Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects

Abstract

Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell's activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.

Figure 1

Schematic of different chimeric antigen receptors (CARs) used to re-direct the T cell immune response. (A) Schematic structure of second-generation classic CAR. Second-generation CARs contain one costimulatory endodomains (illustrated with CD28 or 4-1BB or OX-40 or CD27), cloned in frame with the scFv and the CD3z endodomain. (B) Schematic structure of physiological CAR which contains full length CD27 or NKG2D receptor fused to CD3z endodomain. (C) Schematic structure of universal CAR, which utilize biotin or anti-FITC scFv as binding domain fused costimulatory and CD3z endodomains.

Figure 2

Schema for adoptive cellular therapy with genetically modified CAR T cells. T cells can be isolated from patient blood by apheresis, and genetically modified to express a transgene encoding a tumor-specific CAR. The genetically modified T cells are then expanded in vitro using several approaches before infusion into the patient.