DROP-CARs: Engineering Reversible, Drug-Controlled CAR T-cell Activity with a Clinically Approved Small Molecule

A major limitation in applying chimeric antigen receptor (CAR) T cells to solid tumors is toxicity in healthy tissues caused by a lack of tumor-specific targets. A promising strategy to overcome this deleterious cytotoxicity is to engineer control into CAR T cells beyond that conferred by antigen recognition alone. In a recent issue of Nature Chemical Biology, Scheller and colleagues report the development of a CAR that is inactivated through introducing the small molecule, venetoclax, which is a clinically approved targeted Bcl-2 inhibitor. The authors design venetoclax-dependent release of the CAR extracellular binding domain, thereby disrupting T-cell contact with tumor cells and suppressing cytotoxicity. Furthermore, they demonstrate the reversibility of this approach as withdrawal of the drug restores CAR T-cell function. This work establishes a foundation for clinically translatable remote-controlled CAR T-cell therapy for solid tumors.