title: Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.
abstract: Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor-infiltrating 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 HLA-DPB1*04:01 is present in ∼60% 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.
authors.affiliation: *Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD †Cellular Biomedicine Group Inc., Cupertino, CA ‡Ludwig Institute for Cancer Research and WELBIO §De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.forename: Yong-Chen
authors.initials: YC
authors.lastname: Lu
authors.forename: Linda L
authors.initials: LL
authors.lastname: Parker
authors.forename: Yong F
authors.initials: YF
authors.lastname: Li
authors.forename: Mona
authors.initials: M
authors.lastname: El-Gamil
authors.forename: Mary A
authors.initials: MA
authors.lastname: Black
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.forename: Pierre
authors.initials: P
authors.lastname: van der Bruggen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D002469:Cell Separation; D002999:Clone Cells; D003429:Cross Reactions; D015316:Genetic Therapy; D059868:HLA-DP beta-Chains / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014611:Vaccination; D044465:White People
chemical_list: D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D019496:Cancer Vaccines; D059868:HLA-DP beta-Chains; C505113:HLA-DPB1*04:01 antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell