Figure 2. Receptor expression and engagement of antigen. (I) T cell receptors (TCRs) consist of a heterodimer of a- and b-chains that associate with the g-, d-, e- and z-chains of the CD3 complex. The TCR recognizes processed antigenic peptides presented by major histocompatibility complex class I (MHC) molecules on the surface of a tumor cell. The targets can thus be antigens derived from intracellular or extracellular proteins as long as they are processed and displayed as MHC complexes.

The first generation of TCRs generally had low affinity and specificity for their targets because the immune system naturally avoids making high-affinity TCRs against self-proteins to prevent autoimmune reactions. Thus, second-generation TCRs used endogenous, tumor-targeting TCRs as a starting point and were then optimized for potency and cancer antigen affinity.

(II) Chimeric antigen receptors (CARs) are synthetic receptors made up of a single-chain antibody variable fragment (scFv) linked through a hinge domain to one or more T cell signaling domains capable of activating the T cell response. CARs can target tumor-associated protein, carbohydrate or glycolipid antigens presented in an MHC-independent manner on the outside of cells.

The first generation of CARs included only one T cell-activating signaling molecule and showed limited antitumor effects owing to suboptimal T cell stimulation and proliferation.

The real breakthroughs occurred with second-generation CARs, which consist of two T cell signaling domains that provide enhanced activation of T cells and produce better T cell expansion, proliferation and persistence than first-generation CARs. (Figure based on Figure 1 in Kershaw, M.H. et al., Nat. Rev. Cancer 13, 525-541; 2013.)