Chimeric antigen receptor-engineered T cells for immunotherapy of cancer

Abstract

CD4+ and CD8+ T lymphocytes are powerful components of adaptive immunity, which essentially contribute to the elimination of tumors. Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors (CARs). First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients. However, further improvement is required, which may be achieved by second or third generation CAR-engrafted T cells.

Figure 1

Principles of CAR architecture. CARs consist of a binding moiety, an extracellular hinge and spacer element, a transmembrane region (TM), and the signaling endodomain. Commonly the binding moiety consists of scFv derived from a TAA-specific monoclonal antibody and the signaling domain(s) come(s) from activating and costimulatory immune receptors.

Figure 2

Antitumor effects mediated by CAR-engrafted T cells. CAR-modified T cells can recognize tumor cells via binding of the CAR to its TAA independent of TCR-MHC/Peptide interactions. As a result T cells are activated and can efficiently eliminate tumor cells by the secretion of perforin and granzymes as well as the expression of FasL and tumor necrosis factor-related apoptosis inducing ligand (TRAIL). In addition, other tumor-infiltrating immune cells can be activated by the secretion of various cytokines.

Figure 3

Evolution of CAR signaling capacities. First generation CARs transmitted activating signals only via ITAM-bearing signaling chains like CD3ζ or FcεRIγ, licensing the engrafted T cells to eliminate tumor cells. Second generation CARs contain an additional costimulatory domain (CM I), predominantly the CD28 domain. Signaling through these costimulatory domain leads to enhanced proliferation, cytokine secretion, and renders engrafted T cells resistant to immunosuppression and induction of AICD. Recent developments fused the intracellular part of a second costimulatory molecule (CM II) in addition to CD28 and ITAM-bearing signaling chains, thus generating tripartite signaling CARs. T cells engrafted with third generation CARs seem to have superior qualities regarding effector functions and in vivo persistence.