Isolation and characterization of an HLA-DPB1*04:01-restricted MAGE-A3 T cell receptor for cancer immunotherapy
| Autor: | Paul F. Robbins, Yong-Chen Lu, Xin Yao, Steven A. Feldman, Yong F. Li, Steven A. Rosenberg, Linda L. Parker, Pierre van der Bruggen, Hui Xu, Mona El-Gamil, Mary A. Black |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Adoptive cell transfer medicine.medical_treatment Immunology Antigen presentation Receptors Antigen T-Cell chemical and pharmacologic phenomena T-Cell Antigen Receptor Specificity Cell Separation Biology Cross Reactions Cancer Vaccines Immunotherapy Adoptive T-Lymphocytes Regulatory Article White People 03 medical and health sciences Cancer immunotherapy Antigen Antigens Neoplasm MHC class I medicine Immunology and Allergy Cytotoxic T cell Humans Melanoma HLA-DP beta-Chains Pharmacology Antigen Presentation T-cell receptor Vaccination Immunotherapy Genetic Therapy T-Lymphocytes Helper-Inducer Clone Cells Neoplasm Proteins 030104 developmental biology CD4 Antigens biology.protein |
| Popis: | Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) 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 anti-tumor MHC class II-restricted TCRs. Since 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, two MAGE-A3-specific TCRs were isolated from a regulatory T cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of two 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. |
| Databáze: | OpenAIRE |
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