Fig. 1

Structure of different chimeric antigen receptor (CAR) generations. a The core structure of a CAR, highlighting the major components of the extracellular domain, the transmembrane domain and the intracellular domain (endodomain). b Evolution of the development of CARs from the first generation, which contained only ITAM motifs in the intracellular domain. Second-generation CARs included one co-stimulatory molecule (CM)1, and third-generation CARs contained a second CM. The fourth generation of CARs was based on second-generation CARs (containing 1–3 ITAMs) paired with a constitutively or inducibly expressed chemokine (e.g. IL-12). These T cells are also referred to as T cell redirected for universal cytokine-mediated killing (TRUCKs). The fifth, or ‘next generation’, is also based on the second generation of CARs, with the addition of intracellular domains of cytokine receptors (e.g. IL-2Rβ chain fragment). ITAM immunoreceptor tyrosine-based activation motifs, CD co-stimulatory domain, IL-12 activation of interleukin 12 transcription, IL-2Rβ truncated intracellular interleukin 2β chain receptor with a STAT3/5 binding motif