Abstract Chimeric antigen receptor (CAR) T cell therapy is constrained by on-target, off-tumor toxicities and cellular exhaustion because of chronic antigen exposure. CARs incorporating small-molecule controlled on- and off-switches can enhance both safety and therapeutic efficacy but their design is limited by the scarcity of nonimmunogenic protein elements responsive to nonimmunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here we combine rational design and library-based optimization of a protein–protein interaction (PPI) of human origin to develop venetoclax-controlled drug-regulated off-switch PPI (DROP)-CARs. DROP-CARs enable dose-dependent release of the tumor-targeting scFv and consequent reduction in T cell binding to the tumor cell. Additionally, we present proof of concept for a dual DROP-CAR controlled by different small molecules, as well as for logic-gated synthetic receptors enabling STAT3 signaling. We demonstrate in vitro and in vivo function of DROP-CAR T cells and conclude that the approach holds promise for clinical application.
Scheller et al. (2026) studied this question.