Abstract
Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent "on-target" reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2(336-344)/HLA-A2 (MC2/A2) and MAGE-A3(243-258)/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / immunology*
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Cell Engineering
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Cell Line, Tumor
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Clinical Trials, Phase I as Topic
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Gene Transfer Techniques
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HLA-A2 Antigen / genetics
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HLA-A2 Antigen / immunology
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HLA-DP beta-Chains / genetics
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HLA-DP beta-Chains / immunology
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Humans
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Immunotherapy, Adoptive*
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Melanoma / immunology
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Melanoma / pathology
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Melanoma / therapy*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / immunology
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Skin / drug effects
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Skin / immunology*
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Skin / pathology
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Skin Neoplasms / immunology
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Skin Neoplasms / pathology
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Skin Neoplasms / therapy*
Substances
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Antigens, Neoplasm
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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HLA-A2 Antigen
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HLA-DP beta-Chains
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HLA-DPw4 antigen
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MAGEA3 protein, human
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MAGEC2 protein, human
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Neoplasm Proteins
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Receptors, Antigen, T-Cell, alpha-beta