Abstract A62: NKG2D RNA CAR is effective in treating peritoneal carcinomatosis in a mouse model

Abstract

Peritoneal carcinomatosis (PC) is widely shown in end-stage neoplastic disease, especially in recurrent colorectal cancer, and has become a significant threat to the overall survival of patients. Since NKG2D ligands are commonly up-regulated on cell surface of carcinomas but rarely present on most healthy tissues, they can be the ideal targets in the treatment of NKG2D ligand-overexpressing colorectal PC. In this study, we developed a chimeric antigen receptor (CAR)-T cell therapy approach by arming human T lymphocytes with mRNA coding a chimeric NKG2D receptor to target NKG2D ligands. We constructed first, second, and third generation CARs specific for NKG2D ligands by linking the extracellular domain of the human NKG2D receptor to the CD3-zeta signaling domain and costimulatory moieties. mRNAs of those chimeric NKG2D CARs were electroporated into human T lymphocytes and the anti-tumor activities of engineered T cells were examined afterwards. The NKG2D CAR expression was detectable for at least 6 days and the modified T cells exhibited efficient cytotoxic immune activity against NKG2D ligand-positive tumor cells, but not NKG2D ligand-negative cells. Multiple infusions of the RNA CAR modified T cells in immunodeficient mice bearing established peritoneal human colorectal tumors led to a significant reduction in the tumor burden. Here, we showed that T cells engineered with NKG2D CAR by RNA electroporation can efficiently control the colorectal peritoneal carcinomatosis in the mouse model. Transfection of mRNA encoding a CAR is an economical way to benefit the test of new CARs and it holds great promise in controlling on-target/off-tumor toxicity and cytokine storms. The possibility of using NKG2D ligand-specific RNA CARs to treat colorectal PC warrants further investigation. Citation Format: Zhendong Li, Shijun Zha, Shu Wang. NKG2D RNA CAR is effective in treating peritoneal carcinomatosis in a mouse model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A62.