Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression
Lucia Poncette, … , Felix K.M. Lorenz, Thomas Blankenstein
Lucia Poncette, … , Felix K.M. Lorenz, Thomas Blankenstein
Published December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):324-335. https://doi.org/10.1172/JCI120391.
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Research Article Immunology Oncology

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

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.

Authors

Lucia Poncette, Xiaojing Chen, Felix K.M. Lorenz, Thomas Blankenstein

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Figure 7

TCR-3598_2–transduced CD4+ T cells in combination with TCR-ESO–transduced CD8+ T cells caused tumor regression.

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TCR-3598_2–transduced CD4+ T cells in combination with TCR-ESO–transduce...
(A) Tumor-bearing mice were treated with TCR-3598_2–transduced CD4+ T cells and/or TCR-ESO–transduced CD8+ T cells on day 30, when the tumors were palpable. TCR-1367–transduced CD4+ and/or CD8+ T cells were injected as controls (CD4/CD8-irrelevant) where indicated. Shown are tumor sizes on the indicated days after tumor cell injection. Results from 2 independent experiments were combined. (B) Adoptively transferred CD8+ and CD4+ T cells were detected in the blood 9 days after treatment. Group numbers refer to A. Each dot represents data derived from one individual mouse. One-way ANOVA followed by Bonferroni’s post hoc test was performed for statistical analysis. *P < 0.05, **P < 0.01, ***P < 0.005. (C) CD11b+ stromal cells isolated from tumor material were recognized by TCR-3598_2–transduced CD4+ T cells. As positive controls, CD11b+ stromal cells were loaded with NY-ESO-1116 or anti-CD3/CD28 activator beads (act. beads) were added to the T cells. Intra-assay duplicates with mean values are shown. The results are representative of 3 independent experiments. See also Supplemental Figures 4–8.