Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity

• Published in: Molecular therapy 2021-07, Vol.29 (7), p.2335-2349
• Main Authors: Murad, John P., Tilakawardane, Dileshni, Park, Anthony K., Lopez, Lupita S., Young, Cari A., Gibson, Jackson, Yamaguchi, Yukiko, Lee, Hee Jun, Kennewick, Kelly T., Gittins, Brenna J., Chang, Wen-Chung, Tran, Chau P., Martinez, Catalina, Wu, Anna M., Reiter, Robert E., Dorff, Tanya B., Forman, Stephen J., Priceman, Saul J.
• Format: Article
• Language: English
• Subjects: adoptive cellular immunotherapy; Animals; Antigens, Neoplasm - genetics; Apoptosis; Cell Proliferation; chimeric antigen receptor; cyclophosphamide; Cyclophosphamide - pharmacology; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - genetics; Humans; immunosuppression; Immunotherapy, Adoptive - methods; Male; Mice; Mice, Inbred C57BL; Myeloablative Agonists - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Original; pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; pre-conditioning; prostate cancer; prostate stem cell antigen; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.02.024

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 knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the 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. [Display omitted] Priceman, Murad, and colleagues describe an immunocompetent model that demonstrates the safety and efficacy of CAR T cells for the treatment of PSCA+ solid tumors. Importantly, CAR T cell treatment with cyclophosphamide pre-conditioning provides pro-inflammatory immune modulation resulting in reversion of local T cell exclusion and promotion of protective anti-tumor immunity.