| First Author | Srivastava S | Year | 2019 |
| Journal | Cancer Cell | Volume | 35 |
| Issue | 3 | Pages | 489-503.e8 |
| PubMed ID | 30889382 | Mgi Jnum | J:273225 |
| Mgi Id | MGI:6285344 | Doi | 10.1016/j.ccell.2019.02.003 |
| Citation | Srivastava S, et al. (2019) Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting. Cancer Cell 35(3):489-503.e8 |
| abstractText | 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. |
