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Chimeric antigen receptor‐engineered T ( CAR ‐T)‐cell therapy holds significant promise for the treatment of hematological malignancies, especially for B‐cell leukemia and lymphoma. However, its efficacy against non‐hematological malignancies has been limited as a result of several biological problems characteristic of the tumor microenvironment of solid tumors. One of the main hurdles is the heterogeneous nature of tumor‐associated antigens ( TAA ) expressed in solid tumors. Another hurdle is the inefficient activation and limited persistence of  CAR ‐T cells, mainly as a result of T‐cell exhaustion caused by immunosuppressive factors in the tumor microenvironment. In the present study, to address these problems, we engineered  CAR ‐T cells to produce antagonistic anti‐programmed cell death protein 1 ( PD ‐1) single‐chain variable fragment (scFv), by which  PD ‐1‐dependent inhibitory signals in  CAR ‐T cells and adjacent tumor‐specific non‐ CAR ‐T cells are attenuated. In mouse solid tumor models,  PD ‐1 scFv‐producing  CAR ‐T cells induced potent therapeutic effects superior to those of conventional  CAR ‐T cells, along with a significant reduction of apoptotic cell death not only in  CAR ‐T cells themselves but also in  TAA ‐specific T cells in the tumor tissue. In addition, the treatment with anti‐ PD ‐1 scFv‐producing  CAR ‐T cells resulted in an increased concentration of  PD ‐1 scFv in tumor tissue but not in sera, suggesting an induction of less severe systemic immune‐related adverse events. Hence, the present study developed anti‐ PD ‐1 scFv‐producing  CAR ‐T cell technology and explored its cellular mechanisms underlying potent antitumor efficacy.

cancer science

Improved survival of chimeric antigen receptor‐engineered T ( CAR ‐T) and tumor‐specific T cells caused by anti‐programmed cell death protein 1 single‐chain variable fragment‐producing  CAR ‐T cells