Fig. 1.

Summarized safety strategies for CAR-T cells to overcome toxicity. a HSV-tk phosphorylates GCV, forming toxic GCV-triphosphate compound that competes with triphosphate as a substrate incorporated into DNA, leading to inhibition of DNA synthesis and the cellular death. b Conditional administration of AP1903 forms dimerization with iCasp9 and activates the downstream caspase molecules, resulting in apoptosis of CAR-T cells. c CAR-T cells expressing CD20 or EGFRt could be efficiently and specifically eliminated with clinically approved monoclonal antibody rituximab or cetuximab through CDC/ADCC. d T cells were transduced a CAR with CD3ζ recognizing one antigen and a CCR with CD28 and/or 4-1BB binding another antigen. e TanCAR comprised of two tandemly linked scFvs targeting different tumor antigens coupled with one activation domain. f The synNotch receptor first recognized a tumor antigen, and then leading to the release of a transcriptional activator domain to drive the expression of a CAR that targeting another tumor antigen. g The iCAR consists of a scFv specific to the antigens expressed exclusively on normal tissue, and an inhibitory signaling domain of immunoinhibitory receptors (PD-1 and CTLA-4) to restrict T cell activity despite concurrent engagement of an activating receptors. h CAR-T cells do not directly recognize antigen on target cells, but they are recruited to effector cells through a bispecific small molecule. i On-switch CAR-T cells are activated by antigen recognition and a small molecule to connect the costimulatory domains and the splitting downstream ITAMs