期刊
ONCOGENE
卷 41, 期 34, 页码 4104-4114出版社
SPRINGERNATURE
DOI: 10.1038/s41388-022-02416-5
关键词
-
资金
- National Institutes of Health (NIH) [R01 CA174844, R01 CA181258, R01 CA204484, R21 CA229961, R21 CA263240]
- Klorfine Foundation
The success of CAR-T therapy in treating hematologic malignancies has led to the development of sCAR-T systems. This study investigates the therapeutic potential of sCAR-Ts targeting ROR1 and identifies a switch with low affinity but potent antitumor activity. By converting the same antibody to a conventional CAR-T, it outperforms a clinically tested CAR-T with higher affinity. Therefore, sCAR-Ts have therapeutic utility and can aid in screening conventional CAR-T candidates.
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 similar to 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.
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