Fig. 2

CAR-T cell therapy challenges and their mitigation strategies. A Cytokine Release Syndrome (CRS) (1) Choice of costimulatory domain CD28 or 41BB as well as the length of the hinge domain influence CRS (2) Cytokines released by macrophages and Inflammatory cytokines and immunostimulatory alarmins released during pyroptosis can be mitigated by using specific drugs for each cytokine (e.g., Etanecerpt, Tocilizumab, Corticosteroids, Dasatinib, Emapalumab) B Tumor-associated antigen escape (1) CAR-T cell-mediated killing of target cell if the target antigen is present on the surface (2) Tumor antigen escape in the absence of surface antigen of the CAR-T cell and potential strategies to abet it by using DUAL CARs and BiTE CARs. C Trafficking and tumor infiltration (1) Schematic diagram to demonstrate reduced homing of CAR-T cells to tumor microenvironments due to the presence of different cellular components (2) Improving homing of CAR-T cells to TME by using armored anti-angiogenic CARs as well as self-driving CARs, which express multiple anti-angiogenic factors. D On-target Off-tumor/Lack of reliable TAAs. Schematic diagram to demonstrate targeting of the normal cell by CAR-T cells if the antigen is expressed on normal cells, which can be mitigated by a selection of reliable tumor-associated antigen by integration of artificial intelligence with big data mining. E Immunosuppressive tumor microenvironment (1) Diagram to illustrate suppressive tumor microenvironment comprising different cellular components including low oxygen, cancer-associated fibroblast, high ROS and other components that diminish proliferation of CAR-T cells (2) CAR-T expressing anti-checkpoint inhibitors to promote the growth of T cells in tumor microenvironments (3) HIF1α-inducible CARs, which get activated in hypoxic tumor microenvironment. HIF1α to promote T cell growth (4) Catalase-expressing CAR to scavenge reactive oxygen species in tumors to promote T cell growth. CARs, Chimeric antigen receptors; BiTE, bispecific T-cell engagers; TAAs, tumor-associated antigens; TME, tumor microenvironment; ROS, reactive oxygen species; HIF1α, hypoxia inducible factor 1 alpha