Figure 4.

Overview of adaptor CARs

The universal CAR (UniCAR) is composed of two components: a universal CAR construct, which recognizes the peptide motif included in the adaptor, and an adaptor containing an scFv against the target antigen. Administration of the adaptor is required for CAR-T cell activation and recognition of the target cell.²⁵⁶ RevCAR: bispecific scFvs are used to link the CAR, containing a peptide motif as the extracellular domain, and the target antigen.²⁶² The SUPRA CAR design features a zipCAR containing a leucine zipper instead of an antigen-recognition domain, and the cognate leucine zipper fused to an scFv against the target antigen (zipFv). An AND-gate system is created by separating the co-stimulatory and signaling domains and a NOT gate is achieved through competition: when zipFvs against antigen A and B are both engaged, their complementary zippers are engaged, preventing CAR binding.²⁶³ Co-LOCKR: The colocalization-dependent latching orthogonal cage/key protein system is composed of a “cage” protein that uses a latch domain to sequester a peptide (i.e., Bim) in an inactive conformation. The binding of a key protein triggers a conformational change enabling the peptide to bind to an effector protein (i.e., Bcl-2 fused to a CAR). A second key with a different targeting domain provides an OR gate, while a decoy that sequesters the key can be used to create a NOT gate.²⁶⁴