Abstract IA019: Tumor microenvironment modulation is critical for cellular immunotherapy efficacy

Abstract

Abstract Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of prostate cancer, among other solid tumors. However the role of lymphodepletion was uncertain for application outside of heme malignancies. We studied the effect of chemotherapy preconditioning on the tumor immune microenvironment along with the impact on CAR-T cell activity. Methods: Immunocompetent mice bearing RM9 prostate tumors lentivirally transduced to express human prostate stem cell antigen (PSCA) and treated with PSCA targeted CAR T cells alone, or after 100 mg/kg cyclophosphamide (Cy). Tumors were evaluated for immune cell subsets infiltration in addition to clinical response. As part of a phase 1 dose escalation trial patients received 100 M PSCA-targeted CAR T cells, manufactured at City of Hope’s cGMP facility, alone or after Cy. CAR T persistence and cytokine levels were evaluated by flow cytometry and luminex, respectively. Results: CAR T cells alone had minimal anti-tumor effect in immune competent mice. Cy was associated with increased CD11c+ DCs and reduced CD206+ M2 macrophages in the tumors. With Cy pre-conditioning followed by infusion of PSCA-CAR T cells, over 40% of mice had complete response (CR) and rejected rechallenge of tumor. 10-fold greater T cell infiltration was noted in tumors after Cy preconditioning, with lesser increase and no anti-tumor effect noted with Cy + mock CAR T cells. In the phase 1 human trial greater CAR T cell expansion and cytokine induction were noted with Cy + PSCA-CAR T compared to PSCA-CAR T alone. Conclusion: Cy functions as a modifier of the prostate cancer tumor microenvironment, facilitating CAR T cell infiltration and expansion. This has resulted in greater activity of PSCA-CAR T cells both in murine models and preliminary human testing. Further study of manipulations to optimize the tumor immune microenvironment will likely be important to maximizing efficacy of cellular immunotherapy in prostate cancer. Citation Format: Tanya B Dorff, M Suzette Blanchard, John Murad, Lauren Adkins, Gaurav Dhaploa, Stephen Forman, Saul Priceman. Tumor microenvironment modulation is critical for cellular immunotherapy efficacy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA019.