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].