Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

TLDR: The ON-switch CAR exemplifies a simple and effective strategy to integrate cell-autonomous decision-making with exogenous, reversible user control and highlights the importance of developing optimized bio-inert, orthogonal control agents such as small molecules and light, together with their cellular cognate response components, in order to advance precision-controlled cellular therapeutics.

Abstract: There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control.