title: TCR gene transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 epitopes as melanoma-specific immune targets.
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.
authors.affiliation: Laboratory of Experimental Tumor Immunology, Department of Medical Oncology, Erasmus MC, 3015 GE, Rotterdam, The Netherlands.
authors.forename: Trudy
authors.initials: T
authors.lastname: Straetemans
authors.forename: Mandy
authors.initials: M
authors.lastname: van Brakel
authors.forename: Sabine
authors.initials: S
authors.lastname: van Steenbergen
authors.forename: Marieke
authors.initials: M
authors.lastname: Broertjes
authors.forename: Joost
authors.initials: J
authors.lastname: Drexhage
authors.forename: Joost
authors.initials: J
authors.lastname: Hegmans
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Cor
authors.initials: C
authors.lastname: Lamers
authors.forename: Pierre
authors.initials: P
authors.lastname: van Der Bruggen
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D060846:Cell Engineering; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D018014:Gene Transfer Techniques; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D059868:HLA-DP beta-Chains; C056284:HLA-DPw4 antigen; C072013:MAGEA3 protein, human; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta