Identifying T-cell receptors (TCRs) that bind tumor-associated antigens (TAAs) with optimal affinity is a key bottleneck in the development of adoptive T-cell therapy of cancer1. TAAs are unmutated self proteins, and T cells bearing high-affinity TCRs specific for such antigens are commonly deleted in the thymus2. To identify optimal-affinity TCRs, we generated antigen-negative humanized mice with a diverse human TCR repertoire restricted to the human leukocyte antigen (HLA) A*02:01 (ref. 3). These mice were immunized with human TAAs, for which they are not tolerant, allowing induction of CD8+ T cells with optimal-affinity TCRs. We isolate TCRs specific for the cancer/testis (CT) antigen MAGE-A1 (ref. 4) and show that two of them have an anti-tumor effect in vivo. By comparison, human-derived TCRs have lower affinity and do not mediate substantial therapeutic effects. We also identify optimal-affinity TCRs specific for the CT antigen NY-ESO. Our humanized mouse model provides a useful tool for the generation of optimal-affinity TCRs for T-cell therapy.
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The authors thank G. Willimsky for discussion, S. Kupsch and S. Fürl for technical assistance, and I. Hoeft for animal caretaking. C. Linnemann and T. Schumacher kindly provided the NY-ESO-1157/HLA-A2 multimer. This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich TR36) and the Berlin Institute of Health (BIH).
The Max-Delbrück-Center for Molecular Medicine (T.B., M.O., C.L.) applied for a patent on the MAGE-A1-specific TCRs.
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Obenaus, M., Leitão, C., Leisegang, M. et al. Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat Biotechnol 33, 402–407 (2015). https://doi.org/10.1038/nbt.3147
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