Fig. 1

The structure of TCR and the three generations of CAR. T cell receptor (TCR) includes antigen-binding domain, transmembrane domain (TM domain), and immune receptor tyrosine-based activation motifs (ITAMs). The binding domain of CAR consists of a scFv, comprising the light (VL) and heavy (VH) variable fragments of a TAA-specific monoclonal antibody joined by a flexible linker. The intracellular parts are different between the three generations of CAR. The first-generation CAR only has the signal transduction domain of the CD3-zeta chain (CD3ζ) or Fc receptor γ (FcRγ) which mediated transient persistence, inefficient cytotoxicity, and low-level cytokine secretion. The second and third generation CAR add one or more co-stimulatory domains (CD28, 4-1BB, or OX40) to the first generation, which lead to the enhanced cytotoxicity and cytokine secretion along with prolonged T cell persistence