Project Grant R43CA281523

ENGAGER T CELL: A SIMPLE SOLUTION FOR OFF-THE-SHELF T CELL THERAPY FOR CANCER - PROJECT SUMMARY AUTOLOGOUS CHIMERIC ANTIGEN RECEPTOR T (CAR T) CELL THERAPY POSES LOGISTICAL AND ECONOMICAL CHALLENGES DESPITE CURATIVE POTENTIAL. DONOR-DERIVED ALLOGENEIC OFF-THE-SHELF (OTS) CELL THERAPIES HAVE BECOME THE HOLY GRAIL OF CELL THERAPY AS THEY CAN BE MASS-PRODUCED AND ARE IMMEDIATELY AVAILABLE TO CANCER PATIENTS AT AFFORDABLE PRICES. HOWEVER, CURRENT OTS STRATEGIES INVOLVE COMPLEX MANUFACTURING PROCESS AND GENE-EDITING WITH SAFETY CONCERNS SUCH AS CARCINOGENESIS RISK. NON-AB T CELL-BASED OTS STRATEGIES SUCH AS NK CELLS HAVE POTENCY CONCERNS AS THEY LACK PERSISTENCE AND DURABILITY. IMMUNEBRO THERAPEUTICS IS DEVELOPING A SIMPLE AND NOVEL PLATFORM TECHNOLOGY TO PRODUCE DONOR-DERIVED AB T CELL-BASED OTS PRODUCTS NAMED ENGAGER T CELLS. ENGAGER T CELLS ARE ENGINEERED DONOR T CELLS EXPRESSING AND SECRETING AN ARTIFICIAL MODULAR PROTEIN THAT CAN 1) TARGET DONOR T CELLS TO A DESIRED CANCER TARGET AND 2) CURB DONOR T CELLS' ALLOREACTIVITY OF INDUCING GRAFT VERSUS HOST DISEASE (GVHD). DONOR DERIVED ENGAGER T CELL IS A SIMPLE SOLUTION FOR OTS T CELL THERAPY WITH NO NEED OF GENE EDITING. IT INVOLVES A WELL-ESTABLISHED AND MUCH LESS COMPLEX MANUFACTURING PROCESS IN COMPARISON TO GENE EDITED OTS CAR T CELLS CURRENTLY IN DEVELOPMENT. PRELIMINARY DATA HAVE DEMONSTRATED THAT DONOR DERIVED CD19-TARGETING ENGAGER T CELLS HAVE LOW XENOGENEIC GVHD RISK AND ARE EFFICACIOUS IN TREATING XENOGRAFT CD19+ LEUKEMIA MOUSE MODEL. HOWEVER, IN A SIDE-BY-SIDE COMPARISON, CD19 ENGAGER T CELLS ARE INFERIOR TO 2ND GEN CD19 CAR T CELLS ON EFFICACY DUE TO THE LACK OF CO- STIMULATION. AS EFFICACY IS CRUCIAL FOR REGULATORY AND COMMERCIAL SUCCESS OF ANY DRUG CANDIDATES, THIS PROPOSAL IS AIMING AT DEVELOPING ENHANCED CD19 ENGAGER T CELLS WITH LOW GVHD RISK. SPECIFIC AIM 1 IS TO DEVELOP ENHANCED CD19 ENGAGER T CELLS AND ASSESS TRANSGENE EXPRESSION AND SECRETION. THREE STRATEGIES WILL BE USED TO PRODUCE ENHANCE CD19 ENGAGER T CELLS BY 1) CO- EXPRESSING A CD19 CAR; 2) CO-EXPRESSING T CELL PROMOTING CYTOKINE IL15; 3) CO-EXPRESSING COSTIMULATORY FACTOR 4-1BBL AND CD80. SPECIFIC AIM 2 IS TO DEMONSTRATE ONE OR MORE OF THE ENHANCED CD19 ENGAGER T CELLS HAVE LOW XENOGENEIC GVHD RISK IN IMMUNE DEFICIENT MICE. SPECIFIC AIM 3 IS TO DEMONSTRATE ONE OR MORE OF ENHANCED CD19 ENGAGER T CELLS HAVE COMPARABLE EFFICACY TO 2ND GEN CD19 CAR T CELLS. BY THE END OF PHASE 1 WORK, IMMUNEBRO WILL HAVE ENHANCED CD19 ENGAGER T CELLS AS THE FIRST PRODUCT PROTOTYPE BUILT FROM THE SIMPLE AND NOVEL OTS PLATFORM. THIS PLATFORM CAN BE USED TO BUILD A RICH PIPELINE OF OTS T CELLS TARGETING A VARIETY OF CANCERS WITH LESS COMPLEX MANUFACTURING, SAFER PROFILE, AND COMPARABLE OR BETTER EFFICACY THAN GENE EDITED OTS CAR T CELLS CURRENTLY IN DEVELOPMENT.