Abstract 4092: Development of nucleotide metabolic reprogrammed CAR T cell therapy suitable for solid tumors

Abstract

Abstract CAR T cell therapy has represented an exciting breakthrough in the treatment of patients with hematologic malignancies. In contrast, the antitumor activity of CAR T cell therapy in solid tumors has been modest so far in clinical studies. The suboptimal clinical efficacy is a result of multiple factors including limited T cell trafficking, persistence, and the immunosuppressive tumor microenvironment (TME). While current strategies utilize costimulatory molecules and cytokines to activate CAR T cells, a key but largely overlooked problem of CAR T cell therapy is nutrient competition between tumor cells and T cells in the nutrient-poor TME. In our previous studies, a metabolic screen identified inosine as an alternative fuel for T cells which can support T cell growth and function in the absence of glucose. T cells could metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. Moreover, we demonstrated that T cells have advantage over cancer cells in utilizing inosine, and supplementation with inosine enhances the antitumor efficacy of PD-1 mAb and adoptive T cell transfer in mouse models. In this study, we therefore engineered CAR T cells to express CD26 on the cell surface and a secreted adenosine deaminase (ADA) fused with an anchor. These metabolic reprogrammed CAR (designated as MRCAR) T cells exerts their activities through different mechanisms. ADA irreversibly converts adenosine to inosine, overcoming adenosine-mediated immunosuppression and providing inosine for CAR T cell growth, while CD26 induces a rich chemokine receptor profile enabling CAR T cells to traffic to solid tumors. We demonstrated that CD26-overexpressed CAR T cells displayed superior migration capacity and resisted TGF-beta suppression, while the CD26 expression on unmodified CAR T cells was significantly down-regulated by TGF-beta. We further proved that ADA is conditionally secreted in stress condition (i.e., low pH, lack of nutrient and oxygen) based on ADA’s biological characteristics, suggesting that ADA activates CAR T cells as a trans-signaling to the CAR construct in a tumor specific manner. Remarkably, we observed that the MRCAR T cells inhibit tumor growth more effectively than unmodified CAR T cells in both Huh7 human hepatocellular carcinoma (GPC3-MRCAR) and A549 human non-small cell lung cancer (HER2-MRCAR) mouse models. Thus, MR-CAR T cell therapy represents a promising approach to improve CAR T cell therapy against solid tumors. Citation Format: Yue Hu, Abhijit Sarkar, Kevin Song, Magnus Hook, Andras Heczey, Xiaotong Song. Development of nucleotide metabolic reprogrammed CAR T cell therapy suitable for solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4092.