Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells
Cheng-Fu Kuo, Zhen Tong, Yi-Chiu Kuo, Miso Park, Jeremy King, Kevin Ly, Bea Parcutela, Lawrence A. Stern, Zhiqiang Wang, Jonathan C. Hibbard, Brenda Aguilar, Renate Starr, Wen-Chung Chang, Julie R. Ostberg, Daniel Rossi, Mary C. Clark, Darya Alizadeh, Stephen J. Forman, John C. Williams, Christine E. BrownAbstract
Chimeric antigen receptor (CAR) T cells have transformed cancer treatment, yet challenges for achieving broader clinical success remain, including overcoming tumor antigen heterogeneity and limited T-cell fitness. To address these challenges and enhance CAR T-cell functionality, we leveraged meditope technology, a lock-and-key platform where Fab regions of antibodies are modified to bind a small cyclic peptide termed meditope (meP). We developed a panel of meditope-enabled Fab-based CARs (meCARs), which showed selective binding to the meP and comparable activity to traditional single-chain variable fragment (scFv)-based CARs. Focusing on HER2-targeted meCARs for evaluating platform utility, we exploited the modularity of the meditope platform to detect meCAR T cells using meP-fused fluorescent agents, promote meCAR T-cell expansion via meP-fused IL-15 cytokine, and broaden tumor antigen targeting through meP-fused antibodies to address tumor heterogeneity. These findings establish the meditope technology as a versatile strategy to augment CAR T-cell functionality and overcome key limitations of current CAR-based therapies.