16-02-2017 | Image
a | CARs are created by the fusion of a tumour-specific scFv antibody to either the TCR-associated CD3ζ signalling domain or another intracellular signalling domains from co-stimulatory protein receptors. The scFvs are constructed by cloning the heavy and light chain variable regions of a tumour-specific mAb, separated by a short peptide linker, into a single polypeptide. This structure allows CARs to have the tumour specificity of BCR, and to activate T cells through TCR independently of MHC. CARs can recognize various cell-surface molecules, including proteins, carbohydrate, and glycolipid structures. b | Structure of first-generation to fourth-generation CARs. The first-generation CAR contains one intracellular signalling domain, typically with the CD3ζ signalling domain to allow for TCR signalling. The second-generation CARs have two intracellular signalling domains: a co-stimulatory domain comprising either a CD28 or a 4-1BB signalling domain, coupled with a CD3ζ signalling domain. This arrangement enables T-cell activation and proliferation upon antigen recognition by the scFv region of the CAR. The third-generation CARs have two co-stimulatory domains and a CD3ζ signalling domain. The first co-stimulatory domain is either a CD28 or a 4-1BB domain, with the second co-stimulatory domain consisting of either a CD28, a 4-1BB or a OX40 domain. Fourth-generation 'armoured CAR T cells' combine a second-generation CAR with the addition of various genes, including cytokine and co-stimulatory ligands, to enhance the tumoricidal effect of the CAR T cells. c |Common second-generation CAR T cells. Each academic centre has developed and studied slightly different CAR constructs. Abbreviations: Baylor, Baylor College of Medicine; BCR, B-cell receptor; CAR, chimeric antigen receptor; mAb, monoclonal antibody; MDACC, MD Anderson Cancer Center; MHC, major histocompatibility complex; NCI, National Cancer Institute; Fred Hutchinson, Fred Hutchinson Cancer Research Center; scFv, single-chain variable fragment; TCR, T-cell receptor; UPenn, University of Pennsylvania.