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: Trudy Straetemans, Mandy van Brakel, Sabine van Steenbergen, Marieke Broertjes, Joost Drexhage, Joost Hegmans, Bart N Lambrecht, Cor Lamers, Pierre van Der Bruggen, Pierre G Coulie, Reno Debets
• Journal: Clinical & developmental immunology (Clin Dev Immunol) Vol. 2012 Pg. 586314 ( 2012) ISSN: 1740-2530 [Electronic] Egypt
• PMID: 22400038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• HLA-A2 Antigen
• HLA-DP beta-Chains
• HLA-DPw4 antigen
• MAGEA3 protein, human
• MAGEC2 protein, human
• Neoplasm Proteins
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Antigens, Neoplasm (genetics, immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Engineering
• Cell Line, Tumor
• Clinical Trials, Phase I as Topic
• Dendritic Cells (immunology, metabolism)
• Epitopes, T-Lymphocyte (genetics, immunology)
• Gene Transfer Techniques
• HLA-A2 Antigen (genetics, immunology)
• HLA-DP beta-Chains (genetics, immunology)
• Humans
• Immunotherapy, Adoptive
• Melanoma (immunology, pathology, therapy)
• Neoplasm Proteins (genetics, immunology)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, immunology)
• Skin (drug effects, immunology, pathology)
• Skin Neoplasms (immunology, pathology, therapy)