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Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression

Item Type:Article
Title:Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression
Creators Name:Poncette, L., Chen, X., Lorenz, F.K.M. and Blankenstein, T.
Abstract:Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8(+) T cells, the importance of CD4(+) T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4(+) T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4(+) T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4(+) T cells and caused tumor regression in combination with NY-ESO-1-redirected CD8(+) T cells in a mouse model of adoptive T cell therapy. These data suggest that MHC II-restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I- and II-restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective.
Keywords:Adoptive Transfer, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, HLA-DR alpha-Chains, HLA-DRB1 Chains, Membrane Proteins, Neoplasm Antigens, Neoplasms, T-Cell Antigen Receptors, Transgenic Mice, Tumor Cell Line, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:324-335
Date:2 January 2019
Official Publication:https://doi.org/10.1172/JCI120391
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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