PT  - JOURNAL ARTICLE
AU  - John P. Murad
AU  - Dileshni Tilakawardane
AU  - Anthony K. Park
AU  - Kelly T. Kennewick
AU  - Lupita S. Lopez
AU  - Hee Jun Lee
AU  - Brenna J. Gittins
AU  - Wen-Chung Chang
AU  - Chau P. Tran
AU  - Catalina Martinez
AU  - Anna M. Wu
AU  - Robert E. Reiter
AU  - Tanya B. Dorff
AU  - Stephen J. Forman
AU  - Saul J. Priceman
TI  - Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity
AID  - 10.1101/2020.11.18.388892
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.18.388892
4099  - http://biorxiv.org/content/early/2020/11/20/2020.11.18.388892.short
4100  - http://biorxiv.org/content/early/2020/11/20/2020.11.18.388892.full
AB  - Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer 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 prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.Competing Interest StatementThe authors have declared no competing interest.