ROR1-targeting switchable CAR-T cells for cancer therapy
Peng H, Nerreter T, Mestermann K, Wachter J, Chang J, Hudecek M, Rader C (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 41
Pages Range: 4104-4114
Journal Issue: 34
DOI: 10.1038/s41388-022-02416-5
Abstract
The success of chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies has prompted the development of numerous CAR-T technologies, including switchable CAR-T (sCAR-T) systems that combine a universal CAR-T with bispecific adapter proteins. Owing to their controllability and versatility, sCAR-Ts have received considerable attention. To explore the therapeutic utility of sCAR-Ts targeting the receptor tyrosine kinase ROR1, which is expressed in hematologic and solid malignancies, and to identify bispecific adaptor proteins that efficiently mediate universal CAR-T engagement, a panel of switches based on ROR1-targeting Fabs with different epitopes and affinities was compared in in vitro and in vivo models of ROR1-expressing cancers. For switches targeting overlapping or identical epitopes, potency correlated with affinity. Surprisingly, however, we identified a switch targeting a unique epitope with low affinity but mediating potent and selective antitumor activity in vitro and in vivo. Converted to a conventional CAR-T, the same anti-ROR1 mAb (324) outperformed a clinically investigated conventional CAR-T that is based on an anti-ROR1 mAb (R12) with ~200-fold higher affinity. Thus, demonstrating therapeutic utility on their own, sCAR-Ts also facilitate higher throughput screening for the identification of conventional CAR-T candidates for preclinical and clinical studies.
Involved external institutions
Germany (DE)
United States (USA) (US)How to cite
APA:
Peng, H., Nerreter, T., Mestermann, K., Wachter, J., Chang, J., Hudecek, M., & Rader, C. (2022). ROR1-targeting switchable CAR-T cells for cancer therapy. Oncogene, 41(34), 4104-4114. https://doi.org/10.1038/s41388-022-02416-5
MLA:
Peng, Haiyong, et al. "ROR1-targeting switchable CAR-T cells for cancer therapy." Oncogene 41.34 (2022): 4104-4114.
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