Project Grant R44CA287653

CONTROLLING TUMOR IMMUNE ESCAPE IN PANCREATIC CANCER USING A DUAL T CELL PRODUCT STRATEGY - ABSTRACT WHILE T CELL THERAPIES HAVE SHOWN EFFICACY IN HEMATOLOGIC MALIGNANCIES, EXTENSION OF THIS SUCCESS TO SOLID TUMORS HAS PROVEN TO BE CHALLENGING, MAINLY DUE TO THE IMMUNOSUPPRESSIVE AND HOSTILE TUMOR MICROENVIRONMENT (TME). MARKER PROPOSES TO OVERCOME THE IMMUNOSUPPRESSIVE TME BY DEVELOPING A SECRETED RECOMBINANT FUSION PROTEIN, DECOY. THE PURPOSE OF THE DECOY PROTEIN IS TO TRANSFORM THE IMMUNOSUPPRESSIVE TME INTO ONE THAT WILL SUPPORT THERAPEUTIC T CELL GROWTH AND FUNCTION. WE THEREFORE PROPOSE A BINARY STRATEGY FOR T CELL THERAPY, AS A COMBINATION OF TWO T CELL PRODUCTS. PRODUCT #1 CONSISTS OF DECOY-PRODUCING T CELLS THAT WILL BE DELIVERED TO THE TUMOR AND HAS THE ABILITY TO ALTER THE TME, MAKING CONDITIONS MORE FAVORABLE FOR SUBSEQUENT T CELL THERAPY. PRODUCT #2 IS MT-601, OUR AUTOLOGOUS MULTI-TUMOR ASSOCIATED ANTIGEN (MTAA)-SPECIFIC T CELL PRODUCT THAT RECOGNIZES 6 ANTIGENS PRESENT IN PANCREATIC CANCER CELLS. IT HAS SHOWN AN EXCELLENT SAFETY PROFILE AND INITIAL EFFICACY IN A CLINICAL TRIAL IN ADVANCED OR METASTATIC PANCREATIC CANCER. THE PURPOSE OF THE COMBINATION OF DECOY WITH MT-601 IS TO FURTHER IMPROVE OUR INITIAL CLINICAL EFFICACY BY PROTECTING MT-601 T CELLS FROM THE IMMUNOSUPPRESSIVE TME. THE RATIONALE FOR THE BINARY DELIVERY SYSTEM IS TO MAINTAIN THE SAFETY PROFILE OF MT-601 T CELLS BY SEPARATING THE DELIVERY OF DECOY T CELLS. IN ESSENCE, THIS STRATEGY SEPARATES THE FUEL (DECOY) FROM THE ENGINE (MT 601) DRIVING ANTI-TUMOR ACTIVITY, PROVIDING THE OPERATOR WITH THE ABILITY TO CONTROL THE ENGINE BY ADDING MORE OR LESS FUEL. THIS BINARY APPROACH WILL OVERCOME STRATEGIES IMPLEMENTED BY THE TUMOR TO EVADE IMMUNE SURVEILLANCE. IN THIS PROJECT, WE WILL EVALUATE THE KINETICS AND PARAMETERS TO GUIDE CLINICAL APPLICATION OF PRODUCT #1 (DECOY), DETERMINE THE OPTIMAL CLINICAL ADMINISTRATION OF PRODUCT #2 (MT-601) WHEN COMBINED WITH PRODUCT #1 (DECOY), AND PERFORM GMP-COMPLIANT VALIDATION AND ENGINEERING RUNS FOR CLINICAL IMPLEMENTATION OF THE BINARY PRODUCT STRATEGY. SUCCESSFUL COMPLETION OF THIS PROJECT WILL RESULT IN THE AMENDMENT OF OUR FDA- APPROVED MT-601 IND THAT WILL USE A BINARY PRODUCT STRATEGY THAT USES DECOY (PRODUCT #1) TO ENHANCE CANCER KILLING CAPABILITIES OF MTAA-SPECIFIC T CELLS - MT-601 (PRODUCT #2) IN PANCREATIC CANCER. THIS APPLICATION WILL THEREFORE PAVE THE WAY TOWARDS CLINICAL IMPLEMENTATION OF A BINARY PRODUCT STRATEGY TO ADDRESS AN UNMET CLINICAL NEED FOR PANCREATIC CANCER PATIENTS. IF SUCCESSFUL, THIS BINARY STRATEGY WILL ALLOW FOR A FASTER EXTENSION TO OTHER ADOPTIVE T CELL THERAPIES AND/OR CANCER INDICATIONS FOR THE PURPOSE OF INCREASING CELL PRODUCT POTENCY WHILE MAINTAINING THE SAFETY PROFILE.