期刊
IMMUNITY
卷 55, 期 10, 页码 1953-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2022.09.004
关键词
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类别
资金
- Personalized Health and Related Technologies Postdoctoral Fellowship
- NCCR Molecular Systems Engineering
- Helmut Horten Stiftung
A major challenge in TCR immunotherapy is finding natural TCRs with high activity and specificity to tumor antigens. In this study, we developed a method called TCR-Engine to successfully engineer synthetic TCRs with increased potency and specificity to a clinically relevant tumor antigen. We validated their potential for translation through in vitro and in vivo assessments of safety and efficacy.
A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable tech-nology for engineering of safe and potent synthetic TCRs for immunotherapy applications.
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