Figure 3.

Overview of pharmacologically modulated CAR T cells

Lenalidomide-modulated OFF-switch degradable CAR: administration of lenalidomide (len) targets the CAR construct for CRL4^CRBN-mediated ubiquitination and proteasomal degradation, turning the CAR off.²⁴⁷ ON VIPER CAR: versatile protease regulatable CARs contain the hepatitis C virus NS3 protease, which triggers in cis proteolysis and CAR fragmentation. NS3 inhibitors (i.e., grazoprevir [GZV]) prevent CAR proteolysis and enable the formation of full-length, signaling-competent CARs.²⁴⁸ DARIC CAR: dimerizing agent–regulated immunoreceptor complex CARs are composed of two receptors, one containing the antigen-recognition domain and the other the signaling domain. The small molecule rapamycin induces dimerization of the CAR to form a signaling competent receptor. Rapamycin-prebound scFvs (DARIC Plug-Ins) can redirect the CAR against a second antigen.²⁵⁰ synZiFTR: synthetic zinc-finger transcription regulators are DNA-binding zinc fingers fused to drug-binding domains. synZiFTRs, regulated by small molecules, drive the expression of a conventional CAR.²⁵¹