Development of a high-affinity anti-ROR1 variable region for broad anti-cancer immunotherapy
- Author(s)
- Wong, JKM; Lam, PY; Coleborn, E; Jose, J; Alim, L; Tu, C; Antczak, M; Dietmair, B; Hagh, AG; Noronha, L; Cheetham, SW; Hooper, J; Beavis, PA; Merino, D; Berthelet, J; Aoude, LG; McCart-Reed, AE; Lakhani, S; Simpson, PT; Rossi, GR; Brooks, AJ; Jones, ML; Simpson, F; Souza-Fonseca-Guimaraes, F;
- Journal Title
- Molecular Therapy
- Publication Type
- Online publication before print
- 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.
- Keywords
- Adcc; CAR NK cells; CRISPR/Cas9; Frizzled-Kringle domain; TGFBR2 knockout; antibody drug conjugate; natural killer cells; phage display; scFv; triple negative breast cancer
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1016/j.ymthe.2025.11.021
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-27 11:48:49
Last Modified: 2026-01-27 11:48:55