Figure 1.

Generations of chimeric antigen receptor (CAR) molecules. First generation CARs contain a CD3ζ signaling endodomain. Second and third generation CARs, in addition to the CD3ζ domain, incorporate CD28 (second generation) or two or more additional co-stimulatory domains which may include CD27, 4-1BB, ICOS, or OX40 (third generation). Fourth generation CARs include constitutive or inducible expression of co-receptors or soluble cytokines alongside that of the CAR molecule which further promote T-cell activation.