期刊
CANCER CELL
卷 35, 期 3, 页码 489-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.02.003
关键词
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资金
- National Institutes of Health [R01CA114536]
- Cancer Center Support Grant [P30 CA015704]
- Juno Therapeutics
- Cancer Research Institute
- FHCRC Interdisciplinary Training Grant in Cancer Research
Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1(+) stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1(+) tumor cells but not ROR1(+) stromal cells. SynNotch receptors induced ROR1 CAR expression selectively within the tumor, resulting in tumor regression without toxicity when tumor cells were segregated from, but not when co-localized with, normal ROR1(+) cells. This strategy, thus, permits safe targeting of tumors that are sufficiently separated from normal cells.
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