>> LET'S START BY INTRODUCING OURSELVES. DR. WOOLEY WHY DON'T YOU START. >> DON WOOLEY, ASSOCIATE PROFESSOR. >> MARY HAMMARSKJOLD, UNIVERSITY OF VIRGINIA, PROFESSOR (INDISCERNIBLE) >> (INDISCERNIBLE) MIDWESTERN UNIVERSITY. >> VINCE KIEM FROM SEATTLE UNIVERSITY WASHINGTON AND FRED HUTCHINSON RESEARCH CENTER. MARSHALL STROME SAINT LUKES MEDICAL CENTER NEW YORK. >> (INDISCERNIBLE) TEMPLE UNIVERSITY. >> JACQUELINE CORRIGAN CORIE. >> (INDISCERNIBLE) MEMORIAL SLOAN CANCER CENTER. >> ANDREW BRADLEY, MAYO CLINIC. >> REBECCA DRESSER, WASHINGTON UNIVERSITY. >> PAULA CANNON, UNIVERSITY OF SOUTHERN CALIFORNIA. >> DAVID (INDISCERNIBLE) WAKE FOREST UNIVERSITY. NORTH CAROLINA. >> TOM KOHN UCLA. >> JOE P ALUSKI, UNIVERSITY OF PITTSBURGH. >> DENISE GAVIN, UCLA. >> MARGARET MALINO, MIZZOULA. >> >> I WANT TO INTRODUCE OUR TRANSCRIPTIONIST MARGARET C ROWLEY. SHE'S BEEN WITH US SINCE 1981, THIS WILL BE THE LAST RAC MEETING. WE WISH YOU WELL, THANK YOU FOR ALL THE SERVICE THAT YOU HAVE PROVIDE US. [APPLAUSE] OUR FIRST ATTEMPT ON THE AGENDA IS A PROTOCOL BEING DISCUSSED BY DR. SCOTT PRUITT, A NUMBER OF THIS PROTOCOL IS 1180, IT IS ENTITLED LOCAL MODULATION OF IMMUNE VEEPTOR FUNCTION TO ENHANCE IMMUNE RESPONSES TO DENDRITIC CELL VACCINATION IN SUBJECTS WITH TRIPLE NEGATIVE BREAST CANCER. DR. PRUITT IS ASSOCIATE PROFESSOR OF SURGERY IN THE DEPARTMENT OF SURGERY IN THE DIVISION OF SURGICAL ONCOLOGY, DUKE UNIVERSITY. RESEARCH INTERESTS INCLUDES IMMUNE RESPONSES TO TUMORS AND IMMUNOTHERAPY OF CANCER. ON THE PHONE THERE ARE THREE ASSOCIATES. THEY INCLUDE DR. SHELLEY WANG, CHIEF OF -- AND -- CHIEF OF PRE-SURGERY DUKE UNIVERSITY COMPREHENSIVE CANCER CENTER. DR. PAUL KELLY THE CO-DIRECTOR OF THE BREAST CANCER CLINICAL RESEARCH UNIT AT DUKE UNIVERSITY INSTITUTE AND DR. KIMBERLY BLACKWELL, DIRECTER TO OF THE DUKE UNIVERSITY CLINICAL TRIALS PROGRAM IN BREAST CANCER. ARE YOU ALL ON THE PHONE? >> YES, THIS IS KIM BLACKWELL. >> VERY GOOD. SCOTT. >> THANK YOU. BRIEFLY OUR RESEARCH TEAM, DR. BRUCE BEAR NET IS REGULATORY CONSULTANT OVER THERE IF YOU HAVE ANY REGULATORY QUESTIONS AND DR. WONG MENTIONED DR. DR. BLACKWELL AND DR. WONG BY PHONE. DENDRITIC CELL IMMUNOTHERAPY IS IN EARLY PHASE NUMEROUS CLINICAL TRIALS AND A VARIETY OF KARENS INCLUDING BREAST CANCER. AND IS OFTEN EVALUATED IF PATIENTS WITH ADVANCED METASTATIC DISEASE. DEP CRITIC CELL VACCINES ARE WELL TOLERATED WITH MINIMAL TOXICITY BUT IMMUNE RESPONSES ARE VARIABLE. MOST CLINICAL TRIALS FOCUS ON ANTIGEN DELIVERY AND FEW TRIALS FOCUSED ON OVERCOMING IMMUNE EGGLATORY PATHWAYS. -- REGULATORY PATHWAYS. THEY CAN AUGMENT IMMUNE RESPONSES TO VACCINATION OR IN GENERAL BUT UNFORTUNATELY ANTI-CTOA-4 MONOCLONEAL ANTIBODIES CAN STIMULATE IN MICE AND AUTOIMMUNE FEW IN HUMANS. SOMETIMES HUMANS SEVERE SOMETIMES FATAL COLITIS IS DEVELOPED. DERMATITIS AND OTHER AUTOIMMUNE EFFECTS. THIS DRUG IS APPROVED BY THE FDA FOR TREATMENT OF METASTATIC MELANOMA AND EVALUATED IN NUMEROUS CLINICAL TRIALS AS ADJUVANT THERAPY IN PATIENTS WITH NO EVIDENCE OF ACTIVE DISEASE. ANTI-MONOCLONEAL ANTIBODIES IN MICE HAVE BEEN SHOWN TO STIMULATE AUTO-IMMUNITY. OUR PROPOSAL, APPROACH FOR OUR PROPOSAL IS VACCINATE TRIPLE NEGATIVE BREAST CANCER PATIENTS WITH AUTOLOGOUS MONOZITTIC DENDRITIC CELLS, WE USE TRANSFECTION TO LOAD THE CELLS WITH TRIPLE NEGATIVE BREAST CANCER AND WE CO-TRANSFECT DENDRITIC CELLS WITH RNA AND IMMUNE MODULATORS TO LOCALLY DELIVER MODULATORS TARGETING CTLA-4 TO THE LYMPH NODE AT THE SITE WHERE TUMOR ANTIGEN LOADED DENDRITIC AND T-CELLS INTERACT. THIS WILL AUGMENT THE ANTITUMOR IMMUNE RESPONSE BASED ON PRELIMINARY STUDIES AND AVOID SYSTEMIC POTENTIAL AVOID SYSTEMIC AUTOIMMUNE WHEN THESE MODULATORS ARE ADMINISTERED SYSTEMICALLY. SO FOR OUR TRIAL WE ARE FROM POSED ENROLL SUBJECTS WITH T-2 TO 4 AND M-0 TO 3 TRIPLE NEGATIVE BREAST CANCER AND VACCINATION OCCURS AFTER SURGERY ADJUVANT RADIATION AND CHEMOTHERAPY. AUTOLOGOUS MONOCYTE DETHE RIFED DEP CRITIC CELLS WILL BE GENERATED AN TRANSFECTED WITH THREE BREAST CANCER TRIPLE NEGATIVE BREAST CANCER ANTIGENS IN THIS CASE WE HAVE CHOSEN EPIDERMAL GROWTH FACTOR RECEPTOR MUSIN 1 AN (INDISCERNIBLE) 3. CO-TRANSFECTION WILL BE NO ADDITIONAL RNA AS OUR BASELINE CONTROL GROUP IN ARM A. ADDITIONAL TRANSFECTION WITH SOLUBLE LIGAND TO TARGET GITER MOLECULE,Q.fANTI-CTLA MONO: CLONEAL ANTIBODY RNA HEAVY CHAIN RNA AND CTLA TARGETING. WE HAVE -- THIS IS SUPPORTED BY GRANT FROM THE SUSAN G KOMEN FOR THE CURE FOUNDATION, SUPPORTING THIS PHASE 1 TRIAL. DFROM SO OUR RATIONALE FOR CHOOSING THESE THREE ANTIGENS IN TRIPLE NEGATIVE BREAST CANCER IS THAT EGFR IS EXPRESSD IF OVER 60% OF TRIPLE NEGATIVE BREAST CANCER, MOCK 1 EXPRESSD IF 70% OF BREAST CANCERS AN OVEREXPRESSED IN 92% OF TRIPLE NEGATIVE BREAST CANCER. NH-3 IS I DON'T HAVE EXPRESSED IN 26% OF TRIPLE NEGATIVE BREAST CANCER BUT ACTIVATION IS NOTEDDED IN METASTATIC LESIONS WHEN THE PRIMARY CANCER IS NEGATIVE FROM AGE EXPRESSION. THESE ALL THREE SELECTED ANTIGENS ARE ALSO IMMUNOGENIC, LOW LEVELS OF IMMUNE RESPONSES AGAINST ALL THREE PROTEINS DETECTED IN PATIENTS WITH CANCER. WE ANTICIPATE VACCINATION OF THESE PATIENTS EXPRESSING WITH DENDRITIC CELLS EXPRESSING THREE ANTIGENS WILL BOOST IMMUNE RESPONSES. BY MODULATING IMMUNE RECEPTORS AS DESCRIBED IN THE PROPOSAL WE ANTICIPATE IMMUNE RESPONSE WILL BE FURTHER ENHANCED. WE HAD SPECIFIC RAC REVIEWER COMMENTS THAT I WOULD LIKE TO ADDRESS, DR. HAMMARSKJOLD ASKED WHAT IS EXPRESSION OF TUMOR ASSOCIATED ANTIGENS IN NORMAL TISSUES AND DR. KIEM ASKED WHAT OTHER TISSUES EXPECT TO EXPRESS TARGETED THE TAA AND WHAT RESPONSE TO TISSUES OBSERVED THIS PREVIOUS STUDY THES TARGETING THESE TUMOR ASSOCIATED ANTIGENS. FOR NORMAL EXPRESSION EPIDERMAL GROWTH FACTOR EXPRESSD IF NORMAL AND THIS INCLUDES PANCREAS LUNG LIVER AND SKIN. THERE'S NUMEROUS STUDIES USING MONOCLONEAL ANTIBODIES ESPECIALLY COLORECTAL CANCER AN MAJOR SIDE EFFECT APPEARED TO BE SKIN RASH INTERESTINGLY THE DEVELOPMENT CORRELATED DIRECTLY WITH SURVIVAL BENEFIT. MUSIN 1 IS EXPRESSED AT LOW LEVELS AN EPITHELIAL CELLS WITH BREAST RESPIRATORY AND GENITAL URINARY TRACTS AND DENDRITIC CELL VACCINES HAVE BEEN EVALUATED WITHOUT ANY SERIOUS ADVERSE REACTIONS. THERE'S A CURRENTLY OPEN TRIAL CLINICALTRIALS.GOV DESCRIBING A STUDY FOR STAGE 1 AND 2, T-1 TO 2, N-0 TO 1 PATIENTS WITH TRIPLE NEGATIVE BREAST CANCER WITH A MUCK ONE PEPTIDE WITH ADJUVANT. A CANCER ANTIGEN EXPRESSED EXPRESSIONS LIMITED TO TESTEY SO THAT WON'T COME INTO PLAY IN THIS TRIAL. OUR IMMUNE MODULATORS IN PRE-CLINICAL STUDIES WE USED A MOUSE -- ANTI-MOUSE CTLA-4 MONOCLONEAL ANTIBODIES WE CLONED THE HYBRIDOMA AND GENERATE THOSE RNAs FOR IN VITRO TRANSCRIPTION. FOR HUMAN STUDIES WE TOOK THE -- WE CLONED HEAVY AND LIGHT CHAIN OF ANTI-C FIRST QUARTERLA 4 MONOCLONEAL ANTIBODY AND REPLACED THE MURINE REGIONS WITH HUMAN SEQUENCES. IN OTHER WORDS WE HUMANIZED THIS. THERE'S NO ANTIBODY AGAINST GETTER, NO ANTI-HUMAN GETTING MOAN CLONEAL ANTIBODY AVAILABLE SO WE MADE A SOLUBLE FUSION PROTEIN. THEIOUS OVERRAN RNAS IN A MELANOMA PHASE 1 TRIAL WAS VIEWED BY THE RAC AND THE PROTOCOL NUMBER IS DESCRIBED THERE. AND THAT ACTUALLY THAT CLINICAL TRIAL WAS APPROVED BY THE FDA. THE IND WAS APPROVED BY THE FDA. EXCUSE ME. SO WE HAVE MULTIPLE CLINICAL PRE-CLINICAL TRIALS THAT SUPPORT THE -- OUR CLINICAL TRIAL PROPOSAL. FIRST IS WE CO-TRANSFECT TUMOR ASSOCIATED RNA TRANSFECTED DEP CRITIC CELLS WITH ANTI-GET OR AND CTLA MON CLONEAL ANTIBODIES AND MOUSE MURINE MODEL WAS PROLONGED. WE COMBINE THE TWO IN THE RED WE COMBINE THE TWO WE HAVE THE BEST MOUSE SURVIVAL IN A MOUSE MELANOMA MODEL. THIS WAS A TREATMENT MODEL, NOT A PRE-TREATMENT MODEL. CONTRACT WILL. P METASTASIS. WE DID STUDIES INJECTING THE IMMUNE MODULATOR RNA TRANSFECTED DENDRITIC CELL FROM THE POP SIT SIDE TUMOR ASSOCIATED DENDRITIC CELLS AND NO BOOST IN RESPONSE ONLY ADMINISTERD IF THE SAME TOGETHER IN THE SAME LYMPH NODE DID WE GET ANY IMMUNE STIMULATORY EFFECTS. DOSIMETRY WHEN WE TRANSFECTED DENDRITIC CELLS INCLUDING THE GETTER MONOCLONAL ANTIBODY. A THREE MICE HAD AUTO-IMMUNITY WITH EROSION OFw27 SKIN, LOSS OF HAIR COLORRENING THESE MICE. OF 55 MICE TREATED WITH THE ANTI-GETTER RNA TRANSP IF HE CANNED DENDRITIC CELLS WE SAW NO TRANSFECTED DENDRITIC CELLS WE SAW NO AUTO-IMMUNITY AND IT WAS STATISTICALLY SIGNIFICANT. WITH THE RNA ENCODING THE MODULATORS TO INCREASE FUNCTION MODULATING PROTEINS AND THIS IS FLOW CYTOMETRY AGAINST CTLA 4 EXPRESSING TAG CELLS AND GETTER TARGET CELLS. IN THE 24 TO 48 HOUR PERIOD WE CONTINUE TO GET SECRETION IN THE SUPERNATANT AROUND TRANSFECTED DENDRITIC CELLS SPECIFICALLY RECOGNIZED THE TARGET. WE ALSO SHOWN IN VITRO BREAST CANCER ANTIBODY SPECIFIC IMMUNE RESPONSES ARE STIMULATED BY DENDRITIC CELLS AND IMMUNE MODULATOR TRANSFECTIONNESS HAPSES -- ENHANCES EFFECTS. THIS IS IN A MELANOMA WITH 4 MELANOMA ANTIGENS, TRANSFECTED DENDRITIC CELLS WITH ANTIGENS PLUS GETTER LIGAND AND ANTI-P CTLA 4 AND TESTED AGAINST DENDRITIC ROLE TARGETS ANTIGEN TRANSIF HE CANNED DENDRITIC CELLS WHEN WE COMBINE THE TWO IMMUNE MODULATORS, ALSO SEE AGAINST CONTROL DENDRITIC CELLS TRANSFECTED WITH CONTROL RNA FOR G FIRST QUARTERP, IT WAS NO ACTIVE -- GFP. NONE STIMULATED AGAINST AUTOLOGOUS DENDRITIC CELLS. WE LOOKED AT H LA MATCHED TUMORS THAT EXPRESS THE ANTIBODIES BUT IN 293 CELL YOU CAN SEE NO BACKGROUND KILLING. I DON'T KNOW IF I CALL THAT AUTO-IMMUNITY BUT IT WAS ENCOURAGING NOT STIMULATE ANY IMMUNE RESPONSES AGAINST CONTROL CELLS. AGAIN HERE WE USE DENDRITIC CELLS AND IN THIS CASE BREAST CANCER THE TUMOR ASSOCIATED ANTIBODY OF DIFFERENT 4 AN PREVIOUS STUDY HER-2 NEW MUC1 H 3CA AN STIMULATED IMMUNE RESPONSE AGAINST TUMOR CELLS H HEALTHCAREA MATCHED EXPRESS THE TUMOR ANTIGENS AND NOT AGAINST 293 CELLS WHICH WERE THE NEGATIVE CONTROLS. SAME WITH EGFR TRANSFECTED DENDRITIC CELLS, WE HAD STIMULATION AGAINST THE EPIDERMAL GROWTH FACTOR TRANSFECTED TARGETS BUT NO AGAINST CONTROL GFP RNA TRANSFECTED TARGETS OR DENDRITIC CELLS TRANSIF HE CANNED WITH SOLUBLE GETTER LIGAND AND RNA AS TARGETS. SO THERE WAS TWO SPECIFIC REVIEWER QUESTIONS. WOULD IT BE REASONABLE -- PATIENT SELECTION WOULD IT BE REASONABLE TO EXCLOUD WOMEN WITH NO NEGATIVE DISEASE SINCE THIS GROUP HAS SIGNIFICANTLY BETTER SURVIVAL RATES THAN WOMEN WITH NODE POSITIVE DISEASE. DR. KIEM COMMENTED THE MAIN ISSUE WAS REGARDING INCLUSION OF IN-0 PATIENTS. FOR PATIENT SELECTION FOR THIS STUDY WE PROPOSE TEXAS-2, M 0 TO 3 TRIPLE NEGATIVE BREAST CANCER PATIENTS VACCINATE FOLLOWING STANDARD OF CARE RADIATION CHEMOTHERAPY WITH T H-2 TO 4 SUBJECTS WE DID NOT EXCLUDE THESE FOR A VARIETY OF REASONS. WE FEEL THE RISK OF VACCINATING TOXICITY IS LOW, ALSO THINK THE -- NOTE THESE PATIENTS WILL BE RECEIVING CHEMOTHERAPY REGARDLESS OF NODEAL STATUS. PATIENTS ARE HIGH RISK FOR METASTATIC DISEASE IN THIS POPULATION WOULD BE ONE THAT MOST BENEFIT FROM ADJUVANT IMMUNOTHERAPY IF EFFECTIVE. THERE'S A LARGE NUMBER OF NODE NEGATIVE SUBJECTS HAVE DISTANT DISEASE AT TIME OF SURGERY. FIVE YEAR SURVIVAL FOR PATIENTS WITH WITH NODE NEGATIVE BREAST CANCER IS 73%. FIVE YEAR SURVIVAL WITH TRIPLE NEGATIVE BREAST CANCER PATIENTS IS 62%. AND THE REPORTED -- THERE'S A REPORTED PROPENSITY OF TRIPLE NEGATIVE BREAST CANCER NOT ONLY BY LYMPHATIC BUT HEMATOGENOUS SPREAD. THIS IS AN EXAMPLE THAT THE -- AGAIN, THE SURVIVAL IS SLIGHTLY LOW WITH NODEAL INVOLVEMENT BUT IS STILL SURVIVAL IS ONLY 73% WITH NODE NEGATIVE DISEASE. AGAIN, T-2 TUMORS ALONE DO SPECIFICALLY WORSE THAN T-1 TUMORS. IN THIS STUDY COMPARING NON-BASAL CELL OR NON-TRIPLE NEGATIVE, WE WON'T DEBATE WHETHER THESE ARE THE SAME BUT THEY'RE CLOSE. BASAL CELL LIKE IF IT'S NON-BASAL CELL YOU CAN SEE WHEN YOU HAVE SMALLER TUMORS DO BETTER THAN LARGER TUMORS. TRIPLE NEGATIVE BREAST CANCER, THE SIZE DOESN'T SEEM TO MATTER, THEY DO EQUALLY -- THEY DO EQUALLY POORLY. BASED ON TUMOR SIZE. LYMPH NODE INVOLVEMENT, IT'S WITH NO INVOLVEMENT IN NON-BASAL CELL LIKE CANCER, SURVIVAL IS OVER 80%, NOT AS GOOD WITH NODE POSITIVE DISEASE AND YOU CAN SEE WITH NODE NEGATIVE TRIPLE NEGATIVE BREAST CANCER, THEY DO MUCH WORSE IN PATIENTS WITH NON-BASAL CELL LIKE BREAST CANCER. I WANT MY THREE COLLEAGUES WHO ARE CALLED IN IF THEY MIGHT COMMENT ON PATIENT SELECTION SINCE THERE WERE SOME CONCERNS ABOUT INCLUDING PATIENTS WITH NODE NEGATIVE IN THIS NR STUDY. ANYBODY THERE? >> I'LL START. THIS IS KIM PLAQUEWELL, YOU HAVE DONE A NICE JOB SUMMARIZING THE POOR PROGNOSIS OF TRIPLE NEGATIVE BREAST CANCER INDEPENDENT OF NODEAL INVOLVEMENT MAJORITY OF BREAST CANCER COMMUNITY IS MOVING TOWARDS LOOKING AT PROGNOSIS BASED ON THE UNDERLYING BIOLOGY AS OPPOSED TO THE CLINICAL STAGE WHICH TIME THE CANCER WAS DIAGNOSED. HISTORICALLY LARGE ADJUVANT STUDIES LOOKING AT PREVENTION OF RECURRENCE BREAST CANCER HAVE EXCLUDED NODE NEGATIVE BREAST CANCER PATIENTS. NOT DUE TO BIOLOGY BUT TO THE STATISTICAL POWER AND NUMBER OF PATIENTS THAT WOULD BE REQUIRED FOR A TRIAL IF WE INCLUDED ALL NODE NEGATIVE PATIENTS. MY FEELING, I THINK IT'S REFLECTIVE OF MAJORITY OF BREAST CANCER CLINICIANS IS THAT IN PARTICULAR, IN EARLY PHASE STUDIES WHERE WE KNOW THE PROGNOSIS IS OF PATIENTS IS POOR AS YOU QUOTED, THE LITERATURE ON FIVE YEAR AUNTLIER CAREER SURVIVAL OF NODE NEGATIVE TRIPLE NEGATIVE BREAST CARP, WOMEN FACED WITH POOR PROGNOSIS IN NEGATIVE NODE SHOULD BE ALLOWED TO PARTICIPATE IN THESE THERAPEUTIC TRIALS. >> IS KELLY THERE? >> I WOULD COP CUR, PARTICULARLY WITH THE RATIONALE FOR EXCLUSION NODE NEGATIVE DISEASE, IT'S HARD TO IDENTIFY LOW RISK TRIPLE NEGATIVE BREAST CANCER AND IT PROVIDES JUSTIFICATION FOR (INAUDIBLE). >> SHELLEY. SHELLEY, ARE YOU THERE? SHELLEY, WE'RE HAVING A PROBLEM WITH YOUR LINE, DO YOU WANT TO HANG UP AND CALL BACK? >> ANOTHER SPECIFIC COMMENT, DR. HAMMARSKJOLD COMMENTED TO PARTICIPATE IN THE STUDY SHE FELT THE PARAGRAPH AS WRITTEN MADE TRIP NEGATIVE REST CANCER SOUND LIKE A DEATH SENTENCE, A PROGNOSIS HELPFUL FOR SUBJECTS CAN THE PARAGRAPH BE CHANGED TO REFLECT THIS. AS ALTERNATIVES TO STUDY PARTICIPATION WE ONLY VACCINATE AFTER STANDARD OF CARE THERAPY. ADDITIONAL ADJUVANT THERAPY AVAILABLE FOR PATIENTS ER PR POSITIVE WITH AROMATASE INHIBITORS AND TO MAX FEN BUT NOT AVAILABLE -- TAMOXIFEN. HERCEPTIN MONOCLONEAL ANTIBODY TARGETING HER-2 NEW. THERE ARE NO OTHER ADJUVANT THERAPIES AVAILABLE FOR THESE GROUP OF PATIENTS. IMMUNOTHERAPY, THE APPROACH TO IMPROVE OUTCOME AND SHORT OF PARTICIPATION IN PROPOSED TRIAL OR ANOTHER CLINICAL TRIAL THESE PATIENTS ARE ONLY CLINICALLY UNTIL FURTHER DISEASE DEVELOPS. KELLY -- SHELLEY ARE YOU THERE? DO YOU HAVE ANYTHING TO OFFER AS FAR AS STUDY PARTICIPATION? >> THIS IS KIM, I THINK WATCHFUL WAITING WHICH IS AN AL ATTORNEY THETIVE BUT THERE ARE NO CLINICALLY AVAILABLE STRATEGIES AT THIS POINT TO RISK OF RECURRENT DISEASE. >> ANYTHING ELSE I NEED TO CONSIDER? >> NO, IT'S THE POPULATION WHERE WE ARE TRYING TO OFFER NOVEL THERAPIES. THERE REALLY AREN'T GREAT CANDIDATES AT THIS POINT IN TIME, THE DECLINE OF -- (INDISCERNIBLE) WE ALL I THINK HOPED WOULD BE NEGATIVE DISEASE THE WE HAVEN'T COME TO PASS THOUGH WE CERTAINLY THINK THERE'S SELECTIVITY ON SUBSET. IT SEEMS TO ME THE SUBSET THAT'S RIPE FOR IMMUNE MODULATION FOR DECREASING RECURRENCE. >> SHELLEY, ARE YOU IN THERE, YET? THERE ARE OTHER RAC REVIEWER COMMENTS, WHY THE STUDY BEING DONE, I SIGNATURE THIS IS THE FIRST TIME THE VACCINE WE TEST IN HUMANS. ALSO DR. DRESSER FELT THAT I SHOULD ADD THE STATEMENT TREATING DISEASE IS NOT PURPOSE OF THE STUDY, IT IS OBLIQUELY SHE SAID TO GETTING THE STUDY VACCINE WILL IMPROVE YOUR HEALTH. DR. HAMMARSKJOLD ALSO WANTED TO MAKE SURE THAT I PUT DOWN THIS WAS UNLIKELY TO HAVE A DIRECT MEDICAL BENEFIT. DR. KIEM AGAIN SAID IT WOULD BE HELPFUL TO PUT SURVIVAL INFORMATION FOR THE DIFFERENT STAGES OF TRIPLE NEGATIVE BREAST CANCER. THIS IS EDITED VERSION OF CONSENT FORM, I WANT TO -- DR. DRESSER KNOW THAT I ADDED IN, THIS IS THE FIRST TIME INVENTORY WE TESTED IN HUMANS. I ALSO TREATING DISEASE NOT PURPOSE OF THE STUDY. I HAVE CHANGED IT TO TRY TO MAKE IT LOOK LIKE ALTERNATIVES LIKE TOOK OUT THE LINE ABOUT WATCH AND WAIT SO THAT WE SUGGEST WE'RE GOING TO BE WAITING FOR RECURRENCE TO DEVELOP I WOULD PREFER NOT TO PUT VERY UNLIKELY OR UNLIKELY. I WOULD RATHER GO WITH THERE MAY NOT BE DIRECT MEDICAL BENEFIT TO YOU BUT THAT'S MY PERSONAL OPINION. AND I COULD BE PERSUADED OTHERWISE. BUT I ACTUALLY DID NOT INTEND TO DO THIS TRIAL JUST THAT THERE WAS ACTUALLY NO POTENTIAL BENEFIT AT ALL. I WANT TO BEEFILY REVIEW THE VACCINE MANUFACTURING PROCESS. WE TAKE THE SUBJECTS WITH TRIP NEGATIVE BREAST CANCER, LEUKOFREES THEM, RETRACE THE MONOCYTES CULTURED WITH GMC IL-4, THEY TURN TO IMMATURE DENDRITIC CELLS, WE INDUCE MATURATION WITH CYTOKINE COCKTAIL, WE TEST CULTURE MEDIUM BEFORE TRANSFECTION FOR MICROPLASMA BY PCR BASED ASSAY. WE TRANSFECT WITH THE RNA AND CRYOPRESERVE DENDRITIC CELLS. WE FREEZE -- WE FREEZE THEM DOWN THEN WE TEST THE VILE FOR VIABILITY, ANALYZE THE PHENOTYPE, AND DO A STERILITIESING ON THAT FILE. WHEN WE INJECT WE SAW A FILE, THE LIABILITY SUSPENDED FOR GRAM STAIN ANALYSIS AND TEST FOR ENDO TOXIN. DR. KIEM ASKED IF I COULD EXPAND ON WHAT GENE -- IS THE GENE EXPRESSION CELL PIVOTAL IN TARGET CELLS? ONLY AUTOLOGOUS MONOCYTE DENDRITIC CELLS ARE TRANSFECTED WITH RNA EXVIVO, NO OTHER CELLS CAN BE TRANSFECTED WITH RNA AND IT DOES NOT HAVE TRANSFORMING POTENTIAL. IT IS SHORT LIVED IN CIRCULATION IF ANY GET INTO CIRCULATION. BUT WE DO WATCH THE DENDRITIC CELLS AFTER ELECTROPORE RATION SO ANY CARRY OVER CLOSE TO ZERO. FOR QUALITY CONTROL, WE TEST FOR MICROPLASMA. WE ALSO TEST ONE VILE FOR BACTERIAL FUNGAL TESTING. WE TEST THE PHENOTYPE BY FLOW CYTOMETRY, WE ALSO LOOK FOR TUMOR ASSOCIATED ANTIGEN AND IMMUNE MODULATOR EXPRESSION. USING INTRACELLULAR FLOW CYTOMETRY, WITH WE TALK VAIN DOSE TEST THING. DR. HAMMARSKJOLD ASK WHAT IS THE MINIMUM LEVEL GENE TRANSFER OR EXPRESSION ESTIMATED NECESSARY FOR GENE TRANSFER PROTOCOL TO BE SUCCESSFUL. WILL IT BE DETERMINED FOR TAA BEFORE VACCINATION, BY WHAT METHOD? IS DATA APPROVED FOR DENDRITIC BASED TRIAL. DR. KIEM ASKED HOW ELECTROFOR RATION EFFICIENCY AND DENDRITIC CELL MODIFICATION. HOW ELECTROFOR RATION EFFICIENCY AND HOW DIFFERENT LEVELS OF EXPRESSION IN DIFFERENT ARMS OF THE STUDY. IN OUR EXPERIENCE WE FOUND P THE TRANSFECTION EFFICIENCY OF ELECTROFOR RATION OF DENDRITIC CELLS IS 70%. WE USE RNA INCLUDING GREEN FLUORESCENT PROTEIN AND WE GET ABOUT 70% TRANSFECTION EFFICIENCY. HERE IS ONE EXAMPLE, DENDRITIC CELLS NOT TRANSFECTED WITH ANYTHING, CONTROL RNA AND DENDRITIC CELLS TRANSFECTED WITH GFP RNA. IN OUR OTHER STUDY, RAC PROTOCOL 0708-874 THIS IS A STUDY WE'RE COMPLETING NOW. THIS IS IN MELANOMA AND THERE WERE FOUR TUMOR ASSOCIATED ANTIGENS DENDRITIC CELLS TRANSFECTED GFP MR-1 AND WE DID ASSESS LEVELS OF EXPRESSION OF THESE FOUR ANTIGENS IN EACH DENDRITIC CELL PREPARATION. YOU CAN SEE VARIABLE FOR GP-100, SORRY ABOUT THE DIFFERENT COLORS BUT THEY WERE ON DIFFERENT FLOW SIGH TOM TEARS. WE HAVE DIFFERENT EXPRESSION OF MH-3. WE HAVE DIFFERENT LEVELS OF EXPRESSION MR-IS AND DIFFERENCE EXPRESSION LEVELS OF TIES ARENASE. THIS PATIENT HAD A -- THESE PATIENTS HAD A LOW GP-100 IF YOU CAN REMEMBER AND THEY HAD DECENT -- GOOD RESPONSES. THESE PATIENTS HAD MH-3 EXPRESSION DIFFERENT BUT THE IMMUNE RESPONSES ARE THE SAME. THESE PATIENTS DIFFERENT LEVELS OF EXPRESSION WITH DIFFERENT IMMUNE RESPONSES. WE DIDN'T FIND ANY CORRELATION BETWEEN DENDRITIC CELL TUMOR ASSOCIATED ANTIGEN EXPRESSION AND IMMUNE RESPONSES IN THAT TRIAL. IT WAS A SMALL PHASE 1 TRIAL. WE HAVE ASSESS EXPRESSION OF MH-3 MUC1. EGFR SOLUBLE GETTER LIE BAN GRAND AND ANTI-CTLA 4 USING FLOW CYTOMETRIC METHOD. THIS IS A FIGURE FOR FDA IND APPLICATION SHOWING THE PURPOSE OF THIS PARTICULAR STUDY WAS TO SHOW WE TRANSFECT WITH SIX RNAs RATHER THAN A SINGLE AND THAT WOULDN'T NEGATIVELY AFFECT EXPRESSION. THAT WAS THE CASE BUT WE CAN SEE INTRACELLULAR EXPRESSION OF MH-3, MUC1 EGFR SOLUBLE LIGAND AND MONOCLONEAL ANTIBODY IN TRANSFECTED DENDRITIC CELLS. SO SUMMARY, WE'RE GOING TO EXPRESS THESE -- LOOK FOR ANTIGENS, ALL THREE IN IMMUNE MODULATORS USING ENTER CELLULAR FLOW CYTOMETRY, IT WAS IN OUR PREVIOUS TRIAL WITH THE FDA. APPROVED BY THE IND APPROVED BY THE FDA. WE AGREE THAT WE WOULD NOT BE ABLE TO ESTABLISH A CUT OFF VALUE FOR EXPRESSION THAT WE WOULD MEASURE EXPRESSION LEVELS AND P CORRELATE THOSE WITH IMMUNE RESPONSES. HOPEFULLY IF THIS MOVEED TO PHASE 2 TRIAL WE WOULD USE THAT DATA AS A CUT OFF BUT WE DO NOT HAVE THAT INFORMATION YET. WE DO SIX VACCINATIONS WOKELY INTERVALS AND INTERNODEAL INJECTION BECAUSE OF THE KINETICS OF THE SECRETION OF THE IMMUNE MODULATORS. AS YOU MAY REMEMBER FROM EARLIER SLIDE MOST SECRETION OCCURS WITHIN 6 TO 24 HOURS. DENDRITIC CELLS TAKE 3, 4 DAYS TO MIGRATE AFTER INTERDERMAL INJECTION TO LYMPH NODE WHICH CASE THEY WOULDN'T SECRETE THE IMMUNE MODULATOR SO WE'RE INJECTING DIRECTLY INTO THE LYMPH NODE UNDER ULTRASOUND GUIDANCE. WE HAVE DONE THIS IN TWO MELANOMA PATIENTS, WELL TOLERATED WITH NO PATIENT CLIENTS. WE'RE GOING TO ROTATE BETWEEN THE CONTRA LATERAL AXILLA BECAUSE THE OTHER AXILLA WILL PROBABLY HAVE UNDERGONE DISSECTION OR AT LEAST SENT KNOLL LYMPH NODE BIOPSY. JUST BRIEFLY THIS IS A TIME LINE FOR THE VACCINATION. SCREENING BASED ON LABORATORY EVALUATION, GLUE CO-PHORESES AND THE SIX VACCINATION, REPEAT LEUKOPHORESES AND MONTHLY FOR THE NEXT THREE MONTHS AND NORMAL FOLLOW-UP WITH PATIENTS MEDICAL ONCOLOGISTS. PRIMARY END POINT OF THIS STUDY IS SAFETY AND TOXICITY. SECONDARY END POINT IS ANTITUMOR TRIPLE NEGATIVE BREAST CANCER ANTIGEN SPECIFIC IMMUNE RESPONSES FOR THE ASSESSMENT OF IMMUNE RESPONSES WE CHECK PERIPHERAL BLOOD NUCLEAR CELLS AND SORE RUM BEFORE AND DURING VACCINATION. OUR INITIAL IMMUNE MODULATOR IMMUNE RESPONSE TEST IS INTERFERON GAMMA ELISPOT TEST AND WE HAVE OTHER ASSAYS BASED ON HOW MUCH RESPONSE WE GET WITH THAT SCREENING IMMUNE RESPONSER eIJ-TEST. SO BIOPSY, THE SKIN SITE OF INTRADERMAL INJECTION AT TIME OF FIFTH VACCINATION AND EXTRACTING THE T-CELLS FROM THAT FOR FURTHER ANALYSIS. AS SURROGATE FOR -- AS FOR SURROGATE FOR A TUMOR. WE ALSO CHECK -- GOING TO EVALUATE CIRCULATING TUMOR CELL LEVELS AND CLINICAL FOLLOW-UP. WE HAVE TWO SPECIFIC RAC REVIEWER COMMENTS, DR. HAMMARSKJOLD SAID WILL THERE BE TESTS TO DETERMINE AUTOIMMUNE ACTS IN CELLS IN VITRO OR VIVO, DR. KIEM ASKED TO CLARIFY FOLLOW-UP AFTER LAST LEUKOPHORESES, A SIGNIFICANT NUMBER OF PATIENTS SURVIVE LONG TERM HOW ARE THEY TESTED FOR AUTOIMMUNE ABNORMALITIES. FOR ASSESSMENT AUTO-IMMUNITY WE PERFORM MEDICAL HISTORY, THROUGHOUT THE STUDY, CLINICAL SCREENING SIX WEEKS BEFORE VACCINATION. WEEKLY WE'LL EVALUATE PATIENTS DURING THE VACCINATION PERIOD. TWO WEEKS AFTER 6 VACCINATION AND 1, 2, 3 MONTHS AFTER 6 MONTHS VACCINATION AND REGULARLY SCHEDULED MEDICAL ONCOLOGY FOLLOW-UP AT DUKE MEDICAL CENTER. WE DOTISSING FOR AUTO-IMMUNITY BASELINE, ANTI-NUCLEAR ANTIBODIES RHEUMATOID FACTOR AND ANTIBODIES, WE DO PRIOR TO VACCINATION TWO WEEKS AFTER THE SIXTH VACCINATION. THAT'S IT. KELLY AND KIM AND SHELLEY, IF YOU MADE IT ON THE LINE DO YOU GUYS HAVE ANY COMMENTS? >> I DON'T HAVE ANY QUESTIONS. >>TY I'M FINE. -- >> I'M FINE. EXCELLENT PRESENTATION. >> THANK YOU FOR PRESENTING TO US. LET'S GO TO REVIEWSERS AT THIS POINT. MAIN COMMENT WAS REGARDING N-0 PATIENTS AND COULD YOU AGAIN POINT OUT WHAT WAS GIVEN BETWEEN N-0 AND THE OTHER SURVIVAL? THAT SLIDE YOU HAD? >> IN THIS STUDY, THERE'S A LOT OF STUDIES, THEY ALL SUFFER FROM (INAUDIBLE) SMALL NUMBERS OF PATIENTS BUT IN THIS PARTICULAR STUDY IT WAS A 10% DIFFERENCE. >> WHAT IS THE DOWN SIDE AS PART OF THAT QUESTION? IF YOU DIDN'T INCLUDE THOSE PATIENT? >> I WAS WORRIED ABOUT STUDY ACCRUAL. I DON'T KNOW ANY ISSUES WITH STUDY ACCRUAL. VACCINATING PATIENTS WITH THAT METASTATIC. (INDISCERNIBLE) SO OTHER STUDIES THAT THEY HAVE POOR (INDISCERNIBLE) AND WE HAVE A LOW -- WHEN YOU HAVE A LOWER (INDISCERNIBLE) SURVIVE LONG TERM FOR IMMUNOANALYSIS. MOST IS IMMUNE RESPONSES ARE BLUNTED WHEN (INDISCERNIBLE). SO THE DOWN SIDE (INDISCERNIBLE) RECRUITING ADEQUATE NUMBER OF PATIENTS ENROLLED IN THE STUDY. >> THOSE PATIENT ALSO GET CHEMOTHERAPY SO CRAZY AMOUNT OF CHEMOTHERAPY IMMUNOSUPPRESSION (INDISCERNIBLE) -- >> METASTATIC DISEASE. >> MORE AGGRESSIVE CHEMOTHERAPY? >> MY MEDICAL ONCOLOGIST WOULD HAVE TO ANSWER THAT QUESTION. >> THAT WAS A BIG ONE. >> SCOTT THIS IS KIM BLACKWELL, I CAUGHT SOME OF IT, I'M SORRY TO HAVE TO HAVE CALLED IN BUT YOU HAVE TO REMEMBER THAT T-2 N-0 EARLY STAGE BREAST CANCER IS A LARGE CHUNK OF THE BREAST CANCER THAT WE SEE. T-2 TUMORS CAN BE A SMALL AS TWO CENTIMETERS, AS LARGE AS FIVE CENTIMETERSEN STILL HAVE NEGATIVE NODE. FIVE CENTIMETER NODE NEGATIVE BREAST CANCER HAS THE SAME PROGNOSIS AS 2.5-CENTIMETER WITH N-1, 1 TO 3 POSITIVE NODES. I THINK MOST OF US, I'M CALLING FROM THE SAN ANTONIO BREAST CANCER SYMPOSIUM THIS IS JUST OVER AND OF AGAIN SCIENCE SUGGESTING CLINICAL STAGING IS MORE A RESULT HOW LONG IT TAKES TO DISCOVER THE CANCER THAN BIOLOGY. I AGREE WITH SCOTT THAT T-2 N-0 BREAST CANCER PATIENTS SHOULD BE ALLOWED TO PARTICIPATE IN A STUDY MAINLY BECAUSE THEY CARRY A FAIRLY FOR PROGNOSIS THOUGH SURVIVAL DIFFERENCES BETWEEN N-0 AND N-1 TRIPLE NEGATIVE IS ONLY ABOUT 10%. THIS ONE OUT OF FOUR WOMEN RECURRING WITHIN THE FIRST FIVE YEARS AT LEAST OTHER FORMS OF BREAST CANCER STILL MAKES A POOR PROGNOSTIC GROUP. >> A REASONABLE COMPROMISE IF YOU WANT TO BREAK DOWN BY TUMOR SIZE AND N-0 NODE NEGATIVE WE COULD CERTAINLY LIMIT IT TO AS WE HAVE DONE IN OTHER TRIALS TO THREE SEN METER NODE NEGATIVE. AT THIS POINT GREATER THAN OR EQUAL TO SEPTEMBER-METERS, AT THAT POINT THOSE TUMORS 3-CENTIMETER NODE NEGATIVE SAME PROGNOSIS AS NOTE POSITIVE SMALLER TUMORS. >> VERY HELPFUL. >> A QUESTION RELATEDED TO USE OF CHEMOTHERAPY AND PATIENTS GET FAIRLY AGGRESSIVE CHEMOTHERAPY. TRIPLE NEGATIVE DISEASE CAN BE SENSITIVE, (INDISCERNIBLE) >> SORRY, WE MISSED SOME OF THAT. >> THE LINE BROKE UP A LITTLE BIT. >> CAN YOU REPEAT THAT? >> COULD YOU REPEAT WHAT YOU SAID BECAUSE WE DIDN'T CATCH THAT. SORRY. >> I THINK PART OF THE QUESTION WAS RELATED TO THE USE OF CHEMOTHERAPY AND MORE AGGRESSIVE CHEMOTHERAPY (INDISCERNIBLE) TRIPLE NEGATIVE DISEASE AND P WHILE TRIPLE NEGATIVE DISEASE BENEFITS FROM CHEMOTHERAPY THAT'S NOT ENOUGH DISCRIMINATOR BASED ON THAT SIZE CUT POINT TO EXCLUDE ONE OF THE POPULATIONS BASED ON P THAT BENEFIT. >> MY QUESTION WAS GEARED TOWARDS DO THEY GET CHEMOTHERAPY, WOULD THERE BE MORE IMMUNOSUPPRESSED AND MAYBE (INDISCERNIBLE) >> KIM OR KELLY, THEY WOULDN'T -- T-2 -- N-0 WOULDN'T GET A DIFFERENT CHEMO REGIMEN THAN T-3 N-1. WOULD THEY? >> NO. I MEAN, THEY'RE ALL GOING TO GET AN (INDISCERNIBLE) BASED CHEMOTHERAPY. SO WE DON'T AT LEAST IN THE CLINIC DIFFERENTIATE THE TYPES OF CHEMO RECEIVING. >> IT SHOULDN'T IMPACT STUDY BUT ACCRUAL OBVIOUSLY. >> OKAY. >> THE NEXT QUESTION THAT I HAD IS DIFFERENT INSPECTION STRATEGIES. YOU ANSWERED THAT NICELY, I WAS HAPPY WITH YOUR STUDY MAY NOT CORRELATE AT ALL IN THE END. SO THAT IS I'M OKAY WITH THAT. >> I THINK THE PROBLEM WITH THAT ASSESSMENT IS THAT THE ANTIGEN -- THE PEPTIDE ANTIGEN EXPREGNANT DEPEND NOT ONLY ON EXPRESSION BUT DEGRADATION. SO  THE TRUE MEASURE WOULD BE A MEASURE (INDISCERNIBLE) DENDRITIC CELLS DERIVED FROM THAT, THAT MIGHT BE DIFFERENT THAN ONE TIME POINT OF THE ANTIBODY, DEGREE DIVISION AN PRODUCTION AND WHERE WE CATCH THOSE EACH INDIVIDUAL PROTEINS. >> I'M FINE WITH THAT. NUMBER 3, THE GENE EXPRESSION YOU HAVE ADEGREESED AND NUMBER 4, THE FOLLOW-UP. I WAS CURIOUS YOU ADDRESS THAT WHAT YOU HAVE SHOWN DEVICE WITH LOCAL ADMINISTRATION THERE'S NO AUTO-IMMUNITY, IS THIS ANYTHING IN PATIENTS OR AS WELL THAT WOULD SUGGEST  LOCAL ADMINISTRATION H NOT INDUCE AUTO-IMMUNITY? Q. WE DOPE HAVE ANY DATA TO THAT HOPEFULLY (INAUDIBLE). >> I WAS WONDERING FOLLOW-UP IF THEY GO BACK TO ONCLE GIST OBVIOUSLY THAT MAY GET MISSED. >> IN THE ANTI-CTLA STUDIES SEEMS THE AUTO-IMMUNITY DEVELOPED 6 TO 7 WEEKS SEVERE AUTOIMMUNE COLITIS DEVELOPED IN THAT PATIENTS. THAT'S 6 TO 7 WEEKS AFTER INITIATION OF ANTI-CTLA 4 MONOCLONEAL THERAPY THAT WE,TRAP LATE TO SIX WEEKS WE DONE THINK MAYBE WE CAN'T DO THAT BUT WE'LL SEE PATIENTS EVERY TWO WEEKS INTERVAL AT THAT TIME WHEN AT LEAST IN THAT MELANOMA STUDY AUTO-IMMUNITY WAS BY HUGE DOSES OF SYSTEMIC ANTI-CTLA 4. SO I FELT THE FOLLOW-UP WOULD COVER WHEN WE NEED TO WORRY ABOUT AUTOIMMUNE DEVELOPMENT. >> AFTER LAST VACCINATION HOW MANY WEEKS OF FOLLOW-UP DO YOU HAVE WITH YOU? Q. THEY COME BACK TWO WEEKS LATE TORE GET THEIR EVALUATION AGAIN AND REPEAT LEUKOPHORESES FOR A CELL TO DO IMMUNE ASSAYS WITH AS TARGET CELLS FOR THE GENERATING MORE DENDRITIC CELLS PER TARGET. THEN THEY COME BACK TWO WEEKS LATER AND A MONTH LATER AND A.LATER SO FOR THE THREE MONTHS AFTER VACCINATION I'M SEEING THEM FOUR TIMES. >> ONE MOMENT CAN I INTERRUPT FOR A SECOND? FOLK ON THE PHONE CAN MUTE THEIR LINES IF THEY'RE NOT TALKING, WE'RE GETTING A LOT OF FEEDBACK. THANKS. >> THAT ANSWERS MY QUESTION. THANK YOU. SO HANS, NO OUTSTANDING ISSUES. >> NO. >> DR. HAMMARSKJOLD. >> ALTHOUGH IT DIDN'T SPECIFICALLY COMMENT ON THAT, I ALSO HAD A QUESTION ABOUT INCLUDING PATIENTS WITH RELATIVELY SMALL TUMORS AND NO INVOLVEMENT IN THIS TRIAL AND I THINK YOU -- I THINK THAT THIS COMES DOWN TO HOW BIG YOU THINK THE RISK IS GOING TO BE AND YOU POINT OUT IN SEVERAL OF YOUR ANSWERS THAT YOU DONE EXPECT THE RISK TO BE VERY HIGH. THIS IS A FIRST HUMAN TRIAL IN COMBINATION OF ADJUVANTS. SO I THINK THAT FOR SURE WHAT THE RISKS ARE GOING TO BE WE ALL HOPE THE RISKS ARE GOING TO BE SMALL BUT WE DONE REALLY KNOW SO FOR ME THAT THEN BECOMES VERY IMPORTANT AND I THINK WHAT I HEARD IN THIS LAST DISCUSSION MAYBE LIMITING IT TO T-2 PATIENTS LARGER TOW MORES, THAT SEEMS TO BE A DISTINCTION WHERE YOU HAVE NO NODE INVOLVEMENT AND YOU POINTED OUT THAT YOU MIGHT STILL HAVE NODES NOT YET AT THIS COVERED THAT MIGHT BE (INDISCERNIBLE) SPREAD BUT LIKELY THAT'S GOING TO BE MORE LIKELY WHEN YOU HAVE BIGGER TUMORS SO MAYBE WITHIN THAT T-2 GROUP LIMITEDDED TO PATIENTS WITH BIGGER TUMORS THAT IF THEY HAVE NO NODE INVOLVEMENT I THINK I WOULD BE HAPPIER WITH WITH THAT. WE CAN DISCUSS THAT FURTHER. THAT THEN TAKES CARE OF THAT QUESTION. I HAD A SECOND QUESTION OUT OF MY CURIOSITY I GUESS THAT APART FROM TUMOR SIZE AND LYMPH NODE INVOLVEMENT THERE'S STUDIES THAT INDICATE THAT CERTAIN MARKERS AFFECT THE PROGNOSIS FOR P-53 STATUS BRAC DELETIONS AND OTHER MARKERS. SO I WAS JUST INTERESTED IN KNOWING WHETHER YOU WERE PLANNING TO TEST THE PATIENTS FOR SUCH MARKERS AND IF SO, HOW THAT WOULD PROTECT INCLUSION. YOU ANSWERED THAT. Q. WE'RE NOT MANNING ON DOING THAT UP FRONT. IF WE WERE GOING -- IF WE EVER GET TO PHASE 2 OR 3 STUDY THOSE PROGNOSTIC FACTORS WOULD BE IMPORTANT TO STRATIFY FOR. IF POSSIBLE OR AT LEAST ANALYZE THOSE. >> BUT YOU COULD STILL DO THAT ON THESE CON TOMTANT WITH THE STUDY. >> WE CAN DO THAT, ABSOLUTELY. WE WEREN'T PLANNING TO DO THAT BUT I'LL BE HAPPY TO DO SO. >> SOUNDS GOOD. SO THEN DO YOU HAVE -- THERE WAS PROBLEMS I GUESS YOU -- YOU'RE NOT USING AS YOU POINTED OUT A REGULAR VECTOR, IT'S AN RNA SO IT'S LITTLE BIT DIFFERENT THAN PROBABLY WHAT THIS -- WHAT THIS ORIGINALLY WAS DESIGNED FOR SO THAT RAISES A COUPLE OF QUESTIONS. I WAS ALSO ASKING MINIMAL LEVEL OF GENE TRANSFER AND EXPRESSION ESTIMATE NECESSARY FOR THE PROTOCOL TO BE SUCCESSFUL. AND YOU EXPANDED IN YOUR PRESENTATION IN RESPONSE THAT THIS FACT THAT YOU HAVE FROM THE OTHER DOESN'T SEEM TO BE THE RIGHT CORRELATION WITH GENE EXPRESSION AND IMMUNE RESPONSES. AND THAT THEREFORE IT'S NOT MEANINGFUL TO HAVE A SPECIFIC -- I'M SATISFIED WITH YOUR PRESENTATION AND YOUR ANSWER ON THAT AS WELL. SO YOU ALSO SHOWED SOME DATA M THE PREVIOUS TRIAL WHI CH I ASKED ABOUT. THEN THERE WAS A SECOND -- FIRST QUESTION THAT STATED THIS STUDY END POINTS INCLUDE TESTING OF FUNCTIONAL ACTIVITY OF INDUCED CELLS TO KEY AUTOLOGOUS TUMOR ANTIGEN EXPRESSING MLA CANCER -- HLA CANCER CELL LINES YOU'RE GOING THE TALK ABOUT I THINK IN YOUR PRESENTATION ABOUT DENDRITIC CELLS. AND YOU CLARIFY IN YOUR WRITTEN RESPONSE THAT HLA MATCH BREAST CANCER CELL LINE KILLING WOULD BE DONE IF AVAILABLE MEANING IF YOUR HLA, IF -- >> I HAVE LOTS OF OPTIONS T. >> YEAH. SO HOW DO YOU THINK HOW MANY COULD YOU PREDICT IN HOW MANY CASES THAT'S POSSIBLE? >> BASED ON HLA-2 PREVALENCE WHICH IS ABOUT -- TRIPLE NEGATIVE BREAST CANCER IS MORE COMMON IN AFRICAN AMERICANS, MAYBE THIRD OF PATIENTS WOULD BE HLA-2 SO THAT WOULD BE STRAIGHT FORWARD BECAUSE WE HAVE SEVERAL HLA-2 BREAST CANCER CELL LINES THAT ARE -- WE HAVE IN OUR LAB. OTHER HLA ANTIGENS DEPEND ON WHAT'S AVAILABLE IN BREAST CANCER CELL LINES WHAT'S AVAILABLE AND HOW THE PATIENT MATCHED. >> DO YOU THINK AT LEAST HALF THE PATIENTS WOULD BE POSSIBLE? >> I THINK THEY'RE ALL CAUCASIAN, BECAUSE THAT'S WHAT WE IN MELANOMA, BUT TRIPLE NEGATIVE BREAST KAREN IS MORE COMMON, I THINK IT WILL BE AVAILABLE IN THIRD. >> YOU WILL DO IF THEY ARE AVAILABLE. >> IF WE HAVE HLA MATCHED TO SOME BREAST CANCER CELL LINE EXPRESSION THOSE ANTIBODIES, YES, THAT'S WHAT WE PLAN TO DO. >> ALSO HAD A QUESTION ABOUT EXPRESSION, TAs AND NORMAL TISSUES AND IF YOU WERE GOING TO TEST SPECIFICALLY DETERMINE POTENTIAL IMMUNE REACTS IN VIVO AND IN VITRO AND YOU ANSWERED THAT IN YOUR PRESENTATION. I'M SATISFYED THAT YOU'RE GOING TO BE LOOKING AT THAT. I ASSUME PATIENTS ARE ALSO GOING TO BE INFORMED THAT IF THEY HAVE ANY SKIN REACTS OR ANYTHING LIKE THAT (INDISCERNIBLE) >> ABSOLUTELY. >> THEY'RE GOING TO NOTIFY THEIR PHYSICIANS IN BETWEEN THE VISITS. >> MAKE SURE TO ADD THAT TO THE LAST PARAGRAPH. >> THEN I HAD SOME QUESTIONS AND COMMENTS ON INFORMED CONSENT DOCUMENTK THAT WAS ALSO SOMETHING THAT THROW REVIEWERS HAD IN COMMON WE WANTED TO MAKE SURE THAT THE PATIENTS ARE NOT -- THIS IS UNKNOWN RISKS AND ALSO UNKNOWN BENEFITS THAT THAT'S MADE CLEAR IN THE DOCUMENT, YOU MADE SOME CHANGES. I WOULD STILL LIKE TO SEE -- VERY UNLIKELY BUT MAYBE UNLIKELY WOULD BE A BETTER THING YOU MAY NOT BENEFIT. IF I WERE A PATIENT AND I READ YOU MAY NOT BENEFIT I WOULD PROBABLY THINK THAT STILL MEANS I HAVE A GOOD CHANCE OF BENEFITING AND I THINK YOU SHOULD OVEREMPHASIZE NOT GIVING THAT MAYBE FOR (INAUDIBLE). >> I WILL SEARCH FOR A BETTER WORD THAN UNLIKELY HIGHLY UNLIKELY -- >> OR VERY LIKELY. SOMETHING BETTER THAN WHAT YOU -- (INDISCERNIBLE) THAT'S ALL I HAD. I'M SATISFIED THEN WITH EVERYTHING. >> ALL YOUR POINTS ARE ADDRESSED. >> YES. >> THANK YOU VERY MUCH. >> THANK YOU. I TOO MADE THE COMMENT ABOUT THE NODE NEGATIVE SUBJECTS YOU MENTION STUDIES ARE ALL OVER THE PLACE. I HAD BEEN LOOKING AT A STUDY FROM LAST YEAR THAT 1700 PATIENTS, THEY FOUND NODE NEGATIVE OVERALL SURVIVAL FIVE YEAR WAS 80% VERSUS 65% FROM ONE TO THREE POSITIVE LYMPH NODES, SIMILAR PROGRESSION FREE SURVIVAL WAS A SIGNIFICANT DIFFERENCE. SO I'M NOT SURE THIS IS A GOOD REPRESENTATIVE STUDY BUT THAT WAS THE BASIS OF MY COMMENT AND MAYBE THERE'S A GOOD COMPROMISE WHAT YOU DISCUSSED ABOUT RULING OUT CERTAIN GROUP OF WOMEN MAYBE NOT ALL NODE NEGATIVE. THE SECOND THING I ASKED ABOUT WAS IF YOU WOULD PUT IN THE CONSENT FORM FIRST IN HUMAN TRIAL. YOU AGREE TO DO THAT. AGAIN, THIS ISSUE OF POTENTIAL BENEFIT AS AN ORDINARY WOMAN, THIS STUDY IS ASKING A FAIR AMOUNT OF THE SUBJECTS. I THINK THEY NEED A REASONABLE INFORMATION ABOUT THE LIKELIHOOD OF BENEFIT. YOU WOULDN'T BE DOING IT IF YOU DIDN'T THINK THERE WAS BENEFIT BUT TO ME WHAT YOU HAD MAY OR MAY NOT BENEFIT, THAT'S SOMETHING THAT YOU WOULD GET WITH A PROVEN THERAPY, RIGHT? OFTEN THERE ARE PEOPLE WHO DON'T BENEFIT FROM THOSE. ANOTHER POSSIBILITY WOULD BE EARLY STAGE TRIALS LIKE THIS DO NOT USUALLY PROVIDE BENEFIT TO SUBJECTS. MAYBE WOULD BE ANOTHER WAY. >> THAT WOULD BE PERFECT. >> SO THAT'S ALL I HAVE. THANK YOU. >> DR. PRUITT, I HAVE A FEW QUESTIONS. WHEN THE CROSS REACTIVITY OF THE VARIOUS ANTIBODIES, YOU SAY MH-3 IS SEEN IN TESTES APPROXIMATE YOU SAID IT WASN'T APPROXIMATE ISSUE SO DOES THAT MEAN 14% OF PATIENTS WITH MALE BREAST CANCER WOULD NOT BE ELIGIBLE? >> WE'RE NOT ENROLLING MALE BREAST CANCER PATIENTS. >> IS THERE A BIOLOGIC REASON NOT TO IN Q. NO, BUT THE PROTOCOL WE ALREADY SUBMITED TO THE FDA SAID FEMALE. SO I WASN'T GOING THE CHANGE THAT. I HAVE NOT SEEN ANY MALE TRIPLE NEGATIVE BREAST CANCER IN MY OWN PRACTICE. I HAVE NOT EXPERIENCED THAT 14% MYSELF. I WOULD SAY IN MY 15 YEARS AT DUKE AND PRACTICE FOR BREAST CANCER I HAVE NEVER SEEN A MALE THAT WAS TRIPLE NEGATIVE. >> THAT'S FINE. COMING BACK TO THE ISSUE OF THE N-0 AND N-1 DISEASE, I HAVE MUCH LESS ISSUES WITH IT PERSONALLY. IF YOU LOOK AT BIOLOGIC END POINTS IN TERMS OF IMMUNE REACTION, YOU CAN TELL PATIENTS WITH VERY EARLY BREAST CANCER HERE IN TRIPLE NEGATIVE AND PATIENTS NODE POSITIVE HAVE A DIFFERENT IMMUNE REACTION. SAY IT TURNS OUT THAT THE N-1 DISEASE HAS A VERY ROBUST REACTION TO ALL THREE ANTIGENS. AND YOU CAN SHOW THAT IN YOUR PHASE 2 TRIALS WHICH WE ARE LIKELY TO SEE AND I HOPE TO SEE VERY SOON, WILL YOU THEN CONSIDER CONCENTRATING ONLY ON THE N-1 DISEASE IN ORDER TO SHOW A DIFFERENCE QUICKER? Q. ANY STUDY I WANT TO DO, I WANT TO SELECT A PATIENT TO SEE BIGGEST DIFFERENCE AS RAPIDLY AS POSSIBLE. I THINK THAT THEORY THAT WOULD BE GREAT BUT I THINK THE SMALL NUMBER OF PATIENTS IN THIS PHASE-1 TRIAL PROBABLY WILL MAKE THAT DIFFICULT TO COMPARE N-1 TO N-0 DISEASE BUT WE DEFINITELY LOOK AT IT BUT I THINK THERE'S NOT GOING TO BE JUST ANY STATISTICAL POWER IN THIS SMALL PHASE-1 STUDY TO BE ABLE TO ANSWER THAT QUESTION. >> OKAY. GOOD. ANY OTHER COMMENTS? >> COULD YOU SHARE WITH ME THE DIFFERENCES THAT YOU SEE LONG TERM IN TRIPLE NEGATIVE DISEASE? YOU STOPPED AT FIVE YEARS BUT IT'S MY UNDERSTANDING THAT RECURRENCES ARE TAKING PLACE MUCH LATER. IN CERTAIN SUBSETS OF PATIENTS WITH THIS PROBLEM 10, 15, 20 YEARS OUT. DO YOU HAVE ANY DATA TO TELL US WHAT HAPPENS OVER THAT TIME FRAME WITH TRIPLE NEGATIVE VERSUS OTHER PATIENTS? >> I DON'T FOLLOW THE QUESTIONS Z AS LONG AS LON MEDICAL COLLEGE COLLEAGUES BUT MOST OCCURRENCES TRIPLE NEGATIVE OCCUR IN FIRST THREE YEARS THAN OTHER NON-TRIPLE NEGATIVE BREAST CANCER THAT SEEMS TO BE THERE'S A RECURRENCE RISK IN THE FIRST FIVE YEARS THAT GOES -- IT GRADUALLY DECREASES BUT MOST RECURRENCES IN TRIPLE NEGATIVE OCCUR EARLIER, AFTER THREE YEARS IT SEEMS TO FLATTEN OUT MORE QUICKLY THAN WITH REGULAR NON-TRIPLE NEGATIVE BREAST CANCER. >> KELLY AND KIM, ANY COMMENTS? >> THE NUMBERS MOST OF THE LITERATURE SUPPORTS IS LESS THAN 5% OF RECURRENCE IS A TRIPLE NEGATIVE BREAST CANCER WILL RECUR AFTER THE FIFTH YEAR. THE 60% OF CASES RECUR IN TWO YEARS AND 80% IN THREE YEARS THOUGH THERE ARE STUDIES THAT ARE VARY AROUND THOSE TIME POINTS. MAKES THIS STUDY POPULATION IDEAL PATIENT POPULATION STUDY SHORT TERM A MEAN STRATEGY. >> IF THAT'S THE CASE THEN, WE HAVE A 10% DIFFERENCE BETWEEN (INDISCERNIBLE). THERE'S NO LONG TERM BENEFIT. WE HAVE A NEW FIRST IN HUMAN TRIAL, WE'RE DEALING WITH A SMALL NUMBER OF PATIENTS THAT NEED ACCRUAL SO SHOULDN'T BE HARD TO GET THAT PATIENT ACCRUAL. THIS IS A TOXICITY STUDY, NOT AN EFFICACY STUDY WHICH YOU WOULDN'T HAVE. I STILL HAVE TROUBLE WITH THE N-0 POPULATION BASED ON WHAT YOU JUST HEARD. I HAVE A BIG PROBLEM WITH IT. I THINK MAYBE WHEN YOU SHOW THERE'S SOME EVIDENCE THIS IS DOING SOMETHING THEN IN A PHASE-2 TRIAL, FINE. BUT FOR PHASE-1 TRIAL, I JUST DONE SEE IT. >> DR. ZOLOTH. >> I HAVE THREE THINGS THAT WILL COME UP IN EVERY SINGLE REVIEW SO FAR. MAYBE THEY'RE ENDEMIC BUT THIS IS MY FIRST CHANCE TO LOOK AT THEM. THIS HAS NOTHING TO DO WITH THIS PARTICULAR TRIAL BUT IT'S TRUE FOR EVERYTHING WE LOOK AT AS WELL. THE FIRST IS THIS DEEP PERSISTENT AMBIGUITY BETWEEN LANGUAGE OF SAFETY. BETWEEN PHASE 1 TRIALS AND THE JUST SAFETY TRIALS AN DON'T SEE EFFICACY, AND THE STANCE OF THE INVESTIGATOR, WHO BELIEVES WILL BE A THERAPEUTIC BENEFIT TO INTERVENTION JUST AS IF THERE WAS IN A MURINE MODEL. WHY ARE THEY DOING THIS WHY THEY GET THIS FAR. SO THERAPEUTIC MISCONCEPTION WE DESCRIBE IN PATIENTS IS NOT A MISCONCEPTION AT ALL. IT'S AN EVIDENCE OF RISK TAKING. WHICH MIGHT BE ACTUALLY QUITE SMART. IT'S AWARENESS THAT DESPITE OUR LANGUAGE AN DESPITE CONSENT FORMS THERE REALLY IS ON THE PART OF THE INVESTIGATOR AN OPTIMISTIC HYPOTHESIS THAT MAYBE WE SHOULDN'T CALL THIS THE THERAPEUTIC ANTICIPATION ON THE PART OF THE RESEARCHER. SO THAT'S AN ISSUE THAT'S AN ETHICAL PROBLEM. THEN NOTE AND MOVE ON. THAT'S LANGUAGE IN PROTOCOLS BEING ABLE TO WITHDRAW AT ANY TIME. BUT JEAN TRANSFER THERAPIES, THIS IS NOT THE CASE. WITHDRAWAL LIKELY ONLY MEANS ONE TIME INTERVENTION WILL BE MONITORED TESTIFILY OR NOT. ONCE INJECTION IS GIVEN YOU CAN'T DRAW FROMNA LIKE YOU COULD WITH SHORT ACTING DRUG OR HEMOTHERAPY OR ANY OTHER -- CHEMOTHERAPY OR ANY OTHER INTERVENTION P. SAYING THAT REALLY NEEDS TO BE THOUGHT THROUGH. NOT BREAK IT TO YOU BUT TOWARDS EVERYONE. HERE YOU CAN WITHDRAW FROM FURTHER TREATMENT AS OPPOSED TO SOME WE'LL SEE WHICH IS THEY CAN'T WITHDRAW AT ALL. THING IS DONE. THIRD IS THAT MY PERSISTENT JUSTICE ISSUE HOW ADVERSE INCIDENTS ARE TREATED AND CARE IS NEEDEDDED (INAUDIBLE) THEIR BODIES ARE NEEDED FOR THE TRIAL AND THEY RECEIVE NO MEDICAL BENEFIT FOR THEIR PARTICIPATION AND AS A -- IF A TRIAL THE FAILURE THAT HARMS BODIES WILL BARE ALL THE BURDEN AND NOW ALL THE COST. THAT SEEMS UNFAIR TO ME. THE SUBJECTS EXPECT TO ACT ALTRUISTICALLY BUT EVERY OTHER PARTICIPATE ACTS RELATIVE TO INCENTIVE OF VARIOUS KINDS. IT'S NOT YOUR FAULT, IT'S A LESS SEVERE ASSURANCE IN YOUR PROTOCOL THAN OTHERS WE HAVE SEEN. BUT IT IS SOMETHING I THINK TO CONSIDER. I DON'T EXPECT YOU THE FIX THOSE, I WANT POINT THEM OUT AS WE MOVE THROUGH THIS. THE THING SPECIFIC TO YOUR TRIAL OF INTEREST TO ME IS PATIENT SUBJECT ACCRUAL, YOU SAY IT'S TWICE AS LIKELY PEOPLE WITH TRIPLE NEGATIVE BREAST CANCER WILL BE BLACK. AND SO THAT SHOULD BE ANTICIPATED 30% OF PATIENT ACCRUAL SHOULD BE WELL DONE REPRESENT THAT REALITY. IT WOULD BE IMPORTANT I THINK IF YOU TEST INTERVENTION TO MAKE SHOWER THAT'S THE CASE, THERE MIGHT BE SOCIAL ECONOMIC FACTORS OR OTHER SOCIAL FACTORS, CULTURAL FACTORS I DON'T KNOW HOW YOU MAN TO DO THAT. MAYBE YOU AS PRACTITIONER IN NORTH CAROLINA KNOW -- FEELS CONFIDENT THAT YOU'LL GET THE RIGHT MIX OF ACCRUAL. IT'S IMPORTANT ACTUAL PATIENT POPULATION AFFECTED BY THIS. AND I THINK SENSITIVE TO THAT, MAYBE MORE A PROBLEM IN PHASE 2 BUT IN PHASE 1 SHOULD BE LOOKED AT SINCE THERE'S A STRONG RACIAL DIFFERENCE. I'M UNCOMFORTABLE USING THAT TERM, NOT SHOWER WHAT THE TERM BLACK MEANS AND HOW THAT'S ASCERTAINED, IDENTIFICATION OR WHAT YOU'RE DOING TO CREATE THAT CATEGORY. THOSE ARE PUZZLES FOR ME IN THE PROPOSAL. >> WE DID NOT HAVE ANYTHING TO SPECIFICALLY ADDRESS RECRUITMENT BUT A LOT WAS JUST PLANNING ON TAKING TRIPLE NEGATIVE AS THEY COME. AND ENROLL ONE AT A TIME BASED ON PARTICIPATING OR NOT. I WAS HOPING TO TAKE CARE OF THAT ISSUE BUT WE CAN GO BACK AND SPECIFICALLY LOOK AT THAT. THINK ABOUT ROUTE REACH, IN SOME SENSITIVITY. IF IT'S GOING YOU'RE GETTING ALL CAUCASIAN PATIENTS. EUROPEAN ORIGIN PATIENTS AND P ADJUVANT PATIENTS YOU MIGHT THINK HOW YOU'RE GOING TO DO THAT. >> THE SMALL NUMBER OF PATIENTS PLAN ON ACCRUING FOR THIS STUDY MIGHT BE TOO SMALL TO MAKE A STATISTICAL REPRESENTATION BUT WE'LL DEFINITELY DO OUR BEST TO REFLECT THE POPULATION AT LARGE. >> ANY OTHER COMMENTS FROM RAC MEMBERS? >> IN ONE RESPONSE YOU SAID NONE TARGET ANTIGENS AND IMMUNE MODULATORS WILL BE EXPRESSIONED IN CELLS OTHER THAN INTENDED TARGET DCs, WHEN YOU ACTIVATE THE MONOCYTE WHAT IS'S THE PURI9J CONTAMINATING CELLS AND THEN WHEN YOU PUT YOUR COCKTAIL ON, WHAT PERCENTAGE OF THOSE ACTUALLY BECOME DENDRITIC CELLS? >> WE LOOK AT THE QC, WE LOOK AT MARKERS FOR T-CELLS, B CELLS SO WE LOOK AT CD 19, CD 56 FOR NK CELLS, CD 3 FOR T-CELLS AND WE HAVE LESS THAN 10% CONTAMINATION FOR THOSE CELLS. MONOCYTE ENRICHMENT THAT E WE SWITCH TO AT THE END OF OUR OTHER TRIAL, WE HAD ABOUT 90% PURE MONOCYTES AT THE END OF ATTRITION. SO WE DIDN'T HAVE ANY PROBLEMS OF LEVELS OF CONTAMINATION. THAT'S A FEW EXTRA CELLS IN THERE. DENDRITIC CELL, RNA, THERE'S NO CHANCE OF INCORPORATION OF THE GENOME, NO CHANCE OF LONG TERM EXPRESSION. BUT YOU ARE RIGHT. >> THE LANGUAGE A VERY ABSOLUTE STATEMENT, THERE ARE NO OTHER CELLS. BUT THERE'S ALWAYS THE SMALL FRACTION OF CONTAMINATING CELLS SO IT'S POSSIBLE CONTAMINATING CELLS RNAS TRANSIF HE CANED TO THEM. >> MY READING OF THAT PART OF RESPONDS THEY WERE TALKING VIRAL OR OTHER ENTAKE VECTORS INTO A PATIENT THAT WOULD INFECT OTHER POST CELLS. >> BODY. >> THAT MAY HAVE BEEN MY NARROW ENTERPRETITION. EXVIVO, THERE WILL BE A FEW OTHER CELLS IN THERE. >> HANS. >> >> GAB TO MY FIRST QUESTION. LET ME ASK AGAIN, WHAT ARE THE THREE MAJOR TOXICITIES YOU WOULD EXPECT? >> BUSINESSED ON THE EGFR, SUTUXIMAB MONOCLONEAL ANTIBODY STUDIES, THE LOW LEVELS OF IMMUNE MODULATORS SECRETING I TONE EXPECT THE SEE COMPLICATIONS ASSOCIATED WITH SYSTEMIC ADMINISTRATION OF APT CTLA 4 ORGEAT MONOCLONAL ANTIBODY. I DON'T EXPECT TO SEE THOSE, WE'LL MONITOR FOR THAT CLINICALLY I DON'T ANTICIPATE ANY OF THOSE. MUC1 IS SAFE, OTHER VACCINES YOU COULD ARGUE THE SAFETY OF OTHER VACCINES IS INEFFECTIVE. SO THAT MAY -- THAT'S WHY WITH WE'RE DOING THIS AS A PHASE 1 TRIAL SEQUENTIALLY ADDING THE TWO IMMUNE MODULATORS AND ADDING THEM TOGETHER STOW SEE IF EACH IS SAFE ALONG THE WAY. >> I DON'T HAVE ANY PARTICULAR I ALSO HAD IN MY FIRST QUESTION YOU REALLY MAKE SURE THAT THE PATIENT KNOWS IN THE PROTOCOL CONSENTX! FORM THE DIFFERENCE ISN'T SURVIVAL FOR DIFFERENT PATIENT GROUPS. ONE P LAST OR TWO LAST THINGS, MAYBE CONSENT FORM YOU THINK MAKE IT CLEAR SIMPLY SAY IT IS NOT KNOWN WITH IT, ANY MISLEADING LANGUAGE IN THERE. ONE LITTLE THING, WE DON'T KNOW RIGHT WHEN THE AUTO-IMMUNITY COULD COME ON. MAYBE YOU COULD SEE THE PATIENT BACK AT SIX MONTHS OR A YEAR. SPECIFICALLY LOOK FOR THEM. >> AS ROUTINE AT DUKE THEY'RE FOLLOWED. I BELIEVE KIM AND KELLY ARE STILL THERE. THEY'RE GOING TO BE SEEN EVERY THREE MONTHS FOR GOOD PERIOD OF TIME AFTER VACCINATION. SO THEY'RE CLINICALLY -- WE WOULD BE HAPPY TO SEE THEM BACK IN CLINIC AGAIN. >> SOMEBODY THINKS ABOUT THIS AND LOOKS AT THAT BECAUSE THAT'S A BIG -- YOU POINT THIS OUT IN THE MOUSE MODEL, VERSUS THE SYSTEMIC ADMINISTRATION, YOU SHOULD NOT SEE ANY AUTO-IMMUNITY. >> WE CAN EASILY BUILD IN THREE MONTH FOLLOW-UP FOUR THE FIRST YEAR IF THAT WOULD BE REQUIRED. >> DR. PALUSKI. >> MUCK-1 IS GLYCOSYLATED IF NORMAL TISSUE AN PRESUME IN CANCER TISSUE AS WELL. HAVE YOU LOOKED AT DENDRITIC CELL EXPRESSION OF THE REPEAT PEPTIDE, IT IS GLYCOSYLATED OR PROCESSED IN A WAY SIMILAR TO CANCER CELLS? ASSUME YOU'RE PUTTING DENDRITIC CELLS LOADING THEM WITH RNA SO THEY'LL EXPRESS IN THE CELL SURFACE AND IMMUNOGEN. >> WE'RE EXPECTING THE MUC1 TO BE EXPRESSED INTRACELLULARLY AND DEGRADED IN PEPTIDES SO GLYCOSYLATION IS -- >> PEPTIDE FRAGMENTS NOT PROTEIN -- >> CORRECT. >> OKAY. >> ANY OTHER COMMENTS FROM THE RAC MEMBER? ANYONE ON THE PHONE? PUBLIC COMMENTS? >> I WOULD JUST LIKE TO THANK THE RAC REVIEWERS FOR THEIR EXCELLENT COMMENTS ABOUT CONSENT FORM WHICH ARE RIGHT ON POINT. AND WHICH I AGREED WITH. I WOULD ALSO LIKE TO SAY I THOUGHT DR. ZOLOTH'S COMMENT ABOUT WITHDRAWAL IS VERY GERMANE TO ALL OF THE DISCUSSIONS ABOUT THESE PROTOCOLS. IT STRIKES ME THAT THERE THE REPRESENTATION CONSENT FORM OF RISK TO PATIENTS TO THE PARTICIPANTS IN THESE TRIALS IS NOT FULLY FLESHED OUT WITH THAT IN MIND. SO THAT SEEMS A A VERY IMPORTANT POINT GOING FORWARD IN CONCEPT FORMS, THIS IS A ONE OFF FOR MANY OF THESE TYPES OF TRIALS. AND SOMETHING YOU CAN'T RESCIND. SO THAT'S RISK PARTICIPANTS NEED TO BE MADE AWARE OF, UNLIKELY TO THINK OF THAT ON THEIR OWN, MANY OF US MISSED IT. >> VERY GOOD. LET'S TAKE A FIVE MINUTE BREAK AND THEN READ THE RECOMMENDATIONS OF THE RAC >> DR. PRUITT, IF WE COULD HAVE YOU AT THE PODIUM AGAIN. HERE ARE THE A DRAFT RECOMMENDATIONS FROM THE RAC TO BE CONSIDERED. CLINICAL. ALTHOUGH TNBC OVERALL HAS A POOR PROGNOSIS, STUDIES HAVE SHOWN THE PROGNOSIS IS FAVORABLE IN PATIENTS WITH NO KNOWN LYMPH NODE INVOLVEMENT. WITH AT LEAST ONE STUDY SHOWING AN OVERALL SURVIVAL OF 80% IN NODE NEGATIVE PATIENTS. ALSO PATIENTS WITH SMALL T-1 TUMORS HAVE A BETTER PROGNOSIS. WE UNDERSTAND THE NEED TO TEST THERAPIES EVEN FOR NODE NEGATIVE PATIENTS, CONSIDER MODIFYING ENROLL NODE NEGATIVE SUBJECTS LARGER TUMORS SUCH AS THOSE THREE CENTIMETERS OR GREATER AS RISK OF RECURRENCE AFTER SURGERY IS HIGHER THAN SMALLER TUMORS. NUMBER 2, CERTAIN GENETIC MARKERS FOR EXAMPLE BRA 1 AND 2 AND P-53 ARE ASSOCIATED WITH POORER PROGNOSIS WHILE THIS IS NOT AN EFFICACY TRIAL IT WOULD BE HELPFUL TO DOCUMENT, TEST AND DOCUMENT THE STATUS OF THESE GENE EXPRESSION. AS ALMOST 50% OF WOMEN WITH PNBC ARE AFRICAN AMERICAN, IT MAY BE BENEFICIAL TO HAVE STUDY POPULATION REFLECT THE POPULATION WITH TNBC TO EXTENT POSSIBLE. MAYBE HELPFUL TO THINK ABOUT RECRUITMENT STRATEGIES THAT BRING A REPRESENTATIVE POPULATION. NEXT, TO MONITOR AUTO-IMMUNITY THERE SHOULD BE FOLLOW-UP AT 4 TO 6 MONTHS TO EVALUATE FOR THAT POSSIBILITY. EVERY PHASE 1 TRIAL IS DONE WITH INTENT OF DEVELOPING A NEW THERAPEUTIC, THE REALITY IS 90% OR MORE OF NEW AGENTS WILL FAIL TO BECOME LICENSED THERAPEUTICS. ALREADY IT IS IMPORTANT TO NOT PROMISE THERAPEUTIC BENEFIT WHEN IT IS HIGHLY UNCERTAIN. THE STATEMENT REGARDING BENEFIT, QUOTE, THAT YOU MAY NOT RECEIVE DIRECT BENEFIT UNQUOTE, STILL SEEMS OPTIMISTIC, CONSIDERING THE FOLLOW STATEMENT. QUOTE, PHASE 1 STUDIES SUCH AS THIS WHICH ARE FIRST IN HUMAN STUDIES USUALLY DO NOT OR -- DO NOT PROVIDE ANY MEDICAL BENEFIT TO SUBJECTS. NUMBER 2, WITH GENE TRANSFER AGENTS HAVE THE POTENTIAL TO PERSIST LONGER THAN TRADITIONAL DRUG. CLARIFY WITH WITHDRAWAL FROM THE TRIAL MAYBE WITHDRAWAL FROM FURTHER TESTING BUT THAT THE AGENT HAS POTENTIAL TO PERSIST. THOSE ARE THE CURRENT DRAFT. ANY COMMENTS FROM THE RAC MEMBERS OF PARTICULAR AS RELATES TO THE N-0 STATUS? I DO NOT FEEL STRONGLY THAT HAS TO BE BIGGER TUMORS. I THINK THE LIKELIHOOD THE TOXICITY IS LOW INm I APPRECIATE FEELINGS ABOUT THAT. IF'S MORE DISCUSSION, LET'S TAKE IT UP NOW. >> I HAVE EXPRESSED MYSELF, I DON'T THINK ANY SHOULD BE INCLUDED. THAT'S WHAT I FEEL BECAUSE IT'S A PHASE 1 STUDY AND IT MAY BE LOW BUT WE FUNDAMENTALLY DONE KNOW THAT. AND THE GROUP THAT HAS A REASONABLE, 75% IS FAR FROM TERRIBLE OUTLOOK. SO UNLESS CHANGEED TO ZERO, I'M GOING TO ABSTAIN OR OBJECT. I HAVEN'T DECIDED YET. >> I LIKE THE COMPROMISE OF THREE CENTIMETER OR LARGER TUMORS THAT HAVE R, WORSE PROGNOSIS. >> >> I SPECIFICALLY COMMENT ON THAT, I THINK IF YOU BREAK OFF THE 32% OR WHATEVER YOU BREAK HAVE BEEN COUNSEL VINCEED IF YOU BREAK IT OUT SMALLER NODE NEGATIVE TUMORS IN THE P-2 GROUP LIKELY THAT LARGER TUMORS GO TOWARDS NODE POSITIVE AND (INAUDIBLE) I THINK THAT'S A GOOD COMPLIMENT. >> ANY DISCUSSION? ANYONE ON PHONE? PUBLIC COMMENT? >> THIS IS SHELLEY. TO CLARIFY MOST MEMBERS OF THE RAC FEEL COMFORTABLE WITH INCLUSION OF PATIENTS WHO HAVE A THREE CENTIMETER T-2 N-0 TUMOR OR GREATER. >> DR. PRUITT, ANY COMMENTS? >> THOSE SOUNDS LIKE I CAN RESPOND TO ALTHOUGH. AS FAR AS WITHDRAWING FROM THE STUDY, DIFFERENCE BETWEEN RNA AND DNA VACCINE, THE DNA VACCINE MAY PERSIST AFTER INCOMP INCORPORATION BUT NO FURTHER IMMOWN RESPONSE PERSIST THAT'S WHY WE DO THE STUDY. BUT AS FAR AS WITHDRAWAL FROM THE STUDY DURING THE VACCINATION COURSE THERE WON'T BE RESIDUAL RNA OR GENE PRODUCTS PRODUCED DURING THAT TIME. >> THE WORRY IS WHETHER AUTOIMMUNE WILL PERSIST. IT'S UNKNOWN. WHAT DR. ZOLOTH POINTED OUT, MANY STUDIES IS CORRECT -- DO WE HAVE A MOTION FOR A VOTE? DR. WILLIE, WHY DON'T YOU START. >> YES. >> >> HAMMARSKJOLD, YES. >> (INDISCERNIBLE) YES. >> ZOLOTH. YES. >> >> KIEM, YES. >> STROME ABSTAIN. >> KOHN, YES. >> FONG, YES. >> BRADLEY, YES. >> DRESSER YES. >> (INAUDIBLE) YES. >> ORNILIS, YES. >> KOHN, YES. >> PALUSKY, YES. >> ON THE PHONE. DR. >> MALLINO. YES. >> (INDISCERNIBLE) YES. >> VERY GOOD. SO WE WILL EDIT THESE COMMENTS AND SEND THEM TO YOU, DR. PRUITT. THANK YOU AND YOUR TEAM FOR PRESENTING TO US TODAY. >> WE WILL NOW MOVE TO OUR SECOND PROTOCOL THIS MORNING, THIS IS A DISCUSSION OF PROTOCOL NUMBER 1192, A STUDY TO INFUSE ROR-1 SPECIFIC AUTOLOGOUS T CELLS FOR PATIENTS WITH CLL. THE PI FOR THIS PROTOCOL IS WILLIAM WIERDA FROM THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. HE'S ASSOCIATE PROFESSOR OF MEDICINE AT THE DEPARTMENT OF LEUKEMIA AT THE UNIVERSITY OF TEXAS AND THE MD ANDERSON CANCER CENTER. THE CO-PI IS LAWRENCE COOPER WHO IS ALSO AT THE MD ANDERSON CANCER CENTER IN THE DEPARTMENT OF PEDIATRICS. DR. COOPER IS ALSO IN THE -- IS THE GRANT MARGARET SULLIVAN DISTINGUISHED PROFESSOR IN PEDIATRICIAN AND DIRECTOR OF IMMUNOLOGY LABORATORY OF PHYSICIAN SCIENTISTS IN THE DEPARTMENT OF IMNOLOGY. A -- IMMUNOLOGY. A SPONSOR OF THIS PROJECT IS THE MD ANDERSON CANCER CENTER FROM WIERDA, COULD YOU INTRODUCE COLLEAGUES THAT YOU HAVE WITH YOU TODAY AND YOUR TEAM. >> THANK YOU. I'M BILL WIERDA FROM MD ANDERSON CANCER CENTER. THE MY RIGHT IS LAWRENCE COOPER FROM MDd'L ANDERSON AND THIS IS TOM KITS T FROM UCSD. AND WE'LL START WITH LAWRENCE GIVING INTRODUCTION. >> THANK YOU TO THE COMMITTEE AND REVIEWERS, APPRECIATE YOUR TIME AND EFFORTS. WE'RE GOING THE TALK TODAY ABOUT STUDY TO INFUSE ROLE IN SPECIFIC T-CELLS OF GENETICALLY MODIFIED TO EXPRESS A SO-CALLED CHIMERIC ANTIGEN RECEPTOR, TO RETARGET THE T-CELLS FOR CLL CHRONIC LYMPHOSITIC LEUKEMIA. WE DIVIDED OUR COMMENTS TO THREE PARTS. DR. KITS FROM UCSD GO OVER THE TARGETING OF BIODISTRIBUTION OF ROLL ON, DR. WIERDA WILL EXPLAIN THE PROTOCOL AND THE DESIGN AND I WILL FINISH WITH THE GENE TRANSFER TECHNOLOGY AND THE WAY WE PROPAGATE T-CELLS. SO MY COLLEAGUE DR. KITS. >> THANK YOU VERY MUCH. ROR-1 IS FIRST IDENTIFIED BY DEVELOPMENTAL BIOLOGISTS AND WAS IDENTIFIED AS SIGNATURE GENE EXPRESSED IN CHRONIC LYMPHOSITIC LEUKEMIA WITH LOU INSTITUTE IN COLLABORATION WITH US AND OTHER OTHERS. THIS IS A STUDY THAT DEFINED EXPRESSION OF AUTOANTIBODIES AGAINST OR-1, SO THIS WAS A STUDY APPROVED BY THE COMMITTEE USING CD40 LIGAND ADENOVIRUS RECOMBINANT TO TRANSDUCE LEUKEMIC CELLS WITH INTENT TO MAKE THESE IMMUNOGENIC. SO PATIENTS WERE GIVEN THEIR OWN HOW CHEMOTIC CELLS THAT WERE THEN TRANSDUCED WITH THIS VECTOR. AND P WE NOTED THAT A NUMBER OF PATIENTS MADE AUTOANTIBODIES AGAINST HUE CHEMOIA ASSOCIATED ANTIBODY WHICH THROUGH INTERROGATION FOUND WAS BINDING TO THIS PROTEIN. THE PATIENTS MADE THE AUTOAPP AND WE DID NOT -- ANTIBODY AND WE DID NOT SEE ANY CONNECTED IT SHALL SHOE DISEASESSER OTHER TYPES OF METABOLIC DISORDER. THIS IS IN PART RELATED TO THE ANTIBODY SEEMS QUITE SPECIFIC FOR A ANTIBODY EXPRESSED IN CLL, HIGH RISK AND LOW RISK CLL PATIENTS EXPRESS THE ANTIBODY BUT NOT ON CIRCULATING B CELLS OR OTHER CELLS AS DESCRIBED HERE. THIS IS A TISSUE ARRAY LOOKING AT IMMUNOBLOTS. I THINK THE EXPRESSION OF ROR-H 1 IS IN IMMUNOGENESIS THAT ATTENUATES EXPRESSION AS THE DEVELOPMENT OF PENILE STAGE AN MOST TISSUES AT TERM LACK EXPRESSION OF THIS ROR-1. IT IS A ANOTHER HOMOLOGUE -- ORTHO RECEPTOR ROR-2 IS ALSO EXPRESSED AT EARLY EMBRYO GENESIS. HOWEVER THE ROR 1 IS NOT EXPRESSED, WE HAVE DONE STUDIES TO LOOK AT EXPRESSION OF EARLY HEMATOPOI IT CAN CELLS AN AFTER IMMUNOGENIC DEVELOPMENT WE DID NOT SEE THE EXPRESSION OF THIS ANTIGEN ON CORED BLOOD OR FETAL LIVER HEMATOPOIETIC AND PROGENITOR CELLS. WE HAVE ONGOING STUDIES THE LOOK AT THIS AND WE HAVEN'T SEEN ACTIVITY OF ANTIBODIES AGAINST ROR-# ON HEMATOPOIESIS. WE HAVE DEFINED ROR-1 EXPRESSION OF TYPE OF B CELL CALLED HEMATOGONES DEFINED II PRECURSOR THAT EXPRESSES CD 5 SO LIKE CD 5 PRECURSOR B LYMPHOCYTES. WE PUBLISHED ON THIS. THESE CELLS ARE CD 10 POSITIVE, CD 19 POSITIVE, CD34 NEGATIVE AND CD 2 NEGATIVE. PRIMARILY SEEN IN PARTICULARLY PEDIATRIC KIDS AFTER MYELOABLATIVE CHEMOTHERAPY AND OTHER CONDITIONS. AND TERMED HEMATOGONS. FOR THE MOST PART THIS IS EXPRESSED ON CLL, WE HAVE INTERROGATED NOW OVER 1,000 BUT THIS SLIDE SHOWS 800 CASES OF CLL. EACH OF THESE REPRESENT INDIVIDUAL CASE ON X AXIS. YOU SEE HERE 94% OF ALL CASES WE HAVE EXAMINED HAVE EXPRESSION OF ROR-1. THE SMALL PERCENTAGE OF CASES THAT LACK EXPRESSION WERE INTERROGATING NOW BECAUSE THEY HAVE A DISTINCTIVE TRANSCRIPTOME SIGNATURE AND WE ARE INTERESTED TO FIND OUT WHAT THE BIOLOGY IS. BUT IT IS EXPRESSED ON THE VAST MAJORITY OF CLL SAMPLES. WHEN WE LOOK AT THE EXPRESSION IN OTHER TISSUES, THIS IS LOOKING AT TRANSCRIPTOME DATA PERTAINING TO DEEP SEQUENCING ANALYSIS OF VARIOUS NORMAL ADULT TISSUES. WE DONE SEE EXPRESSION THIS INCLUDES A LIST OF TISSUES ON P THE RIGHT. IT'S REMARKABLE WITH REGARD TO THE EXPRESSION LACKING ADIPOSE TISSUE WHICH IS REMARKED AS A POTENTIAL SITE FOR ALREADY-1 EXPRESSION BY OTHER INVESTIGATORS. WHEN WE SCREEN THIS WITH IMMUNOBLOT OR AS I SHOWED YOU LATER, IMMUNOHISTOCHEMISTRY, WE HAVE SOME VERY HIGHLY SPECIFIC ANTIBODIES WE RAISED IN DIFFERENT TECH NOLS, WE USE TO MAKE ANTIBODIES DEVELOPED BY THE NIH GROUP HERE. SO YOU SEE THE EXPRESSION OF ROR-1 DETECTED ON ROR 1 POSITIVE LYMPHOLYMPHOMA. BUT DID NOT DETECT ON HEART BRAIN OVARY ESOPHAGUS OR PAN CROWIUS TISSUE. AND WHEN WE ALSO JUST RESEASONLY INTERROGATED FRESH FROZEN TISSUE THE ANTIBODIES WE DEVELOPED DO REACT WITH FORMALIN TISSUE BUT ALSO FRESH FROZEN FISH SHOULD FEEL THIS WAS OUTSOURCED TO A PATHOLOGY BIOSCIENCES, THEY TELL US THEY DON'T DETECT ANY ACTIVITY WITH FRESH FROZEN NORMAL HUMAN PANCREAS. SO THIS IS NOTEWORTHY IN CONTRAST TO SOME OF THE OTHER ANTIBODIES DESCRIBED. SO GENERATION REQUIRES THAT WE TAKE HOMODIMER THAT FORMED WITH ANTIBODY AND MAKE IT SINGLE CHAIN MOLECULE APPENDED TO T-CELL RECEPTOR AS SHOWN IN THIS CARTOON. SINGLE CHAIN ANTIBODY USING AFFINITY MEASUREMENTS TO LOOK AT THE BINDING ACTIVITY LESS BINDING THAN THE INTACT ANTIBODY, THE WITH CHAIN MOLECULE, SO THIS IS REASSURING BECAUSE THE AFFINITY IS SIMILAR TO THIS OF THE NATIVE ANTIBODY. PARENTHETICALLY A PAPER WAS PUBLISHED BY THE RADAR GROUP HERE AT THE NIH THAT DESCRIBE THEIR ANTIBODIES AND THEY'RE NOT HAVING SIMILAR SPECIFICITY. THE ANTIBODIES WERE RAISED THROUGH DIFFERENT TECHNOLOGY, THEY HAVE DIFFERENT SPECIFICITY, THEY CROSS REF WITH HUMAN AN MOUSE AN LOWER AFFINITY, THIS IS THE MODEL DATA TO COMPLEX THAT'S USED TO GENERATE BY THE (INDISCERNIBLE) GROUP BY HILL'S GROUP IN SEATTLE WITH THE KU OF ABOUT 33 NANOMOLAR. SO I THINK THAT THE AFFINITIES ARE VERY -- VARIED AND SPECIFITIES ARE VARIED, THIS MAY ACCOUNT FOR CONFERENCES. I WANT TO SUMMARIZE THE SECTION THAT IT APPEARS TO BE EMBRYONIC ANTIGEN, IT'S ATTENUATED THANK YOU DEVELOPMENT, NORMAL TISSUES DO NOT EXPRESS ROR-1 EXCEPT WHAT WE FOUND TO BE HEMATOGONS. ROR 1 IS EXPRESSED BY ALL CHRONIC LYMPHOSITIC LEUKEMIA AND WE GENERATED HIGH AFFINITY MONOCLONEAL ANTIBODIES FOR HUMAN ROR LINE AND SINGLE CHAIN ANTI-ROLE HIGH AFFINITY FOR ROR-1. UP LIKE ANTIBODIES DEVELOPED BY OTHER INVESTIGATORS NOTABLY THE RADAR GROUP THE MONOCLONEAL ANTIBODIES DO NOT CROSS REN'T WITH OTHER TISSUES, INCLUDING ADIPOSE TISSUE, PLEASANTLY SURPRISEED TO SEE LACK OF ACTIVITY. IT GOES BACK TO THE PATIENTS THAT WE HAD IMMUNIZED WITH THEIR LEUKEMIC CELLS THAT WE DID NOT SEE ANY DEVELOPMENT OF DIABETES OR WASTING OR MIXED CONNECTIVE TISSUE DISEASE THOUGH THEY HAD HIGH TITER ANTI-ROR 1 ANTIBODY THAT WILL GENERATE IN RESPONSE TO THIS VACCINE WE HAVE GIVEN EARLIER. BILL. >> SO NEXT I WILL REVUE THE CLINICAL TRIAL. A LITTLE BACKGROUND ABOUT CL WILL BE, IT'S RELATIVELY HETEROGENEOUS DISEASE. WE SEE THIS SLIDE SHOWS YOU THE CONTINUUM OF THE DISEASE. PATIENTS ARE DIAGNOSE THOSED, MONITOR FOR VARIOUS PERIODS OF TIME WHEN THEY DEVELOP ACTIVE DISEASE. SOME NEED FRONT LINE THERAPY. MOST OF THOSE PATIENTS WILL NEED SUBSEQUENT THERAPY. AND BECOME REFRACTORY TO STANDARD TREATMENTS AND MANY OF THESE SUCCUMB THE THEIR DISEASE, TO OTHER PROBLEMS SUCH AS SECOND MALIGNANCIES AND INFECTION. THE GROUP OF MASHES FOR THIS TRIAL, THE ONE HIGHLIGHTED IN ORIGIN FOCUSED ON THOSE PATIENTS ARE THE PATIENTS WITH RELAPSED OR REFRACTORY DISEASE, WE DO ALLOW ENROLLMENT OF PATIENTS WITH 17 P DELETION PREVIOUSLY UNTREATED BECAUSE IT ALSO IS A POPULATION WHICH HAS UNMET THERAPEUTIC NEED WITH NO STANDARD THERAPIES AN CORE OUTCOMES ASSOCIATED. I'M GOING TO SHOW YOU ABOUT INFORMATION AGAIN RELATED TO THAT POPULATION THAT WILL BE ELIGIBLE FOR THIS CLINICAL TRIAL. WE HAVE DONE A NUMBER OF CLINICAL TRIALS, EVALUATING VARIOUS THERAPEUTIC MODAL ITYS FOR THIS PATIENT POPULATION INCLUDING CHEMOTHERAPY COMBINATION, ANTI-BOY BODY BASED THERAPIES SO THIS IS A RECENT UPDATE OF STUDIES IT SHOWS YOU THE RESPONSE RATES. HALF PATIENTS ACHIEVE PARTIAL REMISSION WITH THOSE TYPES OF THERAPIES. WE'RE ABLE TO USE PROGNOSTIC FACTORS WITHIN THIS DISEASE THAT HAVE CORRELATED THOSE WITH WITH VARIOUS CLINICAL OUTCOMES INCLUDING TIME TO FIRST THERAPY, AND THOSE -- MANY OF THOSE PROGNOSTIC FACTORS ALSO CAN BE USED IN THE SALVAGE PATIENTS TO IDENTIFY HIGHER RISK POPULATIONS FOR EXAMPLE THOSE WITH WITH 17 P DELETION. WE HAVE DONE MULTI-VARIANT ANALYSES LOOKING AT TIME TO TREATMENT FAILURE AND USED THIS TO IDENTIFY HIGH RISK GROUPS AND I HAVE DONE MODELING WITH THESE TYPES OF ANAL SEIZE AND BEEN ABLE THE LOOK AT OUTCOMES AN EVALUATE AND ASSESS VARIOUS NEW THERAPEUTIC STRATEGIES. THIS SLIDE SUMMARIZES THE OUTCOMES FOR THOSE VARIOUS TREATMENT MODALITIES AND THE THING I WANTED TO HIGHLIGHT FOR YOU IS THIS IS A HIGH RISK POPULATION. THE MAJORITY OF PATIENTS THAT WILL GO ON THIS TRIAL ARE RELAPSED PATIENTS AND YOU CAN SEE MEDIAN TIME TO TREATMENT FAILURE IS SIX MONTHS, FOR CHEMOTHERAPY REGIMENS, THAT'S LONGER ON THE ORDER OF A YEAR. HIGH RISK, THEY'RE A HIGH RISK GROUP AND HAVE AN UNMET THERAPEUTIC NEED. WE HAVE IN THE LITERATURE AVAILABLE CLINICAL TRIAL DATA RELATING TO DEVELOPMENT OF CARS AND PATIENTS WITH CLL WHICH TARGET CD 19. ONE ISSUE WITH THAT ANTIBODY IS A TARGET WHEN YOU ARIPPLENATE CELLS WITH WITH THAT ANTIBODY YOU'RE ELIMINATING NORMAL B CELLS AND THERE BY FURTHER IMMUNOSUPPRESSING PATIENTS. SO WHAT SEAWANTED TO DO WITH TARGETING -- SO WHAT WE WANTED TO DO WITH TARGETING ROR 1 IS NOT -- DOES NOT TARGET NORMAL B CELLS, JUST TO IDENTIFY LEUKEMIA ASSOCIATED LEUKEMIA SPECIFIC ANTIBODY IN CLL AND NOT ELIMINATE AND IMMUNOSUPPRESS FURTHER BY ELIMINATING NORMAL B CELLS. THE OTHER OPPORTUNITY WE WANT TO EXPLORE IN THIS TRIAL IS STUDYING THE ENDODOMAINS, SIGNALING DOMAIN IN THE CAR CONSTRUCT. PATIENTS IN THIS TRIAL THAT YOU SEE WILL BE POPULATED WITH TWO POPULATIONS OF CELLS, BOTH OF THEM HAVE THE SAME BINDING SPECIFICITY, ONE HAS A CD 3 WITH CD 28 ENDODOMAIN CONSTRUCT. THE OTHER HAS 41BB DOMAIN. LAWRENCE WILL GIVE YOU MORE INFORMATION. BUT PATIENTS WILL BE INFUSED WITH POPULATION OF CELLS COMPOSED OF HALF OF THE CD 28 AND HALF 41BB ENDODOMAIN. IN THAT APPROACH WE WILL BE ABLE TO ASAYS CONSTITUTION AND IN VIVO EXPANSION AND IDENTIFY OPTIMAL CAR BETWEEN THOSE TWO. AND THIS HAS BEEN DONE BY OTHERS. AND THE WORK DONE AT BAILOR IN WHICH PATIENTS WITH CAR DIRECTED AT CD 19 TO ASSESS THIS APPROACH AND EVALUATE THE CD 3 ZETA THE FIRST GENERATION CRICKET VERSUS THE CD 28 SEA TA SECOND GENERATION CONSTRUCT. SO THERE'S A PRECEDENCE FOR THIS TYPE OF STRATEGY. DONE BY THE BAILOR GROUP. THIS SLIDE BASICALLY SUMMARIZES OUR CLINICAL TRIALS IT'S A 3 PLUS 3 DESIGN, I EXPLAINED THE RATIONALE AND PATIENT POPULATION AND I'LL SHOW YOU MORE ABOUT THE PRIMARY AN SECONDARY END POINTS IN THE NEXT SLIDE. THE PRIMARY OBJECTIVE IS TO IDE MAXIMUM TOLERATED DOSE AND TO ASSESS PERSISTENCE OF CAR POSITIVE T-CELLS FOLLOWING INFUSION. THERE ARE A NUMBER OF SECONDARY END POINTS. SO ASSESS -- TO ASSESS FEASIBILITY OF THE STRATEGY AND CLINICAL ACTIVITY IN RESPONSES PEARIAL REMISSION AND COMPLETE REMISSION BY STANDARD CRITERIA WE USE. WE'RE GOING TO ASSESS THE PERSISTENCE OF INFUSED MODIFIED T-CELLS. THEN THERE ARE A NUMBER OF ADDITIONAL CORRELATIVE STUDIES SHOWN AT THE BOTTOM OF THIS SLIDE. TRAFFICKING OF T-CELLS, CYTOKINE PROFILING T-CELL ASSESSING T-CELLS WHICH HAVE BEEN EXPANDED IN VIVO. THESE ARE SUMMARY OF THE INCLUSION CRITERIA, THESE ARE PREVIOUSLY TREATED DISEASE OR THOSE PATIENTS DON'T HAVE STANDARD OF CARE AND HIGH RISK BY VIRTUE OF THE PRESENCE OF 17 P DELETION CONFERRING CHEMOTHERAPY RESISTANCE. THERE'S A NUMBER OF LABORATORY ASSESSMENTS DONE AT SCREENING TO ASSURE PATIENTS ARE IN GOOD SHAPE BEFORE THEY GO ON TREATMENT, THEY MUST SIGN INFORMED CONSENT. THERE ARE A NUMBER OF EXCLUSION CRITERIA, CAN'T BE PREGNANT, HIV NEGATIVE, THEY CAN'T HAVE ANY RECENT TOXICITY FROM RECENT TREATMENT. ACTIVE AUTOIMMUNE PHENOMENA AND MUST PARTICIPATE IN LONG TERM FOLLOW UP PROTOCOL. SO IN TERMS OF LOGISTICS AND OPERATIONAL ASPECTS, IT'S CONDUCTED AT UCSD AND MD ANDERSON. THE INITIAL PLAN WAS TO DO CELL HANDLING AND PROCESSING IN VITRO WORK AT THE GNP FACILITY AT MD ANDERSON. PATIENTS H HAVE BLOOD CHECKED FOR FREESED. THEY'LL BE HANDLED, MANIPULATED, EXPANDED IN OUR GFP FACILITY AT MD ANDERSON AND WITH SOPs THAT HAVE BEEN ALREADY DEVELOPED SHIPPED BECOME FOR INFUSION AT UCSD. SO PATIENTS WILL HAVE THEIR CELLS COLLECTED, THEY WILL BE TRANSDUCED AND EXPANDED AS LAWRENCE WILL SHOW YOU, PRIOR TO INFUSION T-CELLS RECEIVE LYMPHODEPLEASIVE CONDITIONING REGIMEN I'LL TOUCH ON IN A MINUTE THEN INFUSED AT SPECIFIED DOSE ACCORDING TOCOSHORT ASSIGNED. 50% INFUSED CELLS HAVE THE CD 28 ENDODOE MANE, THE OTHER HALF HAVE THE 41BB SIGNALING DOMAIN. THE INFUSION WILL BE A SPLIT DOSE. SO 25% OF THE PRODUCT IS GIVEN FIRST DAY AND 75% ON THE SECOND DAY. A LITTLE BIT ABOUT THE LYMPHODEPLEATIVE REGIMENS. THE POPULATION WILL BE PREVIOUSLY TREATED THEY'LL HAVE HAD -- THERE WILL BE A HETEROGENEITY IN TERMS OF PRIOR TREATMENT. REASON FOR INCLUDING THREE POTENTIAL DIFFERENT REGIMENS IS TO LEAVE OPTIONS WITH WITH SOME LYMPHODEPLEATIVE ACTIVITY IN PATIENTS CONSIDERING HETEROGENEITY WHERE SOME PREVIOUSLY TREATED WITH FCR AND YOU WOULDN'T G THAT AS A LYMPHODEPLEASIVE REGIMEN, YOU CAN USE ANOTHER SUCH AS FBR OR STAIN RETUXIMAB. ALL ARE EVALUATED. DOSES HERE ARE STANDARD. THEY HAVE BEEN EVALUATED AS TREATMENTS FOR CLL. WE HAVE A LARGE KNOWLEDGE BASE IN TERMS OF THE EXPEu, TOXICITIES IN MONOSUPPRESSION NONE GIVEN A SINGLE COURSE WILL RESULT IN A PARTIAL REMISSION OR COMPLETE REMISSION. THE SCHEDULE EVENTS WAS INCLUDED IN THE PROTOCOL, THIS IS SHOWN HERE. THERE ARE NUMBER OF ASSESSMENTS THAT OCCUR. PATIENTS ARE SCREENED, THEY HAVE TO FULFILL SCREENING CRITERIA AND THEN SUBSEQUENT TO INFUSION WILL BE EVALUATED AND LABORATORY BY LABORATORY PHYSICAL EXAM ADVERSE EVENT ASSESSMENT AND AT THE BOTTOM YOU SEE A NUMBER OF SAMPLING TIMES FOR CORRELATIVE STUDIES. SO THINGS WE HAVE PUT INTO THE PROTOCOL TO ASSURE SAFETY, THREE DOSE COHORTS, THE INFUSION IS SPLIT DOSE, 25% FIRST DAY, 75 ON THE SECOND DAY. WE PAUSE BETWEEN PATIENTS 21 DAYS. IF PATIENTS HAVE UNEXPECTED TREATMENT RELATED ADVERSE EVENT IN THE PROTOCOL, WE HAVE CLARIFIED CONSIDER CO-STEROIDS AND IMMUNOSUPPRESSIVE AGENTS CAN BE GIVEN. WITH THAT I'LL HAND IT OVER TO LAWRENCE. >> THANK YOU. THE REMAINING FIVE OR SO MINUTES I HAVE WITH YOU, I WOULD LIKE THE TAKE YOU THROUGH THE GENE TRANSFER AND PROPAGATION TECHNOLOGY THAT WE PLAN TO USE FOR GENERATING THE ROLE ON SPECIFIC CAR MODIFIED T-CELLS. I WANT TO EMPHASIZE TO THE RAC AND PUBLIC THAT THE TECHNOLOGY THAT WE'RE BUILDING ON TO RE-ENGINEER SPECIFICITY IS BASED ON TECHNOLOGIES OPERATIONALLIZED MD ANDERSON TRIALS BEGUN THIS YEAR. IN PARTICULAR I POINT OUT THAT WE HAVE BEEN THROUGH THE RAC AND WE THANK THE RAC FOR THEIR HELP FOUR TIMES TO INFUSE CD 19 SPECIFIC T-CELLS. THIS REDIRECT CD 19 IS SO CALLED SECOND GENERATION CAR WHERE THE ENDODOMAIN IS TRIGGERED THROW CD 28 AND CD 3 ZETA. TWO TRIALS ARE RAPIDLY ACCRUING. THESE TOP THREE TRIALS WHETHER AUTOLOGOUS T-CELLS AND ALLOGENEIC T-CELLS INVOLVE WITH TRANSPLANTATION BIOLOGY. THE FOURTH TRIAL ON THE LIST IS A TRIAL INFUSING CD 19 CELLS DEPLETING CHEMOTHERAPY AKIN TO WHAT CARL JUNE IS DOING AND HIS COLLEAGUES AT THE UNIVERSITY OF PENNSYLVANIA. TECHNOLOGY TO SPRUE TUESDAY THE CAR INTO THE T-CELLS, WHETHER IT BE THE CD 19 OR NOW AS WE PROPOSE FOR ROR-1 HAS TWO FLAGSHIP COMPONENTS. FIRST IS GENE TRANSFOR TECHNOLOGY, MY COLLEAGUE PERRY HA DEBT I THINK WHETHER IS OPT PHONE IS THE INVENTER OF THIS TECHNOLOGY AND CLOSE COLLABORATOR WITH US. I EXPLAIN ALSO WE USE ARTIFICIAL ANTIGEN CELLS, K 56 CELLS, USED IN THE MANUFACTURING PROCESS TO LEK TRANSFER IN THE CAR FORKS THE SLOPE AND BOWTY SYSTEM AND SELECT TESTIFILY PROPAGATE T-CELLS ON THE ARTIFICIAL ANTIBODY PRESENTING CELLS TO ALLOW US TO GENERATE CLINICAL MATERIAL FOR INFUSION. I WILL TAKE THE COMMITTEE THROUGH IT BRIEFLY. WE OBTAIN PERIPHERAL BLOOD BY PUNCTURE OR APHERESIS. WE PURIFY BY CENTRIFUGATION AND P THERE'S AN ELECTROTRANSFER USING COMMERCIAL SYSTEM, USED TO BE KNOWN AS THE (INDISCERNIBLE) SYSTEM OTHERWISE KNOWN AS (INAUDIBLE) TECHNOLOGY, WITH WHERE ONE CODES FOR THE TRANSPOSEON, THE INTRODUCED CHIMERIC RECEPTOR, THE OTHER ONE CODES TO FACILITATE INTEGRATION TO THE GENETIC MATERIAL OF THE T-CELL. THE T-CELLS ARE THEN CO-CULTURED WITH THE ARTIFICIAL ANTIGEN PRESENTING CELL. THESE RK 56 DERIVED, RADIATED AND DECORATED WITH CO-STIMULATORY MOLECULES. WE HAD CYTOKINE SUPPORTEN OVER A PERIOD OF WEEKS WE CAN GROW OUT T-CELLS AT VIRTUALLY ALL EXPRESS IN THE CHIMERIC ANTIGEN RECEPTOR, THESE ARE FROZEN FOR IN PROCESS AS WELL AS RELEASE TESTING AN INFLUENCED AND HAVE DOWNSTREAM ANALYSES. NOW IF THE COMMITTEE DRAWS ATTENTION TO THE BOARD YOU SEE AS I FLASH TO THE NEXT SLIDE SUBTLE CHANGE HERE. THE REASON I EMPHASIZE THIS CHANGE IS WE'RE BUILDING ON THIS TECHNOLOGY. SO WHEREAS BEFORE WE WERE INTRODUCING CD 19 SPECIFIC CHIMERIC ANTIGEN RECEPTOR, WE HAD A K 562 CELL EXPRESSING CD 19 SPECIFIC T-CELLS, WE'RE SWAPPING OUT FOR THE ROLL ON SPECIFIC ANTIGEN RECEPTOR AND WE PUT+wz ROR 1 ON THE ARTIFICIAL ANTI-GENERAL PRESENTING CELL. SO THE PLASMID NOW, THE CARGO LOAD EXPRESSES THE CHIMERIC APT REACCEPT II FOR THE CAR TARGETING ROR 1 VERSUS CD 19. THE SLEEPING BEAUTY SYSTEM AS DESCRIBED BY PERRY HA DEBT IS A TWO PLASMID DNA SYSTEM, THE TRANSPOSEON HAS PROMOTER ASSOCIATED WITH DOWNSTREAM POLYA SIGNAL THANKED BY INTERNAL OR DIRECT REPEATS. -- FLANKED. THIS IS INTRODUCED TO THE DNA BY VIRTUE OF TRANSP POSITION. THE TRANSPOSITION IS MEDIATED BY APPROXIMATE ENZYME THE SLEEPING BEAUTY TRANSPOSEAs, WE USE ONE CALLED SB-11, THAT'S A LOT OF BACK STORY WE CAN GET INTO IF THE COMMITTEE NEEDS TO. THE PRODUCT THEN LISTS ESSENTIALLY THE TRANSGENE, THE CAR, INSERTS TO THE GENETIC MATERIAL REPEATS IN A RANDOMIZED MANNER ACROSS THE POPULATION OF T-CELLS. CONTRAST WITH OTHER GENE TRANSFER EVENTS, THESE ARE PUBLISHED BY DR. JENNA HERE IN THE GALLERY. WHERE ESSENTIALLY HE'S SHOWN IN THIS REVIEW ARTICLE THAT LENTIVIRAL SYSTEMS AS WELL AS RETROVIRAL SYSTEMS ADS WELL AS LENTIVIRAL SYSTEMS CAN BE USED FOR GENE TRANSFOR OF T-CELLS. THERE'S A VARIETY COMPARE AND CONTRAST THAT GOES INTO THE THIS MODEL AND THIS REVIEW ACTUALLY PREVIOUSLY PUBLIC COMMENT BY THE RAC WHEN I DID THE FIRST CD 19 TRIAL. THE ARTIFICIAL ANN GENERAL PRESENTING CELL HAS DIFFERENCES FROM THE PRIOR FOUR RAC APPLICATIONS AND THAT NOW IN ADDITION TO EXPRESSING CD 19 WE EXPRESS THE ROR 1 ANTIBODY TO PROPAGATE THE T-CELLS FROM THE ROR # SPECIFIC CAR. THE CO-STILL WILLTORY MOLECULES SAME -- CO-STIMULATORY MOLECULES ARE THE SAME. WE ALSO EXPRESS CD 64 FOR PURPOSES OF ABSORBING OKT-3 FOR PROPAGATE T-CELLS, THIS IS NOT PART OF THE GENE THERAPY TRIAL. I'LL MENTION BECAUSE IT WAS A CONTROL. THEN WE HAVE A NEW MOLECULE OF MEMBRANE BOUND IL-15. IN THE PAST THE RAC REVIEWED THE APC. WITH THE IL-15 CYTOKINE WHICH STITCH TO SURFACE OF THE ARTIFICIAL ANTIBODY PRESENTING CELL. WE HAVE GENERATED NEXT GENERATION TECHNOLOGY NOW WITH CYTOKINE STITCHED THROUGH THE IL-15 RECEPTOR ALPHA. WE THINK THIS IS A BETTER PHYSIOLOGIC SIGNAL. IN TERMS OF BIOLOGY OF CARS WE'RE INTRODUCING, THE TERMINOLOGY HERE IS FIRST GENERATION CHIMERIC ANTIGEN RECEPTOR, AND ONE ENDODOMAIN CD 3 ZETA TO DRIVE ACTIVATION. THIS TECHNOLOGY IS FADING. DOES NOT PROVIDE A FULLY CONFIDENT T-CELL ACT VISION SIGNAL DEFINED BY PROPAGATION OF T-CELLS. CD 28, CD 3 ZETA TO FIRE T-CELL ACTIVATION EVENT. CD 137 AND CD 3 ZETA. HERE CARTOONED OUT A HOMODIMER OF ONE ANOTHER CARS INTO THE PATIENT. IT HAS A PLAN OF SYMMETRY UP AND DOWN THE BOARD. THE SDS-V DO MAIN FROM KIP'S LAB ON ANTIBODY HE'S SHOWN. APPENDED BY THE MODIFIED STALK. THIS COMPLEX IS STATEMENT AS CD 19 ANTIBODY RECEPTOR SBSB FROM ROR 1 TO -- FROM CD 19 TO ROR 1. THE TUNNELING THROUGH THE MEMBRANE AND THE ENDODOMAIN, IS ACTIVATED THROUGH CD 28 AND CD 3 SE THAT. THE SAME GOING ON IN OUR TRIALS TARGETING CD 19. AS WE SHIFT TO THE SECOND POPULATION GENETIC MODIFICATION CO-INFUSED, THE ENDODOMAIN IS SWAPPED NOW TO 41BB. THIS IS OPERATIONALLIZED USING THE CD PLATFORM TO CARRY FORWARD SEPARATE CULTURES TWO POPULATIONS OF GENETIC MODIFIED T CELLS. ONE THAT EXPRESSES THE CAR ACTIVATED THROUGH CD 28 AND ZETA, ACTIVATED THROUGH 41BB THE CD ZETA, THE PLASMA TO SHOW YOU, THERE'S A LITTLE DIFFERENCE IN APPLICATION HAS THAT WE INTRODUCED MORE GENETIC MATERIAL SO WE CAN DO PCR ON THE PATIENTS AND RETRIEVE AND DISTINGUISH ESSENTIALLY WHICH PRODUCT IS COMING FROM WHICH TRANSGENE. A STATEMENT BY CD 3 ZETA IS MORE LONG LIVEDDED VERSUS CD 37 ZETA POPULATION. THE TECHNOLOGY TO GROW THE ROR 1 SPECIFIC T-CELLS ON OAR OFFICIAL ANTIBODY PRESENTING CELLS IS PROBUST. -- ROBUST. CD 3 POSITIVE T-CELLS MODIFIED T CELLS, WITH CULTURE, AS PART OF OUR EXPANSION TECHNOLOGY WE ADD THE ERADIATED ARTIFICIAL ANTIBODY PRESENTING CELLS EVERY 7 DAYS TO YOU WILL CANTURE. AND IN LOG PHASE GROWTH WE CAN GROW OUT T-CELLS. WE HAVE POPULATIONS OF CAR NEGATIVE T-CELLS THAT ARE CULTURED FOR PURPOSES OF SPECIFICITY CONTROL DOING FLOW STAINING. THESE ARE ELECTROPORATED. SO THEY'RE CAR NEGATIVE IN CONTRA DISTINCTION TO THE POP OF THE ROR 1 T-CELLS AN CD 137. INTERESTING BIOLOGY BEHIND IT, IT CAME UP AS PART OF THE REVIEWER'S COMMENTS. WHEN WE GROUP T-CELLS ACTIVATED THROUGH CD 28 ENDODOMAIN AND CD 137 WE SEE SUBTLE DIFFERENCES. ONE DIFFERENCE IS POPULATION OF GAMMA DELTA POSITIVE T-CELLS IN T-CELLS ACTIVATED THROUGH CD 28 IS NEGLIGIBLE. AND BUT WHEREAS CONSISTENTLY AROUND 8 TO 10% OR SO IN THE T-CELLS MODIFIED THROUGH THE 41BB DOMAIN. WE DONE HAVE PARTICULAR INSIDE TO THIS, RELATED TO THE K 562 CELLS SUPPORT THE PROPAGATION OF GAMMA DELTA T-CELLS. IT SHOULDN'T IMPACT THE PATIENT BECAUSE WE GIVE BACK AUTOLOGOUS T-CELLS. THESE ARE ESSENTIALLY THE SAME TYPES OF T-CELLS WE FOUND IN THE PATIENT THAT NOW AMPLIFIED THROUGH THE PROPAGATION TECHNOLOGY. WHEN WE TERM SPECIFICITY, WE HAVE A NUMBER OF ASSAYS TO PROBE THE ABILITY OF THE T-CELLS TO EXHIBIT REDIRECT SPECIFICITY FOR ROR 1. THE TOP PANEL HERE IS T-CELL ABILITY ACTIVATED THROUGH THE CD 28 ZETA, AT THE BOTTOM IS CD 137 ZETA ENDODOMAIN. IN PANEL A WE HAVE MADE TARGETS BASED ON T-CELL LEUKEMIA FROM THE MOUSE AND THEN PUT IN ROR 1. SO WE IN OTHER WORDS HAVE SPECIFICITY CONTROL. SQUARE IS HERE, ROR 1 NEGATIVE, DARKENED SQUARES ARE ROR 1 POSITIVE. YOU CAN SEE HERE ON THELYSIS ASSAY WHETHER YOU'RE THE CD 28 DRIVEN TECHNOLOGY OR DRIVEN TECHNOLOGY SPECIFICITY FOR ROR 1. Z WITH TURN TO LEUKEMIA CELL LINES THAT EXPRESS ROR 1 CHACV THEY ARE KILLED BY VIRTUE OF THE CAR. WHEREAS THE NON-SIX THE ROR 1 NEGATIVE CELL LINE IS IGNORED. THIS IS ESPECIALLY TRUE FOR THE CD 28 MOLECULE. A LITTLE BIT OF CROSS KILLING BECAUSE ON THE NON6 -- THE ROR 1 NEGATIVE POPULATION ACTIVATED THROUGH CD 137. WE BELIEVE THAT'S GAMMA DELTA CELLS IN THERE. SO TO SUMMARIZE, WE BELIEVE THE PROTOCOL ADDRESSES SOME IMPORTANT QUESTIONS. WE ARE HIGHLY MOTIVATED TO AVOID INADVERA P AT THE PRESENT TIME TARGETING OF NORMAL B CELLS. AND THIS REALLY IS BECAUSE WE ARE TARGETING ROR 1 VERSUS CD 19. WE ARE MOTIVATED TO EVALUATE A CAR DESIGN AND ADVANCE FIELD THAT WILL ALLOW US THE MAKE INSIGHTS ABOUT WHAT ENDODOMAIN HE'S GOING TO PREDICT FOR PERSISTENCE WITH T-CELLS AND GET THE GREATEST THERAPEUTIC POTENTIAL. AND IMPORTANTLY, WE WAN TO BE ABLE TO PROVIDE A VERY AT RISK POPULATION PATIENTS WITH ADVANCE CLL POTENTIAL THERAPY BASED ON T-CELL BIOLOGY. THIS BUILDS ON THE CURRENT PORTFOLIO WE'RE ACCRUING. CD 19 DIRECTED T-CELLS IN A COOKIE CUTTER APPLYING THE SAME TECHNOLOGY TO GENERATE THE ROLE ON SPECIFIC T-CELLS. THIS IS A COLLABORATIVE EFFORT FROM ANDERSON SAN DIEGO, UNIVERSITY OF MINNESOTA WITH PERRY HACKETT AND WOULD BE REMISNOT TO MENTION CARL JUNE AND COLLEAGUES AT UPENN THAT HELPED WITH ANTIBODY PRESENTING CELLS PARTICULARLY FOR THE CD 19 TECHNOLOGY. THOSE ARE OUR PREPARED REMARKS. >> VERY GOOD. THANK YOU VERY MUCH. LET'S GO THE REVIEWERS. SUSAN, WHY DONE WE START WITH YOU. >> I GUESS ALL REVIEWERS HAD SOME CONCERNS ABOUT POTENTIAL OFF TARGET AFFECTS OF -- FIRST LET ME THANK YOU FOR THE PROTOCOL WHICH WAS VERY CLEAR AND EASY TO UNDERSTAND. ESPECIALLY FOR THE REALLY GREAT DESCRIPTION OF YOUR TECHNOLOGY, WHICH IS SLEEPING BEAUTY TRANSPOSEON. SO I'M -- ALL THREE OF US I BELIEVE HAD CONCERN ABOUT POTENTIAL OFF TARGET EFFECTS AGAINST THE ROR 1 GENE. MY FIRST COMMENT DEALT WITH THAT BECAUSE NOT USED AS IMMUNOTHERAPEUTIC TARGET FOR ANTIBODIES OR T-CELLS. I UNDERSTAND THAT PATIENTS IMMUNIZE WITH THEIR OWN CELLS DO DEVELOP ANTIBODIES BUT THAT'S NOT THE SAME THING AS USING IT AS THERAPEUTIC TARGET. I WAS CONCERNED BECAUSE I DID SEE THE DATA THAT FROM OTHER GROUPS THAT IT DOES SEEM TO BE EXPRESSED IN NORMAL TISSUES, PARTICULARLY ADIPOSE TISSUE RELATIVELY HIGH LEVEL. SO I'M STILL NOT COLOR ABOUT WHAT THE DISCREPANCY IS BETWEEN YOUR DATA AND THEIR DATA. >> SO LET ME START AND THEN DR. KITS WILL FOLLOW. WE ALSO ARE EXQUISITELY SENSITIVE TO THE ISSUE OF SAFETY AN SPENT A LOT OF TIME THINKING ABOUT. THE RATIONALE FOR TARGETING ROR 1 WITH RESPECT TO CHL IS CLEAR. CHAIR OF THE COMMITTEE INSIGHT INTO WHETHER OR NOT THESE (INDISCERNIBLE) THERE ARE A NUMBER OF MITIGATING ARGUMENTS. FIRST, WE HAVE IDENTIFIED AN ANTIBODY WITH THE KIPPS GROUP DISTINCT FROM THE ONE IN THE LITERATURE, IT'S IMPORTANT TO COPY AND CONTRAST OUR Z WAS NOT IDENTIFIED FOR THE NIH, NOT ADVANCED THROW THE FRED HUTCHINSON CANCER CENTER AND NOT ONE PUBLISHED ON. THAT BIOLOGY ASSOCIATED WITH THEIR ROR 1 THEY HAVE TO WORK OUT. OUR BIOLOGY ASSOCIATED WITH ROR 1 IS THROUGH THE KIPS LAB. HIS DATA SET, EEL LET HIM SUMMARIZE IT, CLEARLY SHOWS THE ROR ANTIBODY IS NOT EXPRESSED OTHER THAN IDENTIFIED BY THIS ANTIBODY STRUCTURED ON THE CLL LINEAGE. I'LL LET TOM GIVE YOU THE DETAILS TO BE SURE I GET EVERYTHING CORRECT. Q. THERE'S ALSO DISCREPANCY AT THE RNA LEVEL. IF YOU GO THE (INAUDIBLE) ATLAS SAYS ADIPOSE TISSUE IS THE MOST HIGHLY EXPRESSED TISSUE FOR ROR 1. GAS YOU SAID RNA SEEK BUT WONDER WHY THERE'S THAT DISCREPANCY AS WELL. >> THE RNA SEEK IS COCONJUNCTION WITH THE CANADIAN GROUP WITH THE TRANSCRIPTOME DATA. PRIMARILY ACCOUNT FOR THE TISSUE REACTIVITY WITH THE ANTIBODIES. THE ANTIBODIES HAVE DIFFERENT SPECIFICITIES. I WAS LOOKING ACTUALLY WITH THE CONSIDERATION THAT WE WOULD SEE REACTIVITY OF ADIPOSE TISSUE OR PANCREATIC TISSUE, I HAVE BEEN PLEASANTLY SURPRISE SO WE OUTSOURCED WITH OTHER GROUPS THE LOOK AT IT BECAUSE WE ARE DEVELOPING ANTIBODIES FOR ROR # SO WE'RE CONCERNEDN'T THE OFF TARGET EFFECTS. SO THE ANTIBODY WE HAVE WHICH WE GENERATED TO MAKE THIS CAR DOES NOT REACT BY IMMUNOHISTOCHEMISTRY ON FORMALIN FIXED TISSUE FROMMED ADIPOSE OR PANCREATIC TISSUE AN FRESH FROZEN TISSUE. SO THOSE ARE THE DATA. >> I STILL HAVE SOME CONCERNS ABOUT THAT. BUT OBVIOUSLY YOU DONE HAVE FURTHER INFORMATION TO ADDRESS. >> I THINK THE OTHER THING THAT I WOULD ADD CLINICALLY IS WE'RE STARTING AT LOW DOSE OF INFUSED CELLS, WE'RE MONITORING THESE PATIENTS CLOSELY. AND WE'LL HOPE THAT PROTOCOL IF WE SEE ANY SIGNAL THAT THERE'S A PROBLEM WITH CROSS REACTIVITY. WE DON'T EXPECT IT, I DON'T EXPECT BASED ON DATA THAT TOM HAS SHOWN AND WORK HE'S DONE ON THE ANTIBODY BUT WE WILL BE VIGILANT ABOUT MONITORING FOR IT AND THEN STARTING AT LOW CELLULAR DOSE. >> SO MY SECOND COMMENT WAS TO WHETHER ALL PATIENTS WITH CLL EXPRESS HIGH LEVELS OF ROR 1. AND WHETHER YOU WOULD BE SCREENING FOR EXPRESSION. AND P I GUESS BECAUSE MORE THAN 94% OF PATIENTS EXPRESS YOU'RE NOT GOING TO SCREEN, YOU'LL DO IT POST TREATMENT. NONRESPONDERS. >> CORRECT. IT'S RUE. I THINK THAT WE'LL ALSO FAIRLY EASY WITHIN OUR PANEL THAT WE USE CLL RESEARCH CONSORTIUM, WE HAVE ADOPTED THIS INTO OUR PANEL. SO IT'S ONE OF THE MARKERS THAT WE USE IN LOOKING AT CLL CELLS. SO WE WILL KNOW THE ROR 1 STATUS OF PATIENTS ENTERING THIS TRIAL. IN ANY EVENT. >> THEN MY SECOND AND THIRD COMMENTS ARE KIND OF RELATED BECAUSE THEY ARE ABOUT THE USE OF TWO DIFFERENT CAR T-CELLS GIVEN THIS IS A FIRST IN HUMAN TARGET. AND I'M STILL NOT -- I UNDERSTAND THE RATIONALE FOR USING THE TWO T-CELLS BUT I'M CONCERNED ABOUT THE INTERPRETATION IF FOR EXAMPLE THERE IS A -- YOU DON'T SEE -- DO SEE EFFICACY HOW YOU'RE GOING TO DISTINGUISH WHICH T-CELL IS MORE IMPORTANT, IF BOTH ARE WORKING, IF ONE IS CAUSING ADVERSE EVENT, NOT THE OTHER. SO LET ME JUST SAY, BECAUSE I GUESS THE OTHER PROBLEM ONE OF THE GROUPS OF T-CELLS, THE ONE I THINK ACTUALLY A LATER COMMENT, YOU DON'T ACTUALLY HAVE EFFICIENT TRANSDUCTION OF TWO SETS OF T-CELLS WITH EACH CONSTRUCTS. AND YOU'RE GOING TO BE PUTTING IN ONE POPULATION MORE HIGH HIE HI TRANSDUCED VERSUS THE OTHER LESS HIGHLY TRANSDUCED AS I UNIT. >> THESE ARE GOOD COMMENTS. I'LL TO THE SECOND FIRST. THE ABILITY TO PROPAGATE T-CELLS ROUGHLY SPEAKING IS 80% OR SO CAR MODIFIED ON THE CELL SURFACE. THERE'S A LITTLE BIT OF PLAY THERE BECAUSE WHEN WE BUT IN MOLECULE ACTIVATED FOR CD 28, CD 3 ZETA WE GET MORE THAN 80% BUT IT'S NOT REALLY LOWER SO THESE ARE TRANSTUESDAYED T-CELLS WHICH THE MAJORITY ARE EXPRESSED INNER DA. WHERE THE ABILITY TO EXACTLY MATCH THE DENSITY OF THE CAR OPT CELL SURFACE TO THE TWO POPULATIONS IS NOT PARTICULARLY VIABLE. WE DON'T WANT TO SORT CELLS, PRESENCE, GOING FORWARD TO GET THE SAME DENSITY OF CAR ON THE CELL SURFACE. SO WE FEEL IT'S WITHIN ESSENTIALLY BREATHING DISTANCE THAT THE TWO POPULATIONS OF T-CELLS CAN BE CARRIED FORWARD AND DOWNSTREAM EFFECTS BY AD MIXING THEM AT THE TIME OF JUST BEFORE INFUSING ESSENTIALLY FOR POPULATIONS PUTTING THEM TOGETHER. THE IDEA OF DOING A COMPETITIVE REPOPULATION EXPERIMENT BUILDS ON WHAT MALCOLM PRESENTTHER AND HIS GROUP HAS DONE WHEN THEY ADVANCED THE IDEA THAT THESE SECOND GENERATION ANTIBODY RECEPTOR WAS SUPERIOR TO THE FIRST GENERATION CHIMERIC ANTIBODY RECEPTOR, PUBLISHED TRIAL TARGETING CD 19. WE'RE BORROWING FROM THAT TRIAL DESIGN. BECAUSE WE DON'T UNDERSTAND WHY SOME PATIENTS T CELLS ACTIVATED THROUGH CD 28 AND CD 3 ZETA ARE ABLE TO CONTROL DURING DRAMATIC FASHION PUBLISH MISDEMEANOR NEW ENGLAND JOURNAL ADVANCED LEVELS OF RLL. THESE PATIENTS HAVE A (INAUDIBLE) MOMENT. WHEREAS OTHER MOLECULES ARE NOT SO EFFECTIVE. SO IN OURstMATION WE WOULD LICK THE PUT THE TWO TOGETHER IN THE SAME PATIENT. GO TO ISSUES OF EFFICACY, THERE WILL BE SOME DEGRADATION TOTUM IN AND UNDERSTAND WHAT'S GOING ON BUT WE WILL HAVE SOME INSIGHT BASED ON THE ABILITY TO KNOW HOW MANY T-CELLS ARE ACTIVATED FOR FORM BB THERE VERSUS T-CELLS ACTIVATED THROUGH CD 28 THERE. MAKE CORRELATIVE STATEMENTS ABOUT FOR INSTANCE IF THERE IS AN ANTITUMOR AFFECT, THERE'S A LOT OF T-CELLS THAT ARE EXPRESSED IN THE CD 28 ENDODOMAIN, THAT ESSENTIALLY WOULD BE AN ENTHUSIASM THAT THAT MOLECULE, THAT PATIENT FOR THAT AMOUNT OF DISEASE IS PROVIDING USEFUL BIOLOGY AND TUMOR EFFECTS. THE FLIP WOULD BE TOXICITY. WE WOULDN'T KNOW BUT THEN YOU CAN GO ON AND THE FOLD CAN MAKE A STATEMENT AND IN A EXACT COMPARE AN CONTRAST MODEL WE PUT THE SAME POPULATION, THESE TWO POPULATIONS OF T-CELLS INTO ONE PATIENT, SAY FOR INSTANCE THE CD 28 MOLECULE IS MORE FAVORABLE, WE CAN GO ON AND DO THE TYPES OF STUDIES THAT WE NEED TO DO FOR EFFICACY. POWERING OUT ABOUT LOTS OF PATIENTS IN MULTIPLE CENTERS AND SAY YES, WE'RE GOING TO PUT OUR MONEY BEHIND THE CD 28 MOLECULE OR THE FORM DD MOLECULE. Q. THE OTHER THING I WOULD ADD IS WE'RE GOING TO BE SERIALLY SAMPLING THESE PATIENT AND BE ABLE TO ASSESS THE PERSISTENT DISEASE AND T-CELL POPULATION BOTH IN THE BLOOD AND IN THE BONE MARROW WHERE THERE IS A SIGNIFICANT -- WHERE THE ENVIRONMENT IS OPTIMAL FOR THE T-CELLS TO DO THEIR BUSINESS. WE'LL BE ABLE TO LOOK AT ACTIVATION MARKERS ON THE T-CELLS, DISTINGUISH BETWEEN THE TWO POPULATIONS, WE'LL LOOK AT INTRACELL ALREADY CYTOKINE LEVELS AS WELL. SO THOSE ARE CORRELATIVE CITY DIINGS WE HAVE PLANNED. WE WILL GET A DATA SIGNAL GENERATED REGARDING -- BE ABLE TO MAKE A STATEMENT BETWEEN TWO CONSTRUCTS. >> I KIND OF BUY IT FOR THE EFFICACY THING. I'M NOT SURE I BUY IT FOR THE ADVERSE EVENT THING WHICH COULD HAPPEN RAPIDLY. THE ONE DOWN SIDE IS THAT PROBABLY MEANS STOPPING POTENTIALLY PROMISING THERAPY WITHOUT KNOWING WHY. BUT THERE, THE DATA WILL BE ERODED BASED ON T-CELLS ARE DIFFERENT BETWEEN ONE PATIENT AND ANOTHER AND WE CAN'T CONTROL THAT TYPE OF BIOLOGY, LYMPHODEPLETION OFF CHEMOTHERAPY WILL BE DIFFERENT. THERE'S NO EASY WAY TO ADVANCE IT BUT THIS IS AN URGENT QUESTION FOR THE FIELD OF CAR MODIFIED T CELLS. BOTH P-28 DATA MOLECULES AND FORM BB ZETA MOLECULE AS RESPECTIVE TARGETS CD 19 HAVE EFFICACY. WE KNOW IT BECAUSE CD 19 IS ON NORMAL B CELLS AN NORMAL B CELLS GO AWAY. SO YOU DON'T KNOW WHAT IS THE PUNCH THAT GETS RID OF THE CLL CELLS. AND THAT I -- IN OUR BEST ESTIMATION IS ONLY DONE IN THIS TYPE OF COMPETITIVE REPOPULATION EXPERIMENT. >> I HAD A QUESTION ABOUT WHY THE CAR NEGATIVE T-CELLS WERE PROLIFERATING IN THE PRESENCE OF THE ANTIGEN PRESENTING CELLS. AND I GUESS IT'S BECAUSE OF THE GAMMA DELTA T-CELL. >> CORRECT. >> >> ANSWERED THAT QUESTION. THEN I HAD SOME QUESTIONS ABOUT THE INFORMED CONSENT. YOU WORDED YOUR INFORMED CONSENT TO SAY THAT IT WAS TO LEARN IF T-CELLS ARE EFFECTIVE ATTACKING CANCER CELLS WITH C HL, THIS -- CLL, THAT SHOULDN'T BE THE FIRST THING PATIENTS READ BUT THE LATER GOAL. SO YOU REWORD IT AND MAKE IT OBVIOUS THAT IT'S A STUDY TO MAKE THE CELL PERSISTENCE AND THINGS LIKE THAT. MINOR COMMENT ABOUT THE USE OF TYLENOL TO REDUCE RISK OF ALLERGIC REACTION WHICH YOU CORRECTED. I STILL AM NOT CLEAR ABOUT THE COST OF CHEMO CHEMOTHERAPY BECAUSE THAT'S BORNE BY INSURERS. THE CONDITIONING CHEMOTHERAPY IS SORT OF STANDARD CARE BUT AS YOU SAID TODAY, THE TYPE OF THERAPY YOU'RE GIVING IS NOT GOING TO CAUSE PARTIAL OR COMPLETE REMISSION. SO THAT'S -- NOT A MAJOR POINT BUT I WAS STILL CONCERNED ABOUT THE COST TO INSURERS FOR WHAT IS NOT REALLY -- WHICH IS PART OF THE CLINICAL TREATMENT HERE. THE TRIAL. THEN FINALLY IN YOUR LIST OF RISKS I THOUGHT THAT YOU NEEDED TO INCLUDE REASON OF ADVERSE EVENT (INAUDIBLE) AND YOU CHANGED THAT. >> OFALL WITH RESPONSES ARE YOU STILL UNHAPPY ABOUT USING THE TWO POPULATIONS OF T-CELLS AT THE SAME TIME? >> MINE IS BLIPPING. OKAY I STILL HAVE SOME CONCERNS ABOUT THE USE OF PARTICULARLY A FIRST IN PATIENT THERAPY -- I AM CONCERNED ABOUT IT. INVESTIGATORS ANSWERED IT TO THE BEST OF THEIR ABILITY BUT DOESN'T MEAN MY CONCERN HAS GONE AWAY. Q. VERY GOOD. DR. KOHN. >> THANK YOU. I ALSO LIKE THE CONGRATULATE THE TEAM. COMBINATION OF GENE TRANSFER TECHNOLOGY AND KNOWLEDGE OF CLL, PROTOCOL WAS WELL WRITTEN AND CELL PROCESSING DO SEEM ELEGANT AND WELL DESIGNED. SO I GOT TEN QUESTIONS THAT I'LL GO THROUGH BRIEFLY. MANY ARE ONES WE HAVE TOUCHED ON. THE FIST ONE RELATED TO THE DISTRIBUTION OF THE RO-1R ANTIGEN ON NORMAL IT SHALL SHOE. I THINK THE ANSWER YOU GIVE IS BEST POSSIBLE ANSWER WITH CURRENT KNOWLEDGE AND YOU HAVE TO DO IT WITH THE TRIAL AND SEE IF THERE'S TARGET TOXICITIES. ANOTHER PART OF THE QUESTION I'M BEDDED IN A LONG QUESTION BESIDES WHAT PERCENT OF PATIENTS ARE POSITIVE IN THOSE PATIENT WHAT IS TEASE HOMOGENEITY OF EXPRESSION. THAT WASN'T P ADDRESSED. SO 100%, IF A PATIENT HAS ANY RO-1R POSITIVES ARE THEY # HUNDRED% POSITIVE. WHAT'S THE LEVEL OF EXPRESSION VARIABILITY WITHIN A PATIENT? >> WHEN YOU LOOK AT B CELLS WITH -- AMPLIFIERS YOU CAN SEE WHAT LOOKED LIKE A DISTRIBUTION FOR ROR 1 SO YOU DONE SEE CLL A SUBSET OF CELLS WHICH REACT WITH ROR 1 AND REST BEING NEGATIVE. SO YOU SEE VARYING SHIFTS ALONG THIS -- SEE IF I HAVE THIS -- RIGHT HERE. THIS IS A TYPICAL SLIDE. THIS IS THE EXPRESSION OF ROR 1 ON CLL, DEFINES POPULATION LIKE THIS. THIS IS THE HEMATOGONES HERE, THERE'S SOME THAT ARE POSITIVE FOR ROR # AND SOME THAT ARE NOT. BY THIS GATING STRATEGY HERE. SO THERE IS SOME HETEROGENEITY THERE. I THINK I'M VERY INTERESTED IN THIS BIOLOGY BECAUSE THIS MAY DEFINE CD 5B CELL HEMATOGON. UNUSUAL B CELL POPULATION SEEN IN A PARTICULAR CLINICAL SETTINGS. WE LOOK AT THIS BUT WE NEVER SEE IN IN CLL WHERE YOU SEE A. LATION THAT'S NEGATIVE. SO -- A POPULATION THAT'S NEGATIVE. THIS HERE WILL BE VARYING LEVELS AND WE DEFINE NEGATIVE WHEN THIS LEVEL BECOMES SO LOW TO DEFINE MAYBE VERY SMALL POPULATION HERE, SO 20% I ABOVE THRESHOLD WE DEFINE DEFINED LESS THAN 1% OF THE CONTROL ISOTYPE CONTROL STAIN POPULATION. SO SEEMS EXPRESSED ON THE ENTIRE POPULATION. PREDOMINANT PATTERN THAT'S UNIFORM EXPRESS? >> THAT'S CORRECT. >> THE OTHER PART IS STILL THIS ISSUE, THOUGH 94, 96% OF CLL PATIENTS ARE POSITIVE, STILL 5% NEGATIVE, IT WOULD SEEM -- I ASK WERE YOU GOING TO USE THAT AS ELIGIBILITY CRITERIA, YOU SAID NO, NOTE IT AND FOLLOW IT TO LOCK FOR ANTIBODY ESCAPES BUT NOT TO ENROLL -- ANTIGEN ESCAPES. >> I THINK THAT'S SOMETHING WE WOULDN'T DO OBVIOUSLY BUT WHETHER WE NEED THE MAKE A DISTINCTION FOR THAT, WE'RE GOING TO BE LOOKING AT THE ROR 1 EXPRESSION LEVEL BECAUSE IT'S EASY TO DO. AND I'M INTERESTD IF THE ROR 1 NEGATIVE CLL BECAUSE IT'S AN INTERESTING BIOLOGY THERE, WE DONE HAVE TIME TO GO INTO BUT MAYBE A DISTINCT LEUKEMIA. >> SO AGAIN, IT WOULD JUST A, IT MIGHT WEAKEN YOUR EFFICACY DATA IF YOU HAVE PATIENTS OR LACK THE ANTIGEN AN BAD TO HAVE A PATIENT ENROLLED LACK THE ANTIGEN AND HAVE ADVERSE EVENT. >> AGREE. >> I WOULD URGE CONSIDERING CHANGING THAT CRITERIA. MY SECOND POINT RELATED TO AGAIN, EFFICACY DATA THAT YOU SHOWED SO IT'S ALL TARGETING AGAINST CELL LINES. IS IT POSSIBLE, HAVE YOU LOOKED AT KILLING BY THESE CAR POSITIVE CELLS AGAINST PRIMARY PATIENTS CLLs? >> WE HAVE WITH CD 19, IT WORKED BEAUTIFULLY. WE'RE ACCUMULATING THOSE DATA NOW. WE HAVE TO SEND THIS TO YOU. I HAD THE SLIDE DECK INCLUDING IT BUT >> AND REASSURE -- >> AAGREE. (OVERLAPPING SPEAKERS) >> MY FOURTH POINT WAS THE DIFFERENT CONDITIONING REGIMENS. I UNDERSTAND THE CLINICAL REASON FOR CHOOSING DIFFERENT LYMPHODEPLETING REGIMENS BASED ON PRIOR THERAPY, BUT MY CONCERN WAS THAT IF YOU'RE PRIMARY END POINT IS TOXICITY AND THERE ARE DIFFERENT TOXICITIES WITH THE RECOMMEND MEN YOU HAVE THROW SUBGROUPS IN A SENSE THAT MAYBE DIFFICULT TO SORT THAT OUT. SO I ASK, HAVE YOU THOUGHT ABOUT STATISTICAL WAY HOW USING DIFFERENT INDUCTION REGIMENS MAY AFFECT ANALYSIS? >> WE HAVE TREATED HUNDREDS OF PATIENTS WITH THOSE REGIMEN, THE FCR, BR, FEWER PATIENTS HAVE BEEN TREATED WITH FBR. ALL OF THEM HAVE SIMILAR LEVELS OF MYELOSUPPRESSION WHICH IS THE PRIMARY TOXICITY FROM -- FOR EACH OF THEM. SO WE FELT IT WAS IMPORTANT TO HAVE TO HAVE A REGIMEN POTENTIALLY LYMPHODEPLEATIVE GIVEN THE FACT OF HETEROGENEITY OF TREATMENTS IN THE ROLE. THE WORK DONE AT U PENN DIDN'T SPECIFY A CONDITIONING REGIMEN ON THE CD 19 CAR WAS TREATED WITH DIFFERENT -- EACH OF THE THREE PATIENTS THAT THEY HAD MAJOR RESPONSES HAVE MAJOR RESPONSES HAVE RECEIVED A DIFFERENCE LYMPHODEPLETED REGIMEN. >> NEXT POINT WAS JUST INTERNAL DISCREPANCY HOW DID CELL DOSING SPLIT YOU RECTIFIED THAT. MY NEXT POINT WAS ABOUT ADDITION OF THE UCC SAN DIEGO SITE THAT WASN'T EXPLAINED WELL THOUGH IN THE RESPONSE YOU EXPLAIN HOWARD THAT'S BROUGHT ON, AND I THINK DR. COOPER ALSO MENTIONED THAT THE CELL PROCESSING DONE AT MD ANDERSON AND THAT TECHNOLOGY WILL BE TRANSPORTED. SO THAT SEEMED VERY GOOD. MY NEXT POINT WAS A SMALL INTERNAL DISCREPANCY IN THE WORDING STORE WHEN YOU PROGRESS THAT YOU'RE GOING TO ENROLL PATIENTS IN A STAGGERED MANNER WAITING FOR THE PREVIOUS PATIENT TO CLEAR 30 DAYS. THERE WAS JUST ASSESSED BY -- DID NOT MAKE SENSE BUT (INAUDIBLE). MY NEXT POINT WAS OFF STUDY RAISED IN THE PREVIOUS PROTOCOL, SAID IF THE PATIENT IS PREGNANT THEY'LL BE TAKEN OFF STUDY. IF THEY RECEIVED A TREATING AGENT TAKING THEM OFF STUDY SHOULD BE OBSERVED. YOUR ANSWER ADDRESSED IT NICELY I THOUGHT WHICH WAS IF FEMALE SUBJECT BECOMES PREGNANT PRIOR TO TREATMENT THEY WOULD BE TAKEN OFF STUDY. THAT F THEY BECOME PREGNANT AFTER TREATMENT THEY WOULD BE TAKEN OFF STUDY PUT INTO LONG TERM FOLLOW-UP SO THE SAFETY EVALUATION WOULD CONTINUE BUT THEN BECAUSE YOU WOULDN'T BE ABLE TO DO INTERVENTIONS, YOU MAY NOT BE ABLE TO DO BONE MARROW IN PREGNANT WOMAN. SO LONG TERM FOLLOW-UP STUDY IS A WAY TO CONTINUE OBSERVE THEM FOR SAFETY WITHOUT AND TAKING OFF STUDY SO THAT WAS OKAY. MY NEXT QUESTION IS ABOUT DID YOU LISTEN TO MEASURE CYTOKINES OF A PATIENT AND YOU SAID VERY NICE PLAN FOR DOING THAT. LAST QUESTION WAS ABOUT THE CONSENT DID NOT -- I DIDN'T SEE WHERE IT REQUESTED AUTOPSY IN CASE OF SUBJECT DEATH. YOU SAID YOU HAVE (INAUDIBLE) TO IT. >> UH-HUH. Q. SO ARE YOU HAPPY WITH THE RESPONSE? >> MOSTLY. >> WHAT IS LEFT? >> THE ISSUE USING -- I WOULD STILL RECOMMEND USING ROR 1 POSITIVE AND EXCLUDING THOSE THAT WERE NEGATIVE WAS THE MAIN REMAINING POINT. >> DR. KEN. >> I HAVE FOUR POINTS THAT HAVEN'T BEEN ATRESSED OR AT LEAST ADEQUATELY I BELIEVE. THE FIRST ONE, SO FOR THE ROR 1 OFF TARGET YOU SAW IN THE HEMATOGONS IN THE CD 10 POSITIVE CELLS, ARE THESE NORMAL PATHWAY INTERMEDIATES IN B CELL DEVELOPMENTS? FROM >> IT'S A MYSTERIOUS SUBSET THAT WAS IDENTIFIED BY PATHOLOGY AN MORE RECENT WITH THE ADVENT OF SURFACE ANTIGENS AND LIKE BIOLOGY, DEFINE AS PRECOURTSOR B CELLS, CD 5 PRECURSOR B CELL, MOST LIPOIDIA TRICK POPULATION AN RECOVERY OF CHEMOTHERAPY. AND I THINK THAT THE QUESTION REMAINS WHETHER THIS IS GOING TO AFFECT B CELL LYMPHOPOIESIS IN GENERAL. WE HAVE BEEN LOOKING AT STUDIES I DON'T HAVE TO DESCRIBE HERE TRYING TO RECONS TUESDAY T -- RECONSTITUTE T AN B CELLS INTO RAG 2 KNOCK OUTS TO RECONSTITUTE B CELL LYMPHOPOIESIS USING NEONATAL CODE BLOOD CELLS. AND WE'RE LOOKING AT THE GENERATION OF B CELL DEVELOPMENT IN THOSE ANIMALS THAT ARE GIVEN THE ANTIBODY ALONG WITH SE KNOW GRAPHS OF LEUKEMIC CELLS SO ASSAYS CLEAR THE LEUKEMIC CELLS TO LOOK AT NORMAL B CELL LIMB KNOWPOIESIS, THE STUDIES PROGRESS TO DATE WITH SEE B CELL LYMPHOPOIESIS IN ANIMALS TREATED WITH EFFECTIVE RO-1 ANTIBODY THAT DEPLEASE THE XENOGRAPH AND WE SEE T-CELL LYMPHOPOIESIS IN THOSE ANIMALS. WE'RE CHARACTERIZING FUNCTIONAL STUDIES TO SEE IF WE HAVE EFFECTED IN ANY WAY THEIR ABILITY TO RESPOND TO ANTIGENS. IT'S REASSURING WE DONE SEE B CELL DEPLETION, IF WE WERE USING ANTIBODY AGAINST CD 19 OR 20 WE WOULD AFFECT DEPLETION OF B CELLS IN THAT MODEL SYSTEM. SO WE ARE SPARING B CELL DEVELOPMENT. I THINK THAT IT'S AN INTERESTING ISSUE WITH WITH REGARD TO EXPRESSION ON THE HEMATOGONES, THIS IS THE ONLY NORMAL TISSUE THIS WE FOUND THAT REACTS WITH THIS TYPE ANTIBODY. >> OKAY. YOU CLEVERLY ANTICIPATED MISEK QUESTION. IN THE RESPONSE TO PARTICULARLY MY COMMENTS I ASKED IF ANY ANIMALS THAT HAVE ANY PRE-CLINICAL ANIMAL STUDIES DONE AND WERE PLANNED TO TEST THIS BECAUSE ESPECIALLY WITH THIS BEING A FIRST IN MAN FOR NEW TARGET, SO IT SOUNDS LIKE THESE NSG MOUSE RECONSTITUTION EMPERIMENTS ARE SPECIFICALLY ADDRESSING WHETHER ANTI-ROR 1 AFFECT NORMAL B CELL DEVELOPMENT. >> HEMATOPOIETIC PROGENITOR CELLS AFFECT LYMPHOPOIESIS, SO THAT'S SOMETHING WE'RE WORKING ON IN THE LAB. WE ALSO ARE WORKING ON DEVELOPING ANTI-ROR 1 ANTIBODIES THAT ARE EFFECTIVE. >> WOULD YOU ANTICIPATE NOT ENROLLING PATIENTS UNTIL YOU HAVE THAT ANIMAL SAFETY DATA? >> I THINK CERTAINLY IN MY OPINION FROM IMMUNOLOGIST PERSPECTIVE, DEPLETION OF CD 19 POSITIVE CELLS IS MORE DIFFICULT. >> SURE BUT BECAUSE THIS MAY HAVE SAFER THAN A CD 19 DOES NOT NECESSARILY MAKE IT SAFE. >> I THINK THAT HARD TO SAY. IT'S A LITTLE DIFFERENT SYSTEM. THE CARP TECHNOLOGY IS DIFFERENCE THAN THE ANTIBODY TECHNOLOGY. >> SURE. >> I THINK THAT -- >> COULD YOU PUT THE ANTI-ROR 1 CARVE INTO YOUR ANIMAL MODEL? >> I THINK YOU'RE GETTING A GOOD POINT HERE, THAT IS THE LEVEL OF CONCERN WHETHER OR NOT THE T-CELLS TRESPASS LOOK AT NORMAL CELLS. I JUST TO REAHOUR THE COMMITTEE, WE ALREADY ARE DOING TARGETING NORMAL B CELLS. THROUGH INTRODUCING T-CELLS TO PARK PATIENTS TO CD 19. THAT WORST CASE SCENARIO IS ONGOING IN PATIENT RIGHT NOW, WE'RE TRYING TO ADVANCE THE FIELD WITH THE ROR 1 TECHNOLOGY, THE ROR 1 TECHNOLOGY WHERE WE CAN TRY AND SPARE THAT POPULATION OF T CELLS. MY -- OUR FEELING AS A TEAM IS THAT BIOLOGY WILL PLAY OUT NOW IN THE HUMAN. BECAUSE WE ARE PREPARED TO LOOK ESSENTIALLY AT B CELLS HEMATOPOIESIS IN THE FACE OF I WERE FUSING THE T-CELLS AND WE'RE BUT TRESSED BY TOM'S ANIMAL MODEL THAT SHOWS IN AT LEAST ONE SCENARIO USING ANTIBODY WE CAN GET PROCESSION OF NORMAL B CELLS OUT OF UMBILICAL CORED BLOOD CELLS. >> NEXT POINT COMES BACK TO THE ISSUE OF SIMULTANEOUSLY GIVING PATIENTS THE TWO DIFFERENT CARDS. IT WASN'T CLEAR, FOR THE CARD CONTAINING THE CD 137 COMPONENT, WOULD THIS BE FIRST IN MAN? >> THAT'S BEEN GIVEN BEFORE PART OF THE GENE EXPERIENCE AN THIS TRANSLATIONAL PAPER AND THE NEW ENGLAND GENERAL PAPER WITH PORE AS FIRST AUTHOR, THEY GAVE A CD 19 SPECIFIC T-CELL ACTIVATED THROUGH THE CD 30 ZETA ENDODOMAIN. THAT GAVE DRAMATIC RESPONSES THAT WERE REALLY BROADCAST WORLDWIDE. THE REST OF THE COMMUNITY IS USING THE CD 28 ZETA ENDODOMAIN. >> SO AGAIN IT WASN'T CLEAR TO ME YOU'RE PROPOSING USING THE CD 137 BECAUSE YOU BELIEVE THAT WE'LL HAVE GREATER EFFICACY -- >> I THINK IT'S UNKNOWN QUESTION. >> BUT YOU ARE ENCOURAGED TO DO IT BASED ON -- >> CORRECT. >> EXPERIENCE. >> CORRECT. >> MY FINAL QUESTION WAS A COMMENT ABOUT THE INFORMED CONSENT DOCUMENT, I APOLOGIZE, I DIDN'T CAPTURE IT ON FIRST READING. IT'S ABOUT THE AREA YOU DESCRIBE TO THE PATIENTS THE RISK OF RECEIVING A CAR AND YOU CERTAIN LADY TALK ABOUT HOW GENERAL IT CANNILY ALTERED T CELLS HAVE SIDE EFFECTS, THEY CAN CAUSE ALLERGIC REACTIONS, TUMOR CELLLYSIS. I THINK YOU SHOULD ALSO INCLUDE THE FACT THAT THERE CAN BE UNEXPECTED UNANTICIPATED CONSEQUENCES OF GIVING CARS WHICH INCLUDE DEATH AND THAT'S NOT STATED. SO THAT WAS MY FEELING THAT IT WAS A LITTLE NOT THE FULL SPECTRUM OF WHAT COULD OCCUR. >> IT SHOULDN'T IN THERE. IF IT'S NOT I'LL FOR SURE ADD IT. IT MAYBE IN A SEPARATE SECTION. IT'S PART OF OUR STANDARD WORDING FOR ALL CLINICAL TRIALS, THERE MAYBE UNANTICIPATED TOXICITIES. >> WHEN YOU HAVE A LAUNDRY LIST OF THINGS THAT COULD HAPPEN SPECIFICALLY RELATING TO THE GENETICALLY ENGINEERED T-CELLS, SOME WHICH SOUND DRAMATIC, SOME SOUND LESS DRAMATIC, YOU SHOULD ALSO INCLUDE THE FACT THAT THERE ARE THESE OCCASIONAL OCCURRENCES OF COMPLETELY UNEXPECTED CONSEQUENCES WHICH HAVE RESULTED IN DEATH. WE ALL KNOW THAT. >> THANK YOU. >> SO I HAVE A P COUPLE OF QUESTIONS. I COME BACK TO DR.S ARE'S RESERVATION ABOUT THE COMBINATION OF TWO T-CELL POPULATIONS AT THE SAME TIME. CLARIFY WHY NOT DO PARALLEL STUDIES EACH WITH ONE POPULATION AND THEN HIGHEST LEVELS DO A MIXTURE. IT WOULDN'T SLOW YOU DOWN MUCH BECAUSE IT WOULD BE RUN AS PARALLEL TRIALS SO YOU DON'T HAVE TO WAIT FOR THE OTHER POPULATIONS, DOSE ESCALATION. SO NOBODY WOULD BE ON WAIT FOR EVALUATION BEFORE MOVING ON. IT ALLOWS YOU TO DISSECT OUT POTENTIAL ISSUE OF TOXICITY VERY MUCH QUICKER AND -- BECAUSE MY WORRY IS WHAT IF YOU RUN INTO A MAJOR ADVERSE REACTION AT ONE EARLIER DOSES, YOU WOULD NOT KNOW AND WOULD YOU THEN BE FORCED TO TWO BACKWARDS. WHY NOT DO A PARALLEL AND THEN MIXTURE. FOR ME, I'LL LET LAWRENCE WEIGH IN. IT'S RESOURCES, IT IS PATIENTS, WHAT WE WANT TO DO IS DESIGN TRIAL SAFE AND HELP US ADDRESS THE QUESTION OF LIKE THE BAILOR GROUP WHICH CONSTRUCT TO MOVE FORWARD IN OUR PHASE 2 TRIALS IN TERMS OF CLINICAL DEVELOPMENT. SO FOR ME, GIVEN THE APPROACH HAD BEEN DONE PREVIOUSLY, A SIMILAR APPROACH DONE PREVIOUSLY, AND BASED ON THEIR WORK PUBLISHED, I FELT IT WAS REASONABLE TO USE THAT STRATEGY TO DO THIS. WE EXPECT THE CELLS WILL IN VIVO EXPAND. I THINK WITH OUR CORRELATIVE STUDIES THAT WE'RE GOING TO BE DOING WE WILL BE ABLE TO ASSESS WHICH MAY BE THE IDEAL CONSTRUCT, IN TERMS OF THE SAFETY, I THINK WE'LL ALSO HAVE A SIGNAL FROM THAT WITH THE SAME TYPE OF INFORMATION TO GIVE INSIGHT INTO EFFICACY, THE CYTOKINE PRODUCTION INTRACELLULAR CYTOKINE LEVELS, ET CETERA. >> APPRECIATE IT. I THINK WHERE I COME FROM IS THAT IT IS THE PAY SICK SIGN ACTIVIC QUESTION. WE DONE KNOW WHICH CARD DESIGN OBVIOUSLY GETS RID OF A GIVEN BURDEN OF TUMOR. AND IN FACT I THINK MORE DENSE THAN THAT, IT COULD BE THAT CD 19 ON CLL IS DIFFERENT THAN CD 19 ON ALL. SO ON AND SO ON. SO THERE IS ESSENTIALLY A PAUSE IN THE FIELD BUT BEFORE ADVANCING THESE TYPES OF TECHNOLOGIES REALLY ACROSS PLATFORMS ACROSS INSTITUTIONS. WHERE WE SETTLE ON ENDODOMAIN DESIGN. PARALLEL ARM WITH DOSE ESCALATION IS ONE WAY TO GO WHERE I'M TROUBLED IS THERE'S A COUPLE OF THINGS. ONE P IS THE T-CELLS AFTER I WERE FUSION WILL PROPAGATE. THAT ABILITY TO PROPAGATE IN VIVO MAY OR MAY NOT BE RELATED TO THE T-CELLS GIVEN. SOME DRAMATIC ADVANCES WHERE TRANSDUCTION DIDN'T WORK SO WELL AND GAVE SMALL DOSES OF T-CELL SO THAT PARTICULAR PATIENT IN THE T-CELLS FLOURISHED AND TOOK CARE OF LARGE NUMBER OF THE CLL BLACK. SO THIS SHOWS US THERE'S LOT OF PARENT TO PATIENT VARIATION IN THANT OF THE T-CELLS -- THE ABILITY TO T-CELLS TO PROPAGATE BUT MAYBE NOT ON ENDODOMAIN, MAYBE DEPENDENT ON THE TRANSDUCTION EVENT OR T-CELL FROM THAT GIVEN PATIENT FROM THAT PRIOR CHEMOTHERAPY EXPERIENCE. THERE'S HETEROGENEITY BETWEEN PATIENTS WITH PARALLEL COHORTS SO THE ONLY WAY TO GET RID OF THAT HETEROGENEITY IS TO SAY THE SAME POPULATION OF T-CELLS FROM ONE PATIENT BIFURCATED IN THE LABORATORY. THE COMMON MILIEU OF A COMMON PATIENT TO MAKE SIDE BY SIDE COMPARISONS. WHERE THE COMMITTEE HAS CRITICISMS BY US TOO, WHERE YOU'LL BE ABLE TO TICK THOSE DATA AND SAY WOULD YOU SAY ALL THOSE TOXICITIES TO THE CD 28 ACROSS EFFICACY TOO. UNLESS THE SIGNALS PLAQUE AN WHITE, 41BB WHENS EVERYSYME, CD 28 WINS EVERY TIME, WE MY NOT KNOW. BUT AT LEAST GIVE US A SHOT ON GOAL. THE STUDY CAN BE POWERED AND EASILY POWERED TO ASK THE QUESTION WHICH POPULATION OF T-CELLS PURR CYST. IF WE KNOW WHICH POPULATION PERSISTS, THEN THAT IS THE WINNER WE WOULD TAKE FORWARD IN TO THE MORE ADVANCE STUDIES. >> THEN THE OTHER QUESTION TO DR. KIPS THEN MALL STUDIES BEING CONDUCTED THAT LOOK AT T PROGENITOR CELLS IN, HOW MUCH LONGER ARE THOSE GOING TO TAKE? THE ANSWERS WERE GIVEN, THE ANSWERS WERE NO. THE ANIMAL STUDIES PROCEED BECAUSE IT'S GOING TO BE A LONG TIME BEFORE THOSE ANIMAL STUDIES ARE GOING TO BE DONE? >> AGAIN, IT'S A DIFFERENT TYPE OF THERAPY USING ANTIBODIES AS OPPOSED TO CAR. SO DATA WE HAVE TODAY GIVES ME REASSURANCE, WE COMPLETED EXTENSIVE STUDIES WITH DOES DEUCES UCLA AS PART OF A SON SOURCE YUM GRANT UC SAN DIEGO, LOOKING AT ANTIBODIES SEEM TO HAVE ACTIVITY AGAINST LEUKEMIA THAT WE WANTED TO SEE WHETHER THEY WOULD AFFECT HEMATOPOIESIS. THAT'S ALSO HELPED BY STUDIES WITH KYLE (INDISCERNIBLE) AT BRITISH THE COLUMBIA. SO I THINK I FEEL CONFIDENT THAT WE'RE NOT GOING TO RUN INTO A PROBLEM WITH HEMATOPOIESIS PER SE. THE ASPECT HERE OF RECONSTITUTION STUDIES TO DATE WITH THE CORED BLOOD CELLS GIVEN TO RAD KNOCKOUT MICE ALLOW US TO INDICATE THAT NUMERICALLY WE'RE HAVING NORMAL B CELL RECONSTITUTION IN MICE GIVEN ANTIBODY VERSUS CONTROL ANTIBODY. SO I THINK RIGHT NOW WE'RE DOING THE NATURE OF THOSE B CELLS WHETHER THEY REPRESENT PECULIAR PRECURSOR. FROM A BIOLOGIST STANDPOINT I'M INTERESTD IF THAT BECAUSE I'M INTERESTED IN CLL, WHETHER THIS REPRESENTS SOMETHING DISTINCTIVE. BUT I MUST SAY THE HEMATOGONES ARE SOME CELL THAT IS VERY OFTEN TIMES IN NORMAL MARROW, IT'S VERY HARD TO SEE THESE HEMATOGONES, ONLY IN PARTICULAR SETTINGS SUCH AS KIDS RECOVERING FROM MYELOABLATIVE CHEMOTHERAPY. SO I THINK THE POPULATION IS A SMALL ONE AND WE'RE STILL TRYING TO UNDERSTAND WHAT THE SIGNIFICANCE OF THE POPULATION IS. TODAY I DONE HAVE INFORMATION INDICATING THAT WE INHIBIT NORMAL B CELL LYMPHOPOIESIS SO THIS IS NOT A NECESSARY STEP IN B CELL DEVELOPMENT THAT GOES THROUGH THIS. SO I DON'T KNOW HOW BEST TO ANSWER YOUR QUESTION. >> ANY OTHER QUESTIONS? MICHELLE. >> I HAVE A COUPLE OF QUESTIONS. FIRST IN LOOKING AROUND THIS MORNING THE ROR 1 EXPRESSION I FOUND AN ACCEPTED ABSTRACT FOR NEXT WEEK'S MEETING THE AMERICAN HEMATOLOGY ASSOCIATION FROM GERMAN GROUP (INDISCERNIBLE) AND THEY CLAIM THEY HAVE CHARACTERIZED B CELLS THAT EXPRESS ROR 1. SO I WAS WONDERING WHETHER YOU'RE AWARE OF THAT. >> I AM AWARE OF THAT. Q. YOU ARE AWARE OF THAT. SO YOU HAVE ANY COMMENTS? >> YEAH. WHAT THEY HAVE DONE IS USED MAGNETIC BEADS CODED WITH AN ANTIBODY THE TRY AN ISOLATE CELLS WHICH MAY EXPRESS THIS ANTIBODY. ANTIGEN. WHAT THEY'RE TRYING TO DO IS IDENTIFY A SUBSET OF CELLS WHICH MAYBE PRESENT AT .01% OF THE LYMPHOCYTE POPULATION. WHAT THE CHARACTERZATION IS NOT REALLY CLEAR FROM THE ABSTRACT. >> THEY CLAIM NEW IMMATURE NON-ACTIVATED. >> RIGHT. I'M VERY INTERESTED (INDISCERNIBLE) USED TO COAT MAGNETIC EXCEEDS BEADS. OBVIOUSLY I WON'T ENTERTAIN DISCUSSION BUT IT'S FINDING VERY SMALL PROPORTION OF CELL ABLE TO ISOLATE THROUGH ENRICHMENT TECHNIQUES. I THINK THAT I WOULD LIKE TO FIND OUT MORE MYSELF BY TALKING WITH HER. Q. MY SECOND QUESTION HAS TO DO WITH SOMETHING I DIDN'T HEAR AT ALL THIS MORNING ABOUT THE QUESTION INSERTIONAL MUTAGENESIS , BUT SHOW THIS COMES IN WHEN YOU HAVE SOMETHING INTEGRATING. WE'RE WONDERING WHETHER YOU PLAN TO LOOK AT THAT. THERE MIGHT NOT BE APPROXIMATE ISSUE HERE, I THINK YOU POINT OUT IN THE DOCUMENT INFORMED CONSENT YOU DON'T EXPECT TO LIVE VERY LONG BUT INSTEAD INFORMATION FOR FUTURE STUDIES SO ARE YOU PLANNING TO LOOK AT LIKE ANY CLONEAL EXPANSION OR/2 INTEGRATION SITE? >> THE ANSWER IS YES. WE HAVE A LARGE TEAM THAT DOES HIGH THROUGH PUT SEQUENCING ON ALL PRODUCTS TO LOOK FOR INSERTION TYPE. Q. YOU DON'T HAVE VERY MUCH DATA ABOUT THE RELATIVE RISK FOR SLEEPING BEAUTY COMPARED TO IN HUMANS, RIGHT? >> CORRECT. THIS IS AN AREA OF ACTIVE INVESTIGATION. CORRECT. WE HAVE MULTIPLE IND NOW, WE HAVE ACTIVATED THE TWO PROTOCOLS AN ESSENTIALLY ACCRUING TO BE SURE THERE'S NO ADVERSE EVENTS. THIS IS POWERFUL TECHNOLOGY AND HOPEFULLY TRANSFORMATIVE FOR THE FIELD. >> DO YOU HAVE ENOUGH IN THE INFORMED CONSENT DOCUMENT, I READ THROUGH VERY QUICKLY. (OVERLAPPING SPEAKERS) Q. YOU COULD MAKE POINT OUT THE RISKS UNKNOWN. YOU'RE TRYING TO SAY INFORMED CONSENT DOCUMENT THAT THE RISK WOULD BE KIND OF IF YOU READ BETWEEN THE LINE LESS. I DON'T THINK THAT YOU CAN SAY IT BE LESS IF YOU DON'T HAVE ANY (INAUDIBLE). >> WE APPRECIATE THE COMMITTEE MEMBERS FEEDBACK. WE WILL LOOK AT THE INFORMED CONSENT. IT REALLY MIRRORS THE ONGOING INFORMED CONSENT FOR THE OTHER TRIALS. WITH RESPECT TO THE TEAM REDIRECTED T-CELLS THAT LANGUAGE THERE IS CRAFTED TO EXPLAIN ISSUES WE DON'T KNOW FULLY POTENTIAL ADVERSE HE WANTS. >> SO AS ONE PRIMARY REVIEWER DIDN'T WEIGH IN ON THE TWO CAR VERSUS ONE CAR ISSUE, IT'S BEEN DONE BEFORE BUT IN HEARING THE DISCUSSION I WOULD COMMENT BECAUSE IT IS A FIRST IN HUMAN TARGET, WE FIELD ADVERA EVENTS. WE HAVE SEEN TWO TRIALS WHERE NEW TARGET WAS USED. PRE-CLINICAL DATA SUGGESTED IT WAS RESTRICTED TO TUMOR AND SIGNIFICANT IN FACT FATAL OFF TARGET COMPLICATIONS OCCURRED. THAT'S WHY WE ARE SENSITIZEED TO THE ISSUE OF NEW TARGET. SO I GUESS I MIGHT SUGGEST CONSIDERING THAT THE LOWEST DOSE DURING INDIVIDUAL CARS, BECAUSE IT IS PRIMARILY PHASE 1 SAFETY STUDY, THOUGH YOU HAVE MANY IMPORTANT SECONDARY EFFICACY QUESTIONS YOU'RE ASKING ABOUT WHICH ENDODOMAIN IS BETTER, THE SAFETY PROBABLY NEEDS TO BE FIRST, DOING AT LEAST LOW DOSE COHORT INDIVIDUALLY BEFORE COMBINING THEM MIGHT BE A WAY TO ADECEMBER IT. BECAUSE AS I RECALL, SOME OF THE OFF TARGET TOXICITIES WERE LOW DOSES. >> CORRECT. >> ONCE THE CELL CAN EXPAND AND BE POTEEN. SO YOU GET INITIAL ASSESSMENT N OF # 3 WITH THE TWO INDIVIDUALS. >> THE FEEDBACK IS GOOD. APPRECIATE IT, TOP. I -- I THINK WE'RE GOING TO -- I CAN FEEL THE MOMENTUM SHIFTING AND WE WILL GO WITH WHETHER THE RAC WILL RECOMMEND, THESE WILL BE AT LEAST IN THE BEGINNING PARALLEL COHORTS. SO THANK YOU. >> JUST TO CLARIFY WHAT YOU'RE SUGGESTING IS TO -- REDESIGN THE TRIAL THE TAKE THE FIRST DOSE COHORT, TREAT PATIENTS IN EACH GROUP WITH THE SINGLE CONSTRUCT AND THEN BASED ON THAT DATA MOVE FORWARD WITH DOSE ESCALATION WITH COMBINED POPULATION. >> THAT'S MY SUGGESTION TO GO INTO OUR RECOMMENDATION. >> >> WHAT SORTS OF QUALITY CONTROL TESTS ARE DONE ON THOSE K 562 CELLS SO TO MAKE SURE REPLICATING CELLS AREN'T CONTAMINATING? >> THANK YOU. SO THE TESTS ARE RELATED ONE, WE USE A CALIBRATED IRRADIATOR. AND WE HAVE COPIOUS DATA SHOWING THAT IRRADIATOR WHEN GIVEN THE RIGHT EXPOSURE THE CELLS DO NOT PROPAGATE. TWO, WE LOOKED FOR CONTAMINATING PRESENCE OF K 562 CELLS IN THE RELEASED PRODUCT BASED ON EXPRESSION OF TWO MARKERS. ONE, ENDOGENOUS GENE CD 32 SECOND CD 19. >> SO LOOKING FOR THE CELLS IN THE T-CELL POPULATION. WHAT'S THE SENSITIVITY? Q. ABOUT ONE IN A THOUSAND SO TYPICALLY SPEAKING. >> IN TERMS OF IRRIDIATION, -- IRRAID YEAR AGO, ONE MEASURE -- IRRADIATION, ONE MEASURE IS TO HAVE A CONTROL TO MIC SURE THE DOSE WAS DELIVERED THAT DAY TO THAT MATCH OR ALLOQUAT AND TEST AN AN ALLOQUAT OF THE BATCH FOR PROLIFERATION. >> WE USE THE BLOOD BANK -- A CALIBRATED IRRADIATOR, I CAP REMEMBER IF IT'S GMP OR BLOOD BANK BUT THIS IS SET UP ESSENTIALLY FOR CLINICAL USE. THE SO PKs AND -- SOP AND CHAIN OF CUSTODY, THAT'S CALIBRATED, IT WORKS FOR K 562 CELLS AND RELIGIOUSLY FOLLOW THAT EXPERIENCE. >> CALIBRATED DOESN'T MEAN THAT DAY, SOMETHING DIDN'T MALL FUNCTION OR WHOEVER FORMED THE IRRADIATION -- DIDN'T SET THEJ9 DIAL PROPERLY. >> YOUR COMMENTS ARE APPRECIATED THE WAYS IT IS SET UP IS STANDARD DOSE OF IRRADIATION FOR BLOOD BANKING AND WE ESSENTIALLY PART OURSELVES WITH THAT IRRADIATOR. I WOULD ALSO POINT OUT THESE ARE HIGHLY ANGIOGENIC T-CELLS AND WILL KILL THE CELLS. WE CAN'T FIND ANY K 562 CELLS TWO OR THROW DAYS AFTER ADDING IN THE LATTER STAGE EXPANSION TECHNOLOGY. >> IS IT IMPRACTICAL TO TEST ALLOQUAT FOR PROLIFERATION? >> >> I GUESS THE QUESTION WHAT THE LEVEL OF CONFIDENCE IS, HOW TO DO THOSE THINGS. I UNDERSTAND THE COMMITTEE IS SENSITIZED BECAUSE ADVERSE EVENT WHERE PATIENTS HAVE GOTTEN THE PROCESS TO APPARENT MYELOGENOUS LEUKEMIA. WE USED THE PUBLIC COMMENTS THAT WERE STREAMED. IN THAT SITUATION BY DESIGN GIVEN CELLS AS PART OF A CO-STIMULATORY PACKAGE. OUR DESIGN IS DIFFERENT. THIS IS A COMPONENT USED X VIVO TO NOT GO INTO THE PATIENT. >> MINE ONE DO A BATCH OF CELLS, DO ALLO QUALITY AND TEST FOR -- ALLY QUARTER AND TEST FOR QUALITY ASSURANCE. IF THERE'S REASON THAT'S NOT IMPRACTICAL? >> I'M SECRETARYING WHERE WE DRAW THE LINE. DO -- I'M QUESTIONING WHERE WE DRAW THE LINE, ONE A MONTH, ONCE A YEAR, EVERY TIME -- >> ARE LARGE BATCHES IRRADIATED, ARE THEY FROZEN OR USED RIGHT AWAY? >> THAT'S A GOOD POINT. WE HAVE ADVANCED TECHNOLOGY WHERE WE CAN PROPAGATE THE CELLS, IRRADIATE, FREEZE AN WITHDRAW THEM IN A BANK FASHION THAT >> FOR ME BATCH TESTING. ALLOQUAT, YOU HAVE THEM FROZEN. Q. I HAVE TO PAUSE BECAUSE THAT'S NOT THE ONLY WAY WE USE THEM. WE ALSO USE THEM REAL TIME CULTURE HARVESTED. THE IND DONE FOUR TIMES THROUGH THIS RAC COMMITTEE, AND FOUR TIMES THROUGH THE FDA. WE HAVEN'T HAD A PROBLEM. NOT TO SAY WE SHOULDN'T ALWAYS BE VIGILANT, I'M SEARCHING EXACTLY FOR THAT RIGHT TOGGLE SWITCH WHICH ALLOW ME TO HAVE CONFIDENCE IRRATE I DIDN'T DOING CORRECTLY. MAKE WHAT I CAN DO IS NOT TAKE ALL THE COMMITTEE TIME BUT IF THIS IS AN ISSUE IN THE COMING BACK TO US WE WILL DEVELOP A FORMAL RESPONSE. BECAUSE I WANT TO BE SENSITIVE TO THE GMP LOAD AND ALSO THE ABILITY TO GET USEFUL DATA IF THAT'S OKAY. >> ANY OTHER COMMENTS FROM RAC MEMBERS? ON THE PHONE? ANY PUBLIC COMMENTS? SO LET ME READ FOR YOU A DRAFT SET OF RECOMMENDATIONS FROM THE RAC AND THEN WE WILL TAKE ANY OTHER DISCUSSION. FROM A CLINICAL STANDPOINT THIS PROTOCOL PROPOSES TWO DIFFERENT CARS ONE WITH A # 1BB CO-DOMAIN AND OTHER WITH A CD 28. IN ADDITION TRANSDUCTION IS MORE EFFICIENT WITH THE CD 28 DOMAIN. USING TWO POPULATIONS MAY COMPLICATE ANALYSIS OF SAE. THIS IS PRIMARILY A SAFETY STUDY CONSIDER INITIAL SAFETY STUDY IN A SMALL NUMBER OF PATIENTS EVALUATING THE CAR SEPARATELY PERHAPS AT LEAST AT THE LOWEST DOSE ON PARALLEL TRACK BEFORE MOVING TO PROTOCOL TESTING COMPETITIVE RATE POPULATION AT HIGHEST DOSE. NUMBER TWO, SINCE YOU KNOW THE ROR 1 STATUS OF POTENTIAL SUBJECTS, WITH CLL PRIOR TO DOSING, THE PROTOCOL SHOULD EXCLUDE PATIENTS FROM THIS TRIAL THAT IS AS IT IS UNLIKELY, AS IT IS LIKELY THAT THE RISK BENEFIT RATIO FOR THIS POPULATION WOULD NOT FAVOR ENROLLMENT. ETHICAL LEGAL AND SOCIAL ISSUES. UP IN ONE, IN THE SECTION OF THE INFORMED CONSENT DESCRIBING RISK OF RECEIVING A T-CELL IT IS IMPORTANT TO INCLUDE THE FACT THAT THERE CAN BE UNEXPECTED AND UNANTICIPATED CONSEQUENCES INCLUDING DEATH. NUMBER TWO, RISK OF INSERTIONAL MUTAGENESIS IS UNKNOWN WHILE TRUE THAT TO DATE THIS HAVE BEEN NO REPORTS OF INSERTIONAL MUTAGENESIS, BE INTEGRATING VECTOR AND MATURE T-CELLS, IT IS PRESUMED THE RISK IS LOW, IT IS IMPORTANT TO CONSENT COMMUNICATE THAT THE RISK FOR THE SLOPING BEAUTY TECHNOLOGY IS NOT KNOWN -- SLEEPING BEAUTY TECHNOLOGY IS NOT KNOWN THAT.'S CURRENTLY THE DRAFT. ANY ADDITION THES OR CHANGE? >> COULD WE HAVE A RECOMMENDATION FOR BATCH TESTING OF THOSE K 562 CELLS? >> WE WILL ALSO PUT ON RECOMMENDATIONS THAT THERE SHOULD BE SOME PROTOCOL FOR TESTING K 52 CELL FOR PROLIFERATION THAT'S PUT TOGETHER BY YOUR GROUP. ANY OTHER ADDITIONS? DISCUSSIONS? ANYONE ON PHONE? RESPONSES FROM INVESTIGATORS? >> SPEAK TO THE TEAM, SO APPRECIATE YOUR TIME AND CONCERN, THESE ARE HELPFUL COMMENTS. I THINK THE DISCUSSION IS VIGOROUS AN HELPFUL. AND WE'LL GET BACK TO YOU ON THE COMMENTS AND I THINK EVERYTHING YOU SAID IS REASONABLE AND THANK YOUMENT >> LET'S -- THANK YOU. >> LET'S MOVE TO VOTE FOR APPROVAL OF THE COMMENTS. DR. WALLY. >> YES. >> HAMMARSKJOLD, YES. >> (INAUDIBLE). YES. >> ZOLOTH. YES. >> KIEM, YES. >> STROME, YES. >> COHN, YES. >> FONG, YES. >> BRADLEY, YES. >> (INAUDIBLE), YES. >> CANNON, YES. >> ORNELLES, YES. >> KOHN, YES. >> PILEWSKI, YES. Q. S ARE, YES. >> -- >> ROSS, YES. >> THANK YOU, LIT'S TAKE ONE MINUTE, WE WILL -- LET'S TAKE ONE MINUTE WE'LL START AT 11:15. FOR THE NEXT PROTOCOL. LET'S LOAD UP THE SLIDES. >> MS. MALLINO ARE YOU ON THE PHONE? >> I'M HERE. >> WE DIDN'T HEAR YOUR VOTE ON THE LAST PROTOCOL. >> I WAS JUST GETTING READY TO EMAIL THAT OFF. IT'S YES. >> THANK YOU VERY MUCH, MS. MALLINO. >> THIS IS PROTOCOL NUMBER 11906789 A PHASE 1 ONLY LABEL STUDY TO ASSESS THE SAFETY, TOLERABILITY AND PRELIMINARY EFFICACY OF LX-1101 WITH SECONDARY LYMPHODEE MA IN ASSOCIATION WITH TREATMENT OF BREAST KAREN. PI IS STANLEY ROCKSSON FROM STANFORD UNIVERSITY. HE IS THE ALAN TINA NEAL PROFESSOR OF LYMPHATIC RESEARCH AND CONSULTANT CARDIOLOGY AND ASSOCIATE PROFESSOR OF MEDICINE DIVISION OF CARDIOVASCULAR MEDICINE AT STANFORD. I ALSO PRESENT HERE TODAY WILL BE DR. ALAN BOYD AN HONORARY PROFESSOR AT PHARMACEUTICAL MEDICINES IN RURAL COLLEGE OF PHYSICIANS UK AND DIRECTOR AND MEDICAL CONSULTANT TO LAURENTIS PHARMA LIMITED. ALSO HERE DR. BLANK, CHIEF MEDICAL OFFICER OF LAURENTIS, DR. (INDISCERNIBLE) ACADEMIC PROFESSOR MOLECULAR CANCER BIOLOGY PROGRAM FROM THE UNIVERSITY OF HELSINKI, FINLAND. ON THE PHONE WILL BE DR. ANN (INDISCERNIBLE) A PLASTIC SURGEON AT THE TURKU UNIVERSITY CENTRAL HOSPITAL IN FINLAND. AND DR. MARK PELGRAM, THE SUSIE HUEY KUNG PROFESSOR AT THE STANFORD CANCER INSTITUTE. >> THANK YOU VERY MUCH. , DR. FONG, MEMBERS OF THE COMMITTEE, LADIES AND GENTLEMEN. MY NAME IS ALAN BOYD, ON BEHALF OF DR. ROCKSSON AND LAURENTIS PHARMA I WOULD LIKE THE THANK YOU FOR ASKING US TO PRESENT THE PROTOCOL TO YOU TODAY. I'LL GIVE THE PRESENTATION ON BEHALF OF MY COLLEAGUES THEN CLEARLY MY COLLEAGUES ARE HERE TO HELP ANSWER ANY QUESTIONS AND QUESTIONS THAT CAME FROM THE VARIOUS REVIEWERSFUL DURING THE PRESENTATION WHAT I WANT TO DO IS TALK ABOUT DISEASE THAT WE'RE AIMING TO TREAT MAINLY LYMPHODEE MA. I WILL COVER HOW IT'S MANAGED AND DIAGNOSTIC TECHNIQUES USED IN THESE PATIENTS. I'LL THEN TALK ABOUT THE PRODUCT WEAR DEVELOPING, LX-1101 LYMFACTIN AND DESCRIBE THE APPROACH FROM THE PRE-CLINICAL WORK WE DID, THE TOXICOLOGY STUDY, AND THEN GOING TO DISCUSS THE PROTOCOL. IN TERMS OF THE CLINICAL INDICATION, THIS PRODUCT IS VEGF C GENE ADENOVIRAL VECTOR FOR TREATMENT OF PATIENTS WITH SECONDARY LYMPHODEE MA AS A RESULT OF TREATMENT FOR BREAST CANCER. THIS TREATMENT WILL BE GIVEN IN ASSOCIATION WITH A SURGICAL OPERATION I'LL DESCRIBE IN A MOMENT. WHEREBY A LYMPH FORWARD ASSOCIATED FLAP, TISSUE FLAP IS REMOVED FROM THE REGION OF THE PATIENTS AND THEN TRANSFERRED UP TO THE AX LAYER REINWHERE THE PROBLEM IS, AND THEN AS PART OF THAT PROCEDURE IS INJECTED WITH A VEGF-C GENE THEN PUT INTO MACE. THE NAME OF THE THERAPY -- THE AIM IS REINSTATE THE FUNCTIONAL LYMPHATIC SYSTEM BACK INTO THESE PATIENTS WITH THEIR AFFECTED ARM. ON THIS SLIDE I HAVE PATIENT T WITH LYMPHEDEMA. HAVING HAD MASTECTOMY AND BREASTS REMOVED AS PART OF THE TREATMENT THEIR BREAST CANCER, THIS PATIENT UNFORTUNATELY WENT ON TO DEVELOP LYMPHEDEMA, YOU CAN SEE IS A GROSS SWELLING OF THE ARM. THIS IS A CHRONIC PROGRESSIVE SWELLING, THE AFFECTIVE TISSUES DUE TO DESTRUCTION OF LYMPHATIC TISSUE AND VASCULATURE. IT OCCURS BECAUSE OF THEIR APPROACH TREATING THESE PATIENTS DURING SURGERY WHERE LYMPH NODES REMOVE STAGING AND AS PART OF THE TREATMENT, AND ALSO DUE TO RADIOTHERAPY THAT OCCURS IN THESE PATIENTS. THAT CAUSES SIGNIFICANT DAMAGE TO THE LIMB FAT UK SYSTEM. APPROXIMATELY 15,000 NEW CASES OF LYMPHEDEMA ASSOCIATED WITH BREAST CANCER TREATMENT OCCUR IN THE UNITED STATES EVERY YEAR. AT THE MOMENT THERE IS NO SATISFACTORY CURE FOR THE TREAT. ONE BIGGEST PROBLEMS WITH HAVING THIS DISEASE IS HAVING GOT OVER THEIR BREAST CANCER, THESE PATIENTS THEN HAVE THE DISFIGURING, DEBILITATING CONDITION WHICH AFFECTS THEIR QUALITY OF LIFE. HOW OFTEN DOES IT OCCUR AND LYMPHEDEMA OCCUR? THIS STUDY WAS REPORTED OVER TEN YEAR AGO NOW FROM SURVEY JUST UNDER 1300 PATIENTS WHO TREATED FOR BREAST CANCER OVER TEN YEAR PERIOD APPROXIMATELY. FROM THIS GROUP OF PATIENTS JUST UNDER 16% OF THEM SUBSEQUENTLY DEVELOPING LYMPHEDEMA. YOU CAN SEE MOST OF THEM -- MAJORITY OF THE LYMPHEDEMA OCCURRED ABOUT UP TO THE TWO YEAR TIME POINT. IN TERMS OF ASSESSMENTS OF THE DISEASE, THE MAIN PROBLEM IS ACCUMULATION OF FLUID. THE INCREASE IN THE VOLUME AND PROGRESSION TO FIBROSIS AND CUTANEOUS TISSUES IN THE SWOLLEN ARM. AS I MENTION FINALLY THE SEVERE PSYCHOSOCIAL EFFECTS THAT IT LEAVES PATIENTS. THAT CAN BE ASSESSED, RELEVANT LATER IN THE PROTOCOL, HOW WE'RE GOING TO LOOK AT INVESTIGATION AND EFFECTIVENESS OF TREATMENT SO ACCUMULATION OF EXTRA CELLULAR FLUID WE CAN MONITOR THROUGH SPECTROSCOPY. AN THIS IS SENSITIVE TO DETECT PRE-DISEASE IN THESE PATIENTS. THE VOLUME IS MEASURED BY THIS TRUNCATED APPROXIMATION, THE SKIP THICKNESS BY CALIFORNIA PERS AN QUALITY OF LIFE PERFORMD BY INSTRUMENTS. THERE'S NO CURE FOR THIS CONDITION. THE MAIN STAY OF TREATMENT AT THE MOMENT IS THERAPY AND PHYSICAL THERAPY AND I LISTED THOSE THERE WITH EXERCISE AND MANUAL DRAW DRAINAGE. THESE PATIENT VERSUS TO UNDERGO PHYSICAL THERAPIES MOST DAYS TO KEEP THE DISEASE UNDER CONTROL. PEOPLE TRIED DIURETICS, THEY ARE COMMONLY USED. BUT THERE'S NO REAL EVIDENCE THEY BRING CLINICAL BENEFIT AT ALL. FROM A SURGICAL APPROACH, SURGEONS HAVE REMOVED EXCESS TISSUE BY DEBULKING THEs: ARM, ANODALLY FATTIC STENO SEIZE BUT THE EFFICACY IS QUESTIONABLE. MORE RECENTLY UP TO THE PIONEERING WORK OUT OF PARIS AROUND 2006 LYMPH NODE TRANSPLANTATION IS USED. MOVING LYMPH NODES FROM THE REGION TO THE AXILLA. BUT JUST AS LYMPH NODE TRANSPLANTATION IS NOT ASSOCIATED WITH THERAPY. THAT HAS SOME SUCCESS BUT IT IS LIMITED. ONLY ABOUT 20 TO 30% OF THE PATIENTS BENEFIT. WHAT WE'RE HOPING TO DO IS TO COMBINE THE GENE THERAPY APPROACH WITH THIS LYMPH NODE TRANSPLANTATION PROCEDURE. THIS IS THE PROCEDURE AS I BRIEFLY DESCRIBE. THE SURGEON WILL REMOVE A FLAP OF TISSUE FROM THE REGION WHICH WILL CONTAIN LYMPH NODES AND VASCULAR PEDICLE. HAVING REMOVE THAT THE FLAP ADIPOSE IT SHALL SHOE AROUND THE LYMPH NODE WILL BE INJECTED WITH GENE THERAPY SOLUTION. IT WILL THEN BE INSERT TO THE AXILLA OF THE PATIENT AS THE THERAPY. JUST TALKING ABOUT WHY VEGF-C IS IMPORTANT. WORK DONE BY AGAIN PIONEERING WORK BY PROFESSOR (INDISCERNIBLE) WITH US TODAY DID DISCOVER IN TERMS OF GROWTH FACTOR, THREW UP TO 5 GROWTH FACTORS DISCOVERED AND YOU'LL BE AWARE THAT VEGF AFTERA IS RESPONSIBLE FOR GROWING MAINTAINING THE CARDIOVASCULAR SIDE OF THE CIRCULATORY SYSTEM. INDIVIDUAL F C AND D WAS DISCOVERED TO MAINTAIN THE LYMPHATIC SYSTEM. IN TERMS OF THE CELLULAR LEVEL, VEGF A AND B MAINLY INTERACT WITH THE VEGF ALREADY RESTORES ONE AND TWO. AND VEGF C AND D INTERACT WITH -- SO THEY'RE DISTINCT SIGNALING SYSTEMS TO THE CELL AND THAT IS RELEVANT FOR WHAT WE'LL DISCUSS LATER ON. SO THAT'S THE BASICS OF MECHANISM AROUND VEGF C IN TERMS OF DEVELOPING AND RUNNING ANIMAL MODELS IN THE PRE-CLINICAL WORK, I WOULD NOW LIKE TO DESCRIBE SOME OF THAT THAT WE HAVE UNDERTAKEN. ONE PROBLEM WE ENCOUNTERED THERE IS NO LYMPHEDEMA MODEL THAT REFLECTS THE HUMAN SITUATION. WE DON'T KNOW WHY BUT OTHER MAMMALS DON'T DEVELOP LYMPHEDEMA LIKE WE DO. IT IS DIFFICULT TO GET A PRESIZE MODEL OF WHAT'S GOING ON IN ANIMALS RELATIVE TO HUMANS. WE TRY TO COME CLOSE. WE HAVE ENCOUNTERED OTHER PROBLEMS, IN THE EXPERIMENTAL ANIMAL MODELS WHEN YOU ESTABLISH LYMPHEDEMA AND LYMPH NODES AND DESTROYING THE SYSTEM AND TRANSPLANTING THEM AROUND, WE DISCOVERED A SIGNIFICANT SURGICAL MORBIDITY. PARTICULAR ANY LIVE IN THE PIGS WE LOOKED AT AND I'LL TALK ABOUT HOW WE SOLVE THAT PROBLEM IN A MOMENT. ANIMALS HAVE A GREATER CAPACITY THAN HUMANS DO WHEN IT DESTROYS AN ANIMAL, IT WILL GROW BACK MORE PRODUCTIVELY THAN WE HAVE SEEN IN HUMANS. ALSO THERE'S SIGNIFICANT ANATOMICAL DIFFERENCES BETWEEN HUMANS AN ANIMALS. MOST LYMPHATIC SYSTEM IN THE LYMPH NODES IN PARTICULAR IN HUMANS COME IN CHAINS. IN GROUPS OF LYMPH NODES, WHEREAS IN MOST OTHER ANIMALS THEY SOLITARY MUCH LARGER LYMPH NODES, THERE'S AN ISSUE TRYING TO MATCH THAT UP. IN TERMS OF THE PROOF OF CONCEPT THAT WE HAVE DONE WORK, WE USED BOTH MICE AN PIGS. INITIAL WORK DONE IN MICE, INITIAL PHARMACOLOGY, THIS USED NEW MICE WHERE LYMPH NODES WERE DESTROYED AND ALLO GENIC -- ALLOGENEIC LYMPH NODE TRANSFER WAS PUT INTO THE MICE WITH OR WITHOUT THE VEGFC GENE ADMINISTRATION. I'LL GO THROUGH THE HIGHLIGHT OF THOSE RESULTS IN A MINUTE. HOWEVER, WE RECOGNIZE GOING FROM MOUSE TO HUMAN WAS A BIG STEP. WE WANTED TO ENSURE GOING INTO A MUCH LARGER ANIMAL FIRST TO MAKE SURE AND EXPLORE THESE THREE THINGS. IN TRANSPLANTING THE LYMPH NODE AND GIVING THE VEGFC AND GROWTH FACTORS COULD WE GROW THE LYMPHATIC SYSTEM BACK OVER MUCH LARGER AREA? WHICH IS RELEVANT TO THE HUMAN SITUATION.wL[ YOU ALSO NOTICE THAT WE'VE BOTH VEGF C AND D ARE CLOSELY ALIGNED WITH THE LYMPHATIC SYSTEM. WE WANTED TO FIND OUT WHICH WAS THE BEST VEGF GENE LIGAND TO TAKE FORWARD INTO HUMANS. AND WE LOOKED AT THAT. THEN THE OTHER -- THE THIRST THING TO LOOK AT WAS THE MODE OF ADMINISTRATION OF PRODUCT. SHOULD WE PUT IT DIRECTLY INTO THE LYMPH NODE OR AROUND THE LYMPH NODE STOW STIMULATE LYMPHATICS. I'LL SHOW YOU WORK WHICH DID THAT. IN THE ANIMAL WORK THAT WE HAVE DONE, WHAT WE AIM TO DO ON THE WHOLE WAS TO SATURATE AND GIVE MAXIMUM AMOUNT OF VEGF C OR D THAT WE COULD. WE TRIED SOME RANGING WORK BUT IT WAS DIFFICULT TO REFINE THAT AS WE WOULD HAVE DONE NORMALLY. WE LOOKED AT TRANSFER OF LYMPH NODES ALONE OR WITH VEGFC WITH GROWTH FACTORS AND WE'RE ABLE TO INCREASE SUCCESS RATE UP FROM THE 20% TO 80 PERCENT. CONNECTIONS WITH THE HOST LYMPHATIC VASCULATURE. THE LYMPHATIC DRAINAGE WAS INCREASED CONSIDERABLY WITH THE VEGFC AND ALSO AS YOU CAN SEE FROM THE PICTURE HERE, THE LYMPH NODE TWO MONTHS IN THE SECTION WE TOOK WERE MUCH LARGER AND FOLLOWING THOSE ANIMALS OUT, FOR LONGER PERIODS, AT SIX MONTHS THAT WAS MAINTAINED, AND WE SAW MATURATION OF THE LYMPHATIC SYSTEM IN THE VEGFC TREATED ANIMALS. SO THAT WAS THE MOUSE WORK. IN THE PIG MODEL ONE LIMITATION WE HAD WAS LYMPHATIC SYSTEM IN THE LYMPH NODES IN PARTICULAR ARE NOT QUITE THE SAME AS IN HUMANS. IN THE PIG -- THEY TEND TO HAVE A LARGE SOLITARY LYMPH NODE. WE DID TRY TRANSPLANTING LYMPH NODES WITH THE LYMPH NODE FLAPS IN ONE AREA TO A PIG AS WE WANTED TO DO PAUSE WE WANT TO DO IN HUMANS BUT UNFORTUNATELY BETWEEN 50 AND 70% OF THE FLAPS DIDN'T TAKE AT ALL. SO THE ANIMALS WERE JUST NOT GOOD. SO WHAT WE DID IS MODIFYD THE TECHNIQUE. WE TOOK THE LYMPH NODE,ING ISOLATED IT AND HAVING IDENTIFIED WHERE THE LYMPHATIC SYSTEM WAS USING BLUE DYE TECHNIQUE AND SUCH AS THAT THE SUFFER YEN WILL DESTROY THE LYMPHATIC SYSTEM BUT LEAVING THE VASCULAR PEDICLES ON THE VEIN AND NERVE SUPPLY AND ARTERY CONNECTED. WE WILL THEN MOVE THE LYMPH NODE ITSELF, SUTURE BACK DOWN AND INJECT WITH THE VEGFC. SO IT WAS A MODIFICATION OF THE HUMAN SITUATION. SO WE COULDN'T TRANSPLANT FOR PRACTICAL PURPOSES. THESE ARE THE RESULTS THAT WE HAVE OBTAINED. WHAT WE WANTED TO DO IS SEE TO GROW THE LYMPHATIC VESSELS OVER LARGER AREA. IN THIS STUDY RESULT HERE YOU CAN SEE IMAGE FROM THE PIG TO THE VEGF C, D AND CONTROL GENE. HERE IS THE LYMPH NODE HERE, HIGHLIGHTED BY THE STAR. YOU CAN SEE, I THINK I IT DOES SHOW, THERE'S MUCH MORE LYMPHATIC VASCULATURE THERE COMPARED TO THE CONTROL GENE. ON THE SLIDE HERE YOU CAN SEE AGAIN JUST A NUMBER AND FACT THERE'S THE STATISTICAL DIFFERENCE THERE BETWEEN CONTROL. ON THIS SLIDE WE LOOKED AT THE ABSORBANCE AND HOW MUCH THE LYMPHATIC SYSTEM THERE IS. THIS IS FROM THE OTHER SIDE, CONTROL LYMPH NODE FROM THE SIDE THAT WASN'T OPERATED ON COMPARED TO JUST C AND D. WE'RE STORING THE LYMPHATIC SYSTEM CONSIDERABLY. SO FROM THAT WE'RE ABLE TO SAY VEGF C AND D DID INCREASE THE NUMBER AND SIZE OF LYMPH NODES IN THIS MODEL COMPARED WITH THE CONTROLS. HOWEVER, VEGFC WAS BETTER IN TERMS OF PREVENTING FLUID ACCUMULATION. IN VEGF D PIGS TREATED AROUND THEIR WOUNDS THE MAJORITY OF THEM ACCUMULATED FLUID AND HAD TO BE DRAINED. IT'S PROBABLY BECAUSE VEGFC THOUGH GROWING THE LYMPHATIC SYSTEM, VESSELS ARE STILL A BIT LEAKY. SO THERE'S MORE FLUID ACCUMULATION AS YOU CAN SEE FROM THE GRAPH HERE. THIS TOP HERE, MANY HAVE FLUID DRAINED FROM THE SYSTEM. SO THIS WE FELT BUT AN ADVERSE EFFECT. IN TERMS OF STRUCTURE OF THE LYMPH NODE, WE HAVE THE HISTOLOGY, THE CONTROL, VEGF C AND D. AND THE CONTROL YOU CAN SEE THE FIBROUS FATTY TISSUE WITH DEGENERATION OF THE NODE. THERE'S LESS IN THE VEGFD BUT THE VEGF C LOOKS MORE IDENTICAL TO A NORMAL. IT DOESN'T PROJECT WELL BUT DISCREET PAIRS PATCHES THERE WITHIN THE LYMPH NODE. AND SO FROM THAT WE CONCLUDED THAT PROBABLY VEGFC BECAUSE OF THE PROBLEMS WITH S,ROMA AND THE BETTER STRUCTURE TO THE LYMPH NODES THAT WE GOT, THE VEGFC WAS THE MOST APPROPRIATE VEGF LIGAND TO TAKE FORWARD. IN TERMS OF HOW WE SHOULD ADMINISTER THIS DRUG, ONE OF THE PROBLEMS AGAIN WE THOUGHT ABOUT WAS THAT IN THE PIGS WE'RE USING I SAID THE LYMPH NODES ARE QUITE LARGE. ONE OF OUR CONCERNS GOING TO HUMANS WERE LYMPH NODES ARE SMALLER, IS IF WE INJECT DIRECTLY TO HIM OF NODE WE FELT THERE MIGHT BE ARYK OF DESTROYING THE LYMPH NODE. SO WE WANTED TO EXPLORE WAS THERE ANY DIFFERENCE BETWEEN INJECTING TO A LYMPH NODE OR GIVING IT AROUND THE LYMPH NODE NOT DIRECTLY THE PERINODEAL INJECTION. SO WE USE THIS PIG MODEL TO COMPARE PERINODEAL VERSUS THE ENTER NODEAL INJECTION. I HAVE SOME OF THE RESULTS HERE. IN TERMS OF HISTOLOGY OF THE LYMPH NODE, THERE ISN'T MUCH DIFFERENCE THE BETWEEN THEM. IF YOU LOOK AT THE SECTIONS. IF YOU LOOK AT THE LYMPHATIC SYSTEM, THERE'S NO DIFFERENCE BETWEEN THE LYMPHATIC SYSTEM THAT'S THERE. HOWEVER, THE ONE BIG DIFFERENCE THAT WE NOTICED WAS THAT IN THE INTERNODEAL LYMPH NODES INJECTED THERE WAS A MASSIVE INFLUX OF MACROPHAGES AND INFLAMMATORY RESPONSE WHICH WAS NOT SEEN IN THE LYMPH NODES FROM THE PIGS INJECTED PERINODEALLY. PROBABLY PERINODEAL INJECTION BECAUSE OF THIS ISSUE, PLUS THE RISK WE MIGHT DESTROY BY HUMAN LYMPH NODE PERINODEAL WAS THE RIGHT ROOT TO GO. SO TO SUMMARIZE THOSE RESULTS, WE SAW IN THE MICE ASSOCIATED WITH LYMPH NODE TRANSPLANTATION VEGF C INCREASED THE UPTAKE OF THE LYMPHATIC WORK WE HAVE DONE. IT DID INPROVE DRAINAGE CONSIDERABLY AND DIDN'T REDEGREES. FROM THE PIG WORK WE CONCLUDED WE COULD GROW IT BACK OVER A MUCH LARGER AREA EQUIVALENT IN HUMANS, IT WAS THE MOST APPROPRIATE GENE LIGAND TO TAKE FORWARD AND THE PERINODEAL RATE WAS THE BEST ROOT OF ADMINISTRATION SO THAT WAS A QUICK SUMMARY OF THE PRE-CLINICAL WORK. IN TERMS OF TOXICOLOGY AND BIODISTRIBUTION STUDY, WE HAVE DONE A SINGLE IS THE DICOMPARING INTRAVENOUS AND IN THE SAME PIG MODEL USE LARGE DOMESTIC PIGS AND VARIOUS CONTROLS, BUFFERS AND GENES ITSELF, WE HAVE EXPLORED ACROSS THE DOSE RANGE SHOWN HERE ON THE SLIDE FOR ONE TIMES 10 TO TO 10, TO THE 12th. WE FOLLOWEDD THE PIGS 60 DAYS AND LOOKED AT MALES AND FEMALES. IN TERMS OF THE SUMMARY RESULTS, WE -- THE PATHOLOGY MACROSCOPIC LIE AND MICROSCOPICALLY DIDN'T SEE ANY EVIDENCE OF TREATMENT RELATED FINDINGS. HEMATOLOGY AND CLINICAL CHEMISTRY WERE SIGNIFICANT. FOR BIODISTRIBUTION IT WAS TYPICAL WITH THE ADENOVIRUS BEING DISTRIBUTED AND CLEARED THROW THE LUNG, LIVER AND SPLEEN. THE PERINODEAL GROUP INJECTIONS WE WERE PLEASED TO SEE THE CONSTRUCTS IN THE ADENOVIRUS WAS CONTAINED WITH AROUND THE AREA WE INJECTED AND THE OTHER PLACE WAS THE DRAINING LYMPH NODE TO THAT AREA. IT HAD GONE BY ABOUT 30 DAYS ON AVERAGE, IT ISN'T PRESENT IN 60 DAYS SO CLEARED RAPIDLY. WE'RE WAITING FOR THE ANTIBODY, THE VEGF C EXPRESSION DATA WHICH WILL HAVE IN THE FUTURE. FROM THAT WORK, WE HAVE NOW MOVEED TO THE CLINICAL PROTOCOL FOR THE REASON BEING HERE. AS SAID, THIS IS GOING TO BE THE FIRST STUDY, THE PHASE 1 STUDY TO ASSESS PREDOMINANTLY SAFETY AND TOLERABILITY. IT'S AN EXEMPLOYERTORY STUDY IN TERMS OF PRELIMINARY EFFICACY ASSESSMENTS THIS IN THESE PATIENTS WHO LYMPHOTEE MA AFTER BREAST CANCER. THOSE ARE DOSES WE'RE USING DOSE ESCALATION DOSE EXPANSION TYPE GROUP DESIGN WITH PLUS 3 TYPE DOSE ESCALATION TO ESTABLISH THE OPTIMUM TOLERATED DOSE, AND AT THAT DOSE WE TREAT MORE PATIENTS. ANTICIPATING UP TO 24 PATIENTS IN THIS FIRST STUDY. THE PRIMARY AIM IS SAFETY AND TOLERABILITY. SECONDARY OBJECTIVES WE WANT TO LOOK AT THE DOSE TO TICK FORWARD, THE KINETICS, AND ALSO ASSESS THE EFFICACY BY METHODS I'LL TALK ABOUT IN A MOMENT. IN TERMS OF INCLUSION CRITERIA, WE HAVE THE SECOND LYMPHEDEMA AFTER BREAST CANCER, WAY THEY HAVE WILL HAVE LYMPH NODE REMOVED ON AFFECTED SIZE AND UNDERSTOOD GONE VIDEO THERAPY. IN TERMS OF SEVERITY MARKER OF WHERE WE WANT THESE PATIENTS, THESE ARE PATIENTS WHO SHOULD BE USING REGULAR COMPRESSION GARMENTS FOR THE TREATMENT OF LYMPHEDEMA IN AFFECTED ARM AND IT SHOULD BE GREATER THAN 10%. IN TERMS OF VOLUME AND ALSO EDEMA. I SHOULD EMPHASIZE HERE IN THE USA THE PROCEDURE WILL NOT BE PERFORMED AT THE SAME TIME AS BREAST RECONSTRUCTION BECAUSE BREAST RECONSTRUCTION OCCURS SOON AFTER THE INITIAL TREATMENT FOR THE BREAST CANCER. SO THAT WILL BE DONE SEPARATELY SOMETIME LATER. THERE IS ALWAYS A QUESTION ABOUT MINIMIZING THE RISK OF PUTTING A GROWTH FACTOR INTO BREAST CANCER PATIENTS. WE DISCUSSED THIS AT LENGTH AND SURE WE'LL DISCUSS IT AGAIN. AT SCREENING WE'LL BE WORKING CLOSE ASSOCIATION WE WANT RECURRENT OR NO ACTIVE BREAST CANCER IN PREVIOUS TWO YEARS AND PERFORM CT SCANS TO CONFIRM THIS. IN TERMS OF EXCLUSION CRITERIA, CLEARLY WE DON'T WANT THE SEVERE BREAST CANCER PATIENTS THAT HAD SIGNIFICANT EXTRA NODEAL DISEASE. SO WE'LL EXCLUDE PATIENTS WHO HAVE MORE THAN THREE NODES POSITIVE. EXTRA CAPTION ALREADY NODE EXTENSION OF THE DISEASE, STAGE 3 DISEASE, INFLAMMATORY BREAST CANCER, INVASIVE BREAST CANCER AND PATIENTS WITH VARIOUS KNOWN GENE MUTATIONS THAT HAVE BEEN IDENTIFIED TO SHOW THE HIGH RISK AND CLEARLY PATIENTS WHO HAVE METASTATIC BREAST CANCER SO WE THOUGHT ABOUT THIS VERY CAREFULLY IN ASSOCIATION WITH THE ONCOLOGISTS. THERE ARE THEORETICAL CONSIDERATIONS THAT YOU SHOULD BE AWARE OF IN THIS DEBATE ABOUT USE OF GROWTH FACTORS IN THIS PATIENT POPULATION. I WANT TO EMPHASIZE THAT YOU HAVE SEEN FROM THE TOXICOLOGY RESULTS THAT VEGFC EXPRESSION WILL LAST FOR A VERY SHORT PERIOD. WE BELIEVE IT'S THERE FOR ONE OR TWO WEEKS AT THE MOST. AND THEN IT'S GONE. THAT'S PART OF THE SURGERY ANY WARE AND BREAST RECONSTRUCTION THEY WILL HAVE UNDERGONE. LYMPH NODES, VEGFC WE WOULDN'T HAVE THE LYMPHATIC SYSTEM AND MAINTAIN IT SO LYMPH NODES PRODUCE VEGFC ON THEIR OWN. AND TRANSFER IS ALREADY USED IN THIS GROUP OF PATIENTS. IN TUMORS VEGFS ARE EXPRESSED BY CANCER CELLS AND HERE VFC IS PRODUCED BY THE CELLS IN THE LYMPHATIC TISSUE INJECTED TO NORMAL TISSUE DONOR. AND ALSO WE HAVE IDENTIFIEDED THE TREATMENT DOES COUPLE THE LYMPH NODE BACK TO THE NORMAL DRAINING LYMPH NODE -- LYMPHOID VESSELS. IN TERMS OF EFFICACY ASSESSMENTS, THIS IS AN EXEMPLOYERTORY STUDY TO THE TRY TO DETERMINE WHICH BEST ASSESSMENTS TO USE. LINKED TO THE CLINICAL CONDITION OF THE PATIENT. SO MEASURING REDUCTION IN VOLUME SERIALLY OVER THE OBSERVATION PERIOD OF THE STUDY. USING THESE MODIFIED MEASUREMENTS WHICH IS CO-MEASUREMENTS OF THE ARM, I KNOW DR. ROCKSON CAN EXPLAIN IN MORE DETAIL IF HE WANTS. USING THE EXTRA CELLULAR WATER CONTENT USING MEASUREMENTS AND OTHER IMPORTANT ASSESSING THE QUALITY OF LIFE USING A SPECIFIC LEM FEE TEE MALLAM FEE DEE MA QUALITY OF LIFE ACTIVITIES OF DAILY LEVELING BECAUSE THAT AFFECTS THESE PATIENTS AS I SAID. IN TERMS OF POINTS RAISED IN RELATION TO INFORMED CONSENT DOCUMENT CHEER HI THESE ARE IMPORTANT AND WE RECOGNIZE THOSE. WE WANT TO REASSURE THE COMMITTEE WE WILL BE MAKING SURE INFORMED CONSENT DOCUMENT DOES AGREE WITH FINAL PROTOCOL HIGHLIGHTING THOSE RISKS RELATING TO SURGICAL PROCEDURES AND RISK OF TAKING THE -- HAVING THE LYMPHATIC ADMINISTERED TO THE PATIENT IN THE INFORMED CONSENT DOCUMENT. WE'RE HAPPY TO DISCUSS THAT IN MORE DETAIL IF YOU WANT. THEREFORE, IN SUMMARY, CURRENTLY THERE'S NO CURE FOR THIS TREATMENT. THIS TREATMENT IS BEING DEVELOPED FOR THE TREATMENT OF LYMPHEDEMA IN THESE PATIENTS WHICH IS A SIGNIFICANT UNMET MEDICAL NEED. WE HAVE BEEN ABLE TO DEMONSTRATE RECONSTITUTION OF FUNCTIONAL LYMPHATIC SYSTEM IN ANIMAL MODELS, AS I POINTED OUT THERE ARE LIMITATIONS ON THOSE MODELS BUT NOT EXACTLY IDENTICAL TO THE HUMAN SITUATION. BECAUSE ANIMALS DON'T DEVELOP LIMB FEE DEE MA. -- LYMPHEDEMA. TOXICOLOGY STUDIES SHOW IT'S SAFE AND WELL TOLERATED WITH LIMITED BIODISTRIBUTION TO THE SITES. WE HAVE OUTLINED THE PHASE 1 STUDY TO UNDERTAKE AND TO POTENTIALLY WE BELIEVE THIS TREATMENT MAY BECOME POTENTIAL TO BECOME ADDRESS ON THAT UNMET CLINICAL NEED IN THESE PATIENTS. THANK YOU VERY MUCH AND WE OTHER HAPPY TO ANSWER ANY QUESTIONS. >> DR. BOYD THANK YOU VERY MUCH. LET'S START WITH THE FIRST REVIEWER. WALTER. >> THANK YOU VERY MUCH. NICE PRESENTATION. MOST OF MY CONCERNS WERE FROM AS YOU KNOW FROM THE PRE-CLINICAL DATA THE. IN THE DOCUMENT REVIEWED IT WASN'T THERE. YOUR RESPONSE TO REVIEWERS, IT WASN'T THERE, YOU DESCRIBED IT AT MY CORE, I WANTED TO SEE IT. I WANTED TO SEE THE GRASS. I WANTED TO SEE THE NUMBERS. I WANTED THE TO SEE STATISTICAL ANALYSIS. YOU SHOWED SOME TODAY AND THAT WAS MORE THAN WHAT WAS EVER IN ANY DOCUMENT SO THANK YOU FOR THAT. I STILL -- SO I MY REMAINING QUESTION IS THE DATA YOU SHOWED TODAY WAS NOT NECESSARILY WITH INTENDED PRODUCT. >> THIS NEW VECTOR YOU'LL USE IN THE PROTOCOL AND DATA YOU SHOWED IN LIMITED NUMBER OF PIGS YOU HAVE DONE WHAT THE ACTUAL PRODUCT, IT MAY NOT HAVE WORKED OR DIDN'T GIVE YOU THE SAME EFFECT AS REGULAR ADD VEGFC AND I THINK THAT THAT NEEDS A LITTLE BIT FURTHER EXPLORING. >> LET ME ADDRESS THAT QUESTION. THIS WORK HAS GONE OVER A NUMBER OF YEARS. THE ORIGINAL WORK DONE AND REPORTED WAS DONE WITH A STRAIGHT FORWARD ADENOVIRAL 5 VECTOR. WHAT WE HAVE DONE IN THE LATTER STUDIES, SOME OF THE PRE-CLINICAL WORK DONE IN THE MODELING AND TOXICOLOGY STUDY WE USED A BACKBONE IN THE ADENO5 VECTOR CALLED THE (INAUDIBLE) BACKBONE. THAT'S INSERTED FOR MANUFACTURING REASONS. TO REDUCE INCIDENCE OF RCAs DURING THE MANUFACTURING PROCESS. WE HAVE DONE THE FINAL WORK BEFORE THE TOXICOLOGY STUDY. SOME OF THOSE PIGS DID RECEIVE THAT VECTOR. THE TOXICOLOGY BIODISTRIBUTION STUDY WAS DONE ENTIRELY WITH THAT VECTOR MANUFACTURED BY THE SAME ROOT USED IN THE CLINICAL STUDY. I THINK WE HAVE BEEN ABLE TO DEMONSTRATE THE SAFETY OF IT AND THE -- SOME OF THE EFFICACY FINDINGS. I DON'T THINK TO BE HONEST THE BACKBONE VECTOR THERE ANY EXPRESSION OF THE GENE, IF YOU LOOK AT THE WAY THAT BACKBONE VECTOR IS USED IN MANY OTHER GENE THERAPY PRODUCTS IT DOESN'T FROM THE INFORMATION WE HAVE AFFECT THE EXPRESSION OF THAT GENE. >> I DON'T DOUBT THAT, I WOULD HAVE -- AS A SCIENTIST I WANTED TO SEE SOME EFFICACY. IN THE ANIMAL MODEL IT'S NOT IDEAL, I APPRECIATE THE FACT. GOING DOWN THE RECORD FOR DIFFERENT POINTS, I ASKED DOSE RESPONSE CURVE BECAUSE AGAIN, ANY GENE THERAPY IS GOING TO BE APPROVED PRODUCT IT HAS TO BE TREATED LIKE A DRUG AND DOSE RESPONSE. Q. COULD I ASK PROFESSOR ALITALO TO COMMENT ON HA AND ISSUES WE FOUND THERE. >> BASED ON THE MOUSE STUDIES FROM EVERYTHING WE KNOW ABOUT VECTORS WE OTHER OPERATING AND SATURATING LEVELS OF VEGFC FOR THE LYMPHATIC -- YOU SHOULD REALIZE SPECIFIC DIRECTED GROWTH FACTOR WHICH IN THE FULL LENGTH FORM ADMINISTERING EPITHELIAL CELLS. WE FEEL WE'RE MAXIMIZING THE EFFICACY. I DON'T SEE A POINT IN THESE STUDIES TO GO ABOVE THESE DOSE RANGES IN TERMS OF EFFICACY. SO THAT'S A REASON STUDIES ARE CONDUCTED. >> I'M GOOD WITH THAT, YOU'RE GOING TO DO THREE DOSES. MY QUESTION IS BACK TO THE PRE-CLINICAL DATA IN THE MOUSE, THERE WASN'T A DOSE RESPONSE. ONE OF MY POINTS YOU MISINTERPRETED, THAT WAS MY FAULT, NO TRANSPLANTATION WITH VEGFC, I ACTUALLY MEANT PEPTIDE VOICE AND I THINK YOU ADDRESSED THAT, I'M NOT WORRIED ABOUT THAT. I ASKED POTENTIAL CARD ROW VASCULAR EFFECTS AND I'M HAPPY WITH THAT RESPONSE. IN VIVO, IN HUMANS ANY GENE THERAPY ONE OF THE ISSUES IS, IS THERE ANY EXPRESSION OR NOT AND YOU ADDRESS THAT. AND HOPEFULLY YOU CAN GET SOME OF THAT DATA INSTILLED IN ANY -- IN PIG. I DON'T KNOW IF YOU HAVE NEW DATA WITH RT PCR YOU TALKED ABOUT IN EXPRESSION. >> AS I SAID WE'RE STILL WAITING THE RESULTS FROM THE TOXICOLOGY STUDY. WE ARE LOOKING AT EXPRESSION IN THOSE TISSUES. >> THE ONLY I TALKED ABOUT IS NOT WHAT I DO, BUT INFORMED CONSENT IT WASN'T CLEAR WHY YOU WERE GIVING THEM A CT SCAN BEFORE PROCEDURE AND YOU SAID YOU WERE GOING TO ADDRESS THAT, THAT'S FINE. >> OKAY. >> I MIGHT COME BACK WITH MORE AFTER MORE DISCUSSION. >> THANK YOU. >> MOST OF YOUR COMMENTS ARE ADDRESSED THEN. LET'S MOVE TO SECOND REVIEWER, MARSHALL. >> THIS IS A DIFFICULT PROBLEM, I ACKNOWLEDGE THAT BUT I DO HAVE A LOT OF QUESTIONS ABOUT THE PROTOCOL. I SUBMITTED THOSE AND I THINK YOUR -- YOU'RE WELL AWARE. ONE OF THE ISSUES IS THAT IN THE MICE DATA AS I READ IT, YOU SAID THIS WAS A TWOFOLD IN THE PAPER INCREASE IN THE NUMBER OF LYMPHATICS BUT P THOSE NUMBERS WERE PRETTY SMALL, I THINK YOU WENT FROM SIX CHANNELS TO 13 CHANNELS. I'M NOT CONVINCED THAT GOING 6 TO 13 IN HUMAN IS GOING TO MAKE ANY DIFFERENCE AT ALL. THAT ISSUE CONCERNS ME. THE SECOND ISSUE IS THAT THE VAST MAJORITY OF THESE PATIENTS ARE GOING TO BE RADIATED. THESE ANIMALS HAVEN'T BEEN RADIATED. SO I DON'T KNOW THAT THERE'S ANY TRANSPORTABILITY FROM YOUR ANIMAL DATA TO HUMAN DATA. ONE THOUGHT THAT I HAD WAS, IT'S VERY -- I MEAN YOU CAN IRRADIATE ANIMALS, I HAVE DONE IT IN STUDIES THAT I HAVE DONE AND YOU CAN DO THE STUDIES THAT WAY IN IRRADIATED ANIMAL. YOU MIGHT HAVE SOME DATA, YOU MIGHT HAVE NO DATA. THE OTHER IS, IS THAT YOU SUGGESTED THE REGENERATIVE CAPACITY OF THE LYMPHATIC SYSTEM IN THE ANIMAL MODEL FAR EXCEEDS WHAT WE SEE IN HUMAN. I DIDN'T SEE A CRIMINAL WHERE YOU DID THE SURGE ARE AND SAW WHAT THE REGION ARETIVE CAPACITY WAS FOR ANYTHING. THERE'S NO CONTROL WHERE YOU DID IT AND IRRADIATED THAT ANIMAL AND WE LOOKED AT THE LYMPHATICS IN THAT SETTING. SO AS I LOOK AT THE ANIMAL DATA, IT JUST HAS NO RELEVANCE TO HUMAN SITUATION. >> CAN I ASK (INDISCERNIBLE) ADDRESSING THESE AND MAYBE ANNA AS WELL. >> THANKS FOR THOSE QUESTIONS. PART OF THE ISSUE THAT NEEDS TO BE CONSIDERED IS WHETHER PRE-EXISTING RADIATION IN MOUSE MODEL WILL ACTUALLY AFFECT THE BIOLOGICAL PROCESSES THAT MIGHT RESPOND TO THE VEGFC. VERSUS QUESTION OF WHAT IS THE IMPACT OF RADIOTHERAPY ON POTENTIAL DEVELOPMENT OF LYMPHEDEMA. THAT'S WHERE WE HAVE THE DISCONNECT IN THAT THE ANIMAL MODEL DOESN'T GIVE US THE OPPORTUNITY TO ASSESS THE IMPACT OF THE THERAPEUTIC ON THE RESOLUTION OF THE DISEASE. IT GIVES US THE OPPORTUNITY TO STUDY BIOLOGY OF THE RESPONSE TO AEDINE VIRALLY DELIVERED GROWTH FACTOR. WHEN WE TALK ABOUT THE ACCELERATE OR MORE PERFECT REGENERATIVE CAPACITY OF THE ANIMALS HAVING WORKED IN ANIMAL MODELS BOTH MURINE AND OTHERS, THE ISSUE IS AGAIN LOOKING AT THE ULTIMATE DEVELOPMENT OF A SUSTAINED LYMPHEDEMA. IT'S DIFFICULT EVEN WITH WITH RADIATION TO GENERATE AN INJURY THAT THE ANIMAL WILL THEN SUSTAIN AS THE CHRONIC CONDITION THAT WE SEE IN ANIMALS AND TYPICALLY TO GIVE ENOUGH RADIATION TO ALLOW THE LYMPHEDEMA TO PERSIST, HAS UPWARDS OF 50% MORTALITY RATE IN THE TREATED SUBJECTS SO IT BECOMES IMPRACTICAL LABORATORY ASSESSMENT. SO WE'RE REALLY TRYING TO SEPARATE OUT WHAT WE CAN LEARN FROM THE ANIMALS ABOUT BEHAVIOR OF THE VECTOR AND ITS EFFECT ON VIABILITY OF THE NODE WHICH RELIES NOT ONLY ON DEMONSTRATION OF INCREASED NUMBERS OF VESSELS BUT ALSO THE SHEER SIZE AND HISTOLOGY OF THE NODE ITSELFND KATEING ITS FUNCTIONALITY. VERSUS USING ANIMAL MODELS TO TELL US WHETHER THIS APPROACH WILL ACTUALLY HELP TO REVERSE THE PATHOLOGY OF LYMPHEDEMA WHERE I THINK THE ANSWER IS PROBABLY NO, WE DON'T REALLY HAVE A GOOD PLATFORM IN WHICH TO DO THAT. >> NOT JUST COUNT THE NUMBER OF VESSELS BECAUSE THE FUNCTIONAL OUTCOME HERE IS WHAT WE ARE AFTER. THAT WAS VERY WELL SHOWN ALREADY IN THE MOUSE STUDIES. WE INJECTED MATERIAL TO THE PERIPHERY AND MEASURED IN THE BLOODSTREAM LATER HOW MUCH OF THAT HAS BEEN TRANSPORTED VIA VESSELS, HOW MUCH REACHES THE LYMPH NODES AS IT SHOULD, BECAUSE THESE PATIENTS ALSO HAVE RECURRENT INFECTIONS SOMETIMES. SO THEY'RE COMPROMISED IN THE IMMUNE RESPONSE IN THE LYMPHATIC AREA BECAUSE THAT'S NO IMMUNE RECOGNITION LACKING DRAINAGE OF ANTIGENS TO LYMPH NODES. SO ALL THESE FUNCTIONAL OUTCOMES ARE MUCH MORE IMPRESSIVE THAN JUST NUMBER OF VESSELS. AND THE STATUS OF THE LYMPH NODE BASICALLY TELLS THE SAME STORY. THE HISTOLOGY PRESERVED ARCHITECTURE AND SO ON. WHEN WE CAN SAY THAT IS PRESENT IN THE AX LAYER REGION, HERE WE ARE REPLACING CAR TISSUE WITH NORMAL TISSUE. WE BELIEVE THAT THAT ACTUALLY HELPS COULDN'TER ACTING OR FIGHTING SOME OF THE POSSIBLE INFECTIONS IN THE AREA. IN THE HEALING BECAUSE WE'RE TRYING TO REMOVE AS MUCH SCAR AS WE CAN AND REPLACE WITH NORMAL TISSUE FROM THE GROIN. SO THIS FUNCTIONAL OUTCOMES OUTWEIGH THE HISTOLOGICAL CRITERIA IN OUR MOTIVATION TO GO ON WITH THIS THERAPY, SO THEY ARE VERY INTERESTED. THE NUMBER OF VESSELS FURTHERMORE CONNECTED TO THE LYMPH NODES WAS NOT JUST TWOFOLD, IT WAS SEVERAL FOLD. SO WE ARE REALLY INDUCING THE CONNECTION TO THE RIGHT DIRECTION. >> AND I UNDERSTAND THAT. THE REAL QUESTION IS YOU HAVE AN ARM IN THE HUMAN THAT'S HUGE. RELATIVE TO THE SMALL DIMENSIONS YOU'RE USING IN A MOUSE. SECONDLY, YOU HAVEN'T -- IT'S NOT THE SAME TO SAY YOU GET LYMPHATIC DEVELOPMENT AN IRRADIATED BED THAT YOU WILL IN NON-ERADIATED BED. IT'S FUNDAMENTALLY NOT THE SAME. SO I DON'T SEE HOW WE RELATE THE DATA THAT YOU -- I UNDERSTAND THE DATA IS MEANINGFUL IN TERMS OF WHAT VEGFC DOES RELATIVE TO VEGF D AND THERE WERE QUESTIONS ANSWERED. YOU'RE GOING FROM ANIMAL TO HUMAN AND WHAT WE LIKE TO SEE IN AN ANIMAL MODEL IS THAT THE DESIRED EFFECT IS THERE. AND THAT WE MAY DOESN'T TRANSLATE ONE TO ONE BY SENSE OF THE MA'AM NATION TO ANTICIPATE SIMILAR EFFECT IN HUMAN. HERE IF WE'RE LOOKING AT EFFECT IT'S NOT AN IRRADIATED ANIMAL. THAT'S SIGNIFICANTLY DIFFERENT IN TERMS OF WHAT WE CAN DEVELOP WITH LYMPHATIC CHANNELS. AND SO ACCEPTING IT ON FAITH THAT THIS IS GOING TO HAPPEN WHICH IS DIFFICULT TO DO IN A NEW TRIAL. >> IMAGING STUDY IN LYMPHEDEMA PATIENTS THERE'S LYMPHATIC VESSELS DYSFUNCTION. HERE THE SURGERY IS INVOLVED AND HAS BEEN DESIGNED TO REPLACE THE SCAR WITH NORMAL TISSUE. AND THE GROWTH FACTOR THERAPY IS INJECTED TO THE NORMAL TISSUE. IT IS MUCH SAFER THAT WAY. IT PROMOTE THE GROWTH OF NORMAL LYMPHATIC ENDOTHELIAL CELLS STARTING AT THE EDGE OF THEWOMAN. WE PUBLISHED THAT INJECTION OF INVESTMENT F C AT THE WOUND EDGE, CAUSE -- VEGF C AT THE WOUND EDGE AND CONNECTION OF LYMPHATIC VESSELS ON TWO SIDES OF SURGICAL WOUNDS. SO WE BELIEVE THIS TECHNIQUE ADDRESSES MUCH CONCERN. I DON'T HAVE REALISTIC AREA ORIGIN THE SCAR AREAS ARE IN THE PATIENTS BUT I THINK PRINCIPLE THE SURGERY WHEN COMBINED WITH GENE THERAPY SHOULD DO THE JOB. NO REASON TO BELIEVE THERE WOULDN'T BE ENOUGH LYMPHATIC ENDOTHELIAL CELLS THERE TO RESPOND. >> CARRY. CAN I ASK -- KERRY -- ANNA IS A SURGEON IN FINLAND ON THE PHONE HAS CARRIED OUT ALREADY LYMPH NODE TRANSPLANTATION IN THESE PATIENTS WITHOUT THE GENE THERAPY. CLEARLY ALL -- THE MAJORITY OF PATIENTS WOULD HAVE HAD RADIOTHERAPY BEFORE. SO WE'RE ALREADY OPERATING USING THIS TECHNIQUE, ALBEIT WITHOUT THE INDIVIDUAL F C TRANSPLANTING LYMPH NODES IN THIS SITUATION. ARE YOU THERE, DO YOU WANT TO MAKE COMMENTS ON THAT IN >> YES, I WOULD LOVE TO DO THAT. I AGREE THE ANIMAL MODELS ARE FAR FROM PERFECT BUT THIS IS THE BIG MODEL THAT WE HAVE BEEN USING IS THE BEST THAT I HAVE BEEN ABLE TO FIGURE OUT AFTER 15 YEARS OF WORKING ON THIS FIELD. WITH PROFESSOR (INDISCERNIBLE). ONE POINT THAT IS A BENEFIT OF THIS SCAR REMOVAL IS IN THE ANIMAL MODEL THE LYMPHEDEMA PROBLEM IS MORE OR LESS ACUTE BECAUSE THERE IS NO HISTORY OF IRRADIATION AND -- BUT BY REMOVING SCAR TISSUE IN PATIENT'S AXILLA WHICH CAN BE QUITE BIG AREA, WE ACTUALLY ARE MAKING THE LYMPHATIC VESSELS FROM THE UP PER LIMB TO LEAN AGAINST SO CREATING A NEW ACUTE LYMPHATIC ISSUE FOR THE PATIENT. WHEN THOSE CHANNELS ARE REOPENED AND WE PLACE NEW HEALTH TISSUE NOTTER RATEIATED INTO THAT AREA, IT IS -- IRRAID CRATED INTO THE AREA, IT MAKES THE PATIENT SITUATION MORE SIMILAR THAN IN ANIMAL MODELS THAT WE HAVE BEEN USING. BECAUSE IF WE BELIEVE SCAR INTO THE AX LAYER AREA, I AGREE IT WOULD JUST INJECT VEGFC IT MIGHT NOT WORK. NOT SURE IF YOU GET MY POINT. >> YOU KNOW, I CERTAINLY DO, BUT THE DATA THAT WAS JUST PRESENTED TO US SHOWED THAT YOU HAD SOME 20 TO 30% IMPROVEMENT. THAT LEFT 70% THAT WASN'T IMPROVED. THE QUESTION THAT I HAVE IS, IS WHAT DID YOU START WITH? THIS RELATES TO ENTRY CRITERIA. WHAT DEGREE -- IT'S USE CIRCUMFERENCIAL MEASUREMENT. DID PATIENTS IN YOUR STUDY, DID YOU HAVE ARM DIFFERENTIATION 10%, 20%, 30% AT THE ONSET? AND HOW FAR AFTER THE RADIATION THERAPY BECAUSE SCAR IT SHALL SHOE TENDS TO BUILD UP OVER TIME, HOW MUCH -- HOW FAR OUT WERE YOU FROM THE SURGICAL PROCEDURE WHEN YOU DID YOUR INTERVENTION? >> >> THE SURGICAL TECH THEQUE IS NEW, WE HAVE IS FAR TREATED 30 PATIENTS ALL TOGETHER. SO BUT IT LOOKS ALONE THAT'S NOT UNFORTUNATELY WORKING IN THESE PATIENTS. ALREADY TODAY WE ARE THINKING SCAR TISSUE FROM THE AXILLA HEALTHY TISSUE IN THE AREA, AT LEAST IN OUR HANDS (INDISCERNIBLE) WE ARE NOT HAPPY WITH OUR RESULTS. THERE ARE AT LEAST 70 PLASTIC SURGEONS AROUND THE WORLD USING THIS TECHNIQUE TODAY AND I HEAR FROM EVERYBODY THAT THE (INAUDIBLE). SO WE NEED SOMETHING MORE. I HOPE THAT VEGF C IS GOING TO HELP GENOMIC -- >> I STILL LIKE TO KNOW WHAT THE ENTRY CRITERIA WERE FOR DATA BEING DONE FOR THE PATIENTS THAT DONE SO FAR SO WE CAN GET SOME IDEA. I MEAN, IF THEY'RE REALLY IN THE EVOLUTION SO THEY HAVE FIBROSIS AN CAR TISSUE YOU WOULDN'T EXPECT A GOOD RESULT. IF TOO EARLY YOU MIGHT EXPECT A BETTER RESULT. SO THE QUESTION BECOMES IN THESE PATIENTS DONE, WHAT WERE YOUR ENTRY CRITERIA? WAS THERE A 10% DIFFERENCE IN THE ARM OR NOT AND HOW FAR OUT WERE THESE PATIENTS FROM THE TIME THEY HAD RADIATION THERAPY? Z >> BECAUSE THIS IS EXPERIMENTAL SURGERY. WE HAVE BEEN TREATING THOSE PATIENTS THAT COME TO US FOR BREAST RECONSTRUCTION SO WE HAVE BEEN TREATING LATE STAGES OF (INAUDIBLE) EARLY STAGE PATIENTS THAT HAVE LYMPHEDEMA SYMPTOMS LESS THAN A YEAR BUT EVEN WITH THOSE PATIENTS THE EARLY LYMPHEDEMA SEEM IT IS SURGERY DOES NOT ALWAYS WORK OR OFTEN WORK. WE DON'T KNOW THE REAL ANSWER YET. >> ANOTHER CRITICAL QUESTION THEN BECOMES WHAT WAS YOUR COMPLICATION RATE SINCE THERE WASN'T MUCH OF A SUCCESS RATE, WHAT WAS YOUR COMPLICATION RATE? WHAT WAS THE INCIDENCE OF WOUND BREAK DOWN, INCIDENCE OF INFLAMMATION AND WHAT PERCENTAGE OF PATIENTS WITH WORSE BUZZ YOU OPERATED ON THEM AND DIDN'T GET RESULTS SO WHAT PERCENTAGE OF PATIENTS WERE HARMED BY PROCEDURE THE THAT WAS DONE? >> WE HAVE BEEN LUCKY SO FAR IN THE AX LAYER AREA THERE ARE TWO WOUND INFECTIONS IN THE LOW ABDOMINAL WALL BECAUSE SOME OF THESE PATIENTS (INDISCERNIBLE) NOT WOUND HEALING ASSOCIATED PROBLEMS. Q. WHAT ABOUT INCREASE POST-OPERATIVELY THAT YOU MIGHT SAY WAS QUICKER THAN WHAT YOU MIGHT HAVE ANTICIPATED BECAUSE THERE WAS THE INTERVENTION THAT DIDN'T DO ANYTHING? >> THAT IS HARD TO TELL BECAUSE LYMPHEDEMA USUALLY TENDS TO GET WORSE OVER THE TIME. ALL PATIENTS HAVE BASICALLY HAVE BEEN -- WE DON'T SEE ANY REAL EFFICACY IN THE INVESTIGATION. BUT I HAVEN'T SEEN ANY WORSENING OF THE LYMPHEDEMA AFTER THE OPERATION. SO FAR. >> ONE OF THE CONSIDERINGS THAT I HAD WHEN TALKING SURGERY AND SINCE I HAVE YOU ON THE PHONE WAS, WHEN WE TALKED COMPLICATIONS YOU OBVIOUSLY DID HAVE ANY NERVE COMPLICATIONS BUT IN THE PROTOCOL YOU RESTRICT THE NERVES, I CAN UNDERSTAND SKELETONIZING THE BLOOD VESSELS. I THINK IT'S MORE PROBLEMATIC TO TRY AND IDENTIFY NERVES AND SEE SCAR TISSUE. THE REASON THAT I SAY THAT IS BEING A HEAD AND NECK SURGEON, I HAVE DONE A SIGNIFICANT NUMBER OF CAROTIDS AND IF YOU LOOK AT THE DATA RELATIVE TO NERVE REEXPLORATION IN SURGERY, WHEN IT'S DONE INITIALLY YOU HAVE A 2% CHANCE OF INJURY, WHEN IT'S DONE A YEAR LATER OR MORE AS SECOND PROCEDURE FOR TUMOR YOUR INJURY RATE OF SIGNIFICANCE GOES UP TO 25%. WHY IS THAT? BECAUSE NO MATTER HOW GOOD SURGEON IS FOR THE MOST PART IN OUR HANDS SCAR IS VERY DIFFICULT TO SEPARATE FROM NERVE. THEY LOOK UNDER THE MICROSCOPE AND THE BEST SURGEON IS GOING TO HAVE NEURONAL INJURY. WHAT I HAD WITH THE ASPECT OF THE PROTOCOL, WHY IS IT ESSENTIAL TO SKELETONIZE NEURONAL TISSUE. WHEN THERE'S NO PERILYMPHATICS THERE AND THE RISK OF INJURY IS SIGNIFICANTLY INCREASED? >> >> DOESN'T MAKE SENSE TO SKELETONIZE THE NERVES, ONLY THOSE PATIENTS WHO HAVE CONSTANT MAYBE IN THEIR ARMS WHEN YOU REMOVE THE SCAR TISSUE. HEALTHY IT SHALL SHOE IN THAT AREA. (INAUDIBLE) HAS DONE PUBLICATION FROM THAT. IN PATIENTS THAT DON'T HAVE THIS CHRONIC PAIN, MOST OF THE PATIENTS DONE HAVE THIS CORRECT. (INDISCERNIBLE) IN THE UPPER EXTREMITIES. THERE YOU JUST DISSECT SCAR TISSUE UNTIL THE AX LAYER VEIN -- YOU DON'T (INAUDIBLE) TO DISSECT THE NERVES. >> I SUGGEST THAT THAT BE ALTERED? AND CHANGED IN THE PROTOCOLS, AS IT'S WRITTEN. THAT'S AN ISSUE. I KNOW YOU HAVEN'T HAD COMPLICATIONS THE DATE IN THE POST IRRADIATED PATIENTS BUT SOME AXILLAS IF THEY LIKE THE HEAD AND NECK MUST BE CONTRACTED. MY THOUGHT WAS THAT YOU MIGHT CONSIDER A SKIN PANEL OR SOMETHING SO THAT THE THAT CAME TO MIND SO YOU DON'T NECESSARILY HAVE TIGHT CLOSURE ON REVASCULARRIZED REFLAP. ALL THIS LEADS TO THE BIG CONSIDERATION THAT I HAD WHICH IS YOUR ENTRY CRITERIA. THIS IS A STUDY IS PRIMARILY FOR ADVERSE EVENTS. YOU ARE ARE TALKING A 10% DIFFERENCIAL IN THE NORMAL AND ABNORMAL ARM. GIVEN THERE'S BEEN NO SUCCESS TO DATE AND ANIMAL DATA HASN'T GIVEN ME THE INFORMATION THAT I WANT, A 10% DIFFERENCIAL IS TOO LOW. THE INTERVENTION MAKES PEOPLE WORSE SO I UNDERSTAND DIFFERENCE BETWEEN THE LATE STAGE WHERE YOU HAVE THE PROBLEM WITH SCAR TISSUE, FIBROSIS AND FAT DEPOSITION, BUT SOME ROOM IN BETWEEN THERE FOR MODIFICATION OF ENTRY CRITERIA. IF THERE ARE ANY IMPROVEMENT EVEN YOU HAVE NO IMPROVEMENT TO DATE THAT WOULD BE ENOUGH TO PROPEL YOU TO A PHASE 2 STUDY. THERE HAS TO BE SOME PEOPLE, I KNOW ONE PERMLY THAT DEVELOPED A DISSECTION AFTER 20 YEARS GOT LYMPHEDEMA AN WENT I HEAD WITH WITH TRADITIONAL TREATMENTS. AND THE LYMPHEDEMA WENT AWAY. 39% HAVE BENEFIT FROM THE TRADITIONAL METHODS AND NO RESPONSE TODAY. I CAN'T SEE USING 10% DIFFERENCIAL IN THE ARM AT THE TIME. MR. CXFCIATION OF STUDY AS ENTRY CRITERIA. YOU HAVE TO BE BETWEEN 20 AND 30% IF THIS WERE TO GO FORWARD. >> DO YOU WANT THE COMMENT ON THAT? >> THOSE ARE GOOD POINTS, I WANT TO GO BACK, THAT'S THE -- JUST FOR ONE SECOND BACK TO QUESTION OF RAID YES THERAPY. WITH THE EXCLUSION CRITERIA PUT INTO PLACE, THE LIKELIHOOD THAT E WE WOULD ENROLL ANYBODY WHO WOULD HAVE DIRECT RADIATION TO THE AXILLA IS LOW TO NON-EXISTENT. WE WILL DEAL WITH PATIENTS WHO HAVE IRRADIATION OF THE BREAST ITSELF SO MOST SCARRING WILL BE SURGICAL. IT CAN BE SUBSTANTIAL. THERE'S CONTRACTION OF THE AXILLA BUT THE WAY I ENVISION THIS IS WE'RE CREATING A HEALTHY TISSUE BRIDGE BETWEEN VASCULATURE FUNCTIONAL AND THEN THE DRAINING VASCULATURE OF THE ARM TO THE VENOUS CIRCULATION. THE LIKELIHOOD WE WOULD BE SUCCESSFUL ENGRAFTMENT IN THE RADIATION PORT IS PRETTY SUBSTANTIAL. Q. SO YOU EXCLUDE PATIENTS THAT HAVE HAD -- >> AX LAYER -- DIRECT AX LAYER RAID YEAR AGO. IN THE SUBSET OF PATIENTS IDENTIFIED THAT WOULDN'T BE A TYPICAL TREATMENT STRATEGY. THAT'S RESERVED IN THE HIGHER RISK RECURRENCE GROUPS THAT WE'RE TRYING TO EXCLUDE FROM INCLUSION IN THIS STUDY. >> I MUST HAVE MISSED THAT, THOSE WERE EXCLUDED SPECIFICALLY EXCLUDED IF THE STUDY. CAN YOU SHOW THAT? >> THOSE ARE THE CATEGORIES ONE USE AX LAYER RADIATION BUT WE'RE EXCLUDING THEM. >> YES. THIS GROUP OF PATIENTS. >> IF I MAY COMMENT ON THAT. SO SINCE WE HAVE SUBMITTED THE PROTOCOL WE TIGHT BED THE EXCLUSION CRITERIA TO PATIENTS WITH MORE ADVANCED TUMOR STAGE AT TIME OF INITIAL TREATMENT INITIAL SURGERY AND THIS IS WHY STANLEY SAID THE ONES RECRUITED INTO THE STUDY ARE UNLIKELY TO HAVE EVER RECEIVED AX LAYER -- AX LAYER -- >> IT'S IMPLICIT IN THIS LIST. AS FAR AS THE CRITERIA FOR DIAGNOSING PATIENTS WITH LYMPHEDEMA APPROXIMATE INCLUDING THEM TO THE PROTOCOL, THE PROBLEM WITH IT IS THAT EVEN WHEN IT IS IN ITS LAYTANT SUBCLINICAL PHASE IF ONE DOES TISSUE HARVESTING THERE'S ALREADY SUBSTANTIAL TISSUE ARCHITECTURAL DERANGEMENTS AND WHAT HAS BEEN TYPICALLY CALLED IRREVERSIBLE CHANGE OF LYMPHEDEMA. SO THE PROCESSES PROGNOSIS AND ADIPOSE GENESIS AS SOON AS IT INVOKES EPIDODGE MOUSE DANGEROUS SIGNALING SO BY THE TIME ONE WAITS FOR A 10% INCREASE IN VOLUME, THERE'S ALREADY A SUBSTANTIAL STRUCTURAL COMPONENT THAT EVEN IF ONE SUCCESSFULLY RESTORES LYMPHATIC FLOW MAY NOT REVERSE. SO DECISION TO GO TO FANG LYMPHODEE THE MA CERTAINLY MAKES THE DISEASE MUCH MORE WELL ESTABLISHED BUT I POSITIVE THAT TO BE A LESS RESPONSIVE PATIENT POPULATION. IN THE LIMITED EXPERIENCE THAT EXISTS WITH THE AUTOLOGOUS LYMPH NODE TRANSFER IN ABSENCE OF GROWTH FACTOR ADMINISTRATION, SUBGROUP AT 20% THAT RESPONDS IS TYPICALLY THE EARLY ONSET OF DISEASE PATIENTS WHO ARE TREATED SHORTLY AFTER THE APPEARANCE OF EDEMA. WE WILL NOT ONLY USE A VOLUME ASSESSMENT BUT SPECTROSCOPY WHICH WAS DEMONSTRATED TO HAVE A 98% POSITIVE PREDICTIVE VALUE. WITH PRESENCE OF ABNORMAL BIOIMPEE DENSE RATIO AND IMMEASURABLE DISDISPARITY, DISTINCT APPEARANCE OF LYMPHEDEMA WE WILL REQUIRE THE PATIENT TREATED FIRST BECAUSE IN A SMALL NUMBER OF CASES WHERE THERE'S REVERSIBILITY WE WOULD RATHER DO IT WITH LYMPHATIC MASSAGE THAN SURGERY BUT THESE WILL BE PATIENT WHOSE REQUIRE LONG TERM COMPRESSION GARMENTS BECAUSE THEY HAVE CROSSED THAT BRIDGE AS IT WERE AND ARE IN THE ESTABLISHED PHASE OF DISEASE. >> >> THE OTHER THING THAT I DIDN'T HAVE INFORMATION ON THAT I QUESTIONED, IT HAS TO BE DIFFERENT RATES OF PROGREG OF LYMPHODEEIA. PROGRESSION OF LYMPHEDEMA. HAS THIS BEEN A STUDY THAT IDENTIFIES FACTORS THAT CONTRIBUTE TO THAT? YOU WOULD LIKE TO KNOW WHICH GROUP YOU DIAL WITH BASED ON RATES OF PROGRESSION IF THAT DATA EXISTS. IF IT DOESN'T EXIST, THEN I UNDERSTAND THAT THERE'S HISTOPATHOLOGIC CHANGES IN THE ARM. THOSE CAN SIT THERE A WHILE IN SOME PATIENTS. WE'RE TALKING ABOUT AN INTERVENTION THAT'S NEW. I WANT TO GET THE ONES THAT ARE PROGRESSING RELATIVELY QUICKLY. SO THE SUGGESTION THAT I MADE IN MY QUESTIONS WAS LOOK AT A GROUP OF PATIENTS, HERE WE ARE AT EARLY LEVEL, SEE IF PATIENTS IF NOT FROM A FAR DISTANCER MONTH, PICK OUTPATIENTS PROGRESSING RELATIVELY RAPIDLY TO WHAT'S KNOWN AS BASE OF REGREG FOR LYMPHEDEMA AND PICK THOSE PATIENTS OUT ADS STUDY GROUP. THAT'S A FUNCTIONAL WAY OF LOOKING AT IT, IT'S BETTER THAN JUST SAYING ALL RIGHT. I'M GOING TO 2010, 20, 30%. >> SO THERE HAVE BEEN A NUMBER OF STUDIES PUBLISHED OVER THE LAST TWO DECADES ABOUT THE NATURAL HISTORY OF BREAST CANCER LYMPHEDEMA, THEY VARY BY THE METHODOLOGY USED TO FOLLOW PATIENTS AND SO ON BUT IT'S BECOME FAIRLY WELL ESTABLISHED BASED UPON OBSERVATIONAL CRITERIA THAT THE NATURAL TENDENCY OF LYMPHEDEMA IN ESSENCE UNIVERSEALLY TO PROGRESS. THE PROBLEM WHICH I AGREE IS PROGRESSION TAKES FORMS. IN SOME PATIENTS THERE IS PROGRESSIVE HYDROSTATIC ACCUMULATION OF INTERSTITIAL FLUID THAT REMAINS VERY RESPONSIVE TO THE PHYSICAL MEASURES THOSE THOUGH THOSE SIMPLY CONTAIN MEASURES, THEY DON'T REVERSE PATHOLOGY. THE SECOND PATHOLOGY ONGOING IS PROGRESSIVE AD POE GENESIS. AND A TREMENDOUS INCREASE IN THE SUBCUTANEOUS ADIPOSE LAYER IN THE LIMB THAT BEHAVES PHYSICALLY AND BY APPEARANCE IDENTICALLY TO THE HYDROSTATIC EDEMA, EXCEPT IT'S COMPLETELY UNRESPONSIVE TO PHYSICAL MEASURES. IF WE SEGREGATE EVEN IF WE SEGREGATE PATIENTS SHOWING PROGRESSIVE INCREASES IN LIMB VOLUME WHICH THEY WILL, SOME INCREASES ARE GOING TO BE BASED ON ADIPOSE TISSUE AND POTENTIALLY NO RESPONSIVENESS TO THE INTERVENTION WE PROPOSE. THERE'S GOOD DATA ABOUT PATHOGENESIS OF ACQUIRED LYMPHEDEMA IF YOU ABROGATE THE LIMB POTENTIAL BY RESTORING, YOU CAN A REST THE FUTURE DEVELOPMENT OF OTHER BIOLOGICAL PROCESSES WHICH IS WHY WE'RE PREDICATING OUR APPROACH ON TRYING TO IDENTIFY THE PATIENTS AS EARLY AS THEY SELF-IDENTIFY. WE'RE NOT LIMITING OURSELVES TO 10% INCREMENTAL LIMB VOLUME, THAT WOULD BE THE LOWER LIMIT OF WHAT WE FIND ACCEPTABLE. BUT IF THE PATIENT PRESENTS WITH 30, 40% INCREMENTAL VOLUME WE WOULD CONSIDER THEM AS WELL IF THEY MET THE OTHER CRITERIA. >> AGAIN, IT DEPENDS HOW FAT ACCUMULATES BUT IMAGING STUDIES TELL FAT FROM NON-FAT AND YOU SHOULD BE ABLE THEN WITH IMAGING STUDIES TO PICK OUT WHICH ONES PERHAPS HAVE THE FAT DEPOSITION AS OPPOSED THOSE WHICH HAVE FLUID DEPOSITION. >> THEY ALL GET FAT DEPOSITION. QUESTION IS WHAT ARE PROPORTIONS. IF YOU DO DEXA IMAGING STUDIES ON LYMPHEDEMATOUS ARMS STAGE 2 AND BEYOND YOU WILL SEE THE ADIPOSE LAYER IN THE ENTIRE POPULATION. THE QUESTION IS, WHAT IS THE PROPORTION OF HYDROSTATIC EDEMA. >> AND THAT WAS GOING TO BE MY NEXT QUESTION. BECAUSE THE PROPORTION IS GOING TO VARY. IF U YOU PICKED OUT THE ONES THAT HAD THE FAT VERSUS THE HYDROSTATIC OR WHATEVER, YOU MIGHT BE ABLE TO THEN IDENTIFY GROUPS THAT WERE MORE APPLICABLE. THE REASON I BRING THIS UP, WE -- THERE HASN'T BASED ON THE DISCUSSION WE HAD, THERE'S NOT EFFICACY TO DATE, THERE'S HUGE POTENTIAL DOWN SIDE. WE DONE KNOW WHAT THE VECTOR IS DOING. SO WE HAVE A DIFFICULT PATIENT BASE. SO WE HAVE THE MAKE JUDGMENTS. YOU WANT TO PICK OUTPATIENTS THAT SUFFER THE LEAST IF NOTHING HAPPENS. AND MY POINT AGAIN WAS THAT IF YOU TAKE A MORE ADVANCED PATIENT, ALL YOU HAVE TO DO SHOW A LITTLE EFFICACY. AND YOU'RE WAY AHEAD OF THE GAME IN PRELIMINARY TRIAL WITHOUT -- WHEN YOU'RE DOING A TRIAL THAT'S NOT PRIMARILY FOR EFFICACY BUT FOR ADVERSE EVENTSES. SO THAT'S PRETTY MUCH WHERE I WAS GOING. >> MY REJOINER TO THAT WOULD BE WE ARE IN ESSENCE ATTEMPTING TO PUT INTO PLACE WHAT YOU'RE SUGGESTING BY USING BIOIMPEE DENSE SPECTROSCOPY. IF PATIENTS HAD ABNORMAL BIOIMPEE DENSE SPECTROSCOPY THEY HAVE A BY DEFINITION HIGH DOE STATIC EDEMA THAT SHOULD BE RESPONSIVE TO THIS INTERVENTION. IF WE PREDICATE THE POPULATION TOWARD THE MORE ADVANCED DEGREES OF DISEASE, WE KNOW BASED ON NATURAL HISTORY STUDY WE'RE PREDICATING TOWARD THE REVERSIBLE STRUCTURAL CHANGE AT LEAST LIKELY -- THAT ARE LEAST LIKELY TO RESPOND TO THIS THERAPEUTIC. >> TO ME THAT'S A LATER -- THAT'S FOR A PHASE 2 OR PHASE 3 AND I'M NOT GOING TO BELABOR IT ANY MORE. THIS IS PRETTY MUCH WHERE I STAND WITH IT. I CERTAINLY APPRECIATE YOUR RESPONSES. I DID HAVE OTHER CONSIDERATIONS. RELATIVE TO THE INFORMED CONSENT. IT WAS INTERESTING TO ME THAT YOU YOU DIDN'T INCLUDE SMOKERS. THE REASON I SAY THAT, ALL HEAD AND NECK CANCER PATIENTS ARE VASCULAR PATHS AND SMOKERS AND WHAT NOT. WE DID A STUDY LOOKING AT 200 PATIENTS WITH FREE FLAPS AND WE HAD A HALF A PERCENT FAILURE RATE. SO IF YOU TAKE WOMEN THAT AT LEAST BEFORE THE CHEMOTHERAPY MENOPAUSAL, IF LIKELIHOOD OF SIGNIFICANT P VAS COW VASCULAR ISSUES IS SLIM. -- VASCULAR ISSUES IS SLIM. TWO YEARS OUT WHEN YOU DO INTERVENTION, IF THEY WERE TO STOP SMOKING PERIOPERATIVELY, THE RISK SHOULD BE INORDINATELY SMALL. INORDINATE HI SMALL. EXCLUDING THAT GROUP I DON'T SEE THE RATIONALE FOR DOING IT. THAT IS MY CONSIDERATION THERE. WOUND HEALING EVENTS I HAVE DISCUSSEDDED. YOU DID MAKE A STATEMENT IN THE TEXT THAT THE POSSIBILITY VEGFC COULD FACILITATE GROWTH OF MALIGNANCY IS REMOTE. THAT'S LITTLE BIT OF AN OVERSTATEMENT. BECAUSE WE SIMPLY DON'T KNOW. >> I AGREE. THAT'S FINE. WE'LL MODIFY THAT WORDING. >> THENO' YOU KNOW THE -- I'M -- AS YOU CAN PROBABLY TELL, I'M PRETTY BLACK AND WHITE. SO WHEN IT COMES TO LOOKING AT DATA AND DIRECTING TRIALS, I REALLY -- I HAVE AN ISSUE WITH POTENTIAL CONFLICT OF INTEREST WHEN THE MANUFACTURER OF THE PRODUCT IS INVOLVED IN THE TRIAL. I THINK IT SHOULD BE AS COMPLETELY SEPARATE ENTITY. AND DONE BY PEOPLE THAT HAVE NOTHING TO DO WITH THE COMPANY WHATSOEVER. I ALSO HAVE A BIG PROBLEM WITH SAYING THAT THERE'S A ENORMOUS PROBLEM THAT THERE'S GOING TO BE A 90 DAY DELAY FROM THE RIGHT TO SUBMISSION. I JUST DON'T UNDERSTAND THAT. IT JUST -- IN MY WORLD THAT CAN'T EXIST. I UNDERSTAND WHAT YOU SAID IN YOUR RESPONSE BUT FOR ME IT'S PROBLEMATIC. I TALK ABOUT THE SURGICAL PROCEDURE. IT SHOULD BE STATED IN THE INFORMED CONSENT THAT THE AVERAGE HOSPITAL STAY WILL BE FIVE DAYS. I DON'T THINK IT WAS THERE. 2 BASELINE LYMPHEDEMA TEST YOU TAKE THAT AWAY AND I'M HAPPY ABOUT THAT. I HAVE TALKED LONG ENOUGH. THE RISK OF NERVE INJURY MUST BE DISCUSSED POST-OPERATIVE PAIN SHOULD BE STATED AND PAIN CONTROL PROTOCOL SHOULD BE CONCLUDED. I'M DONE. >> YOU'RE PROBABLY GLAD. >> THANK YOU VERY MUCH. >> APPRECIATE YOUR EFFORT. FROM MY PERSPECTIVE AND SUMMATION, WHAT I WOULD LIKE TO SEE IS AN ANIMAL MODEL THAT'S IRRADIATED SHOWING THAT IN THAT SETTING YOU CAN DEVELOP -- YOU CAN ACTUALLY GET SUBSTANTIVE AND MEANINGFUL BEFORE PROCEEDING. I DON'T KNOW IF ANYBODY ELSE HAS THOSE CONSIDERATIONS. >> I DO SHARE THOSE THOUGHTFUL AND TOUGH COMMENTS OF MY CO-REVIEWER. I THINK THIS STUDY WAS WHILE I APPLAUD THE EFFORT TO DEAL IN A STRAIGHT FORWARD FASHION WITH THE DISEASE PROCESS THAT'S TREMENDOUS PAIN AND DIFFICULTY FOR THOUSANDS OF WOMEN, I WAS PLEASED THAT SOMEONE IS PAYING ATTENTION TO THE SIDE EFFECTS THAT ARE IN FACT CAUSED BY THE TREATMENT. PART OF THAT CATEGORY OF A SECONDARY EFFECT BECAUSE CANCER TREATMENT IS GOOD AND WIDESPREAD AN CAUSES TREMENDOUS SIDE EFFECTS AND WOMEN HAVE BEEN DEALING WITH THIS CONDITION VIOLENTLY WITH THE ENTIRE ONUS FOR CARE PLACED ON THEM. IT WAS GOOD TO SEE SCIENTISTS ATENT TO IT. -- ATTEND TO IT. I HAVE SIGNIFICANT PROBLEMS HERE. THE STUDY ON BEHALF OF THE PRIVATE PHARMACEUTICAL COMPANY RAISES THE BAR CONSIDERABLY FOR CONSENT, IN THE INFORMED CONSENT STATES NO BENEFIT FROM THE TRIAL. AND I WONDERED HOW THAT'S THE CASE BECAUSE IT'S A PRIVATE FOR PROFIT COMPANY. IF THEY PAID TO ACCUMULATE PATIENTS MUST BE NOTED. IF HE'S OTHER BENEFITS -- IF THERE'S OTHER BENEFITS IT SHOULD SAY THAT. THERE WAS A QUESTION CV, ONE OF THE PIs WORKS DIRECTLY AS INDIVIDUAL CONSULTANT TO THE PHARMACEUTICAL COMPANY AN FACULTY OF STANFORD, UNCLEAR WHETHER THE MOMENT OF CONFLICT -- POSSIBILITY OF CONFLICT HERE >> YOU TRIED TO CLEAR THAT UP BUT I WASN'T ATTENDTIVE TO THAT. >> IF I CAN COMMENT ON THAT. DR. ROCKSON IS PRINCIPLE INVESTIGATOR, HE WILL BE PAID AS AN INVESTIGATOR FOR THE ACCUMULATION OF PATIENTS AS WHAT HAPPENED IN ANY -- WOULD HAPPEN IN ANY CLINICAL STUDY CONDUCTED BY -- THAT WILL ALL BE DECLARED IF THE INFORMED CONCEPT FORM SO THAT WILL BE QUITE CLEAR. >> I THINK IT NEEDS TO BE EXTREMELY CLEAR THAT IN FACT THEY ARE -- THERE IS A BENEFIT AND THE ONE WHERE THERE IS NO BENEFIT SHOULD BE TAKEN OUT. THERE IS NO DIRECT BENEFIT. PATIENTS NEED TO KNOW. HEAD COUNT. >> WE RECOGNIZE THAT. SO THANK YOU. FROM Z >> THE SECOND PROBLEM IS ONE THAT I RAISED BEFORE BUT ACUTE IN THIS STUDY. YOU CAN'T WITHDRAW FROM THE STUDY. ONCE YOU HAVE BEEN GIVEN THE GENE ALTERED TISSUE AND IT IS IN YOU, THE IDEA SUGGESTION IN THE INFORMED CONSENT PROCESS YOU CAN WITHDRAW ANY TIME IS NOT TRUE AND IT HAS TO BE TAKEN OUT. YOU CAN'T WITHDRAW AND THAT SHOULD BE CLEAR. THIS IS A ONE OFF INTERVENTION AND IT WILL BE THERE UNLESS EVEN IF YOU WENT BACK AND TOOK OUT THE TISSUE, THE EVENT OF HAVING THIS IN YOUR BODY -- >> I THINK IF I COULD PERHAPS CLARIFY THAT BECAUSE OFTENl 6C0@6CJ PATIENTS GO INTO STUDIES, HAVE PROCEDURES LIKE THIS FOR WHATEVER REASON WITHDRAW FROM HAVING IN FOLLOW-UP MEASUREMENTS AND THAT WAS WHAT WE MEANT. PERHAPS WORDING WASN'T PUT THERE APPROPRIATELY. THAT'S WHAT WE MEANT. CLEARLY THE CANCER TREATMENT WE CAN'T TAKE IT OUT. >> IT HAS TO BE CLEAR THEY CAN'T TAKE IT OUT. YOU'RE IN THE STUDY. UNLIKE OTHERS WHICH YOU CAN WITHDRAW THE ONLY THING YOU CAN DO IS REFUSE (INAUDIBLE). THAT'S GOOD TO BE IN PLAIN ENGLISH TO THEM. FROM WE'LL TAKE THAT INTO ACCOUNT. >> THE -- I SHARED I WONTED -- I HAVE THE SAME QUESTIONS ABOUT THE DATA THAT SEEMED SOMEWHAT INCOMPLETE, THERE SEEMED TO BE SOME STUFF. THE CONCEPT HERE WAS ENOUGH TO CHARACTERIZE BECAUSE OF THE OTHER STUDIES THAT HADDEN BEEN DONE. I WAS CONCERNED ABOUT THE NATURE OF THE RISK NOT BEING FULLY EXPLAINED IN THE CONSENT FORM AND IN THIS INSTANCE, HERE WE HAVE GENE TRANSFER WHICH I -- MY IMAGE WAS PEOPLE WHO HAD ABSOLUTELY NO OPTIONS FACEDDED WITH LIFE THREATENING CONDITIONS WOULD BE THE FIRST TARGET FOR FIRST USE OF GENE THERAPY, HERE THIS IS A HIGH RISK TO TAKE ON FOR SOMETHING THAT WHILE DIFFICULT AND PAINFUL AND FRUSTRATING HAS PROVED RESPONDSIVE TO SOME OTHER INTERVENTIONS INCLUDING VERY AGGRESSIVE EXERCISE THAT HAS IMPACT AND BECAUSE SOME PEOPLE WHO ARE POOR CAN'T AFFORD A GYM MEMBERSHIP AN SPEND TWO HOURS A DAY SWIMMING, YOU WONNER IS IT MORE LIKELY IF YOU WERE POOR, IF YOU ARE -- IF YOU CAN'T ACHIEVE THAT DRAMATIC EXERCISE, SO YOU'RE TREATING A DISEASE THAT'S FRUSTRATING PAINFUL BUT NOT USUALLY LIFE THREATENING. THE UNCERTAINTY RELATIVE RISK BENEFITS BURDEN THEN IS MUCH MORE CRITICAL. BECAUSE YOU DELIVER EXCLUDING THE PATIENTS YOU THEN WERE TREATING THE PEOPLE LEAST EFFECTED SO THE RISK BENEFIT RATIO GETS MORE PROBLEMATIC FOR THIS SUBSET OF PATIENTS. >> YOU SEE THESE PATIENTS EVERY DAY WITH THIS CONDITION. >> SO IT HAD BEEN EYE OPENING TO ME Z AS CARDIOLOGIST WHO GOT INVOLVED IN THIS AS VASCULAR CONDITION TO LEARN ABOUT THE CANCER WORLD. I RUN THIS CENTER AT STAN FOR WHERE WE SPECIFICALLY EVALUATE AND TREAT LYMPHEDEMA PATIENTS AND PATIENTS WITH OTHER LYMPHATIC CONDITIONS. I SEE 3 TO 400 NEW PATIENTS A YEAR WITH LYMPHEDEMA AND I WOULD SAY WELL OVER 90% ARE CANCER SURVIVORS AND VERY BIG PROPORTION ARE BREAST CANCER SURVIVORS. IT HAS BEEN VERY EYE OPENING FOR ME TO LEARN DIRECTLY FROM THE PATIENTS THAT THEY FEEL THAT THE ADVENT OF LYMPHEDEMA COMPLETELY ECLIPSES THE CONDITION SURVIVORSHIP. THAT GIVEN THE CHOICE BETWEEN RECURRENT CANCER OR GETTING RID OF LYMPHEDEMA THEY WOULD VASTLY FAVOR THE LYMPHEDEMA. LYMPHEDEMA ALTERS EVERY DAY VIRTUALLY EVERY POWER OF THEIR LIVES, IT ALTERS BODY IMAGE, IT HAS KNOWN EXTRAORDINARY EFFECT ON AFFECTIVE STATE, IT CAUSES SOCIAL ISOLATION WITHDRAWAL WITHIN THE FAMILY, INABLE TO PERFORM IN THE WORK ENVIRONMENT OR HOME ENVIRONMENT. POINT OF THIS IS TO SAY THAT THIS IS A REALLY SIGNIFICANT PROBLEM FOR THIS PATIENT POPULATION. ONE IN WHICH THEY WOULD UNDERTAKE FROM MY KNOWLEDGE OF THEM OVER THE TEN, 15 YEARS I HAVE BEEN DOING THIS, THE RISKS THAT ARE IMPLICIT IN THIS WILLINGLY, THEY VIEW IT EQUIVALENT TO A LIFE THREATENING DISORDER AND DISSATISFIED WITH THE MODEST BENEFITS THAT THEY CAN GET FROM THE MORE CONSERVATIVE THERAPIES WHICH WE TRY TO APPLY AS AGGRESSIVELY AS WE CAN. IT DOESN'T GET THEM WHERE THEY WANT TO BE. SO I DON'T SEE THE MATCH BETWEEN THE INTERVENTION AND PATIENT POPULATION TO BE ENTIRELY DISPARATE BASICALLY RESPONDING TO WHAT'S COMING OUT OF THEIR OWN MOUTHS. >> TWO MORE QUESTIONS FROM TODAY'S PRESENTATION. THE ISSUE WHETHER VEGFC MAY ALSO PROMOTE GROWTH OF TISSUE, IN PARTICULAR THE GROWTH OF CARCINOGENIC TISSUE NEEDS TO BE DECIDED MORE CLEARLY, THE POINT OF THE TRIAL I THOUGHT BUT THE FLOOD TISSUE WITH GROWTH FACTOR AND BRING IT THERE. SO COMPARING THAT RISK TO OTHER INTERVENTIONS SUCH AS TRANSFER CONSTRUCTION THAT ALSO CREATES RISK OF TUMOR GROWTH SEEMS A PROBLEMATIC COMPARISON, APPLES TO ORANGES, BECAUSE IF IT DID AFFECT IT THAT MUCH YOU WOULDN'T NEED THIS TRIAL SO YOU'RE INTO A CIRCULAR ARGUMENT GIVEN THAT SLIDE. THIS RISK SHOULD BE INCLUDED IN THE INFORMED CONSENT DOCUMENT, THEY NEED TO THINK IT THROUGH AND BE HONEST WHAT YOU KNOW AND DON'T KNOW THIS COULD INADVERTENTLY ACCELERATE THE GROWTH UNDERLYING TOW MORE UNDERLYING TISSUES OR CANCER STEM CELLS OR WHATEVER WHICH WE ONLY DIMLY UNDERSTAND. I WAS CONCERNED ABOUT THAT BECAUSE IF YOU WANT TO STIMULATE A CANCER STEM CELL YOU MIGHT PUT VEGFC ON IT TO MAKE IT GROW FASTER. THAT BROUGHT UP AN DEALT WITH. >> WE WILL TAKE INTO ACCOUNT THAT, WE RECOGNIZE THAT. >> ANOTHER SPOT CLEARER I DIDN'T GET IT UNTIL YOU SAID IT CLEARLY TIDE, ANIMALS DON'T GET THIS. THIS IS PURELY HUMAN DISEASE SO USE OF ANIMAL MODELS PROVES SUGGESTS IT'S NOT ACTUALLY THE CASE THERE IS AN ANIMAL MODEL FOR THE DISEASE WHICH THERE SEASON. THE PUZZLE IS IT DOES NOT OCCUR IN PIGS. DOES NOT OCCUR IN MICE. AND P THAT UNCERTAINTY NEEDS TO BE INCLUDING IN THE CONSENT FORM AN DECISION MAKING PROCESS, IT MIGHT BE THAT THE SURGERY ITSELF, IS CAUSING THE DISEASE IN WAYS WE DON'T UNDERSTAND AND THAT HAS TO BE SAID THAT IN CONSENT FORM TALKING ANIMALS, IT'S LITTLE BIT OF A FANTASY, NARRATIVE BUT THEY HAVE THE DISEASE APPROXIMATE LOOK AT THEM BUT DOESN'T AND THAT NEEDS TO BE VERY CLEAR IN THE CONSENT FORM. >> OKAY. THANK YOU. WE'LL DO THAT. >> MS. MALLINO. >> I'M SO GLAD -- CAN Y'ALL HEAR ME? >> YES, WE CAN. >> OKAY. MY PHONE BATTERY IS DOWN. I DONE HAVE ANY FURTHER COMMENTS. WITH THE PREVIOUS COMMENTS AND REVIEWERS, AND THE TWO QUESTIONS PRIMARY QUESTIONS I HAD AS PUBLIC WERE BOTH ADDRESSED. I'M GOING TO LEAVE IT AT THAT BECAUSE I HAVE SWITCH PHONES OUT. >> THANK YOU VERY MUCH MS. MALLINO. LET ME JUST AGAIN COME BACK AND I ASKED DR. ROCKSON TO COME TO THE MICROPHONE FOR A SECOND. A FEW ISSUES ARE CLEAR IN THE CONSENT FORM IT TALKS THE POSSIBILITY OF SECONDARY SARCOMA FROM VEGF C LOW LIKELIHOOD BECAUSE AGAIN CHRONIC LYMPHEDEMA CAN CAUSE LYMPH SARCOMA, MY BIGGEST WORRY IS THE FACT YOU'RE ABOUT TO PUT VEGF C IN AN AREA WITH THREE POSITIVE LYMPH NODES AND THEREFORE THE NEXT LYMPH NODE HAD POSITIVE CANCER YOU MIGHT VERY WELL PROMOTE GROWTH OF THAT TUMOR IN THE LOCAL AREA WHERE YOU'RE DELIVERING VEGF C. WHILE I TOTALLY UNDERSTAND THE REASON FOR THIS PROTOCOL AND THE DISTRESS THAT FOLKS ARE GOING THROUGH FOR LYMPHEDEMA, I LIKE THAT TO THE CONSENT FORM TO BE A LITTLE BIT MORE CLEAR, NOT A THEORETICAL CANCER AN RARE CANCERS BUT RESIDUAL CANCER THAT'S LEFT IN THE PATIENT IN THE LOCAL AREA THAT CAN BE SIMULATED BY A LOCAL GROWTH FACTOR THAT IS ABOUT TO BE PUT THERE. BUT MY OTHER QUESTION COMES BACK TO WHAT MARSHALL WAS TALKING ABOUT. I HAVE SEEN PATIENTS WITH SEVERE LYMPHEDEMA IN MY PRACTICE AND YOUER RIGHT. THOSE PATIENTS ARE TERRIBLY DISTRESSED AND LIFE -- MANY TIMES HORRIBLE FOR THEM AND THEY WILL DO ANYTHING TO GET RID OF THE LYMPHEDEMA. IS THAT THE 10% GREATER SIZE IN THE ARM POPULATION? BECAUSE THAT GROUP IS NOT IT. >> SHORT ANSWER IS YES. I HAVE NOT SEEN ANY GRADE OF LYMPHEDEMA THAT IS MODEST ENOUGH THAT THERE AREN'T SIGNIFICANT NUMBERS OF PATIENTS WHOSE LIVES ARE UNDONE BY THAT. ADMITTEDLY, THERE MAYBE AN ELEMENT WHERE THE LYMPHEDEMA BECOMES A SURROGATE FOR THE OVERALL DISEASE. I APPRECIATE THAT. BUT THE FACT REMAINS THAT FOR THESE PATIENTS THAT ARE MILDER FORMS THEY'RE SO FEARFUL OF CAUSING EXACERBATIONS BY ACTIVITIES IN LIFE THEY BECOME HERMITS. THEY'RE AFRAID TO USE THE, THEY LEAVE IT HANGING FOR FEAR IT WILL BECOME LARGER THAN ALREADY. SO THE IMPACT EVEN OF MILD DISEASE BECAUSE OF IMPLICATION OF PROGRESSION, BECOMES AS SEVERE AS INDIVIDUALS WHO CAN'T WEAR A PIECE OF CLOTHING THEY USED TO WEAR. >> BACK THE A PRACTICAL CONCERN. IN THE UNITED STATES WHO PIAFFES LYMPH NODE TRANSPLANT? -- PAYS FOR IT? >> I BELIEVE THAT THERE ARE THIRD PARTY PAYERS WHO ACTUALLY WILL -- THIS IS IN THE UNITED STATES THERE ARE CENTERS THAT PRACTICE THIS AS A NON-EXPERIMENTAL THERAPEUTIC. >> WHAT DEGREE OF ARM SWELLING HAS TO HAPPEN FOR A PATIENT FOR LYMPH NODE TRANSPLANT IN THIS COUNTRY IN >> FIRST I NEED TO SAY THAT I DONE REFER MY PATIENTS FOR THAT SURGERY BECAUSE I DON'T SUBSCRIBE WITH THE ABSENCE BECAUSE I KNOW IT DOESN'T WORK FUNDAMENTALLY. MY UNDERSTANDING IS IT IS A QUALITATIVE ASSESSMENT BY THE SURGEON PERFORMING THE PROCEDURE THAT THERE IS A -- LIKE MANY MEDICAL CONDITIONS, THAT IF IF DIAGNOSIS OF LYMPHEDEMA IS DELIVERED, THAT IT IS APPROPRIATE, THE PATIENT IS PROPERLY COVERED TO HAVE PROCEDURE PAID FOR. AND I SAY THAT BY INFERENCE BECAUSE I KNOW FOR EXAMPLE THAT THE GROUP AT MT ANDERSON WHERE THIS SURGERY IS PRACTICED HAVE MADE IT CLEAR THAT IT IS THE MILDER FORMS THAT TEND TO RESPOND IF ANYBODY IS GOING TO PERFORM. SO I DON'T THINK THERE'S A LOWER LIMIT BELOW WHICH THE INSURANCE COMPANY WILL APPROVE IT. >> OTHER COMMENTS FROM RAC MEMBERS? DR. HAMMARSKJOLD? >> I FEEL THAT I WOULD BE REMISIF I DIDN'T BRING UP SOME EXTRA COMMENTS AND CONCERNS AN QUESTIONS BECAUSE WE HAVEN'T TALKED MUCH ABOUT THE VECTOR THAT'S BEING USED HERE. IT IS MY UNDERSTANDING THIS IS ESSENTIALLY IN THE PROTOCOL FIRST GENERATION AEDINE VIRUS VECTOR (INDISCERNIBLE) WHICH HAVE BEEN PROBLEMATIC IN PREVIOUS STUDIES, ONE CONCERN IS THAT'S OBVIOUSLY A HUMAN VEHICLE II THAT BEHAVES POTENTIALLY VERY DIFFERENT IN ANIMALS THAN IN HUMANS. FIRST YOU WOULDN'T HAVE TO DEAL WITH PRE-EXISTING IMMUNITY WHICH MIGHT BE A CONCERN HERE. SECOND, IT'S NOT CLEAR THE EXPRESSION PATTERN IS THE SAME IN ANIMALS. THERE'S A DEFINITE REPLICATION DEFICIENCY, 72 KD DNA BEHINDING PROTEIN POLYMERASE ARE NOT MADE AND THAT'S EVEN IF THERE'S SOME LEAK IN THE E-1 DELETION ITSELF, IT WILL NOT G YOU GENE EXPRESENTATION. SAME IS NOT TRUE IN HUMAN CELLS. I USED TO DO POST-DOCTORAL RESEARCH WITH THE U ADENOVIRUS VECTORS IN HUMAN CELLS THAT'S DOSETY PEN TEN. IT'S NEEDED BUT NOT ABSOLUTELY NEEDED. I THINK THERE ARE SEVERAL PREVIOUS FIRST GENERATION ADENOVOICE TRIALS NOTHING WAS DONE, E-2 OR 4 THAT INDICATED THAT THERE WERE IMMUNE RESPONSES GENERATED BY THE VECTOR, ALSO LESS LONG GENE EXPRESSION THAN YOU WANT TO HAVE BECAUSE OF THOSE IMMUNE RESPONSES. AND INNATE IMMUNE RESPONSE. I WAS WONDERING WHETHER YOU ARE GOING TO LOOK AT THAT FIRST OF ALL, I KNOW YOU'LL LOOK AT IMMUNE RESPONSE, PRE-EXISTING IMMUNE RESPONSES AS WELL AS CONCLUSION OR NOT INCLUSION, THAT'S ONE QUESTION. THE SECOND THING I GUESS IS THAT IN ADDITION TO LOOKING AT IMMUNE RESPONSE TO THE VECTOR BECAUSE THAT COULD ASSUME TO BE REMAINING PROTEINS, MORE IS DIRECTLY ADDRESS THE QUESTION OF WHETHER YOU HAVE EXPRESSION FROM THE VECTOR ITSELF THAT YOU HAVE ADDED, I WOULD LIKE TO SEE SOMETHING YOU LOOK AT 72 KD BOUNDING PROTEIN, THERE IS A VERY GOOD MON CLONEAL (INDISCERNIBLE) ALSO WONDERING HOW LONG YOU GET VEGF EXPRESSION AND HOW THAT CORRELATES TO PRE-EXISTING IMMUNITY. Q. WE WILL BE LOOKING AT IMMUNE STATUS OF PATIENTS AND ASSESSING THEIR ANTIBODY STATUS GOING IN AND MEASURING THE ANTIBODY RESPONSE. AFTERWARDS. WE WILL NOT BE ENTERING PATIENTS BASED ON THEIR PRE-EXISTING IMMUNITY. BECAUSE I THINK WE OOH EAR GOING TO A GENERAL POPULATION WITH THIS, IT SEEMS INAPPROPRIATE TO EXCLUDE THOSE PATIENTS. IN TERMS OF LOOKING FOR VEGF EXPRESSION, I THINK THAT'S GOING TO BE DIFFICULT IN THE PATIENTS. WE ARE DOING THAT WORK IN THE TOXICOLOGY STUDY. >> FOR RNA. >> YES. KERRY, DO YOU WANT TO COMMENT ON THIS FROM YOUR EXPERIENCE? >> VEGF C AN FACTORS RELATED TO VEGF C ARE LOCAL FACTORS. SERUM HALF LIVES ARE SHORT. YOU DON'T PICK UP SORE RUM LEVELS OF THESE FACTOR WHEN THEY ARE LOCALLY USED IN SCALE THAT WE HAVE DONE TO PROMOTE LYMPHATIC. IT MEANS YOU WOULD HAVE SOME KIND OF MEASURE TO TAKE THE SAMPLE AND USER LOY SAY PLATFORM FOR EXAMPLE. >> LIPID RNA EXPRESSION. MANAGE LIKE THAT. YES. SO YOU DON'T CURRENTLY HAVE ANY IDEA HOW LONG YOU WOULD EXPECT EXPRESSION. >> BASED ON THE MOUSE STUDIES WHICH IS BASICALLY THE SO CALLED 3 C ASSAY, BIOASSAY WHICH REPORTS THREE STIMULATING ACTIVITY I WOULD SAY THAT IN IMMUNOCOMPETENT ANIMALS, EFFICACIOUS LEVELS PERSIST BETWEEN ONE AND TWO WEEKS. NO MORE. IF YOU ARE GOING TO SEARCH FOR ADENOVIRAL GENOMES YOU PROBABLY CAN'T PICK THEM UP MUCH LATER UP TO FOUR WEEKS. IF YOU'RE LOOKING FOR THE DNA. AND FOR THE RNA WE HAVEN'T ACTUALLY ANNOUNCED. >> I KNOW THIS IS NOT DIRECTLY RELATED, BUT ARE YOU THINKING ABOUT GOING TO A (INDISCERNIBLE) VECTOR BECAUSE THEY PERSIST LONGER PERIODS OF TIME AND YOU WILL GET EXPRESSION FOR LONGER PERIODS OF TIME. >> MY UNDERSTANDING IS THAT ADAPT IS CURRENTLY USED A LOT BY PROFESSOR (INDISCERNIBLE) WHO HAS DONE A LOT OF HUMAN GENE THERAPY WITH ADENOVIRAL VECTORS USING VEGF IN PATIENTS WHO HAVE PROBLEMS CLOTTING (INAUDIBLE) AND THERE ARE OVER 400 STUDIES WITH AEDINE VIRAL VECTORS IN GENERAL. HE HASN'T PROPERLY TREATED SLIGHTLY LESS THAN 100 PATIENTS WITH THESE VECTORS. IT'S CLOSELY WORKING WITH THESE SAME VECTORS. HE HAS BEEN PROPOSING -- >> THAT'S GOOD DATA NOW YOU GET LONGER EXPRESSION WITH (INAUDIBLE) VECTORS THAN FIRST GENERATION, MAYBE AN E-2 -- Q. INHERENT IN ALL ADENOVIRAL TRANSFERS IS NF KAPPA B ACTIVATION AND THERE'S A SLIGHT EDEMA WITH THE CAPSID SO WE SEE HERE A BUILD UP OF FLUID IN THE TISSUE JUST BECAUSE DURING PHASE OF LYMPHATICS THE PERMIBILITY IS MORE. BUT THERE IS REMODELING PROCESS, ENDOGENOUS AUTONOMOUS PROCESS THAT LEADS TO THE COLLECTING VESSELS WE DESCRIBED IN THE MOUSE. >> I DIDN'T MEAN TO PROLONG THIS DISCUSSION ANY MORE BUT LIMBTITION OF YOUR ANIMAL STUDIES THAT COMPLICATES BECAUSE THESE VECTORS DON'T -- THINK THAT'S THE MOST SIGNIFICANT P COMMENT I WANTED THE MAKE. >> ANY OTHER COMMENTS FROM THE RAC MEMBERS? >> NORM POST HERE, MANY REVIEWERS SAID WHAT I TAKE TO BE TO BE SERIOUS CONCERN AND CLEARLY SOME WERE ANSWERD IF IN A WAY SATISFACTORILY, BUT NOT ALL, CAN REVIEWERS CLARIFY WHETHER THEY THINK THEIR SERIOUS CONCERNS HAVE BEEN SATISFACTORILY ANSWERED OR THEY STILL HAVE SERIOUS RESERVATIONS ABOUT THE PROTOCOL AS PRESENTED? >> DR. ZOLOTH. >> I AM THINKING OF ABSTAINING BECAUSE I THINK THEY NEED MORE WORK TO ANSWER THE QUESTIONS RAISED TODAY. INCLUDING THE LAST TROUBLING ONE. I WOULD LIKE TO SEE SOME MORE WORK AND SEE IT AGAIN AFTER SOME OF THE QUESTIONS WERE ADDRESSED AND SUGGESTIONS I MADE THAT ARE PROMISE TO BE IN THE CONSENT FORM ARE IN THE CONSENT FORM AND WE CAN LOOK AT THEM ACTUALLY ASSIGNED. >> MARSHALL. >> I APPLAUD THE EFFORT BECAUSE IT'S -- IT IS AN INCREDIBLY DIFFICULT POPULATION. I'M VERY CONCERNED. THE REASON I'M CONCERNED IS THERE'S NO REAL SUCCESS RATE TO DATE IN THE HUMAN. THE POTENTIAL IS THERE WITH GRAPH A WHICH WILL OCCUR TO DO REAL HARM PARTICULARLY IF THERE'S INFECTION. I JUST -- I NEED SOMEBODY MORE. I NEED -- AND I KNOW THAT YOU SAID THEY'RE IN THE GETTING RAID YEAR AGO BUT IF YOU GET THREE NODES IN THE AXILLA, THOSE PATIENTS YOU DO IT. DON'T THEY GET TREATED WITH RIDIATION TO AXILLA? SO THEY AREN'T GOING TO BE TREATED WITH RADIATION THERAPY. AND THE RISK IS ININCREDIBLE. I WOULD LIKE TO SEW ANIMAL WORK DONE WHERE WE DEFINE WHAT THE LYMPHATICS ARE IN AN IRRADIATED BED, IF WE CAN GET THE SAME AMOUNT OF GROWTH THAT WE HAD BEFORE. I WOULD LIKE TO SEE THIS GO FORWARD AT SOME POINT AND I AGREE WITH WHAT WAS SAID BEFORE BUT I JUST THINK IT NEEDS MORE WORK. >> ANDREW. >> I TAKE CARE OF THESE PATIENTS AS WELL AND RECOGNIZE HOW DESPERATE SOME CIRCUMSTANCES ARE. ONE THING I HAVEN'T HEARD A LOT OF DISCUSSION ABOUT AND I EXPECTED TO WAS ASSOCIATION BETWEEN INDIVIDUAL F AN BREAST CANCER DISEASE PROGRESSION. AND THERE'S A SIGNIFICANT LITERATURE, MOST OBSERVATIONAL, THAT LINKS VEGF LEVELS TO DISEASE RECURRENCE, WIDESPREAD METASTASIS, ET CETERA. SURPRISED WE DIDN'T HAVE A BIG DISCUSSION ABOUT THAT. BREAST CANCER IS A DISEASE WHICH IS NOTABLE FOR LATE RECURRENCES. SO THE FACT THAT THERE'S NO EVIDENCE OF DISEASE AT TWO YEARS DOESN'T P MAKE ME FEEL A LOT BETTER. SO I HAVE GREAT CONCERNS ABOUT GIVING VEGF TO PATIENTS WHO MAY HAVE SUBCLINICAL DISEASE WITHOUT THE BENEFIT OF LONG TERM FOLLOW-UP. SO ONE OF TWO THINGS SHOULD BE CONSIDERED GIVEN THAT CONCERN. CONCERN -- POSSIBLY NUMBER 1 IS TEST THIS INTERVENTION IN A NON-BREAST CANCER POPULATION FIRST. RECOGNIZING DIFFICULTIES ASSOCIATED WITH REFERRAL -- ACCRUAL WITH THAT. THE SECOND IS, AT LEAST MEASURE WITH LONG TERM FOLLOW-UP RATE OF DISEASE RECURRENCE IN TREATED INDIVIDUALS. I APPRECIATE THOUGHTS AND DISCUSSIONS ABOUT THOSE NUANCES. >> MARK, ARE YOU OBJECT PHONE? >> -- ON THE PHONE. >> I AM. >> DO YOU WANT THE RESPOND TO THAT? >> SURE. I SHARE THE SAME RESERVATIONS VIS-A-VIS PATHOGENESIS OF BREAST CANCER AND INCREASED RISK OF RELAPSE LOCAL, REGIONAL AND DISTANT IN COHORTS HA HAVE HIGH INTERTUMORAL EXPRESSION. SO FOR THAT REASON WE ADDED A NUMBER OF EXCLUSION CRITERIA THAT YOU HAVE SEEN ON THE PRESENTED SLIDES. BUT YOU'RE ABSOLUTELY RIGHT. SOME PATIENTS WILL HAVE LATE RECURRENCE EVEN WITH MORE FAVORABLE TOW MORE CHARACTERISTICS AND LONG LATENCY APPROXIMATE THERE'S NOTHING YOU CAN DO TO GET AROUND THAT. FOLLOWING IN THE CONTEXT OF PHASE 1 TRIAL WOULD LIKELY NOT BE VERY INSIGHTFUL WITH SUCH A SMALL NUMBER OF CASES, IT'S VERY UNLIKELY WE SEE VERY MANY RECURRENCES IN THE SMALL COHORT. THAT WOULD HAVE TO BE DONE IN PHASE 2 AND 3 AND NO DOUBT WILL BE A MAJOR SAFETY END POINT IF THIS MOVES ON TO FURTHER PHASES OF DEVELOPMENT. AND PHASE 1 I DON'T SEE ANY -- I DON'T SEE MUCH UTILITY IN LONG TERM FOLLOW-UP OF THESE EARLY PATIENTS JUST BECAUSE OF THE SMALL SAMPLE SIZE. WE HAVE DONE WHAT WE CAN TO MITIGATE AGAINST VEGF C DRIVEN POPULATIONS BY EXCLUDING THE HIGH STAGE HIGH RISK PATIENTS. THERE'S ALSO LITERATURE ON MICROPAPILLARY REST CANCER EXPRESSING HIGH LEVEL OF VEGF C SO THAT'S EXCLUDED. THE LAST THING I'LL POINT OUT THOUGH IS THAT IT'S UNLIKELY EVEN BASED ON THEORETICAL CONSTRAINTS THAT YOU CAN CONVERT AY NON-RELAPSE PATIENT I NTO A RELAPSE PATIENT WITH THIS PARTICULAR VECTOR. IF THERE IS TO BE RELAPSE THEN BY DEFINITION THERE MUST HAVE BEEN MICROMETASTATIC DISEASE PRESENT ULTIMATELY THAT WOULD HAVE ULTIMATELY RELAPSED ANYWAY. SO PERHAPS ONE MIGHT CONSIDER CHANGING THE TIME COURSE LOCAL RECURRENCE VEGFC GIVEN LYMPHATIC REGION, HOWEVER I DOUBT YOU WOULD CONVERT A SURVIVOR INTO A NON-SURVIVOR BASED ON VEGFC EXOGENOUS ADMINISTRATION. THAT'S NOT TREMENDOUSLY REASSURING, I UNDERSTAND THAT. BUT IT IS A FACT THAT PROBABLY ARE NOT GOING TO CONVERT SOMEONE FROM A CURE INTO RELAPSE WITH THIS VECTOR. >> I AGREE YOU DONE KNOW THE IF YOU CONVERT CURE TO RELAPSE. IT'S STRONG THE SAY IT'S A FACT THAT YOU WON'T. >> TO RESPOND TO DR. BRADLEY' COMMENTS, I THINK I'M NOT A PRIMARY REVIEWER BUT I READ THIS OF INTEREST BECAUSE OF DISCUSSION AND CONCERNS OF THE ADENOVIRAL VEHICLE II AND I ALSO SHARE DR. HAMMARSKJOLD'S CONCERNS AND CONSIDERATION BUT I WOULD LIKE THE KIND OF STREAM TOGETHER A FEW VERY UNLIKELY BUT LOW RISK FACTS THAT ARE RELEVANT PERHAPS IN THIS CASE FOR ONE I THINK IF I'M NOT MISTAKEN, ADVANCED BREAST CANCER LIKE -- TUMORS SHOW INCREASE LEVEL OF ADENOVIRUS RECEPTOR, SO METASTATIC CAN INCREASE THE AMOUNT OF CAR PRESENT ON THE SURFACE. THE ADMINISTRATION OF FIRST GENERATION VIRUS IS UNLIKELY THE LEAVE VIRAL PARTICLES THAT CAN INFECT OTHER CELLS BUT IF THEY WERE PRESENT, IF IT REPLICATES IN IMMUNE SUBSET WE' NOT AWARE OF, THIS COULD PRESENT THE POSSIBILITY OF THIS OCCURRING. IN ADDITION TO THAT, THERE ARE OTHER REPORTS THAT VEGF C IN PARTICULAR EXPRESSED IN HUMAN CELL LINES BECOMES -- SHOWS INCREASE META STAYS IN A MOUSE MODEL. SO THIS ALL COMBINATION DOESN'T INCREASE THE LEVEL OF RISK ALBEIT EACH IS SMALL AND UNLIKELY BUT IT DOES MAKE SOME CONCERN PERHAPS A DIFFERENT VECTOR CHOICE MIGHT BE AN IDEAL. I THINK I ALSO WANT THE APPLAUD RETING THIS PARTICULAR CONDITION I THINK DESERVES TO BE ATTACKED IN SOME MANNER BUT THERE'S A SERIES OF CONCERNS THAT COME OUT, ALBEIT LOW RISK AND UNLIKELY, BUT IT MAKES ME UNEASY AS I HEAR THIS. >> OTHER COMMENTS? I THINK THE THEME YOU'RE HEARING FROM EVERYONE IS WORRY THAT IN THIS TRIAL YOU CONVERT LYMPHEDEMA TO SOMEBODY LYMPHEDEMA EARLY CANCER RECURRENCE WHICH IS WORSE. SO AGAIN IT COMES BACK TO EVERYBODY THINKS IT'S A GREAT TARGET TO ATTACK. IT'S INCLUSION CRITERIA, LEVEL OF RISK, SO ONE LAST QUESTION THEN FOR DR. ROCKSON, IF NO ONE AT STANFORD CURRENTLY DOES LYMPH NODE TRANSPLANT, WHO IS GOING TO GO DO THIS IN? >> SORRY IF THAT WAS MISLEADING. THE VICE CHAIR DEPARTMENT OF SURGERY AT STANFORD IS A PLASTIC SURGEON TRAINED IN THIS TECHNIQUE. WE'RE CORP HI NOT PRACTICING IT BECAUSE WE ARE CONVINCED IN A STAND ALONE FASHION WE'RE NOT NECESSARILY BENEFITING THE PATIENTS. BUT WHEN THE TRIAL IS APPROVED THEN IS ABLE TO BE EXECUTED THERE WILL BE CLOSE COLLABORATION BETWEEN DR. SARISTO IN FIN LAND AND DR. JEFF GERTNER AT STAND FORD SO THE SURGICAL HE CAN NEBBING IS IDENTICAL AS YOU CAN MAKE TWO INDIVIDUALS -- TECHNIQUE IS IDENTICAL FOR INTERVENING AND INTEND THE TWO SITES TO BE UNDERTALKING A SURGICAL INTERVENTION. >> VERY GOOD. THANK YOU. >> HERE ARE THE -- THE DRAFT RECOMMENDATIONS FROM THE RAC. FROM PRE-CLINICAL WHILE INTENT NOT TO -- NOT ENROLL PATIENT WHOSE HAVE DIRECT RIDIATION TO AXILLA PRE-CLINICAL MODEL USING IRRADIATION TO AX HA SHOULD BE DONE TO DEMONSTRATE THAT THE SAME BENEFITS OF THE APPROACH OCCURS IN AN AXILLA SCARRED BY RADIATION. CLINICAL, NUMBER ONE, GIVEN THIS IS A SAFETY STUDY AND THERE IS ALWAYS THE RISK OF MAKING LYMPHEDEMA WORSE CONSIDER WHETHER THE INCLUSION CRITERIA CAN BE REVISED TO FURTHER TARGET THOSE SUBJECTS WITH LYMPHEDEMA THAT MAY HAVE THE GREATEST POTENTIAL FOR BENEFIT. FOR EXAMPLE STATING IMPEE DENSE TESTING CRITERIA THAT WILL MAX MAZE THOSE LIKELY TO BENEFIT FROM THIS PROCEDURE. NUMBER TWO, GIVEN POTENTIAL OF VEGF TO PROMOTE TUMOR GROWTH, SUBJECTS ENROLLD IF THIS TRIAL SHOULD BE FOLLOWED LONG TERM TO OBTAIN INFORMATION IN -- ON RECURRENCE OF THE CANCER. NUMBER 3, WHILE THE PATIENT POPULATION TO BE ENROLLED IS UNLIKELY TO HAVE HAD RADIATION DIRECTLY TO AXILLA BECAUSE OF A DISEASE SPECIFIC INCLUSION, THERE SHOULD BE A SPECIFIC EXCLUSION CRITERIA FOR PATIENTS WHO HAD DIRECT RADIATION TO THE AXILLA AS THIS MAY INCREASE THE RISK OF PROCEDURE DUE TO SCARRING AND THE ANIMAL MODELS WHICH THIS APPROACH IS BASED ARE UNLIKELY TO BE REPRESENTATIVE OF THESE PATIENTS. SURGICAL PROCEDURE CALLS FOR REMOVAL OF SCAR TISSUE INCLUDING AROUND THE NERVES, IT CAN BE VERY DIFFICULT TO DISTINGUISH SCAR TISSUE FROM NERVES WHEN PERFORMING THE SURGERY AND THE ATTEMPT TO REMOVE SUCH SCAR TISSUE INCREASE THE RISK OF NEURONAL INJURY. PROTOCOL SHOULD BE AMENDED SO THAT PERINEURAL SCAR TISSUE IS NOT RESECTED UNLESS THE INTENT IS TO RESECT THEREFORE THERAPEUTIC REASON SUCH AS LYMPHEDEMA ASSOCIATED WITH PAIN. ETHICAL AND SOCIAL LEGAL ISSUES. THE FINAL INFORMED CONSENT SHOULD REFLECT THE COMMENTS RAISED IN THE WRITTEN REVIEWS BY RAC MEMBERS. IN PARTICULAR, LESS ON MISTIC STATEMENTS ABOUT THE POTENTIAL FOR BENEFIT IN THE MORE EXPLICIT DESCRIPTION OF RISK OF PROCEDURE AND IN PARTICULAR TO MAKE IT CLEAR TO POTENTIAL SUBJECTS RISK OF GENE TRANSFER ISEN KNOWN AND MAKE IT VERY CLEAR THAT THEY ARE -- THERE COULD BE UNKNOWN SERIOUS RISKS. IN PARTICULAR, IF POTENTIAL RISK OF VEGF TO PROMOTE TISSUE -- PROMOTE TISSUE GROWTH INCLUDING POTENTIAL LEAD TO CANCER CELL GROWTH, THIS SHOULD BE SPECIFICALLY STATED THAT THIS COULD INCLUDE STIMULATING RESIDUAL CANCER CELLS IN THE AXILLA, THIS IS PARTICULARLY IMPORTANT GIVEN IN LYMPHEDEMA WHILE CERTAINLY DEBILITATING DISEASE IT IS NOT A LIFE THREATENING DISEASE. NEXT, ONE DIFFICULTIES OF DEVELOPING THIS THERAPY IS THE FACT THAT THERE IS NO ANIMAL MODEL FOR THIS DISEASE. THIS MAKES IT DIFFICULT TO KNOW IF THE RESULTS WILL TRANSLATE INTO THE -- INTO THERAPY FOR WOMEN WITH THIS CONDITION. CONSENT SHOULD EXPLICITLY STATE LIMITATIONS OF ANIMAL MODELS. THE INFORMED CONSENT NEEDS TO BE EXPLICIT ABOUT THAT THE PE WILL RECEIVE FINANCIAL PAYMENTS RELATED TO THEIR PARTICIPATION IN THE STUDY STATEMENT THAT THERE'S NOT DIRECT BENEFIT TO PICS SHOULD BE REMOVED. IT IS IMPORTANT TO MAKE CLEAR YOU CANNOT WITHDRAW COMPLETELY FROM STUDY. WHILE YOU CAN WITHDRAWAL FROM FURTHER TESTING THE THE PATIENT SHOULD UNDERSTAND THE SURGICAL FLAP AND VECTORS ARE ADMINISTERED AND WILL PERSIST. ANY ADDITIONS OR DISCUSSIONS TO THIS DRAFT? ANYONE ON THE PHONE? RESPONSE FROM THE INVESTIGATORS. >> I THINK WOULD YOU SUGGEST THAT WE DO ANIMAL MODEL WITH AXILLA OF THE ANIMALS RADIATED, THEN TO DEMONSTRATE THAT WE SEE INCREASED GROWTH OF LYMPHATIC VESSELS UNDER SUCH -- (INAUDIBLE) >> LET ME COME BACK THE THAT AND ASK DR. ROCKSON TO RESPOND TO THIS. PATIENTS WHO HAD RADIATION HAVE A HIGHER DEGREE OF LYMPHEDEMA IN THE -- SO IF YOU WERE TO PROPOSE A THERAPY FOR PATIENTS LYMPHEDEMA YOU WANT TO KNOW WHETHER LYMPHATICS GROW IN THOSE PATIENTS. TRUE? >> SO THE CURRENT UNDERSTANDING IS THAT SURGERY BY ITSELF AND RAID CRYOTHERAPY BY ITSELF HAVE ROUGHLY EQUIVALENT RISK FACTORS ASSOCIATED WITH THEM VICTIMLY SOMEWHERE BETWEEN 15 AND 30% PATIENT POPULATION AND THEY ARE ADDITIVE AND SOME DEGREE SITHER JUSTIC. IF THE RADIOTHERAPY INCLUDES -- SYNERGISTIC. IF IT INCLUDES THE AXILLA THE RISK GOES UP HIGHER BUT THOSE WITH RID YEAR AGO TO THE SURGICAL SITE -- RADIATION TO SURGICAL SITE HAVE INCREMENTAL RISK OVER SURGERY ITSELF AS WELL AS PASSING THE THRESHOLD REMOVING MORE THAN FOUR LYMPH NODES, SO UNDER FOUR IS SENTINEL NODE TECHNIQUE AND THE RISK IS ROUGHLY QUARTER WHAT IT IS ABOVE THAT THRESHOLD. SO WE KNOW THOSE ATTRIBUTES BUT BY EXCLUDING INDIVIDUALS WHO HAD AX LAYER RADIATION WE WILL NOT BE SIGNIFICANTLY REDUCING THE PATIENT POPULATION. THAT WE'RE TREATING BUZZ THOSE PATIENTS FALL IN THE MINORITY WITH THOSE IN SURGERY AND RADIO THERAPY. >> IT'S INTERESTING BECAUSE IN THE RESPONSE THAT I THINK THAT I HAD WHERE I SAID RADIATION SHOULD BE EXCLUDED IN THE AXILLA, THE RESPONSE WAS THAT YOU WOULDN'T HAVE ENOUGH PATIENTS. >> NO, NO. WHAT I MEANT -- NO, I DIDN'T SAY THAT. I'M SORRY IF I GAVE THAT IMPRESSION. IN THE WRITTEN RESPONSE. >> LET ME COME BACK TO IT. EVENTUALLY IF THIS THERAPY IS KNOWN TO BE EFFICACIOUS YOU WANT TO KNOW WHETHER PATIENTS WITH RADIATION CAN BENEFIT FROM IT. >> THOSE WITH AX LAYER RADIATION. WITH THE PROVISO THAT IT MAYBE DECADES BEFORE WE FEEL COMFORTABLE ENOUGH GIVING EXOGENOUS VEGFC TO THAT VERY HIGH RISK PATIENT POPULATION WHO HAVE A MUCH AUGMENTED LIKELIHOOD OF RECURRENCE, THAT'S WHY WE'RE EXCLUDING THEM. WE'RE TAKING THE GROUP THAT FOR THE MOST PART NOW HAS SURVIVORSHIP THAT RIVALS NORMAL POPULATION FOR THEIR AGE COHORT. SO I THINK IT'S GOING TO BE A GOOD LONG WHILE BEYOND INITIAL PHASE 3 EVALUATION IF WE GET THAT FAR BEFORE WE WOULD BE ADDRESSING THAT SUBGROUP THAT IS HIGH RISK. Q. I THINK THIS IS A LITTLE BIT WHERE MY LIMITS OF KNOWLEDGE IN BREAST CANCER MAY SHOW OFF BUT REALITY YOU SAID UP TO THREE NODES. >> POSITIVE NODES. >> POSITIVE NODES. DON'T THEY GET RADIATE TO THE AXILLA AS -- RADIATION AS PART OF THE TREATMENT PROTOCOL? >> NOT TO THE AXILLA. THEY MIGHT GET POST LUMPECTOMY TANGENTIAL TO THE BREAST WHICH CLIPS THE MINORITY AXILLA TO BE EXACT BUT THEY DO NOT GET DIRECTED AX LAYER NODEAL RADIATION UNLESS THEY HAVE EXTRA EXTENSION NODEAL DEPOSITS, ET CETERA, THAT MIGHT OTHERWISE INFLUENCE RADIATION ONCOLOGIST TO DO DIRECTED AX LAYER RADIATION. SMALL NUMBER OF POSITIVE NODES AREN'T DIRECTED AX LAYER RADIATION ROUTINELY. >> REGARDING THAT STATEMENT ABOUT PERSISTENCE, MIGHT IT BE MORE CLEAR TO SAY THE EFFECTS OF THE VEGF C ADMINISTRATION MIGHT PERSIST? THE EFFECTSES, NOT THE VECTOR ITSELF. >> OTHER RESPONSES FROM THE INVESTIGATORS? >> JUST ONE QUESTION. AGAIN, SORRY TO COME BACK TO THE CLARITY AROUND WHETHER GIVEN WE'RE EXCLUDING PATIENTS WITH RADIATION TO THE AXILLA, WHETHER YOU DO WANT US TO DO THE ANIMAL STUDY NOW. WE'RE STILL A BIT CONFUSED ABOUT WHAT YOU WANT US TO DO HERE. >> I THINK IT'S THE GENERAL FEELING THAT IF IN THE FUTURE YOU EPIVISION THIS THERAPY TO INCLUDE PATIENTS WHO HAD RADIATION TO THE AXILLA, THAT AT SOME POINT THAT SHOULD BE DONE. Q. OKAY. THAT'S CLEAR. THANK YOU VERY MUCH. >> AND I WOULD ASSUME IF THIS IS A SUCCESSFUL THERAPY THAT YOU WILL BE INTENDING TO INCLUDE THOSE PATIENTS. >> THAT'S FINE. THANK YOU FOR THAT CLARIFICATION. THAT HELPS. >> ANY ADDITIONS OR CHANGES? THEN I WILL -- >> CAN YOU READ THE INCLUSION CRITERIA AGAIN? WHAT DID WE SAY THERE? WHAT WILL BE THE INCLUSION CRITERIA FOR CONSIDERATION -- >> WHETHER INCLUSION CRITERIA CAN BE REVISED TO FURTHER TARGET SUBJECTS IN EDEMA GREATEST POTENTIAL FOR BENEFIT BY STATING BUOY IMPEE DENSE TESTING CRITERIA TO MAXIMIZE THOSE LIKELY TO BENEFIT FROM THE PROCEDURE AND EXCLUDING THOSE WHO HAVE DIRECT AXILARY RADIATION. >> THAT'S NOT VERY SPECIFIC. (INAUDIBLE). Q. WHAT WOULD YOU PROPOSE? >> I THINK 10% IS TOO LOW FOR THE INITIAL TRIAL. SO I DON'T KNOW P WHAT THE RIGHT NUMBER IS BUT I -- THIS IS AGAIN, A PHASE 1 STUDY, YOU'RE TAKING SOMEONE WITH A 10% DIFFERENCIAL IN THE ARM AND EXPOSING THEM TO RISK. SO I DOPE KNOW WHAT THE RIGHT -- DON'T KNOW WHAT THE RIGHT NUMBER IS BUT FUNDAMENTALLY I THINK 10% IS TOO LOW. I THINK THAT NUMBER HAS TO GO UP. >> SHOULD IT BE QUALITY OF LIFE INSTRUMENT? OR -- THAT'S WHY WE WENT WITH IMPEE DENSE AND -- OR SOME MORE STRICT CRITERIA BECAUSE AGAIN, IT'S A WEIGHING OF BENEFIT AND RISK. AND THESE PATIENTS ARE ABOUT TO HAVE A SURGICAL PROCEDURE. AND GENE TRANSFER SO IT IS REAL ISSUE. WHAT IS THAT ANSWER? SO LET ME ASK INVESTIGATORS WHAT THEY WOULD PROPOSE THE CHANGE BE TO. >> PERHAPS MAYBE IF I CLARIFY THIS WAY. I DON'T THINK THE LANGUAGE IS CLEAR. THESE ARE PATIENTS WHOM AN INITIAL PUNITIVE DIAGNOSIS OF LYMPHEDEMA RELATED TO REST CANCER IS MADE, WHO COMPLETED PHYSIOTHERAPY AND USING MAINTENANCE COMPRESSION GARMENTS SO WE'RE POSITING A 110% LIMB VOLUME OF THE AFFECTED LIMB BEYOND AVAILABLE THERAPIES FOR THE PATIENT. THIS IS NOT THEIR INCEPTION VOLUME, THIS IS WHAT THEY GET TO WHEN THEY'RE OPTIMALLY TREATED AND THAT IS A SUBGROUP BASED UPON THE THEORY BEHIND INTERVENTION THAT IS MOST LIKELY TO BENEFIT FROM THE CLEARANCE INTERSTITIAL FLUID AND RESTORATION OF RELATIVELY MORE NORMAL LIMB. ONCE WE TALK BIGGER VOLUMES EVEN AFTER PHYSIOTHERAPY, WE'RE TALKING ABOUT A SUBGROUP THAT IS VEERING VERY HEAVILY TOWARD STAGE 3 DISEASE WHERE THERE'S GOING TO BE SOME REASONABLE LIKELIHOOD OF IRREVERSIBILITY AND WE'RE CLOUDING THE THE ISSUE BECAUSE THOSE STRUCTURAL COMPONENTS OF LYMPHEDEMA MAY NOT RESPOND AT THAT LATE STAGE TO RESTORATION. >> WHAT I SAID WAS IS THAT THIS IS AN ADVERSE EVENT CONSIDERATION AND SMALL NUMBER OF PATIENT. UNTIL YOU KNOW YOU'RE DOING NO HARM TO THIS GROUP, WHICH POTENTIALLY HAVE A LOT OF HARM MORE ISSUE. FOR PHASE 2 I AGREE COMPLETELY. PHASE 1 I DONE. AND THAT'S THE LINE NEEDS TO BE DRAWN. IF WE WANT TO USE THEM AS A LABORATORY TO SHOW EVERY OTHER ASPECT OF THE INTERVENTION IS SAFE WE CAN DO THAT BUT I WOULD TAKE OUT THE BIOIMPEE DENSE PIECE SO THEY WOULD BE STAGE 2 OR 3 LYMPHEDEMA WITH A SPECIFIED LIMB VOLUME THRESHOLD BEYOND FIZZ YES THERAPY. >> WHAT DO YOU THINK REASONABLE IN PHASE 1 TRIAL FOR LIMB SIZE? >> BECAUSE I AGREE, PHASE #, 3, YOU COULD STRATIFY LIMB SIZE AND GO ONCE YOU KNOW THIS IS RELATIVELY SAFE, IF THEY EXPERIENCE FROM FINLAND IS VERIFIED HERE THERE ARE NO SURGICAL COME MY CASES OR LOW SURGICAL COMPLICATIONS AND THAT THE VECTOR AND THE VEGF DID NOT PRODUCE SIDE EFFECTS, THEN TO DO A STRATIFIED STUDY INCLUDING PEOPLE WITH LOW SIZE LIMBS WOULD BE REASONABLE. IN A PHASE 1 REFLECTS ANXIETY ABOUT THE NOVEL THERAPY FOR A DISEASE. >> BASED ON THE CLINICAL POPULATION THAT I INTERFACE WITH IF UP THE PREDICATE THE TREATMENT MORE IN THAT DIRECTION I WOULD SAY WE REMOVE THE BIOIM CRITERION, INCREASE THE LIMB VOLUME RATIO TO 120%, NOT HIGHER THAN THAT OR YOU WON'T HAVE A REASONABLE PATIENT POPULATION TO TREAT. AND I WOULD SPECIFY THE PATIENT HAVE AFTER THERAPEUTIC INTERVENTION NO CHANGE IN BEHAVIOR OF THE LIMB WITH OVER NIGHT RECOUPLE PANSY. SO THAT REPRESENTS -- REBUM CAN'T SO THAT REPRESENTS AN ADVANCED STAGE LYMPHEDEMA. >> IF THOSE ARE INCLUDED, LET'S GO, I MOVE THAT WE TAKE A VOTE AS TO THE RECOMMENDATIONS DR. WOOLY. >> YES. >> -- WOOLEY. >> YES. >> EXCUSE ME. JUST WANT TO CLEAR WE'RE VOTING TO APPROVE IF ALL THE CONDITIONS IN YOUR SUMMARY ARE ACCEPTED. IS THAT RIGHT? >> YES. >> >> (INDISCERNIBLE) YES. >> KIEM, YES. >> STROME, YES. >> COKE, YES. >> BRADLEY, YES. >> CANNON, YES. >> ORNELLES, YES. >> KOHN, YES. >> PILEWSKI, YES. >>S ARE -- ROSS, YES. >> MS. MALLINO. >> (INAUDIBLE). ABSTAIN. >> MALLINO, YES. >> MY QUESTION IS, I WOULD ABSTAIN IF WE'RE NOT GOING TO SEE IT AGAIN, IF THIS IS AN APPROVAL FOR GOING FORWARD AND SEEING NEXT ROUND I SAY YES. IF WE'RE NOT GOING TO SEE THEM AGAIN THEN I ABSTAIN. BUZZ THERE'S NO WAY TO -- >> WE DON'T REREVIEW THEM, WE MAKE OUR RECOMMENDATIONS ONCE THEY DON'T NEED TO COME BACK TO A REREVIEW. >> I'M GOING TO CHANGE MY YES TO OBTAIN GIVEN THAT. -- TO ABSTAIN GIVEN THAT. >> THANK YOU VERY MUCH FOR PRESENTING TO US. >> OKAY. THANK YOU VERY MUCH FOR THE QUESTIONS. APPRECIATE IT. THANK YOU. >> WE OTHER RUNNING QUITE BEHIND -- WE'RE RUNNING QUITE BEHIND. , WE'LL GRAB BOX LUNCHES AND TAKE A QUICK BREAK AND START RIGHT AT 1:30. >> LET'S MOVE ON TO OUR NEXT ITEM. LET'S EVERYONE BE SEATED GET STARTED FOR THE AFTERNOON. NEXT ITEM IS PROTOCOL NO. 1182, THAT IS THE GRAIN TRIAL THAT'S OTOLOGOUS ACTIVATED T-CELLS. PRESENTING FOR US THIS AFTERNOON IS DR. CRYSTAL LOUIS FROM THE TEXAS CHILDREN'S CANCER CENTER. SHE IS ASSISTANT PROFESSOR IN THE DEPARTMENT OF PEDIATRICS IN THE SECTION OF HEMATOLOGY ONCOLOGY. HER COP. CIVIL MALCOLM BRENNER WHOM WE ALL KNOW WELL FROM THE CENTER OF CELL AND GENE THERAPY IN BAYLOR COLLEGE OF MEDICINE. DR. LOUIS, IF THERE ARE OTHER MEMBERS OF YOUR TEAM HERE PLEASE IN PRODUCE THEM FOR US. SPEAK IN TO THE MICROPHONE PLEASE. >> IS THIS NOT HIGH ENOUGH? >> WE CAN HEAR YOU. >> DR. PIETRE DOTTY IS HERE. DONE WORK WITH THE GENERATION. >> THANK YOU VERY MUCH. GO AHEAD. >> YOU'VE READ THE TITLE. THEN EXPLAINED A LITTLE BIT HOW 24 WORKS SO PEDIATRIC ONCOLOGIST AT TEXAS CHILDREN'S A, I WORK WITH OUR CENTER WITH TRANSLATIONAL LAB AS WELL AS PEOPLE IN OUR BASIC LABORATORY IN ORDER TO CREATE PROTOCOLS FOR OUR CHILDREN WITH REFRACTORY TUMORS. I'M GOING TO TAKE THIS -- MY LITTLE TWO SECOND SPIEL FROM THE VERY BEGINNING. A LOT OF YOU GUYS HAVE HAD MULTIPLE YEARS OF EXPERIENCE WITH THIS BUT I THOUGHT EASIER THINK WAS TAKE VERY BASIC LEVEL THEN GO FROM THERE. SECOND THING I'LL ADD IS I CAN OCCASIONALLY TALK A LITTLE BIT FAST IF THAT IS HAPPENING SOMEBODY SHOOT ME A SIGNAL, TELL ME TO SLOW DOWN A LITTLE WE'LL GO FROM THERE. NEUROBLASTOMA THE DISEASE WE'LL TALK ABOUT, THE MOST COMMON EXTRA CRANIAN SOLID TUMOR IN CHILDREN. DISEASE OF NEURAL CRUST ORIGIN. INCIDENCE OF 10.5 PER ONE MILLION CHILDREN UNDER THE AGE OF 15. SLIGHT MALE PREDOMINANCE. THERE'S BEEN SOME INTERESTING WORK SHOWING THAT THEY ARE POTENTIALLY DIFFERENCES IN RESPONSE ESPECIALLY FOR PATIENTS WITH HIGH RISK DISEASE BASED UPON RACE. MEDIAN AGE OF DIAGNOSIS IS APPROXIMATELY 23 MONTHS. WHILE NEWER ROW GLASS TOE MA ACCOUNTS FOR THE CANCERS IT UNFORTUNATELY LEADS TO ABOUT 15% OF PEDIATRIC CANCER DEATHS. THAT'S REALLY BECAUSE WHILE SURVIVAL IS VERY GOOD FOR THOSE PATIENTS WHO HAVE LOWER INTERMEDIATE RISK DISEASE EVEN OUR PATIENTS AFTER TREATMENT WITH CHEMOTHERAPY, SURGERY, RADIATION THERAPY, STEM CELL TRANSPLANT AND MAINTENANCE THERAPY THOSE KIDS WITH HIGH RISK DISEASE OUR HISTORICAL RESPONSE RATE IS PRETTY POOR. WE STILL HAVE A LOT THAT WE NEED TO BE ABLE TO DO. OUR GROUP WANTS TO USE IMMUNOTHERAPY. YOU HAVED SOME COUPLE DISCUSSIONS ABOUT THAT TODAY THE THE REASON WE WANT TO USE IT VERY SIMPLY BEING ABLE TO USE BODY'S IMMUNE SYSTEM TO HELP ELIMINATE CANCER SAND DISEASE AND IF DONE RIGHT ALLOWS TARGET PARTS OF THE TUMOR THAT ARE NOT COMMONLY SEEN ON NORMAL CELLS, SUCH THAT TREATMENT SHOULD BE ASSOCIATED WITH FEWER SIDE EFFECTS WHICH AGAIN BECOMES VERY IMPORTANT IN THIS HIGHLY PRE-TREATED PATIENT POPULATION. OUR GROUP ALSO DONE QUITE A BIT OF WORK WITH T-CELL BASE THERAPY. THE REASON WE DO THAT BECAUSE T-CELLS ARE ABLE TO GO THROUGH THE PLANES. FURTHERMORE, T-CELLS OF EFFICACY AGAINST SOLID TUMORS AND WITH OUR STUDIES IN NPC AS WELL AS THOSE IN HODGKIN'S AND NON-HODGKIN'S ALSO T-CELLS HAVE SIGNIFICANT EFFICACY EVEN IN PATIENTS WITH BULKY DISEASE. FURTHERMORE FROM CELL STUDIES THAT WAS DONE T-CELLS ONCE ADOPTIVELY TRANSFERRED ARE ABLE TO USE ABILITY'S ONLY HOMEO STATIC KIEMKINES. THE QUESTION BECAME HOW DO WE MODIFY THESE ARE USE THESE FOR PEDIATRIC PATIENTS THAT HAVE SOLID TUMORS. AND THE FIRST STUDY THAT WE DID REALLY LOOKED AT MOD HOT FILING T LYMPHOCYTES TO EXPRESS A A CHIMERIC ANTIGEN RECEPTOR. MAKING IT AN EXCELLENT TARGET WHEN LOOKING AT WAYS TO TREAT IT. SO, AGAIN I'M SURE YOU GUYS HAVE SEEN THIS SLIDE MULL TIME TIMES IT STARTS BY TAKING VARIABLE FRAG MANTLING IT TO THE SIGNALLING PORTION T-CELL RECEPTOR COMPLEX SO THACK A TIFT TO LEAD TO TUMOR KILLING. THEN FIRST STUDY WHERE WE USE THESE T-CELLS WE WERE ENROLLED OUR LAST PATIENT IN 2009 PRIMARY OBJECTIVE WAS TO LOOK AT THE SAFETY OF THESE CELLS ADMINISTERED TO PATIENTS THAT HAD HIGH RISK NEUROBLASTOMA. I SHOULD SAY ON THIS PARTICULAR STUDY THERE WERE TWO T-CELL PRODUCTS. AN ACTIVATED ONE AS WELL AS PRODUCT THAT WAS SPECIFIC FOR EPSTEIN BAR VIRUS. THE SECOND WAS TO EVALUATE PERSISTENCE IN EFFICACY OF THESE CELLS AFTER GIVEN TO PATIENTS. WE TREATED 19 PATIENTS ON THIS STUDY AT THREE DIFFERENT DOSE LEVELS. MEDIAN AGE AT THE TIME OF INFUSION WAS SEVEN YEARS, OUR YOUNGEST PATIENT WAS 12 -- WAS TWO OUR OLDEST PATIENT WAS 20. AGAIN BECAUSE THERE WERE TWO PRODUCTS THAT WERE 22 INFUSIONS OF 44 LINES THAT'S BECAUSE THREE OF THE 19 PATIENTS RECEIVED ADDITIONAL INFUSIONS AND WE NOTED NO DOSE LIMITING TOXICITIES. WHEN WE LOOKED AT THE PATIENTS AT THE TIME OF INFUSION THERE WERE EIGHT THAT HAD NO EVIDENCE OF DISEASE, THREE WERE IMMEDIATELY AFTER HIGH RISK THERAPY AND THERE WERE FIVE PATIENTS THAT HAD A HISTORY OF RELAPSE BUT HAD NO EVIDENCE OF DISEASE AT THE TIME OF THEIR INFUSION. THERE WERE FOUR PATIENTS WITH RELAPSED WITH ACTIVE BUT LIMITED DISEASE, THREE WITH SOLITARY BONE LESIONS AND ONE WITH BONE MARROW DISEASE. THERE WERE SEVEN PATIENTS WHO HAD RELAPSED ARC ATIVE BULKY DISEASE. CLINICALLY WHAT WE SAW AFTER INFUSION WAS THOSE EIGHT PATIENTS WITH NO EVIDENCE OF DISEASE MEDIAN TIME TO RELAPSE WAS APPROXIMATELY 411 DAYS. THAT'S ACTUALLY SIGNIFICANTLY DIFFERENT FROM WHAT WE SEE WITH A LOT OF PHASE ONE AND TWO TESTING WITH SOME OF THE COG STUDIES LOOKING AT TIME TO RELAPSE IN THE POPULATION WITH TIME OF APPROXIMATELY THREE TO SIX MONTHS. ABLE TO GET OUT. OUR FOUR PATIENTS WITH ACTIVE LIMITED DISEASE THERE WERE THREE COMPLETE RESPONSES. TWO OF OUR PATIENTS WITH SOLITARY BONE LESIONS WHO ARE NOW SEVEN AND FIVE YEARS OUT RESPECTIVELY. AND ONE PATIENT WITH BONE MARROW DISEASE WHO UNFORTUNATELY DID HAVE SYSTEMIC RELAPSE AND HAS SINCE DIED. OF OUR SEVEN PATIENTS WITH BULKY DISEASE CURRENTLY ONE ALIVE WITH DISEASE AT THE TIME. SO WHEN LOOKING AT OVERALL RESULTS WHAT WE FOUND OF THOSE PATIENTS WHO HAD ACTIVE DISEASE FELT OF THEIR T-CELL INFUSIONS WE HAVE THREE COMPLETE RESPONSES, ONE PATIENT WITH PARTIAL RESPONSE, ONE PATIENT WITH STABLE DISEASE AND THEN TWO PATIENTS WHO HAD EVIDENCE OF TUMOR NECROSIS. THIS IS THE MRI AND MIBG SCAN OF PATIENT WHO IS NOW SEVEN YEARS OUT WHO HAD METASTATIC LESION. SIX WEEKS AFTER INFUSION WHO STARTED TO SEE IMPROVEMENT BASED ON MRI AND IMBG SCANNING THEN FOUR MONTHS OUT HAD SEEN COMPLETE RESOLUTION AND SHE'S NOW SEVEN YEARS OUT WITH NO EVIDENCE OF ACTIVE DISEASE AT THE TIME. WHEN WE LOOKED IN THE BLOOD OF THE PATIENTS WHAT WE SAW WAS ACTUALLY A LITTLE BIT SURPRISING. IN THAT WE WERE ABLE TO DETECT THESE CHIMERIC ANTIGEN RECEPTOR T-CELLS UPWARDS OF 192 WEEKS. BUT THE CATCH TO ME MOST IMPORTANT PART OF THIS SLIDE IS WHO YOU'RE TALKING ABOUT EXCEEDINGLY LOW LEVELS OF THESE CELLS ABLE TO BE DETECTED IN THE PERIPHERAL BLOOD. NOW, OF THOSE THAT WE WERE ABLE TO DETECT FOR EXTENDED PERIOD OF TIME WHAT WAS SPECIAL ABOUT THEIR PRODUCT? WHAT WE FOUND WAS WHEN WE WENT BACK AND LOOKED WHAT WAS SPECIAL ABOUT THEIR PRODUCT WAS THE PERCENTAGE OF CD4T HELPER CELLS WITHIN THE PRODUCT. THE GREATER THE PERCENTAGE OF CD4 CELLS THE MORE LIKELY WE WERE TO BE ABLE TO SEE THE T CELLS LAST FOR A LONGER PERIOD OF TIME. IS PERSISTENCE IMPORTANT? ON THIS PARTICULAR STUDY IT APPEARS THAT IT WAS. FOR THOSE PATIENTS WHO WE WERE NOT ABLE TO DETECT CELLS FOR SIX WEEKS OR MORE, THEIR RISK OF RELAPSE AND RATE OF RELAPSE WAS EXCEEDING LEHIGH. THOSE PATIENTS WHO WE WERE ABLE TO PERSISTENCE OUT FOR SIX WEEKS OR GREATER YOU HAD STATISTICALLY IMPROVEMENT IN THEIR TIME TO PROGRESSION. IN CONCLUSION WHAT WE LEARNED FROM THIS STUDY LOOKING AT FIRST GENERATION CHIMERIC ANTIGEN RECEPTOR T CELLS, MOST IMPORTANTLY THERE WERE 2340 -- WE WERE ABLE TO DETECT THESE CELLS FOR EXTENDED PERIOD OF TIME BUT AGAIN AT LOW LEVELS. AND FOR US VERY IMPORTANT PART WAS KNOWING THAT HAVING A HIGH CD4 PERCENTAGE WAS ACTUALLY VERY IMPORTANT AS FAR AS PERSISTENCE. WE WERE SEEING CLINICAL RESPONSES INCLUDING COMPLETE PARTIAL OR STAIN DISEASE RESPONSE RATE OF 45% IN THOSE WITH ACTIVE DISEASE. AND THAT PERSISTENCE OF THESE CELLS WITHIN PERIPHERAL BLOOD WAS ASSOCIATED. CLEARLY THERE ARE THINGS THAT WE CAN DO BETTER WE STARTED THIS STUDY QUITE SOME TIME AGO THERE HAS BEEN A LOT OF SCIENCE AND TECHNOLOGY THAT'S BEEN DONE IN ORDER TO MAKE IT BETTER. WE REALLY THINK FROM AN ANTI-TUMOR PERSPECTIVE THE THINGS THAT WE NEED TO FOCUS ON ARE HAVING THE CELLS BE ABLE TO PROLIFERATE ONCE WE'VE INFUSED THEM AGAIN BASED ON US SURVIVAL ONCE WE'VE INFUSED THEM. FIRST GENERATION PERSPECTIVE WHAT -- WE ARE ABLE TO GET CYTOTOXICITY USING REDIRECTED T CELLS AND TARGETING GD2. WE GET INCOMPLETE ACTIVATION OF THESE CELLS BECAUSE YOU DON'T GET CO-STIMULATION FROM THE TUMOR. DOWN REGULATES TO CLASS ONE AND TWO AND DOWN REGULATES AS FACTORS SUCH THAT IT'S NOT ABLE TO PROVIDE THAT ADDITIONAL STIMULATION FOR T CELLS. SECOND GENERATION CHIMERIC ANTIGEN RECEPTORS HAVE INCORPORATED THE CD28 THAT YOU CAN HAVE IMPROVED ACTIVATION AND PROLIFERATION. BUT WHAT WE ALSO KNOW, I LIKE THIS SLIDE A LOT, IS THAT WHILE FIRST GENERATION DID GREAT JOB WITH CYTOTOXICITY, SECOND GENERATION CHIMERIC ANTIGEN , A LOT OF THE RECENT DATA, THIRD GENERATION CELLS$ JOB. AS PART OF THE TNF RECEPTOR SUPER FAMILISM OUR GROUP DECIDED ON OX 40 FOR A NUMBER OF REASONS. ONE THERE'S DATA WELL BACK TO THE EARLY 2000s THAT THE COMBINATION OF CD28 PLUS OB40 IS IMPORTANT FOR CD4 CELLS REGULATION. AGAIN IN OUR HANDS IN THAT INITIAL STUDY THIS IS ACTUALLY EXCEEDINGLY IMPORTANT FOR US TO BE ABLE TO HAVE INCREASED PERSISTENCE AND ANTI-TUMOR ACTIVITY. IN COMPARISON TO 41BB MORE A NEGLECT ON CD8 CELLS. FURTHERMORE PRESENT HERE IN THE PAST THERE WAS SEVERE ADD A VERSE EVENT IN A PATIENT WHO RECEIVED HER 2 RECEPTOR WITH 41BB. WHICH CAUSED CTYOKINE STORM. A PEDIATRIC POPULATION STUDY WE'RE LOOKING THE ALL THE WAYS WE CAN DO THIS IN THE SAFEST POSSIBLE MANNER. ON TOP OF THE SCIENTIFIC REASONS THAT WE'D LIKE TO DO IT AND SAFETY REASONS WE LIKE TO DO IT, WE THEN TOOK STEP BACK SAIDS THERE AN ADDITIONAL LEVEL OF SAFETY THAT WE CAN ADD TO THIS PRODUCT. THAT REALLY GOES BACK TO WORK THAT PIETRO AND DR. BRENNER HAS DONE AS FAR AS ADDING THE SAFETY SWITCH DATA WAS PRESENTED HERE IN MARCH ABOUT RESULTS OF THIS STUDY. IN ADDITION RESULTS HAVE BEEN PUBLISHED IN NEW ENGLAND JOURNAL LAST YEAR. IT'S REALLY USING THE CELL'S OWN MECHANISM TO CAUSE APOPTOSIS OR CELL DEATH. UNDER NORMAL CIRCUMSTANCES THE MITOCHONDRIA HAVE BINDING OF THESE MOLECULES. ONCE IT'S ACTIVATED FURTHER ACTIVATES THAT LEADS TO I MOP TOES. WHAT HAS BEEN DONE IN THE LAB USING A MODIFIED FORM OF THIS MOLECULE LINKING TO MODIFIED 506 BINDING SITE THAT ALLOWS YOU TO HAVE SIGNIFICANT BINDING TO A SMALL MOLECULE CALLED AP1903. ONCE YOU GET BINDING OF AP1903 THIS TEN DIME MER RISES ONCE YOU HAVE DIMERIZATION OF YOUR MOLECULE THAT THEN LEADS TO CELL ACTIVATION THEN APOPTOSIS. SO ON THAT PARTICULAR STUDY WHICH WAS DONE IN PEDIATRIC PATIENT POPULATION AFTER BONE HARROW TRANSPLANTATION WHERE THEY RECEIVED A PRODUCT TO HELP WITH DECREASE VIRAL INFECTIONS AFTER TRANSPLANT THEN POTENTIALLY DECREASE RISK OF RELAPSE AFTER TRANSPLANT ONE. THINGS THAT YOU ALWAYS CONCERNED ABOUT IS DEVELOPMENT OF -- IN THAT STUDY THAT WAS ONE OF THE CRITERIA THAT STARTED THE ACTIVATION OF PATIENTS HAVING IT ADMINISTRATION. THIS ONE PARTICULAR PATIENT AFTER THEIR SECOND INFUSION OF T CELLS THEY DID DEVELOP KIN GRAFT DISEASE. WITHIN 30 MINUTES THERE WAS 90% DECREASE DARN DASH IN THE NUMBER OF CELLS DETECTED THAT HAD DECREASED TO ABOUT 99% WITHIN 24 HOURS. I WAS NOT THERE BUT IN SPEAKING TO YOU ARE NURSES THEY SAID IT WAS ACTUALLY PRETTY IMPRESSIVE THAT YOU COULD VISUALLY SEE THE RASH GET BETTER AS THE INFUSION WAS GOING THROUGH AND WITHIN 24 HOURS THE RASH HAD COMPLETELY DISSOLVED. SO IN THE END IT'S TAKING ALL OF THIS DATA THAT'S BROUGHT US TO WHERE WE ARE TODAY. WE REALLY WANT TO COMBINE NOT ONLY THE A FOLKS OF THE GENERATION CD2 CHIMERIC ANTIGEN RECEPTORS BUT DO IN WAY THAT IS SAFE BY ADDING THE SAFETY SWITCH AND OUR HYPOTHESIS THAT INFUSION OF THEE CELLS WILL LEAD TO SUSTAINED PROLIFERATION OF PERSISTENCE OF GD2T CELLS IN THE PERIPHERAL BLOOD OF OUR PATIENTS WHO HAVE RELAPSED. AND THAT IF WE UNFORTUNATELY GET IN TO SITUATION WHERE WE HAVE TO USE 181903 THAT THEY CAN BE CONTROLLED BY THE USE OF THE DIMERIZING DRUG. SO THIS PARTICULAR CLINICAL TRIAL, OUR PRIMARY OBJECTIVE IS TO DETERMINE THE MAXIMUM TOLERATED DOSE AND SAFETY PROFILE OF THESE CELLS AFTER THEY HAVE BEEN ADDED TO PEDIATRIC PATIENTS. SECONDARY OBJECTIVE TO LOOK AT -- IN OUR PATIENTS WITH RELAPSED AND REFRACTORY DISEASE WHO OTHERWISE HAVE SIGNIFICANTLY POOR OUTCOME. AND TO ASSESS A NEGLECT OF THE DRUG IF WE HAVE TO USE IT IN PATIENTS TO LOOK WHAT IT DOES TO ANY POTENTIALLY RELATED TOXICITY. THE STUDY IS DESIGNED AS A PHASE 1 PLAQUES MUM TOLERATED DOSE LEVEL FINDING STUDY, WE HAVE THREE DOSE LEVELS, I THINK UNFORTUNATELY WHEN YOU GOT THE FIRST COPY OF THIS THERE WAS A TYPOGRAPHICAL ERROR REALLY IT'S A MATTER OF THE DOSES BEING PER METER SQUARE TO THE PERKY LOW WHICH I THINK IS WHAT GOT SENT OUT.Sjx WE HAVE IT SET UP SUCH THAT YOU CAN'T RECEIVE ADDITIONAL DOSES UNTIL YOU'VE GOTTEN THROUGH AT LEAST A SIX WEEK SAFETY PERIOD AFTER YOUR LAST ADMINISTRATION. PATIENTS EITHER HAVE TO HAVE -- HAVE TO HAVE ACTUALLY BOTH, NO EVIDENCE OF DOSE LIMITING TOXICITY NOR EVIDENCE OF PROGRESSION AFTER THE INFUSION TO POTENTIALLY QUALIFY. THERE IS ADDITIONAL SUBSET OF PATIENTS WHO ON FIRST STUDY THAT WE ADDED IN, HENCE THE REASON ADDED IN TO THIS ONE, IF YOU HAVE HAD AT LEAST A DISEASE, NO DOSE LIMITING TOXICITY WITH INITIAL INFUSION THEN GONE ON WITH LIFE, THEN UNFORTUNATELY YOUR DISEASE COMES BACK LATER, YOU HAD CHEMOTHERAPY AND/OR INVESTIGATIONAL AGENTS AND PROGRESSEDF WE STILL HAVE -- LIKE ABILITY TO GIVE CELLS AT THAT TIME TO THOSE PATIENTS. AGAIN THAT'S IF CELLS ARE AVAILABLE, NO DOSE LIMITING TOXICITY NOT RESPONDED TO ANYTHING ELSE AND AGAIN MAXIMUM OF TWO ADDITIONAL DOSES PER EACH SITUATION. FOR THE T CELL ADMINISTRATION IT WOULD BE DONE THE WAY THAT WE STANDARDLY DO IT. SHORT STAY ADD A MISSION IN TO CLINICAL RESEARCH CENTER. PATIENTS RECEIVE PREMED OCCASION WITH BENADRYL AND TYLENOL. GIVEN OVER FIVE TO TEN MINUTES BY IV. WITH THIS REGIMEN FOR FIRST TWO MONTHS THEN EVERY THREE MONTHS FOR THE FIRST CALENDAR YEAR THEN PER FEDERAL REGULATION EVERY SIX MONTHS FOR THE NEXT 15 YEARS. FOR ADMINISTRATION OF AP1903 AGAIN THIS IS DONE IN CONJUNCTION WITH THE DATA THAT WE KNOW FROM THE PHASE ONE STUDY, FROM THE PREVIOUS STUDY THAT WE TALKED ABOUT IN CONJUNCTION WITH THE FDA, IT'S FOR GRADE THREE OR GREATER TOXICITY THAT IS DIRECTLY ATTRIBUTABLE TO THE T CELL INFUSION. DOSE AGAIN IS .4 MILLIGRAMS PER KILO GIVEN OVER TWO HOURS. BLOOD WILL BE SAMPLED OVER 48 HOUR TIME PERIOD MAKE SURE WE GET RESPONSE THAT WE ANTICIPATE SEEING F. UNFORTUNATELY WE ARE NOT SEEING RESPONSE OR THEY'RE WORSENING SYMPTOMS YOU HAVE ABILITY TO RECEIVE UP TO THREE ADDITIONAL DOSES. BUT IT SHOULD BE NOTED THAT PATIENTS WITH SEVERE PERSISTENT WORSENING SYMPTOMS WILL ALSO BE TREATED WITH HIGH DOSE STEROIDS WHICH SHOULD KILL THE T CELLS THEMSELVES. WE WANT TO DO THIS IN SAFEST POSSIBLE MANNER THAT IS NOT ONLY INCLUDED SAFETY SWITCH. IT WAS REALLY WHEN TRYING TO THINK OF THE BEST WAY TO STATISTICALLY DESIGN THE STUDY, AGAIN BECAUSE WE'RE TALKING ABOUT PEDIATRICS, WE FOUND THAT THERE'S BEEN -- USING MODIFIED, CONTINUAL REASSESSED METHOD DESIGN WITH THE CORE -- WE WILL TREAT TOTAL OF SIX PATIENTS AT THE MAXIMUM TOLERATED DOSE LEVEL IN ORDER TO OBTAIN ADDITIONAL SAFETY DATA. THAT IS BECAUSE SIMULATION STUDIES IN ADDITION TO THE STUDIES THAT WE HAVE ACTUALLY ALREADY PREVIOUSLY EXECUTED REALLY SHOWS THAT USING THIS PARTICULAR MODEL IS BETTER THAN STANDARD THREE BY THREE BECAUSE ALLOWS FOR HIGHER PROBABILITY OF DECLARING THE APPROPRIATE DOSE LEVEL AS MAXIMUM TOLERATED DOSE, BUT IT DOES THAT BY HAVING A SMALLER NUMBER OF PATIENTS THAT ARE ACCRUED TO LOWER UNLIKELY INEFFECTIVE DOSE LEVELS WHILE LOWER AVERAGE NUMBER OF PATIENTS THAT ARE REQUIRED TO PARTICIPATE ON THE STUDY. WE ANTICIPATE AGAIN THAT THERE WILL SOMEBODY WHERE BETWEEN TWO TO 14 PATIENTS THAT WILL ACCRUE OVER THE TIME THE STUDY IS OPEN. FURTHERMORE OUR TRIAL OVERSIGHT IS DONE VERY STANDARDLY WITH OUR DSMB FOR INVESTIGATOR STUDIES WITHIN OUR CENTER. AS WELL AS HAVING CONDUCT OVERSIGHT OF THE TRIAL DONE BY OUR CENTERS AND QUALITY CONTROL PROGRAM. IN CONCLUSION WHAT I WANT TO YOU TAKE AWAY AFTER ALL OF THE MUMBO JUMBO IS THIS SLIDE. WHAT WE LEARNED THE FIRST TIME AROUND, EXCELLENT EXAMPLE AS A IT TRANSLATION FALL SCIENTIST GOING FROM THE BENCH TO THE BEDSIDE THEN BACK FROM THE BEDSIDE TO THE BENCH. IN THAT FROM OUR FIRST STUDY, FIRST GENERATION GD2 CHIMERIC ANTI--- SURPRISINGLY WE SAUDI TECHS FOR EXTENDED PERIOD OF TIME. BUT WE KNOW THAT -- THAT WAS EVIDENCE BY WHAT WE SAW FROM -- IN TAKING IT BACK TO THE BENCH, THAT'S WHERE I HAND THINGS OFF TO DR. DOTTI THEN HAS PROCEEDED TO MAKE THINGS A LITTLE BIT BETTER WITH THE DATA THAT IS OUT THERE IN HELPING TO CREATE OUR THIRD GENERATION GD2 CHIMERIC CELLS. IT'S IMPORTANT, HOW CAN I MAKE MY KIDS BETTER FOR A LONGER PERIOD OF TIME. IF THIS ALLOWS US TO DO THAT THEN AT THE END OF THE DAY THAT'S WHAT'S MOST IMPORTANT. HOW DO WE DO IT SAFELY. WE'VE ADDED ADDITIONAL SAFETY SWITCH, TALKING ABOUT USING THIS MODIFIED CRM STATISTICAL PLAN HAVE OUR FOLLOW UP. AS YOU CAN IMAGINE IT TAKES A VILLAGE IN ORDER TO BE ABLE TO DO THIS. IF YOU HAVE ANY QUESTIONS WE'RE WILLING TO TAKE THEM AT THIS TIME. THANK YOU. >> LET'S START WITH THE REVIEWERS AND THEIR COMMENTS. DR. BADLEY. >> THANK YOU, DR. LOUIS FOR THAT NICE PRESENTATION. I APPLAUD YOU AND YOUR TEAM FROM WHERE YOU'VE COME SO FAR CLEARLY THE RATIONAL FOR USING GD2 AS TARGET ANTIGEN AND RATIONAL FOR USING SECOND OR THIRD GENERATION CAR IS CLEAR. THE QUESTION BEFORE US IS, THE RATIONAL FOR USING OX 40CD28 COMBINATION ESPECIALLY SINCE PREVIOUS CD2841BB CONSTRUCTS HAVE HAD ISSUES. ANILY CLINICAL DATA, ANIMAL OR HUMAN USING THIS NOVEL CONSTRUCT THAT TO MY KNOWLEDGE HAS NOT BEEN USED. I THINK THROUGH THESE ANSWERS THE ANSWER STILL IS, NO. THAT HASN'T BEEN TRIED IN HUMAN OR ANIMAL STUDIES. >> IT HAS NOT BEEN TRIED IN HUMAN STUDIES, THAT'S CORRECT. THIS WOULD BE A -- WE DO HAVE PRECLINICAL DATA AS FAR AS WHAT HAPPENS IN THE LABORATORY, MORE SPECIFICALLY THAT'S A QUESTION THAT IF YOU LIKE TO ANSWER. >> WE FOUND THAT COSTIMULATION. ALLOWS PROLIFERATING RESPONSE TO THE ANTIGEN WE DID CLINICAL STUDY IN DIFFERENT TUMOR WE FOUND ACTIVITY OF THESE T CELLS. >> I GUESS ACTIVITY ISN'T THE QUESTION. THE SAFETY IS THE QUESTION IN THE OTHER THIRD GENERATION CONSTRUCT AND 41BB THE PROBLEM WAS IF ANYTHING -- CAUSE SIGHT KIEM STORM AND TUMORLISIS. HAS THIS CONSTRUCT BEEN TRIED IN AN ANIMAL MODEL AT THE LEAST SO THAT WE HAVE SOME DEGREE OF COMFORT SAYING THAT THE WE PUT THIS IN TO A MULTI-CELLULAR ORGANISM, TUMORLISIS SIGHT KIEM STORM WON'T OCCUR. >> WE USE THIS CONSTRUCT IN MOUSE MODEL AND TUMOR WAS -- >> SECOND QUESTION I ASKED. HOW ACTIVE IS THE NINE SYSTEM IN THESE CELLS AND RESPONSE WAS IT'S PREVIOUSLY WORKED IN OTHER CELLS AND WE'RE WELL AWARE OF THAT. SPECIFICALLY DO YOU KNOW IF THE CELLS YOU MAKE WITH THIS CONSTRUCT THERE'S NO REASON TO SUSPECT IT WOULDN'T I JUST WANT TO MAKE SURE IT DOES WORK. >> THE ANSWER IS, YES, IT'S WORKING. A LITTLE BIT DIFFERENT FOR THE THE -- SELECTABLE MARKET BECAUSE THIS WASN'T ACCEPTING. WE PULL OUT ALL A THE -- WHEN IN VITRO, WE EXPOSE THE T-CELL -- WE HAVE SIMILAR ELIMINATION OF THE CELLS. IN MICE WE DID AN EXPERIMENT AND ALSO ELIMINATED T-CELLS. >> HOW MUCH ELIMINATION DO YOU CONSIDER TO BE ENOUGH. >> USUALLY WE FOUND FOR THE TRANSPLANT WE HAD -- THE EXPRESSION IS VERY LOW AND -- >> IF I RECALL CORRECTLY FROM THE PROTOCOL A PHASE ONE STUDY OF USING THE DIME MER RISING DRUG THAT WAS WELL TOLERATED UP TO GOOD DOSES. >> WE NEVER USE SECOND DOSE BECAUSE FIRST ONE WAS SUFFICIENT. >> I THINK YOUR PROTOCOL SAYS YOU MAY USE THE DRUG AGAIN. >> CORRECT. IN CASE THE FIRST DOSE IS NOT SUFFICIENT. WE WANT TO BE ABLE TO USE SECOND DOSE JUST IN CASE. >> THAT BRINGS IN TO RELEVANCE THEN WHAT YOU KNOW ABOUT THE SAFETY OF REDOSING. DO YOU HAVE ANY DATA ON REDOSING? >> WE DON'T HAVE ACTIVE -- FORTUNATELY OR UNFORTUNATELY DEPENDING HOW YOU THINK 'A BOUT IT BECAUSE WE NEVER HAVE TO DO IT. THIS IS WHERE IN ADDITION TO THE POTENTIAL FOR REDOSING AND THAT -- REDOSING SCHEDULE REALLY CAME IN WORKING -- HALF LIFE OF THE DRUG WAS AND WHY WE REDOSE AT 48 HOUR SCHEDULE VERSUS REDOSING SOONER. ALSO BECAUSE IT WAS ACTUALLY WRITTEN TO POTENTIALLY REDOSE IN A LOT OF DISCUSSION HAD WITH THE FDA WITH THE ORIGINAL TRIAL AGAIN WITH COMING UP WITH THE PARTICULAR REGIMEN OF DOING IT EVERY 48 HOURS. IN KNOW WHERE YOU'RE GOING WITH THIS PART OF WHY IT'S IMPORTANT TO ME AND PART OF WHY WE'VE ADDED THAT SECOND LINE IS BECAUSE IF IT DOESN'T LOOK LIKE IT'S WORKING I'M NOT EXACTLY AS A PRACTICING PHYSICIAN GOING TO WANT TO WATCH THAT FOR 48 HOURS. ABILITY TO HAVE HIGH DOSE STEROIDS AS A OUT IF THINGS DON'T LOOK LIKE DIME MER RISERS ARE TAKING CARE OF SYMPTOM MA WILLING TO IS -- >> YOU POINTED OUT THE TYPO. SECOND WAS CLARIFICATION OF THE PROLONGED PROPOSED FOLLOW UP YOU CLARIFIED THAT. LAST WAS CONCERN FOR INSERTION FALL MUTOGENESIS OF THE TRANSDUCED T CELLS YOU CLARIFIED THAT. NICE PROTOCOL THANK YOU FOR CLARIFYING. GOOD LUCK. >> THANK YOU. >> DON'T GO ANYWHERE. >> DR. FONG. >> CAN YOU HEAR ME? >> YES, WE CAN. THANK YOU. LET ME GET MY -- MY FIRST QUESTION WAS ABOUT HOW MANY ADULTS MIGHT BE AVAILABLE TO DO THIS ON PERHAPS DIDN'T PHRASE MY QUESTION SPECIFICALLY ENOUGH. I WAS LOOKING FOR SOMETHING MORE LIKE NUMBERS. I'M A PEDIATRICIAN, I KNOW THIS IS PRIMARILY PEDIATRIC DISEASE. MY QUESTION WAS WHETHER THERE -- SINCE THERE ARE SOME ADULTS THAT ARE APPARENTLY GOING TO BE AVAILABLE WHETHER THERE WERE ENOUGH TO DO THE STUDY IN ADULTS. I INFER FROM THE ANSWER THAT THE ANSWER TO THIS IS, NO. I JUST WAS LOOKING FOR SOME MORE SPECIFICITY TO HOW MANY 'ADULTS YOU MIGHT HAVE ACCESS TO. SECOND QUESTION IN THE PRIOR STUDY, THERE WAS A QUOTE, THREE PATIENTS HAVE DISEASE GO AWAY, END COAT, ID WITH HOW LONG DID IT GO AWAY. THE ANSWER IS, ONE IS DISEASE FREE AT FIVE YEARS OR MORE. I THINK WHATEVER IS IN THE CONSENT FORM IN FORMING PATIENTS ABOUT PRIOR STUDY TO BE MORE SPECIFIC ABOUT THAT. THIRD QUESTION WAS CLARIFICATION ABOUT WHY WAS 28 PEOPLE WERE TAKING PART IN THE STUDY ONLY 14 WOULD BE TREATED THAT WAS EXPLAINED. I UNDERSTAND THAT NOW. FOURTH, CONSENT FORM DESCRIBED POSSIBILITY THAT THE A. BODY MAY RESPOND WITH BRAIN CELLS. SUCH AS WHAT THE CLINICAL CONSEQUENCE THAT HAVE MIGHT BE. I THINK THE ANSWER IS, IT'S MAINLY THEORETICAL AND NO INFORMATION ON WHAT MIGHT HAPPEN. THERE FOR INAPPROPRIATE TO SPECULATE AND I THINK THAT'S APPROPRIATE. FIFTH UNDER THE BENEFIT SECTION, IT'S STATED IN VARIOUS WAYS BUT IMPLIES THERE IS A REASONABLE LIKELIHOOD OF BENEFIT, OR AT LEAST ACCEPTABLE BENEFIT RISK RATIO WHICH IS GENERALLY NOT THE CASE WITH PHASE ONE STUDIES, RESPONSES THAT THE PREVIOUS STUDIES HAD SALUTARY A FOLKS WHICH IS VERY ENCOURAGING. I'LL NEED TO RELY ON MY COLLEAGUES ON THE RAC WITH MORE SCIENTIFIC KNOWLEDGE TO KNOW IF PRIOR SUCCESS SYS REALLY IS SUFFICIENT TO PREDICT SUCCESS WITH THIS CONSTRUCT WHICH FIRST IN HUMANS. SO I'LL NEED SOME HELP ON WHETHER INVESTIGATORS CLAIM THAT SUCCESS THAT THEY GOT IN THE PREVIOUS TRIAL WARRANTS A MORE ROSY STATEMENT ABOUT SUCCESS THAN WE USUALLY SEE IN PHASE ONE STUDY. SIXTH, NO ASSENT FORM WAS PROVIDED FOR GHE CHILDREN AND RESPONSE IS THAT BAYLOR ESSENTIALLY DOESN'T REQUIRE ASSENT FROM CHIRP, ALLOWS FOR CONSENT FORM TO SAY, QUOTE, WHEN YOU SIGN THIS YOU ALSO NOTE THAT YOUR CHILD UNDERSTANDS AND AGREES TO TAKE PART IN THIS STUDY ACCORDING TO HIS OR HER UNDERSTANDING, END QUOTE. ALLOWS THE PARENT TO TESTIFY THAT THE CHILD DOES IN FACT ASSENT. NOT LIKELY TO BE RELEVANT FOR MOST CHILDREN IN THIS TRIAL WHO ARE LIKELY TO BE WELL BELOW THE AGE OF MEANINGFUL ASSENT BUT THAT OPTION THAT BAYLOR PRESENTS SEEMS TO BE INAPPROPRIATE. IT'S A STEP REMOVED FROM ASSENT IT DOESN'T REQUIRE ANYBODY ON INVESTIGATIVE TEAM TO TALK TO THE CHILDREN EVEN WHEN THEY'RE CAPABLE OF ASSENTING. WHILE IT MAY NOT HAVE LOT OF RELEVANCE FOR THE YOUNG CHILDREN IN THIS STUDY, I THINK IT MIGHT BE APPROPRIATE FOR -- OUR LETTER TO INCLUDE COMMENT THAT COULD GET TRANSMITTED TO THE INSTITUTIONAL OFFICIALS, THE IRB THAT THIS SEEMS TO ME NOT A MEANINGFUL IMPLEMENTATION OF WHAT WE EXPECT FROM ASSENT. AND FINALLY, THE PROTOCOL REFERRED TO MONITORING PLAN BUT WASN'T ANY INFORMATION ON SPECIFICS OF THAT. I'M GLAD I ASKED BECAUSE WHEN WE GOT THE SPECIFICS IT INCLUDED DESCRIPTION OF INSTITUTION FALL DATA MONITORING PROCESS THAT HOE CURES AND ONE FEATURE IS THAT IT'S CHAIRED BY THE DIRECTOR OF RESEARCH. SEEMS TO ME SOMETHING LESS THAN]-v AN INDEPENDENT DATA SAFETY MONITORING PLAN, DATA MONITORING COMMITTEES ARE USUALLY PRECEDED BY THE WORD INDEPENDENT HAVING THE DIRECTOR OF RESEARCH BE THE CHAIR OF THE DATA MONITORING COMMITTEE STRIKES NOT IDEAL WAY TO DO THAT. THE PLAN THERE, BAYLOR PLAN DOES INCLUDE REQUIREMENT THAT MAJORITY OF THE MEMBERS MUST BE INDEPENDENT. IT WOULD BE PREFERABLE FOR THE CHAIR TO BE SOMEBODY WHO HAS LESS OF A DIRECT CONFLICT OF INTEREST AND I DON'T THINK IT'S ENOUGH TO TURN DOWN THIS APPLICATION, I THINK IT MIGHT BE APPROPRIATE TO PASS THAT SUGGESTION ON TO THE INSTITUTION THAT THE REST OF THE RA A C MEMBERS AGREE. THAT'S IT. >> OVERALL, ARE YOU SATISFIED WITH THE RESPONSES? >> YES. VERY GOOD. LET ME GO TO QUESTIONS, OVERALL I'M FAIRLY SATISFIED, I JUST HAVE COUPLE OF CLARIFICATIONS TO GO ON. I HAD NUMBER OF ISSUES, FIRST WAS THAT IN THE STUDY DESIGN I HAD THE AP WITH 190 IS GIVEN. WHILE MTDs ARE GAUGED BY GRADE FOUR AS A USUAL AND GRADE THREE NONINFECTIOUS AT FIRST EVENTS. MY WORRY 'A BOUGHT ALL OF THAT, WILL THEY BE JUMPING THE GUN BY TREATING FOR SOME GRADE THREE TOXICITIES THAT AREN'T CLINICALLY IMPORTANT. FOR EXAMPLE, FIVE-TIME ELEVATION OF GDT FOR EXAMPLE, LIKELY HAVE VERY LITTLE CLINICAL SIGNIFICANCE BUT MAY TRIGGER A TREATMENT WITH A RESCUE DRUG SO I HAD SOME WORRIES ABOUT THAT. INVESTIGATORS STATED THAT THEY WOULD USE SOME CLINICAL JUDGMENT BUT MY RECOMMENDATION HAD BEEN TO WRITE IN TO THE PROTOCOL THAT SOME ADJUDICATING PROCESS WHERE BY FOUR AP 1903 IS ADMINISTERED THAT CLINICAL JUDGMENT IS EXERCISED. SECOND IS THAT IN PROTOCOL, PRELIMINARY DATA AND PAST DATA SHOWS THAT THE AP18903 WHEN ADMINISTERED ELIMINATED MORE THAN 90% OF INJECTED CELLS WITHIN 30 MINUTES OF DRUG ADD A MANAGES. BUT THAT WITHIN PROTOCOL THEY STATE THAT THEY WILL NOT REDOSE THE DRUG FOR 'A BOUT 48 OURS. THIS COMES BACK TO SOME OF THE THINGS THAT ANDREW WAS ASKING ABOUT. IS THERE ANY TOXICITY DATA ON REDOSING OF THIS DRUG WHICH IS WHAT ANDREW ASKED ABOUT, IS THERE ANY HUMAN -- ON GIVING THIS DRUG MULTIPLE TIMES? >> I WILL GO BACK AND LOOK. MY READING OF THE PHASE ONE STUDY WAS WITH SINGLE DOSE ADD A MANAGES. >> OKAY. >> AGAIN WHERE THAT RECOMMENDATION CAME FROM WAS WITH DESIGN OF THE LAST STUDY IN DISCUSSION WITH FDA AND KNOWING HALF LIFE OF THE DRUG THAT WAS THE DECISION THAT WAS MADE AT THAT PARTICULAR POINT IN TIME. HENCE THE REASON WE CONTINUED WITH IT. BUT AS FAR AS MULTIPLE DOSING, I DON'T BELIEVE IT WAS IN THAT PHASE ONE STUDY. >> DO YOU THINK IT WILL HELP -- >> DO YOU THINK IT WILL HELP? >> YES. >> TO BE HONEST? >> YEAH. >> THAT'S FAIR QUESTION WHAT YOU SAW WAS PREVIOUS STUDY WAS THAT YOU'RE GETTING RID OF 90% WITHIN FIRST 0 MINUTES, GETTING RID OF 99% WITHIN FIRST 24 HOURS THOSE CELLS THAT REMAINED EVEN WHEN TRACKED OUT UPWARDS OF SIX MONTHS YOU HAVE RECONSTITUTED YOUR IMMUNE SYSTEM WITH THESE PARTICULAR LEVELS THEIR LEVEL OF EXPRESSION WAS RELATIVELY LOW. THERE IS POSSIBILITY THAT REDOSING MAY NOT HELP YOU. BUT AGAIN PART OF WHY IT THEN BECOMES IMPORTANT FOR, WHAT'S YOUR OUT. WHAT IS YOUR BACK UP IF REDOSING DOESN'T WORK. THAT'S THE INCLUSION OF HIGH DOSE STEROIDS. >> IN THIS PROTOCOL IS WRITTEN YOU'D GET HIGH DOSE STEROIDS LONG BEFORE YOU GIVE SECOND DOSE, RIGHT? >> IT'S WRITTEN THAT YOU ARE ASSESSING AGAIN WITHIN 48 HOURS. IF YOU ARE ASSESSING WITHIN 48 HOURS YOU STILL HAVE GRADE 3 OR PROGRESSION THEN GRADE 3 CAN GET UP TO THREE ADDITIONAL DOSES. THOSE THAT ARE GRADE 4, THREE ADDITIONAL DOSES PLUS STEROIDS. ALWAYS POSSIBILITY IF THERE IS WORSENING WE CAN DOSE THE STEROIDS IN SUPPORT OF CARE. >> LET'S PLAY OUT FIRST 48 HOURS AFTER FIRST DOSE. SOME OF THE GRADE FOUR TOXICITY VERY SICK, YOU GAVE A DOSE. PATIENT STILL VERY SICK TWO HOURS LATER, WHAT ARE YOU GOING TO DO? >> TWO HOURS LATER? >> YES. >> ALL DEPENDS, I DON'T MEAN TO BE FLIP, ALL DEPENDS HOW VERY SICK IS. >> HYPOTENSIVE. >> IF YOU ARE HYPO -- >> IN THE ICU. >> IF YOU ARE HYPOTENSIVE IN THE ICU, YOU ARE OTHERWISE STABLE ALTHOUGH CRITICALLY ILL DO YOU HAVE -- AFTER GETTING DATA SEE WHAT THE CELLS ARE DOING WITHIN THE BODY, DO YOU RIDE IT OUT? ASSESSMENT OF ALL OF THAT. IF IT LOOK LIKE 30 MINUTE MARK OR TWO HOUR MARK THAT THINGS AREN'T MAKING A DIFFERENCE YOU'RE NOT GETTING ANYWHERE AT THE END OF THE DAY YOU HAVE THE DISCUSSION, WHAT IS THE SAFEST THING TO DO FOR THE CHILD. NOT IN THE END WHAT'S BEST THING TO DO BECAUSE OF HALF LIFE OF THE DRUG, IF I HAVE A KID WHO IS DECOMPENSATE INK FRONT OF ME WITH WHAT SHOULD BE APPROPRIATE MANAGEMENT BUT DOESN'T LOOK LIKE IT'S GETTING THERE, YOU TREAT THAT CHILD -- >> WHAT I'M ASKING, MY QUESTION, WILL GIVING A SECOND DOSE AT THAT TWO OR SIX OR EIGHT HOURS DO YOU HAVE ANY DATA THAT SAYS DOES IT HELP OR DOESN'T HELP, BECAUSE THAT'S GOING TO COME UP. HAVING NO DATA YOU WON'T BE ABLE TO MAKE THAT DECISION, OBVIOUSLY YOU WILL GO WITH STEROIDS AND OTHER THINGS BUT HAVING TEN PERCENT OF THE ACTIVATED T CELLS COULD BE A LOT. >> THESE ARE RELATIVELY SMALL DOSES COMPARED TO A LOT OF DOSES THAT YOU GUYS HAVE SEEN ON OTHER STUDIES. I WOULD HAVE TO SAY THESE ARE SMALL DOSES, CAN SMALL DOSES STILL CAUSE A PROBLEM, ABSOLUTELY. BUT WHEN LOOKING AT IF WE ARE SEEING A SITUATION WHERE AT THAT -- WITH WHAT WE EXPECT ON THE OTHER STUDY THAT WE ARE NOT SEEING THE APPROPRIATE AMOUNT OF DECREASE OR STABILIZATION USING OTHER SUPPORTIVE MEASURES I THINK YOU HAVE THE DISCUSSION AT THAT PARTICULAR POINT, IF YOU STILL HAVE HIGH PERCENTAGE OF THE CELLS DO YOU GIVE THAT ADDITIONAL DOSE. OR DO YOU -- YOU SAY, AT THE END OF THE DAY THIS KID LOOKS LIKE HE'S GETTING WORSE I THINK YOU GIVE STEROIDS AT THAT PARTICULAR POINT IN TIME. I PERSONALLY AM HIGHLY CONSERVATIVE. AS PERSON WHO WILL BE HELPING THE ICU TO HELP MANAGE THESE KIDS, YES, THERE'S WATCHFUL WAITING. BUT FOR ME WHAT IS THE SAFEST THING TO DO FOR THE CHILD AT THE END OF THE DAY. IF THAT GIVING THEM SLUG OF STEROIDS WE WATCH IT THEN THAT'S WHAT WE DO. >> THEN STILL COMES BACK TO WHY THE 48 HOURS. >> IN THAT DISCUSSION, EVEN BEHIND THE SCENES DISCUSSION DASH IT IS A MATTER THAT HAVE 48 HOUR DECISION CAME FROM THE DISCUSSION OF WHAT THE HALF LIFE OF THE DRUG IS AND WHAT THE EXPECTATIONS WERE IN DISCUSSION WITH THE FDA THAT'S HOW WE CAME UP. I THINK THAT'S ALWAYS PART OF CONVERSATION. BUT IF IT'S GOING THROUGH MECHANISM TO TALK TO THE FDA VERSUS DOING SOMETHING THAT YOU KNOW WILL WORK. >> CLINICAL EXPERIMENT WE USE MULTIPLE DOSES. >> HOW FREQUENTLY CAN YOU USE IT STILL HAVE A -- >> DIFFERENT PHARMACOKINETICS WITH EVERYTHING. WITH THE ADD A MANAGES OF THE DRUG IF WE DO SECOND DOSE AFTER 48 HOURS YOU HAVE ADDITIONAL -- >> HAVE YOU TREATED SOONER TO SEE IF THERE IS AN AFFECT IN MICE? OKAY. QUESTION WAS THE DOSING, YOU ANSWERED THAT AS WELL AS IN THE RESPONSES. THAT WAS VERY REASONABLE. I ASKED WHAT WOULD HAPPEN IF THERE WAS FAILURE IN TRANSDUCED T CELL PRODUCTION YOU SAID RELEASE CRITERIA WEREN'T MET WE WOULD ATTEMPT TO REMAKE THE CELLS IF THE PATIENT'S CONDITION PERMITS. VERY REASONABLE. WHAT ARE THE YIELD LESS THAN INTENDED DOSE WOULD HAPPEN, YOU SAID PATIENT WOULD BE TREATED BUT DATA WOULD NOT BEi+y COUNTED TOWARDS DOSE ESCALATION CALCULATIONS WHICH IS FINE. THEN I ASKED, WILL EXTRA DOSES BEYOND WHAT IS USED FOR TREATMENT BE STORED IN CASE THERE IS A GOOD RESPONSE DOWN THE LINE MIGHT WANT TO RETRIEVE USING THE SAME DOSES, YOU SAID ALL DOSE WILL BE STORED UNTIL THEY ARE EITHER GIVEN OR PATIENT DIES WHICH IS VERY REASONABLE. THEN ASKED ABOUT DESIGN OF -- TWO SUBJECT ESCALATION, YOU ANSWERED THAT VERY NICELY IN YOUR PRESENTATION. THEN I ASKED ABOUT GUIDELINES FOR DISCHARGE, YOU POINTED OUT THAT THESE PATIENTS WILL BE TREATED AS OUT PATIENTS WILL BE OBSERVED FOR FOUR HOURS AND IF THEY ARE FINE THEY WOULD BE ALLOWED TO GO. YOU SENT ME SOME REFERENCES ON HOW YOU JUDGE THAT. THAT WILL BE FINE. THEN I ASKED YOU -- PART OF THE ENROLLMENT SECTION YOU SAID THAT PART OF THE ENROLLMENT WILL BE THAT THE DIAGNOSIS OF HIGH RISK IN THE NEUROBLASTOMA MUST BE -- I SUGGESTED CHANGING IT TO RECEIVED BY THE CENTER OF CELL AND GENE THERAPY. DOCUMENTATION THAT WAS RECEIVED BEFORE TREATMENT I THINK IS IMPORTANT. OVERALL I AM FAIRLY SATISFIED, I STILL WONDER SINCE THIS IS ABOUT PART OF THE STUDY IS ABOUT ABILITY TO RESCUE. FROM THERAPY. I STILL WONDER IF YOU'VE NEVER TRIED RESCUING BEFORE IS THERE A BETTER DESIGN TO EITHER ANIMALS OR OTHER THINGS THAT UNDERSTAND WHETHER THERE WILL BE ANY HELP BY GIVING SECOND DOSE BEFORE 48 HOURS SINCE THAT IS PART OF WHAT YOU'RE TESTING. THAT STILL NAGS AT ME. THEN LAST QUESTION I HAVE FROM YOUR PRESENTATION IS THIS, IF YOUR LAST STUDY IN MINIMAL RECURRENT DISEASE FOUR OF THE PATIENTS WERE TREATED THREE HAD COMPLETE RESPONSES WHY ISN'T THAT IN A BIGGER TRIAL AND EXPANDED THERAPY? 75% COMPLETE RESPONSE IN RECURRENT NEUROBLASTOMA. WHERE HAS THAT PATH GONE? >> THAT PATH HAS ACTUALLY GONE TO THIS PATH. I WOULD HAVE TO SAY FOR LOGISTICAL REASONS, ONE OF THE THINGS THAT IS VERY -- ONE OF THE THINGS FOR ME, I'M GOING TO SPEAK FOR ME NOT NECESSARILY FOR THE CENTER. ONE OF THE THINGS THAT WAS REALLY IMPORTANT FOR ME WAS BEING ABLE TO BRING THIS FORCE TO OUR PATIENTS, SORT OF THE CATCH THAT WE RAN IN TO WITH THE PREVIOUS STUDY. PREVIOUS STUDY HAD TWO DIFFERENT LINES THAT IT LOOKED AT. ACTIVATED T CELL LINES, THEN EBV SPECIFIC LINES WHICH WE CAN ONLY GROW ON PATIENTS WHO HAVE EVB, BEEN INVECTED WITH EBV. 98% OF US HAVE BEEN INFECTED WITH EVB IN PEDIATRIC POPULATION ONLY 50% OF PATIENTS HAVE BEEN INFECTED. AT THE END OF THE DAY THOSE KIDS THAT ARE COMING SAYING, CAN I PARTICIPATE ON THIS TRIAL MORE THAN 50% I'M HAVING TO TURN OFF FROM JUMP BECAUSE THEY JUST DON'T MEET CRITERIA TO BE ABLE TO GROW CELLS IN THAT PARTICULAR STUDY. THIS WE'RE DOING ACTIVATED T CELL POPULATION ONLY. ANYBODY WHO PRESENTS THAT MEETS ALL OF THE OTHER ELIGIBILITY CRITERIA WOULD BE ABLE TO PARTICIPATE. FOR ME THIS REALLY IS THE NEXT STEP BECAUSE YOU GO BACK TO, IF I'M STILL NOT BEING ABLE TO TREAT 50% OF THE KIDS WHO POTENTIALLY RUN IN TO THIS SITUATION, DOES IT REALLY BEHOOVE ME TO SHOW ADDITIONAL DATA IN THAT STANDPOINT OR WE'VE GOT ADDITIONAL PRECLINICAL DATA AND FROM OTHER STUD EATS MOVING TO ADDITIONAL GENERATION, DO WE DO THAT. IN DOING THAT KNOWING I WON'T BE ABLE TO HAVE THE CONVERSATION WITH THE FAMILY, I'M SORRY YOUR CHILD HASN'T BEEN INFECTED WITH EVB, DO I TAKE THEM OUT HAVE THEM GET A COLD. THIS GIVES ME THE ABILITY TO POTENTIALLY TREAT ANYBODY THAT WALKS IN THE DOOR. >> JUST THAT WE SEE LOT OF PHASE ONE DATA FLOAT AROUND. MOST WE SEE NO RESPONSES. HERE IS A TRIAL WHERE THERE WAS 75% OF THE PATIENT POPULATION THAT TERRIBLE THINGS HAPPEN TO. YOUR TRIAL THERE ENDED IN 2009, YOU HAVE AGENTS. THEREFORE, TO SEE SOMETHING ENCOURAGING, NOT MOVE FROM PHASE ONE FORWARD AT LEAST FOR ME IT TRUCKS ME I DON'T SPEAK FOR THE REST OF THE COMMITTEE BUT I'M GLAD YOU'RE MOVING FORWARD WITH VERY NICE PROTOCOL IN THE AREA OF NEED. AGAIN, OVERALL I AM PRETTY SATISFIED WITH THE RESPONSES. ANY OTHER COMMENTS FROM OTHER RAC MEMBERS? >> I HAD A QUESTION ABOUT RETRO-VIRUS PRODUCTION IN YOUR RESPONSE TO APPENDIX M, INTEGRITY OF THE TRANSGENE WILL BE IDENTIFIED -- OR PG13 PRODUCER CELL LINE. LATER DESCRIBES THE LINE HAS THE -- SO IT'S IMPLIED BUT NOT EXPLICIT TEE STATED THAT THE VECTORS JUST TRANSECTED IN FOR VIRUS PRODUCTION NOT STABLEY INTEGRATED OR SELECTED IN THE PG134. CAN YOU CLARIFY THAT? >> THE WAY WE MAKE -- WE START WITH PG13, IT IS TRANSDUCED MULTIPLE TIMES. THEN WE DO SINGLE SITE CLONING ON THE PG13 TO IDENTIFY ONE TWO OF CLONES THAT ARE PRODUCING. >> THE ENVELOPE. >> CORRECT. WE SELECT THE -- MADE MASTER CELL BANK FOR THAT. >> I THINK IT'S SUE TOE TYPE VECTOR PUT IN THE PACKAGING LINE. >> TRANSECTED IN. >> THAT HAS THE GALVE ENVELOPE TRANSECTED IN. >> CORRECT. >> SO THESE THINGS PRODUCE VIRUS ALL THE TIME THEN? >> CORRECT. THESE MASTER CELLS HAVE -- >> INSIDE. NOW YOU PUT -- >> EVERYTHING IS AVAILABLEY TRANSECTED. >> VIRUS CANNOT INFECT AGAIN. >> ANY OTHER COMMENTS FROM THE MEMBERS OF THE RAC? ANYONE ON THE PHONE? >> WHEN YOU ASKED ME IF I WAS SATISFIED, I ANSWERED TOO QUICKLY. I MENTIONED COUPLE OF ITEMS I WASN'T COMPLETELY SATISFIED LIKE DATA MONITORING PROCESS BUT I DON'T THINK THOSE ARE SUFFICIENT TO WITHHOLD APPROVAL. >> OKAY. >> CAN I THROW IN TWO COMMENTS? WHILE THE CHAIR OF OUT RESEARCH IS THE CHAIR OF THAT COMMITTEE IT IS A MATTER OF NOT VOTING ON ANY PROTOCOLS THAT COME THROUGH. THERE IS BEING THE CHAIR THEN ACTIVELY PARTICIPATING VOTING APPROVING, SO FORTH. THOSE ARE TIMES WHEN AN ASSISTANT CHAIR OR -- I CAN'T THINK OF RIGHT WORD RIGHT NOW, A PROKY CHAIR IS PUT IN PLACE IF THE CHAIR IS ON THE STUDY THAT IS COMING UP AND BEING ASSESSED. WHILE I COMPLETELY UNDERSTAND THE CONCERNS ABOUT POTENTIAL CONFLICT THIS IS THE SITUATION WHERE THEY ARE NOT A VOTING MEMBER AT THE TIME THAT THAT PARTICULAR STUDY IS BEING ASSESSED. THE OTHER QUESTION ABOUT AS SENT. IT IS BAYLOR POLICY THAT THERE IS AN ASSENT LINE WITHIN OUR PROTOCOL, WHAT WE TYPICALLY DO WITH ASSENT AGAIN FOR OUR CHILDREN THAT ARE UNDER THE AGE OF ASSENT THAT'S ONE THING. FOR THE CHILDREN WHO GET TO BE THE AGE OF ASSENT THEY HAVE THE ABILITY TO PLACE THEIR NAME ON THE CONSENT, THAT IS AFTER DISCUSSION WITH THE CHILD ABOUT WHAT IS GOING ON IN A SITUATION WHERE WE HAVE RUN IN TO WHERE CHILD HAS HAD ADDITIONAL QUESTIONS, OUR STANDARD POLICY IS TO GET OUR CHILD LIFE SERVICES INVOLVED SO THEY'RE AWARE WHENEVER WE HAVE KID COMING IN FOR A STUDY ANYWAY. THEN A DISCUSSION OF, WITH OUR CHILD SPECIALIST THIS IS WHAT THE PROTOCOL IS. THIS IS WHAT IS GOING TO HAPPEN. THESE ARE THINGS THAT ARE GOING ON. BY ALL MEANS WE HAVE ASSENT AT THAT POINT IN TIME IF THERE ARE ANY QUESTIONS WOULD BE COMPLETELY INAPPROPRIATE TO POTENTIALLY HAVE CHILD PARTICIPATE ON"QUE IF THEY'RE ASKING QUESTIONS ABOUT IT. >> I THINK WHAT DR. FOST WAS ASKING IF THERE IS STANDARDIZED ASSENT PROCESS AT BAYLOR. >> THAT'S WHAT IRB HAS DEEMED MINIMALLY NECESSARY FOR WHAT IS GOING ON. HOW THAT ASSENT IS DONE, THERE ISN'T STANDARD SOP THAT IS WITHIN THE BAYLOR FACILITY. WHAT WE DO FOR THESE STUDIES IS THAT PARTICULAR PROCESS. >> WITH ALL RESPECT, I DON'T THINK THOSE ARE ADD AEQUAT. ON DATA MONITORING THING, FIRST OF ALL UNDER ROBERT'S RULE A CHAIR SHOULD NEVER VOTE ANYWAY REGARDLESS OF WHETHER HE OR SHE IS INVOLVED WITH THE PROTOCOL. CHAIR OF THE COMMITTEE IS A POWERFUL COMMISSION WHEN THE CHAIR HAS RESPONSIBILITY TO MOVE RESEARCH FORWARD FOR THE INSTITUTION THAT IS A BIT AWAYS FROM INDEPENDENT COMMITTEE. REGARDLESS WHETHER HE OR SHE HAPPENS TO BE INVOLVED WITH THE EXES I HAVE I CAN PROTOCOL. ON ASSENT, AS DR. FONG SAID MORE ROBUST PROTOCOL OR POLICY THAT REQUIRES TALKING TO THE CHILD AND CHILD APPROPRIATE LANGUAGE ABOUT WHAT IS GOING ON AND ASKING SOME REASONABLE QUESTIONS ABOUT WHETHER HE OR SHE WANTS TO GO FORWARD. NOT RELYING ON THE CHILD TO SOMEHOW BE AGGRESSIVE AND ASK QUESTIONS AND RAISE CONCERNS. >> THERE IS ALWAYS DISCUSSION WITH THESE PARTICULAR STUDIES THAT IS ALWAYS THE WAY THAT IT IS DONE. CAN I SAY THAT IS ALWAYS WHAT HAPPENS ACROSS THE BCM SYSTEM, NO. I CAN TELL YOU THAT IS OUR POLICY. CONSENT PROCESS WITH OUR STUDIES IS NOT SIMPLY A COME IN, ONE PARTICULAR TIME YOU'RE DONE. TYPICALLY THIS IS CONSENT, ASSENT PROCESS THAT IS HAPPENING FOR QUITE SOME TIME. WHEN A FAMILY CONTACTS US ABOUT THE STUDY WHAT GENERALLY HAPPENS FIRST DISCUSSION WITH THE ONCOLOGIST OF RECORD. AFTER -- ACTUALLY NOT PATIENTS WITHIN OUR SYSTEM THERE ARE PATIENTS THAT COME TO US FROM OTHER INSTITUTIONS. WE THEN SEND COPY OF THE CONSENT TO THE FAMILIES AHEAD OF TIME BEFORE THERE IS ANY TRAVEL THAT'S INVOLVED. MULTIPLE CONVERSATION, IS THAT TAKE PLACE ONCE THEY ACTUALLY HAVE COPY OF THE CONSENT IN HAND THEN ONCE THEY COME TO OUR CAMPUS WE ARE MEETING THEM AGAIN IT IS AT THAT POINT THAT THERE ARE ANOTHER SET OF CONVERSATION THAT TAKE PLACE. THIS ISN'T A, HI, THIS IS FIRST TIME I MEET YOU WE ARE GETTING IN TO THIS. TAKEN PLACE NOT ONLY WITH THE PRIMARY ONCOLOGIST AND I HAVE HAD CONVERSATIONS WITH SOME OF OUR -- >> DR. SMITH? >> FROM THE OFFICE OF HUMAN RESEARCH PROTECTION. >> THANK YOU. I JUST WANTED TO FOLLOW UP ON WHAT DR. FOST WAS SAYING ABOUT ASSENT PROCESS SAYING I AM CONFUSED. BECAUSE IT SOUNDS LIKE AT ONE POINT YOU WERE SAYING THAT ASSENT DECISIONS WERE MADE AT THE INSTITUTION FALL LEVEL, AT THE BAYLOR LEVEL. >> WITHIN NEED I CAN CONTENT. THAT IS BOILERPLATE LANGUAGE HOW ASSENTS ARE DONE F. STUDIES TO GO OVER AND ABOVE THAT BY ALL MEANS YOU CAN. THIS IS THE SITUATION WHERE WE HAVE SENT, IT'S WAITING FOR ANY ADDITIONAL -- THAT YOU MAY REQUEST OF US. >> JUST TO CLARIFY AS MOST PEOPLE KNOW IT'S REGULATORY REQUIREMENT THAT THE IRB TAKES A LOOK AT THE PROMOSSAL FOR ASSENT ALSO DOCUMENTATION OF ASSENT. PRESUMABLY THE IRB WILL HAVE EYES ON WHAT'S GOING TO ACTUALLY HAPPEN HERE. >> WAS DR. FOST'S RECOMMENDATION THAT WE PUT IN TO OUR DOCUMENT MAKE SURE THE IRB LOOKS AT THAT. THAT IS THE RECOMMENDATION. ANY OTHER COMMENTS FROM THE RAC? DR. SMITH? >> MAKE ONE MORE COMMENT JUST STRUCK ME WHEN I WAS READING THIS CONSENT FORM. IT'S HIGHLY TECHNICAL. THE LEVEL OF ENGLISH IS VERY HIGH LEVEL. THERE'S NO WAY THAT ANY KID IS GOING TO UNDERSTAND THIS I WONDER ABOUT PARENTS AS WELL. I LIKED THE FACT THAT YOU TAKE A NICE WALK THROUGH OF WHY YOU'RE DOING THIS STUDY AND RATIONAL, BUT IT DOESN'T BECOME VERY LONG AND SO I DON'T HAVE ANY QUICK FIXES FOR THAT BUT JUST WANTED THAT. IT WAS VERY NOTABLE. >> I JUST TOOK TIME TO LOOK UP WHAT YOU SAID ABOUT THE STUDY AT THE FOUNDATION, PRIVATE FOUNDATIONS THAT ARE FUNDING IT. THEY ARE GREAT AT MAKING IT ACCESSIBLE ON THE WEBSITES. I WOULD URGE YOU, THERE IS DISCREPANCY BETWEEN FORMS AND KIND OF ACCEPTABLE LANGUAGE THAT ARE DESCRIBING YOUR TRIALS IN. >> I'M SORRY. >> I DO BIOETHICS I'M INTERESTING WHERE THE MONEY IS. I WENT TO EACH OF THOSE FOUNDATIONS SEE IF THEY IN FACT WENT BACK TO -- CIRCLED BACK THAT I COULD READ ABOUT IT FROM THEIR PERSPECTIVE SEE WHAT THEY WERE SAYING. VERY OPTIMISTIC, VERY CLEAR WRITING IT WAS EXACTLY WHAT YOU WERE LOOKING FOR FOR HOW YOU MIGHT EXPLAIN IT TO FAMILIES. >> ANY COMMENTS FROM THE PUBLIC? LET ME READ DRAFT RECOMMENDATION FROM THE RAC. NUMBER ONE, CURRENTLY INVESTIGATORS PROPOSE THAT 18-190 WHEN GRADE THREE ATTRIBUTABLE TO THE GD2T CELL INFUSION. FOR SOME GRADE 3 TOXICITIES PROBABLY TOO EARLY TO GIVE AND PREMATURE ADMINISTRATION MAY DECREASE CHANCE OF SEEING TUMOR RESPONSE. FOR EXAMPLE, IF ASYMPTOMATIC PATIENTS HAVE -- PATIENT WHO HAD TRANSFUSION OF PLATELETS TO ENTER THE STUDY HAD COUNT GO LESS THAN 50,000 THIS MAY NOT BE INDICATION FOR ADMINISTRATION OF A A P190. IN ORDER TO PREVENT PREMATURE ADMINISTRATION OF THE DRUG AND MORE SPECIFIC -- A MORE SPECIFIC CRITERIA, OR ADJUDICATION PROCESS SHOULD BE ARTICULATED IN THE PROTOCOL. NUMBER TWO, CURRENT PROTOCOL STATES THAT THE SECOND DOSE OF AP19 WILL NOT BE GIVEN BEFORE 48 HOURS. HOWEVER IF THERE IS A SEVERE REACTION TO THE CELL THAT IS NOT AMELIORATED BY A SINGLE DOSE LIMITATION ON THE TIMING OF THE SECOND DOSE SHOULD BE RECONSIDERED TO BE RESPONSIVE TO CONTINUED LIFE THREATENING TOXICITIES THAT ARE NOT RESPONSIVE TO STEROIDS OR OTHER INTER-ACTIONS. IT MAY BE HELPFUL TO MODEL MORE FREQUENT DOSING IN AN ANIMAL MODEL. NUMBER THREE, DATA MONITORING COMMITTEE CHAIRED BY DIRECTOR OF RESEARCH, THIS COULD COMPROMISE INDEPENDENCE OF THE DMC OR AT LEAST CREATE APPEARANCE THAT IT IS NOT TRULY INDEPENDENT. WHILE HAVING DIRECTIVE RESEARCH PARTICIPATE IN THE DMC NOT AN ISSUE CONSIDER APPOINTING INDEPENDENT CHAIR WHO DOES NOT HAVE CONFLICT KNOWLEDGE ALLEGIANCES. SOCIAL, LEGAL, ETHICAL, ICD REFERENCES THE PREVIOUS STUDY, IN PARTICULAR DATA ONCOMING CALORIE SONS IT STATES THAT THREE PATIENTS HAVE DISEASE GO AWAY. SHOULD BE ADDITIONAL DETAILS PROVIDING -- PROVIDED REGARDED HOW LONG THESE PATIENTS HAVE BEEN IN REMIX AND IN PARTICULAR ONE OF THOSE PATIENTS RELAPSED AFTER THREE MONTHS. NUMBER TWO, ALTHOUGH MANY PATIENTS WILL NOT BE OF AGE -- OF ASSENT THOSE WHO CAN ASSENT -- FOR THOSE WHO CAN ASSENT SPECIFIC ASSENT ICD OR STANDARD PROCESS TO OBTAIN ASSENT SHOULD BE INCLUDED IN THE PROTOCOL. LASTLY, IN ADDITION TO LANGUAGE OF THE CONSENT STILL QUITE COMPLEX NEEDS TO BE SIMPLIFIED. THOSE ARE COMMENTS SO FAR. ANY CHANGES FROM THE RAC MEMBERS OR ADDITIONS? ANY COMMENTS FROM THE INVESTIGATORS? >> SORT OF. NOW IT'S EASY TO HAVE A DIALOGUE. >> I COMPLETELY APPRECIATE WHERE YOU'RE COMING FROM AS FAR AS CONSENT AND CONSENT LANGUAGE. AS MEMBER OF THE BAYLOR IRB HAVING TO READ YOUR CONSENT TYPICALLY WHY I BOUNCED THAT BACK. I CAN TELL YOU I WORKED REALLY LONG ON THAT CONSENT, IF WE CAN HAVE PEOPLE ADDITIONALLY LOOK AT IT, CATCH 22 THAT WE FIND THAT WE GET IN TO IN THESE SITUATIONS WHICH IS PART OF THE REASON WHY THERE ARE MULTIPLE CONVERSATIONS TAKE PLACE, BECAUSE YOU GET IN TO A SITUATION THE MORE YOU TRY TO GET IT TO THIRD GRADE LANGUAGE LONGER THE CONSENT BECOMES. WHEN YOU GET TO THE POINT THAT CONSENT SO LONG THAT YOU HAVE LOST PEOPLE BECAUSE CONSENT SO LONG. I ABSOLUTELY APPRECIATE THAT THERE IS WALKING THAT FINE LINE BETWEEN POSITIVELY MAKING IT APPROPRIATE LANGUAGE FOR FAMILIES TO UNDERSTAND BUT THEN ALSO HAVING IT NOT BE SO EXHAUSTIVE THAT THEY DON'T GET THROUGH IT JUST BECAUSE IT'S SO LONG. WE WILL CONTINUE TO WORK ON THAT. JUST SO THAT YOU KNOW I REALLY TRIED. >> VERY GOOD. ANY OTHER COMMENTS? LET'S MOVE THAT WE TAKE VOTE ON THIS RECOMMENDATION. >> DAWN WOOLEY, YES. >> YES. >> DR. STROME YES. >> FONG, YES. >> BRADLEY, YES. YES. >> ROSS, YES. >> ON THE PHONE? DR. FOST? >> FOST, YES. >> YES. >> ARE YOU STILL WITH US? >> YES, I AM. AND YES. >> THAT CONCLUDES AGENDA ITEMS FOR THE 131ST MEETING, I THANK THE INVESTIGATORS FOR BEING HERE. I THANK MISS CROWLY ALL THE YEARS OF SERVICE WITH RAC AND WONDERFUL MINUTES THAT TURNED OUGHT ALL THESE YEARS, THANK YOU. >> I'D LIKE TO THANK EVERYONE FOR COMING. ALSO I'D LIKE TO RECOGNIZE STAFF WHO ALSO DO ALL THE WORK BEHIND THE MEETING THEY'RE ALL IN THE CORNER THERE.