Abstract
Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self‐renewal, multi‐lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T‐cell (CAR‐T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs‐targeted CAR‐T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR‐T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity.
Highlights
The hypothesis that tumours originated from “stem cells” was first proposed about 150 years ago
We analysed the feasibility of targeting cancer stem cells (CSCs) by using chimeric antigen receptor T (CAR-T) cells, summarized published studies on CSCs-targeted chimeric antigen receptors (CAR)-T therapy, pointed out the challenges of targeting CSCs by CAR-T cells related to toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, tumour heterogeneity and purposed promising strategies, such as novel CAR containing a JAK-STAT signalling domain, modulation of chemokine signalling, directing CAR-T cell to target vascular endothelial growth factor receptor 2(VEGFR2), combining CSCs-targeted therapy with FDA- approved PD-1/PD-L1 checkpoint inhibitors, multi-target CAR-T cell therapies and transgenic modification of the CAR structure, for the future development of CSCs-targeted therapy
After carefully investigating laboratory studies on targeting CSCs with CAR-T therapies from very limited number of reports, we proposed that the existing laboratory research on CSCs-targeted CAR-T therapies can be divided into two categories (Table 2): (1) the first category is targeting specific antigen molecules of CSCs, such as CD133, EpCAM or ALDH and designing corresponding CAR-T cells for carrying out in vitro killing experiments and in vivo animal experiments for verification and (2) the second category is targeting “general” antigens on CSCs
Summary
The hypothesis that tumours originated from “stem cells” was first proposed about 150 years ago. Cancer stem cells have some unique characteristics, such as slow rate of division, high expression of drug efflux pumps,[9] heightened activation of DNA repair mechanisms[10] and microenvironment characteristics: hypoxia and acidosis,[11] which is due to the expression of specific surface markers These surface markers can be used as specific targets for CAR-T therapy to eliminate CSCs. In addition, the expression of MHC molecules on the surface of CSCs is low, which causes MHC restriction when immunotherapy is used to target CSCs.[8] in CAR-T therapy, CAR-T cells can recognize the target antigen with no MHC restrictions,[8] which endows some advantages for the application of CAR-T therapy to eliminate CSCs. In this review, we analysed the feasibility of targeting CSCs by using CAR-T cells, summarized published studies on CSCs-targeted CAR-T therapy, pointed out the challenges of targeting CSCs by CAR-T cells related to toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, tumour heterogeneity and purposed promising strategies, such as novel CAR containing a JAK-STAT signalling domain, modulation of chemokine signalling, directing CAR-T cell to target vascular endothelial growth factor receptor 2(VEGFR2), combining CSCs-targeted therapy with FDA- approved PD-1/PD-L1 checkpoint inhibitors, multi-target CAR-T cell therapies and transgenic modification of the CAR structure, for the future development of CSCs-targeted therapy. A variety of strategies mentioned above have been used to target CSCs, these
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