Figure 2. Overcoming toxicities through CAR-engineering strategies.

CAR T cells show different levels of activation and cytokine production depending on (A) costimulatory domain, (B and C) length of the transmembrane domain, and (D) nature and composition of the hinge/transmembrane domain (E). CAR T cells have been engineered to secrete soluble IL-1 receptor antagonists or induce a targeted deletion on the gene encoding for GM-CSF associated with toxicities (F). Administration of a protease inhibitor controls CAR surface expression, acting as an “on/off switch” based on a complex composed of a self-cleaving protease and a degron moiety. TM, transmembrane; AICD, activation-induced cell death.