期刊
NATURE BIOTECHNOLOGY
卷 36, 期 9, 页码 847-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.4195
关键词
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资金
- NIH Cancer Center support grant [P30 CA008748]
- US National Institutes of Health [5 P01 CA190174-03, 5 P50 CA192937-02]
- Annual Terry Fox Run for Cancer Research
- Kate's Team
- Carson Family Charitable Trust
- Leukemia & Lymphoma Society Specialized Center of Research Program [7014]
- William Lawrence and Blanche Hughes Foundation
- ARD Foundation
- Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1(+) hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.
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