Fig. 1.

The structure of four generations of chimeric antigen receptor (CAR). Chimeric antigen receptor contains a single-chain variable region (scFv) of an antibody, hinge region, transmembrane region, co-stimulatory domain (except first-generation CAR) and a T-cell-activation domain. First-generation CAR has a single signaling molecule such as CD3ζ and lacks a co-stimulatory domain such as CD28 or 4-1BB. The second-generation CAR has a co-stimulatory domain derived from either CD28 or 4-1BB and can generate double signals via costimulatory domain to enhance the activity and persistence of CAR-T cell in vivo. Third-generation CAR has two costimulatory domains such as CD28 and 4-1BB. Fourth-generation CAR can produce and release transduced cytokines to enhance the activity of CAR-T cells and change the tumor microenvironment