Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells

Abstract 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 fragment antigen-binding (Fab) regions of antibodies are modified to bind a small cyclic peptide termed meditope peptide (meP). We developed a panel of meditope-enabled Fab-based CARs (meCAR), which showed selective binding to the meP and comparable activity with traditional single-chain variable fragment–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 IL15 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. See related Spotlight, p. 1536