TCR Gene Transfer : MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 Epitopes as Melanoma-Specific Immune Targets

• Published in: Clinical & developmental immunology 2012-01, Vol.2012 (2012), p.1-14
• Main Authors: Straetemans, Trudy, van Brakel, Mandy, van Steenbergen, Sabine, Broertjes, Marieke, Drexhage, Joost, Hegmans, Joost P. J. J., Lambrecht, Bart N., Lamers, Cor, Bruggen, Pierre van Der, Coulie, Pierre G., Debets, Reno
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Engineering; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Dendritic Cells - immunology; Dendritic Cells - metabolism; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Gene Transfer Techniques; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; HLA-DP beta-Chains - genetics; HLA-DP beta-Chains - immunology; Humans; Immunotherapy, Adoptive; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Skin - drug effects; Skin - immunology; Skin - pathology; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy
• ISSN: 1740-2522; 1740-2530
• DOI: 10.1155/2012/586314

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-C2336-344/HLA-A2 (MC2/A2) and MAGE-A3243-258/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.