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

Fingerprint

T-Cell Antigen Receptor
Immunotherapy
T-Lymphocytes
Neoplasms
Adoptive Transfer
Clone Cells
Clinical Trials
Regulatory T-Lymphocytes
Melanoma
Vaccination
Lymphocytes

Keywords

  • Cancer immunotherapy
  • Cancer-germline antigens
  • Tumor immunology

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Isolation and characterization of an HLA-DPB1∗04 : 01-restricted MAGE-A3 T-cell receptor for cancer immunotherapy. / Yao, Xin; Lu, Yong Chen; Parker, Linda L.; Li, Yong F.; El-Gamil, Mona; Black, Mary A.; Xu, Hui; Feldman, Steven A.; Van Der Bruggen, Pierre; Rosenberg, Steven A.; Robbins, Paul F.

In: Journal of Immunotherapy, Vol. 39, No. 5, 2016, p. 191-201.

Research output: Contribution to journalArticle

Yao, X, Lu, YC, Parker, LL, Li, YF, El-Gamil, M, Black, MA, Xu, H, Feldman, SA, Van Der Bruggen, P, Rosenberg, SA & Robbins, PF 2016, 'Isolation and characterization of an HLA-DPB1∗04: 01-restricted MAGE-A3 T-cell receptor for cancer immunotherapy', Journal of Immunotherapy, vol. 39, no. 5, pp. 191-201. https://doi.org/10.1097/CJI.0000000000000123
Yao, Xin ; Lu, Yong Chen ; Parker, Linda L. ; Li, Yong F. ; El-Gamil, Mona ; Black, Mary A. ; Xu, Hui ; Feldman, Steven A. ; Van Der Bruggen, Pierre ; Rosenberg, Steven A. ; Robbins, Paul F. / Isolation and characterization of an HLA-DPB1∗04 : 01-restricted MAGE-A3 T-cell receptor for cancer immunotherapy. In: Journal of Immunotherapy. 2016 ; Vol. 39, No. 5. pp. 191-201.
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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.",
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AU - Black, Mary A.

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AU - Feldman, Steven A.

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