Abstract The major hurdles in the treatment of solid tumors with chimeric antigen receptor (CAR) T cell therapies are antigen heterogeneity and the immunosuppressive tumor microenvironment. To address these challenges, we developed a universal and switchable CAR T cell therapy platform (zCART) that utilizes cotinine, a pharmacologically inert hapten, as a molecular bridge between anti-cotinine CAR T cells and tumor cells via cotinine-conjugated affibodies. First, we generated two affibody switches targeting distinct tumor-associated antigens and one affibody switch targeting an immune-oncology molecule. In vitro studies demonstrated that all three cotinine-conjugated affibodies, when combined with anti-cotinine CAR T cells, induced potent, dose-dependent cytotoxicity against target-expressing tumor cells. The combination of distinct affibody switches resulted in enhanced anti-tumor activity. These results highlight that the cotinine-based, switchable CAR T cell therapy platform enables flexible, multi-target control of CAR T cell activity and effective elimination of heterogeneous solid tumors. By decoupling antigen recognition from CAR T cell activation, the zCART platform offers a safe, versatile, and next-generation approach to overcoming tumor antigen variability and the immunosuppressive microenvironment, positioning it as a promising strategy for solid-tumor immunotherapy. Citation Format: Ki Hyun Kim, Soohwan Kim, Eun-Hoe Lee, Soo-Youn Lim, Tack-Jin Yoo, Sung Min Kim, E-Young Kim, Ji-Hun Park, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, Junho Chung. A universal and switchable CAR T cell therapy platform (zCART) targeting tumor antigens and the immunosuppressive microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1533.
Kim et al. (Fri,) studied this question.