Structure of chimeric antigen receptors (CAR). CARs are composed of a single-chain fragment variable (scFv, containing the heavy chain variable domain (VH) and the light chain variable domain (VL) of a monoclonal antibody attached together via a flexible linker) linked via a spacer sequence to a transmembrane (TM) domain and to the CD3ζ chain (first-generation CARs). Second- and third-generation CARs additionally contain one or two costimulatory domains, respectively. VH, heavy chain variable domain; VL, light chain variable domain; TM, transmembrane domain; co-1, costimulatory domain 1; co-2, costimulatory domain 2.