Isolation and characterization of an HLA-DPB1∗04: 01-restricted MAGE-A3 T-cell receptor for cancer immunotherapy

Xin Yao, Yong Chen Lu, Linda L. Parker, Yong F. Li, Mona El-Gamil, Mary A. Black, Hui Xu, Steven A. Feldman, Pierre Van Der Bruggen, Steven A. Rosenberg, Paul F. Robbins

Research output: Contribution to journalArticle

Abstract

Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumorinfiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4+ T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4+ T cells can also induce tumor regressions in cancer patients. In this study, 2 MAGE-A3-specific TCRs were isolated from a regulatory T-cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of 2 melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1∗04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4+ T cells transduced with 6F9 TCR. Because HLADPB1∗ 04:01 is present in B60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.

Original languageEnglish (US)
Pages (from-to)191-201
Number of pages11
JournalJournal of Immunotherapy
Volume39
Issue number5
DOIs
StatePublished - 2016
Externally publishedYes

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Keywords

  • Cancer immunotherapy
  • Cancer-germline antigens
  • Tumor immunology

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Yao, X., Lu, Y. C., Parker, L. L., Li, Y. F., El-Gamil, M., Black, M. A., Xu, H., Feldman, S. A., Van Der Bruggen, P., Rosenberg, S. A., & Robbins, P. F. (2016). Isolation and characterization of an HLA-DPB1∗04: 01-restricted MAGE-A3 T-cell receptor for cancer immunotherapy. Journal of Immunotherapy, 39(5), 191-201. https://doi.org/10.1097/CJI.0000000000000123