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Background 177Lu-PSMA-617 is an FDA-approved targeted radiopharmaceutical therapy (RPT) for metastatic castration-resistant prostate cancer (mCRPC), but its long-term efficacy is limited.1 While chimeric antigen receptor (CAR) T cell therapy has revolutionized B cell malignancies, its application in mCRPC faces challenges. In a phase 1 clinical trial (NCT03873805) evaluating CAR-T cells targeting Prostate Stem Cell Antigen (PSCA), we observed promising safety and therapeutic responses in patients who underwent cyclophosphamide (Cy) lymphodepletion, but the several challenge must be addressed to improve overall responses: 1) antigen heterogeneity, and 2) the immunosuppressive tumor microenvironment (TME).2 Preclinical evidence suggests radiation enhances CAR T cell efficacy by priming the TME,3 4 yet focal radiation lacks the capability to target multi-metastatic disease systemically. Here we describe the combination of 177Lu-PSMA-617 RPT and CAR-T cell therapy - both systemic in effect - to improve efficacy and durability by overcoming the heterogeneous immunosuppressive prostate TME.Methods Using human PSCA knockin (hPSCA-KI) syngeneic mouse models, we evaluated the immunomodulatory effect and therapeutic efficacy of combining 177Lu-PSMA-617 RPT and PSCA CAR-T cells with Cy. Murine prostate cancer cell line overexpressing human Prostate Specific Membrane Antigen (PSMA) and/or PSCA were engrafted subcutaneously and treated with RPT, Cy, and CAR-T cells. Solid tumor and tumor-draining lymph nodes were collected for flow cytometry and single-cell transcriptomic analysis to assess the immunological changes. Tumor burden, survival, body weight, and blood chemistry were monitored to evaluate the efficacy and safety.Results RPT and Cy treatment alter the endogenous immune landscape in the murine prostate TME. We observed phenotypic changes in tumor-infiltrating lymphocytes and myeloid populations in response to the treatment. In syngeneic mouse models bearing homogenous (PSMA+ and PSCA+) or heterogenous (PSMA+ or PSCA+) tumors, the combination treatment was well-tolerated. RPT synergized with Cy and PSCA CAR-T cells to improve the therapeutic efficacy and overall survival.Conclusions Our study shows a promising outcome by combining 177Lu-PSMA-617 RPT and PSCA CAR-T cell therapy. The combination was well tolerated in the syngeneic mouse model, with favorable TME changes, enhanced therapeutic responses, and extended durability. By using the two therapies (177Lu-PSMA-617 and PSCA-CAR T cells) that are FDA approved or in clinical development, we aim for rapid translation of this combination strategy to patients with mCRPC and other advanced lethal cancer types.References Freedland SJ, Davis M, Epstein AJ, Arondekar B, Ivanova JI. Real-world treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer (mCRPC) in the US medicare population. Prostate Cancer Prostatic Dis. 2024 Jun;27(2):327-333.Dorff TB, Blanchard MS, Adkins LN, Luebbert L, Leggett N, Shishido SN, Macias A, Del Real MM, Dhapola G, Egelston C, Murad JP, Rosa R, Paul J, Chaudhry A, Martirosyan H, Gerdts E, Wagner JR, Stiller T, Tilakawardane D, Pal S, Martinez C, Reiter RE, Budde LE, D’Apuzzo M, Kuhn P, Pachter L, Forman SJ, Priceman SJ. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2024 Jun;30(6):1636-1644.Kostopoulos N, Costabile F, Krimitza E, Beghi S, Goia D, Perales-Linares R, Thyfronitis G, LaRiviere MJ, Chong EA, Schuster SJ, Maity A, Koumenis C, Plastaras JP, Facciabene A. Local radiation enhances systemic CAR T-cell efficacy by augmenting antigen crosspresentation and T-cell infiltration. Blood Adv. 2024 Dec 24;8(24):6308-6320.Quach HT, Skovgard MS, Villena-Vargas J, Bellis RY, Chintala NK, Amador-Molina A, Bai Y, Banerjee S, Saini J, Xiong Y, Vista WR, Byun AJ, De Biasi A, Zeltsman M, Mayor M, Morello A, Mittal V, Gomez DR, Rimner A, Jones DR, Adusumilli PS. Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy. Cancer Immunol Res. 2023 Oct 4;11(10):1314-1331.