Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application

  • Griffioen M
  • van Egmond H
  • Barnby-Porritt H
 et al. 
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Abstract

BACKGROUND: Donor lymphocyte infusion is an effective form of adoptive immunotherapy for hematologic malignancies after allogeneic stem cell transplantation. Graft-versus-host disease, however, often develops due to recognition of ubiquitously-expressed minor histocompatibility antigens. Transfer of T-cell receptors recognizing hematopoiesis-restricted minor histocompatibility antigens to virus-specific T cells may be a powerful anti-tumor therapy with a low risk of graft-versus-host disease. The purpose of this study was to develop an optimal T-cell receptors-encoding multi-cistronic retroviral vector and an efficient method for generating T-cell receptors-engineered virus-specific T cells. DESIGN AND METHODS: Retroviral vectors encoding the T-cell receptors for the hematopoiesis-restricted minor histocompatibility antigen HA-2 with and without selection markers were compared for T-cell receptors surface expression and HA-2-specific lysis. In addition, two different methods, i.e. peptide stimulation of CD8(+) cells and Pro5 MHC pentamer-based isolation of antigen-specific T cells, were investigated for their efficiency to generate T-cell receptors-transduced virus-specific T cells. RESULTS: Bi-cistronic vectors without selection markers most efficiently mediated T-cell receptors surface expression and HA-2-specific lysis. Furthermore, both methods were useful for generating gene-modified cells, but the purity of virus-specific T cells was higher after pentamer isolation. Finally, the capacity of gene-modified cells to express the transgenic T-cell receptors at the cell surface markedly differed between virus-specific T cells and was correlated with lysis of relevant target cells. CONCLUSIONS: Our data support T-cell receptors gene transfer to pentamer-isolated virus-specific T cells using bi-cistronic retroviral vectors and illustrate the relevance of selection of gene-modified T cells with appropriate transgenic T-cell receptors surface expression for clinical gene therapy

Author-supplied keywords

  • Antigens
  • Cells,Cultured
  • Gene Therapy
  • Genetic Engineering
  • Genetic Vectors
  • Histocompatibility
  • Histocompatibility Antigens
  • Humans
  • Immunotherapy
  • Minor Histocompatibility Antigens
  • Protein Engineering
  • Receptors,Antigen,T-Cell
  • Retroviridae
  • Risk
  • Stem Cell Transplantation
  • T-Lymphocytes
  • genetics
  • immunology
  • metabolism
  • methods
  • therapy
  • transplantation
  • virology

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Authors

  • M Griffioen

  • H M van Egmond

  • H Barnby-Porritt

  • M A van der Hoorn

  • R S Hagedoorn

  • M G Kester

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