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Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy.

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Molecular therapy : the journal of the American Society of Gene Therapy 📖 저널 OA 84.1% 2024: 1/1 OA 2025: 22/22 OA 2026: 35/46 OA 2024~2026 2026 Vol.34(3) p. 1382-1398
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Wong JKM, Lam PY, Coleborn E, Jose J, Alim L, Tu C

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an emerging target in cancer immunotherapy, recognized for its consistent and elevated expression across several epithelial tumors, including

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APA Wong JKM, Lam PY, et al. (2026). Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy.. Molecular therapy : the journal of the American Society of Gene Therapy, 34(3), 1382-1398. https://doi.org/10.1016/j.ymthe.2025.11.021
MLA Wong JKM, et al.. "Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy.." Molecular therapy : the journal of the American Society of Gene Therapy, vol. 34, no. 3, 2026, pp. 1382-1398.
PMID 41338184 ↗

Abstract

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an emerging target in cancer immunotherapy, recognized for its consistent and elevated expression across several epithelial tumors, including triple-negative breast cancer (TNBC). TNBC is an aggressive and difficult-to-treat cancer, with limited effective therapeutic options currently available. Therapeutic approaches centered on targeting ROR1 have therefore become increasingly popular, with ROR1 chimeric antigen receptor (CAR) T cells currently in clinical trials to treat TNBC patients. While ROR1-targeting therapies have shown promising preclinical results, single arm treatment has often shown low efficacy as well as off-target toxicity. Natural killer (NK) cell-based immunotherapies, such as antibody-dependent cell cytotoxicity-inducing monoclonal antibodies and CAR NK cells, have also been shown to induce cancer cell cytotoxicity; however, with less toxicity compared with CAR T cells. Here, we developed and characterized a phage-derived single-chain fragment variable (scFv) against a highly specific ROR1 region and generated scFv-derived chimeric monoclonal antibodies and anti-ROR1-CAR NK cells, which show anti-cancer efficacy against TNBC cells. Additionally, we found TGF-β inhibition using either small-molecule inhibitors or CRISPR-Cas9-edited NK cells could further enhance ROR1-targeting therapy persistence and efficacy in controlling TNBC tumor growth.

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