Project Grant R21CA288900

PILOT IN VIVO TRIAL WITH T-CELL-BASED DELIVERY OF IMMUNOSTIMULATORY PROTEINS - PROJECT SUMMARY IN THIS PROJECT, THE INVESTIGATORS WILL EXPLORE THE FEASIBILITY OF USING THEIR CELL-BASED PLATFORM FOR DELIVERING IMMUNOSTIMULATORY PROTEINS (IS) TO ACHIEVE TUMOR REGRESSION IN AN IN VIVO PILOT. CERTAIN IMMUNOSTIMULATORY PROTEINS HAVE ACTIVITY AGAINST THE MINIMAL DISEASE IN MOST SOLID TUMORS. HOWEVER, THEIR SYSTEMIC DELIVERY DOES NOT PERMIT SUFFICIENT CONCENTRATIONS TO TREAT ADVANCED DISEASE, AND THEIR EXCESS IS ASSOCIATED WITH SEVERE TOXICITIES. THE CHALLENGE IS TO ENABLE A LOCALIZED DOSE AT HIGH CONCENTRATION THAT CAN TREAT ADVANCED DISEASE WITHOUT UNDESIRED SIDE EFFECTS. THE TEAM'S MISSION IS TO HARNESS THE IMMUNE SYSTEM TO TREAT SOLID TUMORS. IN LINE WITH THIS MISSION, THEIR OBJECTIVE IN THIS PROJECT IS TO RE-CONFIGURE THEIR CURRENT CELL-BASED DELIVERY SYSTEM TO SYNTHESIZE CALIBRATED AMOUNTS OF IMMUNOSTIMULATORY PROTEINS WITHIN THE TUMOR MICROENVIRONMENT (TME); AND VALIDATE THE ANTITUMOR EFFECT IN A HIGH-GRADE SEROUS OVARIAN CANCER (HGSOC) MOUSE MODEL. THE FEASIBILITY OF THE PROPOSED EXPERIMENTS IS SUPPORTED BY OUR PREVIOUS PUBLICATIONS AND NEW PRELIMINARY DATA. OF PARTICULAR RELEVANCE TO THE PRESENT APPLICATION IS THE LOCALIZED EXPRESSION OF THE IMMUNOSTIMULATORY PROTEIN, WHICH OTHERS HAVE SHOWN TO EXERT ANTITUMOR EFFECTS BUT IS ALSO TOXIC WHEN DELIVERED SYSTEMICALLY. THE TEAM HAS ALREADY MODIFIED TUMOR CELLS FOR REPORTING THE ACTIVITY OF THEIR CELL-BASED DELIVERY SYSTEM IN VITRO AND DEVELOPED AN ANIMAL MODEL WITH THESE TUMOR CELLS TO ASSESS THE EFFICACY IN VIVO. THE RATIONALE IS THAT THE CELL-BASED DELIVERY PLATFORM WILL ENABLE HIGH, TME-LOCALIZED DOSES OF THE IMMUNOSTIMULATORY PROTEIN, PROPORTIONATE TO THE TUMOR BURDEN. THE TEAM PLANS TO PURSUE THIS PROJECT IN TWO AIMS: 1) SCALE UP THE CELLS ENGINEERED TO PRODUCE THE IMMUNOSTIMULATORY PROTEIN UPON ENGAGING HGSOC CELLS; AND 2) DEMONSTRATE FUNCTION IN AN HGSOC MOUSE MODEL. THIS PROJECT IS SIGNIFICANT BECAUSE IT WILL A) ENABLE A STRATEGY FOR SITE-SPECIFIC DELIVERY OF HIGH DOSES OF IMMUNOSTIMULATORY PROTEINS TO TARGET HIGH TUMOR BURDEN, AND B) RESULT IN A PROCESS THAT CAN BE SCALED UP DURING PRECLINICAL STUDIES IN IMMUNOCOMPETENT MICE, AS WELL AS ADDITIONAL IND-ENABLING STUDIES IN COMPLIANCE WITH CGMP PROTOCOLS. WE BELIEVE THIS PROJECT IS INNOVATIVE AND A SUBSTANTIVE DEPARTURE FROM THE STATUS QUO BECAUSE INSTEAD OF ATTEMPTING TO IMPROVE IMMUNOSTIMULATORY PROTEIN BIOAVAILABILITY BY EXOGENOUS DELIVERY OR BY INDUCING ENDOGENOUS EXPRESSION THAT IS ONLY EFFECTIVE AGAINST THE MINIMAL DISEASE, WE WILL USE OUR CELL- BASED TECHNOLOGY FOR ENHANCING IMMUNOSTIMULATORY PROTEIN DELIVERY TO THE TME. THIS WILL ENABLE SUFFICIENT LOCAL IMMUNOSTIMULATORY PROTEIN CONCENTRATIONS TO TREAT ADVANCED DISEASE.