW IS ESPECIALLY FIRST PHASE 1 TRIAL IT'S VERY IMPORTANT FOR PARTICIPANTS TO UNDERSTAND THAT THIS INCLUDES UNKNOWN RISKS AND THERE'S REALLY THERAPEUTIC BENEFIT IS NOT ESTABLISHED IN STEP WITH THIS PHASE 1 CAR TRIAL STARTING TO ELUCIDATE. SO IN SUMMARY, WE BELIEVE STRONG PRE-CLINICAL DATA SHOWS EXCELLENT EFFICACY IN SEVERAL TUMOR MODELS. CRCS 1 CAR T-CELLS TARGET A UNIQUE TARGET THAT WILL BE BROADLY APPLICABLE ACROSS MANY DIFFERENT CANCER TYPES. WITH AWARENESS OF POTENTIAL TOXICITIES, WE DESIGN THE TRIAL CONSERVATIVELY WITH MULTIPLE SAFEGUARDS AND WE BELIEVE THE TRIAL WILL PROVIDE CRITICAL INSIGHTS INTO THE IMMUNOGENICITY OF TOXICITY PROFILE PROMISING THERAPEUTIC STRATEGY. THANK YOU. >> THANK YOU VERY MUCH FOR THAT PRESENTATION. I HAVE HEARD SEVERAL PEOPLE CLICKING ON THE PHONE, MAYBE ARE THERE ANY RAC MEMBERS WHO JOINED BY PHONE? ARE THERE NICO INVESTIGATORS ON THE PHONE? IF SO CAN YOU SAY HELLO AND IDENTIFY YOURSELVES? >> THIS IS (INDISCERNIBLE) DANA-FARBER. >> WELCOME. ANYONE ELSE? THANK YOU. WE WILL START WITH RAC REVIEWERS, DR. KIEM FIRST. >> THANK YOU VERY MUCH FOR A NICE PRESENTATION, VERY IMPORTANT PROTOCOL I THINK. AID FEW COMMENTS AND I HAD SENT TO YOU AND THEY WERE PRETTY MUCH ALL ADDRESSED IN YOUR PRESENTATION. FOR THE RECORD I WOULD LIKE TO GO THROUGH AGAIN BRIEFLY MY MAIN COMMENT WAS REALLY THE OFF TARGET POTENTIAL EFFECT AND YOU HAVE ADDRESSED THIS I THINK IN YOUR MONITORING AND OUTLINE VERY NICELY HOW YOU WILL ADDRESS THIS NOW AND HOW YOU WILL AVOID PATIENTS WITH INFLAMMATION OR INFECTION AND NO PRIOR CHEMOTHERAPY AND RADIATION. I THINK IT WAS -- I'M SATISFIED WITH THESE CRITERIA THAT YOU HAVE OUTLINED. ONE ADDITION A.M. POINT WAS ANIMAL MODEL WHERE THIS COULD BE TESTED ON AND ALSO -- YOU ALSO ADDRESSED THAT POINT AS WELL CURRENTLY -- THERE IS NO ANIMAL MODEL, THERE'S NO MOUSE MODEL, THERE'S ALSO NO PRIMATE MODEL WHERE YOU CAN TEST THESE. SO I AGREE WITH THAT, BASICALLY IN THE PRESENTATION IN THE LITERATURE AND I ALSO THINK A CONSERVATIVE APPROACH IS PROBABLY WILL APPROPRIATELY ADDRESS THESE CONCERNS. ONE ADDITION A.M. ISSUE I HAD WAS THE -- ADDITIONAL ISSUE, YOU MENTIONED LOOKING FOR INSERTIONAL MUTAGENESIS, IT WILL BE NICE FOR FUTURE TRIALS TO HAVE CONSENT CONFIGURED VECTOR SYSTEM. AS YOU ALSO POINT OUT AS WE KNOW FOR F CELLS SO FAR NOT A PROBLEM, YOUR CURRENT VECTOR. YOU HAVE ADDRESSED THAT AS WELL. ONE ISSUE IN CONSENT FORM, I POINTED OUT THAT YOU SHOULD PROBABLY INCLUDE THE RISK OF DEATH FROM CYTOKINE RELEASE SYNDROME SINCE THIS CAN OCCUR. IN THIS SETTING. I HAVE NOTICED YOU HAVE ALSO CHANGED BASED ON THE FDA, A STAGGERED APPROACH FOR ALL COHORTS NOW WHICH I THINK IS VERY GOOD. IN ADDITION TO QUESTIONS I HAD IN MY COMMENTS THAT I SENT TO YOU I WAS WONDERING HOW SOON WILL THE DSMB MEET? AFTER THE FIRST -- >> I BELIEVE THE MEETING INTERVAL IS EVERY SICK MONTHS, WE WILL ACTUALLY DISCUSS THE STUDY WITH THE DSMB THIS FRIDAY. SO WE CAN CERTAINLY CLARIFY AND TRY TO HAVE THEM REVIEW THE FIRST PATIENT TIME. >> INVOLVED I KNOW NHLBI DSMB IS INVOLVED. ONE LAST QUESTION I HAD, SO IN YOUR INCLUSION CRITERIA, HOW DO YOU DEFINE REASONABLE IF THERE'S NO REASONABLE STANDARD TREATMENT AVAILABLE FOR THESE PATIENTS WITH AML? NDS? >> SO THOSE WILL BE PATIENTS WHO HAVE ALREADY RECEIVED INDUCTION CHEMOTHERAPY AND HAVE PERSISTENT DISEASE AND ARE NOT ELIGIBLE -- PERSIST TENT NOT ELIGIBLE FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION. >> THANKS. >> THANK YOU. DR. ZOLOTH. >> YOU ADDRESSED MANY ETHICAL ISSUES BUT I THINK WE JUST DISAGREE ON SOME OF THE LANGUAGE. THE STATEMENT THAT STRUCK ME WAS THE ONE ALL CANCER TREATMENT VERSUS SIDE EFFECTS THAT RANGE FROM MILD AND REVERSIBLE TO SEVERE WHICH PLACES THIS MISSED OTHER CANCER TREATMENTS AND IT HAS TO BE MADE ABUNDANTLY CLEAR THE WORD TREATMENT SHOULDN'T BE IN INFORMED CONSENT DOCUMENT. I'M SAD THAT IT IS THERE IN THE CLASSIC INFORMED CONSENT DOCUMENT AT DANA-FARBER, IT'S A PROBLEM TO COMPARE PHASE 1 CLINICAL TRIAL TO OTHER CANCER TREATMENTS. IT'S -- I THINK THAT REDEFINES PATIENT SENDS THEY'RE GETTING A TREATMENT. AND I THINK IT HAS TO GO. WHEN YOU PLACE IT IN CONTEXT WITH THE OTHER THINGS THAT ARE SAID, THEN IT SEEMS IT LESSENS THE OPTIMISM OF THAT STATEMENT. BUT I STILL THINK IT HAS A PLACE IN INFORMED CONSENT. I CONSIDER IT AS A TREATMENT H TAKING IT DOWN A ROAD THEY JUST AREN'T ON. IF WE -- WE HAVE TO MAINTAIN THAT BOUNDARY OR WE CAN'T -- WE HAVE TO FINDS OUT IF THIS WORKS IT'S A WONDERFUL IDEA, THE SCIENCE IS FASCINATING TO ME, PERHAPS AS LITTLE MORE BUT UNDERSTAND LESS FAILURES BUT I THINK IT'S IMPORTANT TO SAY AND IT HAS TO BE TESTED AND YOU'RE PART OF A TEST. ANIMAL TIMES. SO TREATMENT TAKEN OUT. THE OTHER PROBLEM IS YOU CAN STOP RESEARCH STUDY AT ANY TIME, I SAY THIS FOR EVERY GENETIC INTERVENTION, YOU SAY YOU WILL TAKE THAT LANGUAGE OUT AND UNDERSTAND THE ONLY THING THEY CAN STOP BEING PART OF IS OBSERVATION. THE OTHER THING THAT YOU DEBATE REALLY, AND MY CRITIQUE WAS YOU SHOULD MAKE IT CLEAR TO THEM THEY ARE BEING CHOSEN SPECIFICALLY BECAUSE OF THE BLEAKNESS OF THEIR CONDITION. AND THAT MAKES THEIR CHOICE TO DO THIS ALL THE MORE NOBLE. AND THEY SHOULD GET CREDIT BUT IF AT THIS TIME'S YOUR STRATEGY NOT TO MENTION THAT INFORMED CONSENT DOCUMENT, THEN IT CREATES -- IT CONTINUES THE ILLUSION OF RARE AND INTERESTING KIND OF TREATMENT AS OPPOSED -- BECAUSE YOU SAID WE DON'T MENTION HOW GRIM THEY ARE, HOW GRIM PROGNOSIS IS IN THE INFORMED CONSENT DOCUMENTS. I THINK YOU SHOULD GIVE THOUGHT TO THAT. OTHER PROTOCOLS WITHIN THE DOCUMENTS TO MAKE INFORMED CONSENT PROCESS MORE VIVID. ON THE RAC SAMPLE PROTOCOL, THOSE EXAMPLES OF THAT LANGUAGE YOU MIGHT FIND USEFUL OPPOSED TO DRUG INTERVENTION LANGUAGE FROM MY WII YOU'RE TAKING TEMPLATE. SO THAT WAS -- THOSE ARE MY QUALIFICATIONS ON IT. YOU DID SAY THAT YOU WILL TAKE MORE SERIOUSLY THE RISKS ABOUT THE CYTOKINES RELEASE SYNDROME AND THAT CAN BE -- WE HAVE YET TO SEE THAT, I TRUST, THAT YOU UNDERSTAND OUR CRITIQUE AND MODIFY THE LANGUAGE ACCORDINGLY. >> I THINK IT'S OUR GOAL TO MAKE IT VERY CLEAR IN THE CONSENT THAT THIS IS AN EXPERIMENTAL THERAPY, PHASE 1 TRIAL, A RISK FOR -- THAT THE RISKS ARE UNKNOWN AND IT'S NOT TOO CLEAR THE PATIENT HAS THERAPEUTIC BENEFIT AND TRY TO ALSO STATE THAT PATIENTS DON'T HAVE GOOD OTHER TREATMENT OPTIONS AND ANY OTHER TREATMENT OPTIONS ASSOCIATED WITH RISK AS WELL, CERTAINLY IT'S IMPORTANT FOR PATIENTS TO UNDERSTAND THAT THERE'S NOTHING KNOWN ABOUT THIS THERAPY AND IN HUMAN AND THAT AS WELL AS ON THIS TRIAL THEY'RE TAKING A RISK. BECAUSE THE TOXICITIES ARE NOT YET DEFINED. >> NORM FOST HERE, IF YOU SAY THIS THERAPY MAY NOT HAVE BENEFIT YOU'RE IMPLYING THE THERAPY MAY HAVE BENEFIT OR MAY NOT THAT'S HOW THAT STATEMENT IN NORMAL LANGUAGE IS USED. I ALSO THINK INSTEAD OF THERAPY USE EXPERIMENT. THAT'S A WORD THAT'S USED IN 6TH GRADE TO SAY NOT TRIAL, NOT THERAPY, THIS EXPERIMENT. THIS EXPERIMENT IS THIS, THIS EXPERIMENT IS THAT. THAT GIVE AS VIVID SENSE OF NO BILLTY OF WHAT THEY'RE DOING. P P >> I THINK OTHER AREAS OF CONSENT TRY TO MAKE THAT CLEAR THIS IS EXPERIMENTAL THERAPY AND THAT'S A PHASE 1 TRIAL DESIGN. BUT WE'LL CERTAINLY -- >> IT'S NOT -- IT'S AN EXPERIMENT F YOU SAY EXPERIMENT AL THERAPY, THEY WILL HEAR THERAPY. THE POINT OF CLINICAL TRIALS IN HUMANS IS TO SEE IF THE DRUG, IF THIS IDEA IS A GOOD ONE BECAUSE IT'S LOGICAL OR IF IT WILL KILL THEM. AND YOU DON'T KNOW YET. >> TRUE. >> SO THAT'S WHY WE HAVE THIS WHOLE LAB IN PROCESS OF DOING, OTHERWISE JUST SAY EXPERIMENT WITH NOT TERM THERAPY CONNECTED, THAT'S HELPFUL FOR PATIENTS, TO UNDERSTAND WHAT THEY'RE DOING, WHAT THEY'RE DOING IS VERY COURAGEOUS. >> WE'LL CERTAINLY TRY TO MAKE SURE OF THAT HAVE DURING IRB REVIEW PROCESS AS WELL. >> ANYTHING ELSE? >> NO. >> OKAY. THANK YOU. DR. WHITLEY. >> MY CONCERNS I THINK WERE ADDRESSED IN YOUR WRITTEN RESPONSE FOR PURPOSES OF THE COMMITTEE YOU MIGHT NOT HAVE HAD A CHANCE TO READ IT. WHEN I FIRST READ THE PROTOCOL I THOUGHT IT COULD BE SIMPLIFIED, MADE MORE USER FRIENDLY WHICH IS WHAT MY COMMENTS WERE DIRECTED FOR, WITH MAYBE A COUPLE OF EXCEPTIONS. ADDRESS OFF TARGET EFFECTS, WE SHARED THAT COMMON CONCERN AND THAT'S BEEN ADDRESSED. YOU SHOWED US WHERE ENROLLMENT IS SEQUENTIAL AND NOT SIMULTANEOUS, I THOUGHT THAT WAS IMPORTANT TO STATE UP FRONT. IN RELATIONSHIP TO THE THREE PLUS THREE DESIGN, I THOUGHT THAT'S FINE, BUT WHAT I WANTED TO SEE OKAY OCCUR, ONE DISEASE STATE MAY NOT EQUAL THE OTHER IN TERMS OF POTENTIAL TOXICITIES AND THAT CAN BE DONE BY A DATA SAFETY MONITORING BOARD WHICH YOU ADDRESS APPROPRIATELY FROM MY PERSPECTIVE WHICH WAS A CONCERN THAT I HAD IN THE BEGINNING. SO I'M NOT WORRIED ABOUT THAT. I HAD CONCERN ABOUT DISEASES, US HEMTITIS B AND C AND I DIDN'T KNOW TO WHAT EXTENT YOU WANTED TO GO BEYOND THAT FOR OTHER INTRACELLULAR ORGANISMS SO THERE WERE SIMPLE THINGS YOU CAN DO LIKE IF YOU WERE WORRIED ABOUT LATENT TB BUT IF YOU'RE NOT CONCERNED ABOUT REACTIVATION OF LATENT INFECTIONS ANY GREATER EXTENT YOU DON'T NEED TO PARTICULARLY WORRY ABOUT, FORGET THE ACRONYMS YOU HAVE TAKEN CARE OF IT, FORGET THE CELL PROCESSING AND MY CONCERNS BECAUSE I WAS CONCERNED ABOUT WHETHER OR NOT IT WAS AN FDA APPROVED LABORATORY AND IT IS. THE REASON I BROUGHT IT UP IS I HAVE BEEN AROUND WITH OTHER INSTITUTIONS ABOUT WHETHER FDA APPROVED OR NOT FDA APPROVE AND JUST BECAUSE IT'S HARBORED DOESN'T NECESSARILY MEAN WE SHOULD BELIEVE IT'S FDA APPROVED. YOU'RE RIGHT ABOUT THE CYTOKINE RELEASE SYNDROME AND MACROPHAGE RELEASE SYNDROME IS HELPFUL IN TERMS OF DIAGNOSIS AS WELL AS IN TERMS OF MANAGEMENT AND I THINK THE CONSENT REFLECTED THAT PARTICULARLY AS IT RELATES TO MANAGEMENT AND AS YOU PRESENT IT TODAY YOUR THOUGHTS ABOUT HOW TO FOLLOW THOSE PATIENTS BECAUSE I THINK YOU FOLLOW THEM MORE CAREFULLY IF YOU'RE WORRIED ABOUT CYTOKINE RELEASE SIN DRONE DROPPLE THAN YOU WOULD OTHER PATIENTS WHERE IT'S NOT A CONCERN, IT COMES UP TO THIS COMMITTEE WHEN WE CONSIDER OTHER INSERTS AND OTHER VECTORS WHERE IT'S BASICALLY THE SAME ISSUE. THOSE ARE MY COMMENTS. SO I THOUGHT IT'S A PROTOCOL THAT NEEDS TO BE DONE AND ANXIOUS TO SEE THE RESULTS. H H >> THANK YOU. DR. SADELAIN WHO CAN'T BE HERE TODAY SENT SOME QUESTIONS LAST WEEK SO I HAVEN'T SEEN -- I THINK YOU HAD WRITTEN REPLIES SO I'LL GO THROUGH THEM WITH YOU. I THINK SOME HAVE BEEN ANSWERED, A FEW MAYBE NOT. SO COMMENTS WERE NKG 2D LIGANDS EXPRESSED IN SOME TUMORS THE TUMOR VASCULATURE INFECTED TISSUES AND GUT EPITHELIUM. WHAT OTHER TISSUES CONSTITUTIVELY INDUCED AS LIGANDS? >> SO WE'RE NOT -- AS I MENTION, SMALL AREAS OF THE THYMUS, HAVE BEEN REPORTED TO EXPRESS THE LIGAND. BUT THEY SERVE A FUNCTION TO REALLY HELP IDENTIFY COMPLETE DEVELOPMENTAL PROGRAM BEFORE THEY GO TO THE PERIPHERY AND I DON'T THINK THIS IS THE DON'T HAVE PROBLEMS IN A CLINICAL TRIAL. I THINK WE HAVE A FOCUS ON POTENTIAL GI TOXICITIES BECAUSE THERE WAS AN INITIAL REPORT OF EXPRESSION IN THE GUT EPITHELIUM BUT REALLY THE CONSENT SHALLOWSCATION OF THAT IS INTRACELLULAR. SO I THINK WE WILL CERTAINLY VERY VIGILANT WITH RESPECT TO THAT, BECAUSE OF THE POTENTIAL OF LOW LEVEL EXPRESSION THERE. I SHOULD NOTE THAT SOME AUTOIMMUNE DISEASES SUCH AS INFLAMMATORY BOWEL DISEASE AND ARTHRITIS, THE LIGANDS ARE EXPRESSED AND PLAY A LEVEL P NCI AND CERTAINLY AS I MENTIONED, LIGANDS CAN BE INDUCED AND UNDER CERTAIN CONDITIONS, CELLULAR EXPRESSION OR DAMAGE, SO I THINK WE HAVE TO MONITOR VERY CLOSELY AND BUT THE PRE-CLINICAL MODEL DOESN'T SUGGEST THAT. >> DID YOU SAY HEMATOLOGIC CONDITIONS SO LIKE SYNOVIUM EXPRESSES ITS AND WOULD THAT BE SOMETHING TO EXCLUDE PATIENT WHOSE HAVE ACTIVE -- >> WE ACTUALLY ARE EXCRUDING PATIENTS WITH ACTIVE AUTOIMMUNE DISEASE, YES. THAT'S AN EXCLUSION COLLUSION CRITERIA. >> OKAY. >> SO A QUESTION I THOUGHT OF WHILE SPEAKING. THE FLIP SIDE BESIDES NORMAL TISSUES THE EXPRESSION ON THE TARGETS LEUKEMIA, OR MYELOMA CELLS T HOW UNIFORM IS IT AND WHAT'S THE POTENTIAL TO TURN IT OFF? AND ESCAPE? >> YES. SO THERE IS ONE PAPER AND ABOUT 200 PATIENTS WITH LEUKEMIA THAT SHOW OVER 75% EXPRESS NKG 2D EXPRESS MULTIPLE LIGANDS AND 100% OF THE PATIENTS HAVE DETECTABLE SOLUBLE LIGANDS THAT, IS ONE FEATURE OF TUMOR CELLS THEY ARE ABLE TO SHED SOLUBLE LIGANDS AND THAT IS IN FACT ASSOCIATED WITH (INDISCERNIBLE) IN MANY OF THESE DISEASES. AND TO THAT EFFECT I SHOULD MENTION WE HAVE DONE SOME STUDIES THAT SHOW THAT EVEN IN THE PHASE OF SOLUBLE LIGANDS THE CAR T-CELLS ARE ABLE TO EFFECTUATE KILLING THOSE TUMOR CELLS. >> THEN ANOTHER QUESTION FROM DR. SADELAIN WAS DO -- ACTIVATED T-CELLS EXPRESS THESE LIGANDS? THERE'S VARYING REPORTS IN VITRO. THERE'S ALSO REPORTS OF HIV INFECTED T-CELLS EXPRESSING SOME LIGANDS, IN PARTICULAR THERE'S ONE REPORT LOOKING AT NKG 2D CAR T-CELLS IN VITRO WHERE THE INVESTIGATORS ACTUALLY LOOKED AT LIGANDS EXPRESSION DURING CULTURE AND OBSERVED THERE'S A PEAK EXPRESSION? ABOUT 20% MAXIMUM OF THE T-CELLS IN VITRO, THAT'S IN DECLINE BY DAY TEN, 81% OR SO EXPRESSION. AND THE INVESTIGATORS ENRICHMENT OF CD8 OF NG 2D CAR EXPRESSING T-CELLS DURING THAT PROCESS SO THAT PERHAPS EXPRESSION IN VITRO CULTURE PROCESS LEADS TO SOME (INAUDIBLE) T-CELL CULTURE BUT CERTAINLY IN OUR HANDS THE T-CELLS PROLIFERATE VERY WELL, IT MIGHT ALSO BE DEPENDENT ON THE WAY T-CELLS ARE ACTIVATED AND STIMULATED. WE ALSO SEE A SHIFT TO CD8 POSITIVE NKG 2D CAR T-CELLS AND THAT MIGHT HAVE TO DO WITH WE HAVE LOOKED AT LIGANDS IN OUR SYSTEM. THAT WE DON'T ANTICIPATE, AND IMPORTANTLY AS I HAVE SHOWN YOU WHEN T-CELLS ARE CULTURED, AND INTERFERON GAMMA TOGETHER, INTERFERON GAMMA PRODUCTION IS MEASURED THEY DO NOT MAKE INTERFERON GAMMA WHICH SUGGESTS THIS IS NOT A RISK FOR THE PATIENT TO RECEIVE THE T-CELLS. >> GAY THEIR'S WHAT HE WAS ASKING ABOUT. ANOTHER QUESTION, DID SOME OF THE NKG 2D POSITIVE OR NEGATIVE CELL LINES ITS TARGET GUT EPITHELIUM? I DON'T REMEMBER ANY OF THE CELL LINES WERE COLON OR CANCER OR ANYTHING ELSE THAT NIGHT ADDRESS THAT ISSUE OF GUT OFF TARGET TOXICITY. >> I MEAN, COLON CANCER WAS EXPECTED TO HAVE SOME OF THE LIGANDS BUT AS I MENTION, THE LIGAND EXPRESSION REALLY IS INTRACELLULAR SO I THINK IT'S DIFFICULT TO MIMIC THAT IN VITRO, WHILE THIS IS A CONCERN I DON'T THINK -- I DON'T NECESSARILY THINK CELLS ARE RECOGNIZED HEALTHY GUT EPITHELIUM. >> ANOTHER QUESTION, INVESTIGATORS DID NOT INCORPORATE A SUICIDE GENE IN THEIR VAT STRATEGY, WHY NOT. >> THERE WERE OTHER CAR T-CELL TRIALS INCORPORATED IF NOT SUICIDE GENE BUT OFTEN A MARKER GENE THAT CAN SUCH AS GFR THAT COULD BE TARGETED WITH ANTIBODY. I THINK TO OUR KNOWLEDGE THE SAFETY AND EFFICACY OF INCLUDING APPROACHES ISN'T VALIDATED IN THE CAR T-CELL FIELD AND TO MY KNOWLEDGE THAT HASN'T BEEN EMPLOYED IN CLINICAL CAR T-CELL TRIALS WHEN PATIENTS WERE SIGNIFICANTLY ILL. SO AND I THINK ON THE OTHER HAND THERE IS EMERGING EVIDENCE THAT INTERVENENING INFLAMMATORY CASCADE SUCH AS WITH TOTOLIZAMAB CAN IMPROVE THE CONDITION WHILE RETAINING THE THERAPEUTIC BENEFIT OF THE CAR T-CELL THERAPY. SO THAT THIS IS WHAT WE HAVE PROVIDED AS MANAGEMENT ALGORITHM AND PROTOCOL AND CERTAINLY (INAUDIBLE) AVAILABLE IF WE SEE SIGNIFICANT TOXICITY. >> OKAY. THEN THE LAST ONE WHICH I'M NOT SURE, MAYBE -- A QUESTION ABOUT DOSE ESCALATION, THE ESCALATION FROM DOSE 3 TO 4 WAS STEEP, AS I SAW I THINK THEY'RE HALF LOGGED INCREMENTS, WAS THERE -- >> THEY ARE HALF LOG INCREMENTS AND PERHAPS I WAS LOOKING AT THE ORIGINAL PROTOCOL WHICH ESCALATED IN LOCK STEP BUT BASED ON THE FDA FEEDBACK DURING THE IND APPROVAL PROCESS WE ADJUSTED THAT TO HALF LOG ININCREMENT. >> I HAVE ANOTHER QUESTION WHICH IS MECHANISTIC THAN ABOUT THE TRIAL. IT WAS INTERESTING TO SEE HOW YOU SEEM INTO DEUCE HOST IMMUNE RESPONSE OF SECONDARY EFFECT. , IF YOU WANT TO SPECULATE OR TELL US WHAT YOU KNOW ABOUT THAT, HOST IMMUNE RESPONSE THAT'S GENERATED AS A RESULT OF THIS FIRST ROUND OF T-CELL. >> COMMENT. >> FROM -- IF I UNDERSTOOD I THINK THAT'S WHAT YOU WERE SAYING IS THERE WAS A -- >> WE HAVE DONE A NUMBER OF STUDIES LOOKING AT HOW THESE CELLS FUNCTION AND I THINK THE THING THAT'S EXCITED ABOUT CELL THERAPY THEY DON'T KILL TARGETS ONE BY ONE, THAT CAN HAVE AN EFFECT TO CHANGE THE MICROENVIRONMENT AROUND THE TUMOR. SO WE HAVE SHOWN INTERFERON GAMMA FROM THESE CELLS IS IMPORTANT TO CHANGE MYELOID CELLS AND WHAT THEY CAN DO T. AND THEY ALSO IN SOME TUMORS LOOKS LIKE SOME OF THESE IMMUNOSUPPRESSING CELLS TUMOR BRINGS IN USES TO PROTECT HIMSELF AND PREVENT LOCAL IMMUNE RESPONSES EFFECTIVE, THESE IMMUNOSUPPRESSIVE CELLS, CAN IN FACT EXPRESS LIGANDS TOO. SO YOU HAVE EXPERIMENTAL EVIDENCE WHEN WE GIVE CAR T-CELLS THEY CAN ELIMINATE THOSE CELLS AS WELL SO COMBINATION OF ATTACKING THE TUMOR WITHIN TUMOR ANTIGENS GETTING RID OF THAT MICROENVIRONMENT ALLOWS THE HOST IMMUNE SYSTEM TO COME. SO THAT'S A -- >> VERY INTERESTING. THANK YOU. DOES ANYONE HAVE ANY QUESTIONS -- FURTHER QUESTIONS? >> SO I HAVE ANOTHER QUESTION ABOUT POTENTIAL OFF TARGET EFFECTS. SO YOU ARE AWARE OF THIS CYTOKINE RELEASE SYNDROME AND YOU HAVE A INTERVENTION AIMED AT TAKING CARE OF THAT. BUT THAT COULD ALSO BE OFF TARGET EFFECTS THAT WILL NOT BE HELPED BY THAT THERAPY, THEY ARE IN TISSUE OFTEN DISEASE BRAIN, GUT OR SOME NORMAL TISSUE. AND ESPECIALLY IF YOU DON'T HAVE A SUICIDE GENE INCORPORATED, SEEMS TO ME IT WOULD BE IMPORTANT TO BE PREPARED FOR THE UNEXPECT SOD I HAVE BEEN SITTING HERE LOOK AT EXPRESSION IN NORMAL TISSUES AND FOUND REVIEW ARTICLE, REVIEWS A COUPLE OF YEARS AGO THAT IS BEYOND SELF-EVIDENCE FOR NKD 2D LIGANDS EXPRESS IN CELLS. AND BRIEFLY LOOKING THROUGH THAT ARTICLE IT SEEM THERE'S A LOT OF CONFUSION AND CONTROVERSY PARTIALLY BECAUSE OF THE FACT THAT THERE SEEMS TO BE A LOT OF POST TRANSCRIPTIONAL AND POST TRANSLATIONAL MODIFICATION, SOMETHING INTRACELLULAR, NEVER MAKE IT TO THE -- TO THE LIGAND OVER THERE. SO I WAS WONDERING WHETHER YOU HAVE CONSIDERED LOOKING MORE COMPREHENSIVELY FOR PROTEIN EXPRESSION TO KIND OF IF YOU HAVE mRNA EXPRESSION OR PROTEIN EXPRESSION YOU DON'T HAVE TO WORRY BUT YOU DO HAVE PROTEIN EXPRESSION IN SOME OF THOSE CELLS HAVE BEEN SHOWN TO HAVE mRNA EXPRESSION THAT MIGHT BE A CONCERN. SO ONE WAY OF DOING THAT WOULD BE TO LOOK AT IMMUNOHISTOCHEMISTRY OR SIMILAR METHODSTOR LOCAL EXPRESSION SO I WAS WONDERING WHETHER YOU CONSIDER THAT SINCE THERE SEEMS TO BE CONTROVERSY IN THE PUBLISHED LITERATURE AND YOU MAY NOT BE ABLE TO GET GUIDANCE FROM THAT. >> I SHOULD POINT OUT THAT THE ORIGINAL PAPER THAT ALSO DESCRIBED EXPRESSION IN THE GUT EPITHELIUM ACTUALLY LOOKED AT IN MANY DIFFERENT ORGANS INCLUDEING THE BLAIN AND DID NOT FIND LIGAND EXPRESSION THERE H. AS YOU MENTIONED MANY TISSUES MIGHT HAVE LIGANDS AT THE mRNA LEVEL AND IT APPEARS THEY ARE EITHER REGULATED BY MICRORNA SO WITH RESPECT TO MANAGEMENT, IT'S -- IF THERE WERE TO BE ANY TOXICITY TO THE BRAIN WE ALSO INCORPORATED POTENTIAL (INDISCERNIBLE) TO FACILITATE BETTER PENETRATION OF THE BRAIN BARRIER. >> AND THE PROTOCOL? >> THAT IN THE PROTOCOL. YES. >> OTHER QUESTIONS OR COMMENTS? >> SO YOU HAVE LEFT OUT THE LYMPHODEPLETING CHEMOTHERAPY OF COURSE SO CONCERN THAT THAT WILL ERODE THE EFFICACY. WHAT IS THE EXPERIENCES HAS THERE BEEN A CLINICAL EXPERIENCE WITH ADOPTIVE TRANSFER CAR Ts IN ABSENCE OF LYMPHODEPLETING CHEMOTHERAPY? >> I BELIEVE THERE HAVE BEEN, I THINK WE DON'T KNOW IT MIGHT BE HELPFUL TO GIVE LYMPHODEPLETING CHEMOTHERAPY AND CREATE AN NICHE FOR THE INCOMING CAR T-CELLS. BUT I THINK IF -- >> THE QUESTION IS IT NECESSARY NOT AWARE OF ANY -- ADENOVIRUS ADOPTIVE T-CELL THERAPY APPROACHES CLINICALLY EFFICACIOUS WITHOUT LYMPHODEPLETING REGIMENS LYMPHODEPLETING CHEMOTHERAPY MORE RECENT TRIALS IS BETTER EFFICACY BUT I JUST THINK THAT WILL BE SOMETHING PERHAPS WHERE A TRIAL WE JUST DON'T KNOW ABOUT WHAT THAT WOULD DO TO HEALTHY TISSUE TO JUSTIFY THAT AT THIS POINT. THAT MAYBE BETTER TO DO IT BUT I THINK AT THIS POINT WE JUST WANT TO GET A FIRST SAFETY. >> SO THE GUT TOXICITY AND THESE CELLS HAVE INVESTED IN MAKING THE PROTEIN, SURE IT'S NOT JUST SO IT CAN BE HANG AROUND INTRACELLULARLY, THAT IT MUST BE RAPIDLY INDUCIBLE WITH LITTLE PROVOCATION SO I WOULD THINK A LITTLE BIT MORE ABOUT BEING MORE STRINGENT ABOUT THE ELIGIBILITY CRITERIA TO INCLUDE NON- NON-AUTOIMMUNE INFLAMMATORY TYPE GUT DISEASES AND CERTAINLY DIVVY TICKLITIS AND BE MUCH MORE SPECIFIC ABOUT THAT, PERHAPS DIVEER TICK LOWSIS, THAT WOULD BE MY BIGGEST CONCERN WITH THIS IS THE GUT TOXICITY OBVIOUSLY WITH THE ANTI-CTLA 4 WITH INTESTINAL PERFORATION, ET CETERA. IN YOUR GI TOXICITY MANAGEMENT ALGORITHM, REALLY WASN'T VERY SPECIFIC SO I CONSIDER BEEFING THAT UP A BIT. JUST KIND OF VAGUELY SAYS WE EEL STARTS IMMUNOSUPPRESSIVE THERAPY BUT I THINK SPECIFIC DOSING SCHEDULE OF THE INTRAVENOUS, GOING TO USE WHETHER OR NOT YOU'LL INCORPORATE INFLIXIMAB, ET CETERA, PAY MORE ATTENTION TO THAT SO YOU'RE -- EVERYBODY IS READY, SURE YOU ARE BUT I WOULD INCORPORATE INTO THE CLINICAL PROTOCOL. SIMILARLY FOR THE CYTOKINE RELEASE SYNDROME, I DIDN'T SEE THAT THERE WAS THE POSSIBILITY OF INCORPORATING ANTI-IL-6 ANTIBODY, ET CETERA. I'M SURE YOU THOUGHT ABOUT THAT. >> THE ALGORITHMS DIFFERENT IN THE PROTOCOL, WASN'T RECOMMENDED (INAUDIBLE) TO GET WITH CRS. >> SO TO FOLLOW-UP ON THE ISSUE YOU HAVE PRAISED ABOUT LYMPHODEPLETION, WE WERE DISCUSSING THAT ALSO. AS FAR AS WE CAN RECALL THE TRIALS THAT HAVE IT USE THAT -- HAVE SHOWN EFFICACY WITH ONE TARGETING GD 2 IN NEUROBLASTOMA, AND THEN ALSO ONE USING THE VIRAL SPECIFIC T-CELLS LIKE THE ONES IN THESE STUDIES FROM BAILOR, WHERE THERE MIGHT BE SOME ENDOGENOUS PARTICLES DRIVING THE T-CELLS TO EXPAND MOST HAVE USED LYMPHODEPLETION ING THISH HUMAN TO SEE THIS THOSE PEOPLE ARE PRIOR THERAPY LYMPHODEFICIENT DO THEY HAVE A BETTER RESPONSE IN PATIENTS WITH NORMAL T-CELL NUMBERS, YOU MIGHT WANT TO -- GETTING BASELINE IMMUNE FUNCTION ANYWAY, THAT MIGHT BE A CORRELATE TO LOOK AT WHO CAN RESPOND (INDISCERNIBLE) >> I JUST WANTED TO MAKE ONE POINT, THERE WAS A LOT OF DISCUSSION ABOUT OFF TARGET EFFECTS AND THAT DIDN'T POTENTIALLY HIT NORMAL CELLS BUT IN THE ANSWER TO WHY YOU SEE IMMUNITY, THERE WAS COMMENT THAT LIGANDS ARE ON TREGS AND MYELOID DERIVED SUPPRESSOR CELLS WHICH ARE CLEARLY NORMAL CELLS, WE CERTAINLY RAISE THE ISSUE THEY COULD BE OTHER ACTIVATED IMMUNE CELLS AND INCREASE IF YOU'RE ELIMINATING THOSE CELLS YOU NOT ONLY POTENTIALLY INCREASE IMMUNITY AGAINST TUMOR BUT CERTAINLY INCREASE AUTO-IMMUNITIES SINCE THOSE CELLS MAYBE PREVENTING COLITIS OR OTHER AUTOIMMUNE REACTIONS SO IN THE ABSENCE OF SUICIDE GENE I THINK IT JUST ADDS TO SCOTT'S COMMENT ABOUT THE TYPE OF THINGS YOU HAVE TO BE PREPARED FOR AND SELECTION CRITERIA. >> ANY OTHER QUESTIONS OR COMMENTS FROM MEMBERS HERE? OKAY. THEN WE'LL TAKE A BREAK TO GO THROUGH OUR RECOMMENDATIONS. -- I'M SORRY, PUBLIC COMMENTS BEFORE WE BREAK? ANYONE ON THE PHONE TO COMMENT? ANY RAC MEMBER? THANK YOU. WEAL TAKE A BREAK. WE'LL TAKE A BREAK. >> THE FIRST ONE IS A CLINICAL COMMENT. GIVEN POTENTIAL EXPRESSION OF NKG 2D ON GUT EPITHELIUM CONSIDER EXPLICITLY EXCLUDING PATIENTS WITH INFLAMMATORY BOWEL DISORDERS BEYOND AUTOIMMUNE DISEASE SUCH AS KNOWN DIVRITICLITIS. 'S IMPORTANT TO DEVELOP A SPECIFIC PROTOCOL FOR GUT RELATED TOXICITY INCLUDING DOSE STEROIDS OR OTHER INTERVENTION. THE SECOND POINT IS THE STUDY WILL NOT USE LYMPHODEPLETION DUE TO CONCERNS OF UPREGULATION OF NKG 2D FROM CHEMOTHERAPY. MOST STUDY USING CARS LYMPHODEPLETION INCLUDING THOSE SHOWING EFFICACY NOR ADDITIONAL INFORMATION ABOUT ROLE OF -- CONSIDER I ASSESSING IMMUNE IS THE STATUS PARTICULARLY T-CELLS STATUS. AND THEN THE THEY RECALL COMMENTS ARE SORT OF ETHICAL LEGAL SOCIAL DOMAIN. ALTHOUGH THE CONSENT PROVIDES DETAILED INFORMATION OBJECT THE POSSIBILITY OF A SEVERE REACTION DUE TO CYTOKINE RELEASE SYNDROME, IT'S STATED THERE'S RISK OF DEATH FROM THIS SYNDROME. IT GUESS IT DIDN'T -- HADN'T SAID IT COULD BE FATAL. THE SECOND IS THERE'S A STATEMENT THAT ALL CANCER TREATMENTS CAN HAVE SIDE EFFECTS RANGING FROM MILD REVERSIBLE TO SEVERE LUNG LASTING POSSIBLY LIFE THREATENING. THAT'S A GREAT DEAL OF VARIABILITY AMONG SIDE EFFECTS OF DIFFERENT CANCER TREATMENTS AMONG INDIVIDUALS, THIS IS MISINTERPRETED THAT THIS APPROACH IS EQUIVALENT TO OTHER ESTABLISHED TREATMENTS. THE WORD TREATMENT SHOULD BE AVOIDED IN EARLY PHASE 1 TRIAL. THE NEXT COMMENT, THERE'S NOTHING IN THE CONSENT THAT INDICATES THESE RESEARCH PARTICIPANTS HAVE LIMITED THERAPEUTIC OPTIONS AND HAVE A TERMINAL DISEASE. THEREFORE, THE DECISION TO ENROLL IS VERY ALTRUISTIC AS PROSPECT OF DIRECT BENEFIT SUN KNOWN AND STATISTICALLY MOST PHASE 1 TRIALS DON'T RESULT IN THERAPY. ACKNOWLEDGING REALITIES BALANCES STATEMENTS OF 15 YEAR FOLLOW-UP IN PREGNANCY WHICH COULD BE SEEN AS POSSIBLE INDICATIONS OF THE INVESTIGATORS EXPECT LONG TERM SURVIVAL FOR RESEARCH PARTICIPANTS. WHILE THIS IS A SENSITIVE ISSUE IN WRITING, LANGUAGE SUCH AS QUOTE THERE IS NO TREATMENT THAT WE KNOW THAT CAN CURE DISEASE END QUOTE, WE COMMUNICATE THIS MORE CLEARLY. THEN OUR FINAL COMMENT T LANGUAGE ON WITHDRAWAL SHOULD INDICATE ONCE YOU RECEIVE THE CELLS THEY CAN PERSIST INDUMMIESTLY, THEREFORE WITHDRAWAL FROM THE STUDY MEANS WITHDRAWAL FROM MONITORING AND NOT EFFECT OF EXPERIMENTAL INTERVENTION. THOSE ARE P WHAT OUR RECOMMENDATION LETTER SAYS. ANY COMMENTS AMONG RAC MEMBERS ABOUT THESE RECOMMENDATION? WE CAPTURE EVERYONE'S CONCERN? >> MINOR POINT IN THAT LAST SENTENCE YOU READ. WHICH WAS THAT THIS THERAPY CAN LAST A WHILE. THE INTERVENTION CAN LAST, WE STILL USE THE LANGUAGE OF THERAPY. YOUR LAST SENTENCE YOU READ. >> EXPERIMENTAL INTERVENTIONS. >> WE LOOK BEFORE THAT. >> THE LANGUAGE WITHDRAWAL INDICATE ONCE YOU RECEIVE THE CELL THEY PERSIST INDEFINITELY THEREFORE WITHDRAWAL FROM STUDY MEANS WITHDRAWAL FROM HONORING AND NOT EFFECT OF EXPERIMENTAL INTERVENTION SO I MAY HAVE SAID THERAPY. ANY OTHER COMMENTS FROM THE RAC? DID YOU HAVE ANY COMMENTS IN RESPONSE TOWER RECOMMENDATION? TOE TO OUR RECOMMENDATION? >> THOSE ARE GOOD POINTS AND CERTAINLY INCORPORATE THEM INTO (INAUDIBLE) COMPONENTS OF THAT PROTOCOL. >> THANK YOU. ANY OTHER COMMENTS FROM ANYONE ON THE PHONE? OKAY. THEN CAN WE HAVE A MOTION ON OUR RECOMMENDATIONS, DR. WHITLEY? >> SO MOVED. >> SECOND. DR. KIEM. DR. ROSS. OKAY. >> SO DR. DONAHUE. >> DONAHUE, YES. >> CHATTERJEE, YES. >> PILEWSKI, YES. >> KAUFFMAN, YES. >> ATKINS, YES. >> ZOLOTH, YES. >> WOOLEY, YES. >> DRESSER YES. >> KOHN, QUESTION. >> HAMMARSKJOLD, YES. >> CANNON, YES. >> KIEM, QUESTION. >> HERRING YES. >> WHITLEY, YES. >> ROSS, YES. >> ANYONE ON THE PHONE? >> (INAUDIBLE), YES. >> THANK YOU. >> HARDISON YES. >> HARDISON YES, ALSO. THANK YOU VERY MUCH. GOOD LUCK WITH YOUR STUDY. EXCITED THE SCIENCE IS EXCITING WE HOPE IT TURNS OUT TO BE A THERAPY. USE THAT WORK IN THE FUTURE. AND I THINK WITH THAT, WE ARE ADJOURNED. THANK YOU. >> THANK YOU VERY MUCH. >> THANK YOU.