Chimeric antigen receptor T cells: a novel therapy for solid tumors

Abstract

The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

Keywords: CAR-T cell; EGFR; HER2; Mesothelin; Solid tumors.

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

Fig. 2

Antitumor mechanism of CAR-T. a TCR recognizes TAAs depending on the MHC presentation. The advantage is that TCR could recognize intracellular and extracellular antigens. While tumor cells often downregulate MHC expression to escape the killer T cells, b CAR-T cells can specifically recognize the tumor antigens in a MHC-independent manner. And then, the T cells were activated through the phosphorylation of ITAMs followed by enhanced cytokine (include IL-2, IL-4, IFN-γ, IL-12, and TNF) secretion, T cell proliferation, and cytotoxicity. IL-12 could recruit and reinforce the functions of innate immune cells such as NK cell and macrophage. Activated T and CAR-T cells perform cytotoxicity mainly through secretion of perforin and granzyme granules, also through the death receptor pathway such as Fas/Fas-L. Due to added co-stimulatory signal to endodomain, antitumor activity mediated by CARs is stronger than TCRs