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Fig. 2 | Journal of Hematology & Oncology

Fig. 2

From: A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy

Fig. 2

Building strategies to improve the safety of CAR-modified T cells therapy. For upper left, when the release of cytokines by CAR-T cells after killing tumor cells becomes more pronounced than at basic levels, such as interleukin-2 (IL-2) and interferon-γ (IFN-γ), the inducible caspase 9 (iCasp9) can be dimerized, which usually leads to the rapid apoptosis of T cells expressing the iCasp9 suicide gene by addition of a synthetic dimerizing drug AP1903. For upper middle, to achieve the precise regulation of the CAR-T cells, the inhibitory strategy usually harnesses an inhibitory receptor structure comprising an antigen recognition domain with specificity to antigens only presented on normal tissue, and an inhibitory signaling domain to abort T cell behavior despite concurrent engagement of an activating receptor. In this way, the iCAR-T cell can distinguish the tumor and off-tumor cells, and reversibly restrict CAR-T cell functions in an antigen-selective manner, such as the PD-1- and CTLA-4-based iCARs. For upper right, the modified-T cell cotransduced with a CAR, which stimulates an activation signaling pathway upon binding to the first antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen to provide the costimulatory signal, can eliminate the cancer cells expressing both antigens rather than either antigen alone. This dual receptor pattern provides a safe path to restricting the activity of engineered T cell in vitro and in vivo. For lower left and lower middle, the split CAR-T cell with two physically separate ports exert the therapeutic functions in the presence of tumor antigens and a heterodimerizing small molecule, AP21967. For lower right, bispecific antibodies are used as a switch to control the interaction between the cancer cell and CAR-T cell. The lower three strategies are similar, in which the cytotoxicity of CAR-T cell are dependent upon presence of exogenous molecule and tumor antigens

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