Figure 4.

The generations of chimeric antigen receptor T-cells. Chimeric antigen receptors (CARs) target tumor antigen independently of major histocompatibility complex I (MHC-I). They consist of an ectodomain, a hinge domain, a transmembrane domain, and an endodomain. First-generation CARs consisted of single chain variable fragment (scFv) (light chain variable region [VL] and heavy chain variable region [VH]) and cluster of differentiation 3ζ (CD3ζ) alone. Second-generation CARs were generated to mediate T-cell activation by the immunoreceptor tyrosine-based activation motif (ITAM) of the CD3ζ chain with a single costimulatory molecule, either CD28 or 4-1BB. Improved third-generation CARs were generated by combining the ITAM of CD3ζ chain with two costimulatory molecules, such as CD27 plus 4-1BB or CD28 plus OX40.