Figure 1:

Generations of chimeric antigen receptor (CAR). The single chain scFv- derived from the heavy (VH) and light (VL) antigen-binding domains of antibodies- is fused through a hinge and a transmembrane domain to CD3ζ, the primary signalling domain from the T-cell receptor (TCR) complex; this is the first-generation CAR. Additional intracellular domains (such as CD28 and 41BB) added for costimulatory signals, to yield second- and third- generation CARs. In addition to costimulatory signals, the fourth generation CAR (also referred to as “TRUCK”) incorporates transgenic expression of stimulatory molecules (cytokines, enzymes, or ligands).