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| Item Type: | Article |
|---|---|
| Title: | Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system |
| Creators Name: | Chen, X.T., Leisegang, M., Gavvovidis, I., Pollack, S.M., Lorenz, F.K.M., Schumacher, T.N., Daumke, O. and Blankenstein, T. |
| Abstract: | Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1(157-165) restricted to HLA-A*02:01. We compared the functions of the murine-derived TCR with human-derived TCRs and an affinity matured TCR, using in vitro co-culture and in vivo adoptive T cell transfer in tumor-bearing mice. Alanine scan, x-scan, LCL assay were employed to address the cross-reactivity of the NY-ESO-1(157-165) specific TCRs. We also used human tissue cDNA library and human primary cells to assess the safety of adoptive T cell therapies targeting NY-ESO-1 antigen in the clinic. One of the murine-derived human TCRs, TCR-ESO, exhibited higher functional avidity compared to human-derived NY-ESO-1(157-165) specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an in vitro affinity-matured TCR, TCR 1G4-α95LY, which was applied in clinical trials. TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-α95LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies. |
| Keywords: | Adoptive T Cell Therapy, TCR Engineering, Humanized Mice, NY-ESO-1, HLA-A*0201, Animals, Mice |
| Source: | Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Publisher: | Frontiers Media SA |
| Volume: | 15 |
| Page Range: | 1524629 |
| Date: | 24 December 2024 |
| Official Publication: | https://doi.org/10.3389/fimmu.2024.1524629 |
| PubMed: | View item in PubMed |
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