Project Grant R44CA291521

A PHASE 1 STUDY OF PATIENT-DERIVED MULTI-TUMOR-ASSOCIATED ANTIGEN SPECIFIC T CELLS (MT-601) ADMINISTERED TO PATIENTS WITH RELAPSED NON-HODGKIN LYMPHOMA - ABSTRACT THIS APPLICATION PRESENTS MT-601, A NOVEL MULTI-TUMOR ASSOCIATED ANTIGEN (MTAA)-SPECIFIC T CELL PRODUCT FOR THE TREATMENT OF NON-HODGKIN'S LYMPHOMA (NHL). NHL IS THE MOST COMMON HEMATOLOGIC MALIGNANCY WITH ~80,550 NEW CASES AND >20,000 DEATHS IN THE US EXPECTED IN 2023. ADOPTIVE T CELL TRANSFER, E.G., CAR T CELLS, HAVE IMPRESSIVE POTENCY IN NHL YET ARE ALSO ASSOCIATED WITH CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY. ADDITIONALLY, RELAPSE RATES ARE UP TO 60% POST-CAR T THERAPY DUE TO LOW ANTIGEN LEVELS OR LOSS OF CD19 EXPRESSION. TO DATE THERE ARE NO APPROVED THERAPIES FOR NHL PATIENTS WHO RELAPSED AFTER CAR T CELL THERAPY, RESULTING IN A HUGE UNMET MEDICAL NEED FOR ALTERNATE TREATMENT OPTIONS FOR NHL. MT-601 REPRESENTS A NOVEL T CELL-BASED IMMUNOTHERAPY THAT SIMULTANEOUSLY TARGETS 6 TUMOR-ASSOCIATED ANTIGENS (TAA) (PRAME, NY-ESO1, SURVIVIN, MAGE-A4, SSX2, WT1) THAT ARE OVEREXPRESSED IN NHL BUT ABSENT OR WITH LIMITED EXPRESSION IN HEALTHY TISSUE, THEREBY MINIMIZING TUMOR ESCAPE AND ENHANCING ANTI-TUMOR RESPONSE. MANUFACTURED FROM AUTOLOGOUS APHERESIS MATERIAL, MT-601 RECOGNIZES TARGET CELLS VIA NATIVE T CELL RECEPTORS BY INTERACTING WITH TUMOR ANTIGEN-EXPRESSING TARGET CELLS PRESENTING ANTIGEN IN THE CONTEXT OF BOTH CLASS I AND II HLA, LEADING TO KILLING OF TUMOR CELLS EXPRESSING ANY OF THESE ANTIGENS AND RECRUITING THE PATIENT'S IMMUNE SYSTEM IN THE ANTI-TUMOR RESPONSE. ALTHOUGH OTHER CELLULAR IMMUNOTHERAPIES ATTEMPT TO ADDRESS CD19 CAR T CELL FAILURES BY TARGETING 2-3 ANTIGENS, THEY ARE LIMITED BY 1) NARROW EPITOPE RECOGNITION, AND 2) LEAVING THE TUMOR SUSCEPTIBLE TO RELAPSE. IN ADDITION TO BROAD-SPECTRUM ANTIGEN TARGETING, MT-601 IS THE ONLY CELLULAR THERAPY BEING EXPLORED IN NHL PATIENTS WHO RELAPSED FOLLOWING CAR T THERAPY. ADDITIONAL ADVANTAGES OF MT-601 INCLUDE OUT-PATIENT ADMINISTRATION AND NO GENETIC ENGINEERING. FURTHERMORE, MARKER'S MULTITAA-SPECIFIC TECHNOLOGY WAS PROVEN CLINICALLY SAFE IN >180 PATIENTS WITH VARIOUS KINDS OF CANCER. IN A PHASE 1 TRIAL OF LYMPHOMA PATIENTS USING MULTITAA-SPECIFIC T CELLS TARGETING 5 TAAS, PATIENTS HAD DURABLE RESPONSES FOR MUCH LONGER THAN THOSE TYPICALLY ASSOCIATED WITH CAR T CELLS (6 YEARS VERSUS 28 MONTHS). NOTABLY, MARKER RECENTLY TREATED OUR FIRST CAR T CELL RELAPSED NHL PATIENT, WHO SHOWS A COMPLETE RESPONSE AT 12 WEEKS POST-INFUSION. BASED ON THIS PROMISING CLINICAL DATA, MARKER PROPOSES A SINGLE-ARM PHASE 1 CLINICAL STUDY TO ADVANCE MT-601 FOR PATIENTS WITH NHL THAT RELAPSED AFTER THIRD LINE CAR T TREATMENT AND DO NOT HAVE OTHER APPROVED THERAPY OPTIONS. THE OBJECTIVE OF SPECIFIC AIM 1 IS TO MANUFACTURE MT-601 AND EXECUTE THE CLINICAL PROTOCOL BY TREATING NHL PATIENTS WHO HAVE RELAPSED AFTER CD19 CAR T CELL THERAPY WITH MT-601. SPECIFIC AIM 2 WILL CORRELATE BIOLOGICAL CHARACTERISTICS IN THE PRODUCT PROFILE WITH CLINICAL SAFETY AND EFFICACY OUTCOMES. SUCCESSFUL COMPLETION OF THIS GRANT WILL PROVIDE CLINICAL PROOF OF CONCEPT FOR MT-601 AS A TREATMENT FOR CAR RELAPSED NHL PATIENTS, AND SUPPORT FUTURE CLINICAL TRIALS LEADING TO FUTURE BLA FILING AND COMMERCIAL APPROVAL OF MT-601.