Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Protective Immunity.

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knock-in (hPSCA-KI) immunocompetent mouse model, we evaluate safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells as well as endogenous and adoptively-transferred T cells, resulting in long-term anti-tumor immunity.

Molecular therapy : the journal of the American Society of Gene Therapy. 2021 Feb 26 [Epub ahead of print]

John P Murad, Dileshni Tilakawardane, Anthony K Park, Lupita S Lopez, Cari Young, Jackson Gibson, Yukiko Yamaguchi, Hee Jun Lee, Kelly T Kennewick, Brenna J Gittins, Wen-Chung Chang, Chau P Tran, Catalina Martinez, Anna M Wu, Robert E Reiter, Tanya B Dorff, Stephen J Forman, Saul J Priceman

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA., Department of Urology, University of California, Los Angeles, CA 90095, USA., Department of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USA., Department of Molecular Imaging and Therapy, City of Hope, Duarte, CA 91010, USA., Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: .