3.2 Chimeric antigen receptor T cells (CAR-T) therapy is another new strategy for the treatment of NSCLC
CAR-T cells are genetically engineered T cells that express synthetic CAR vectors. On the basis of self proliferation, CAR-T cells specifically recognize and bind antigens (such as CD19) on tumor cells and specifically kill tumor cells[125-126]. Since 2017, Kymriah (CTL019) and Yescarta (KTE-C19) CAR-T therapies have successively been approved for use. Furthermore, CAR-T therapy has emerged as a novel treatment strategy with promising results against blood tumors [127].However, when the research further turned its attention to solid tumors, which account for 90% of all tumors, CAR-T therapy did not get satisfactory results. The particularity of solid tumors themselves and their microenvironment brought great challenges to CAR-T cell therapy[128].
Unlike CD19, tumor cells in solid tumors generally express multiple targets abnormally, and these abnormally expressed antigens are also expressed in normal tissues. For example, the current research targets for glioma include prostate-specific antigen (PSMA), carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), epithelial cell adhesion molecule (EpCAM), and Mesothelin[129-130]. Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components in the tumor microenvironment [131], constituting the tumor stromal layer that releases certain inhibitory cytokines. Immunosuppressive cells such as Treg cells, bone marrow-derived suppressive cells, and M2 type macrophages secrete TGF-β, IL-10, and other cytokines to negatively regulate CAR-T cell immune response. In addition, solid tumor cells lose cytokine receptors and escape immune cell surveillance. CAR-T cells cannot effectively respond to chemotaxis secreted by tumor cells, which inhibits their homing ability. However, the high expression of immunosuppressive receptors in solid tumors inhibits the effective activation of CAR-T cells and lowers the efficacy of CAR T-cell therapy [132-134].
As a new strategy for treating NSCLC, CAR-T therapy has made considerable breakthroughs and entered a rapid development stage[135-136]. Thus far, more CAR-T studies have focused primarily on NSCLC [137-138]. The most common target antigens of NSCLC include human epidermal growth factor receptor (EGFR), mesothelin, mucin 1 (MUC1), PD-L1[139], carcinoembryonic antigen (CEA)[140], and HER2 [141]. Studies have shown that T cells redirected to EphA2 by EphA2-specific CAR have effective antitumor activity against NSCLC in vitro and in vivo. Thus, these antigens are potentially novel targets for NSCLC treatment [142].