Adoptive T cell transfer of engineered T cells with a chimeric antigen receptor (CAR) can harness the patients' immune system to recognize a specific antigen and redirect T cells to target disease. Conventional CAR T cells, however, are specific to a single antigen. While remarkably effective, antigen escape, due in part to the heterogeneous nature of a tumor, renders these CAR T cells ineffective. In order to address the disadvantage of conventional CAR T cells, we developed a switchable CAR T cell system. Specifically, we replaced the antigen-binding domain of a conventional CAR with a meditope and used meditope-enabled monoclonal antibodies (memAbs) to alter antigen specificity. As the T cell decoration is similar to how a bike rack is used to transport bicycles on cars, we have coined the technology a Fabrack. To fully examine our switchable CAR T cell system, Fabrack CAR Jurkat-NFAT-Luc cells were established to quantitate T cell activation through NFAT-regulated luciferase expression. Multiple memAbs with unique antigen specificity were combined with the Fabrack CAR Jurkat cells and target tumor cells and demonstrated the feasibility, specificity and robustness of the in vitro system. Next, native human T cells transduced with Fabrack showed dramatic tumor-killing effect when coupled with an antigen specific memAb. The engaged Fabrack T cells proliferated with remarkably increased CD107a and IFNγ, indicating functional activation of T cells. Live cell imaging demonstrated selective killing of target cells in the presence of corresponding memAbs. Furthermore, tumor burden in immunocompromised mice with OVCAR3 xenografts was largely reduced when mice were treated with Fabrack T cells and memAbs. Collectively, these studies suggest the feasibility of switchable CAR T cell and support further development for future clinical use in cancer immunotherapy.

Citation Format: Yi-Chiu Kuo, Jeremy D. King, Cheng-Fu Kuo, Victor Kenyon, Miso Park, Wen-Chung Chang, Lawrence Stern, Christine E. Brown, John C. Williams. Antibody-based redirection of meditope-CAR T cells selectively kill antigen bearing tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6591.