TCR gene transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 epitopes as melanoma-specific immune targets

Clin Dev Immunol. 2012;2012:586314. doi: 10.1155/2012/586314. Epub 2012 Feb 12.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology*
  • 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*

Substances

  • 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