Poncette et al. found that NY-ESO-1-specific TCRs isolated from ABabDR4 mice – which express human HLA-DR-4-restricted TCRs, but lack tolerance-inducing human antigens – had higher functional avidity and recognition of NY-ESO-1-positive cell lines than NY-ESO-1-specific TCRs derived in vitro from human CD4+ T cells. In a mouse model of adoptive transfer in which HLA-DR-4 was expressed on host stromal cells but not NY-ESO-1+ tumor cells, the combination of CD4+ T cells with ABabDR4-derived NY-ESO-1 TCRs and NY-ESO-1-specific CD8+ T cells induced superior tumor regression, though it was short-term due to antigen loss.

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.

Author Info: (1) Max Delbruck Center for Molecular Medicine, Berlin, Germany. (2) Institute of Immunology, Charite Campus Berlin Buch, Berlin, Germany. (3) Max Delbruck Center for Molecular

Author Info: (1) Max Delbruck Center for Molecular Medicine, Berlin, Germany. (2) Institute of Immunology, Charite Campus Berlin Buch, Berlin, Germany. (3) Max Delbruck Center for Molecular Medicine, Berlin, Germany. (4) Max Delbruck Center for Molecular Medicine, Berlin, Germany. Institute of Immunology, Charite Campus Berlin Buch, Berlin, Germany. Berlin Institute of Health, Berlin, Germany.

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