Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX

J. de Vrij, T. G. Uil, S. K. van den Hengel, S. J. Cramer, D. Koppers-Lalic, M. C. Verweij, E. J.H.J. Wiertz, J. Vellinga, R. A. Willemsen, R. C. Hoeben

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Adenovirus vectors have great potential in cancer gene therapy. Targeting of cancer-testis (CT) antigens, which are specifically presented at the surface of tumor cells by human leukocyte antigen (HLA) class I molecules, is an attractive option. In this study, a single-chain T-cell receptor (scTCR) directed against the CT antigen melanoma-associated antigen (MAGE)-A1 in complex with the HLA class I molecule of haplotype HLA-A1 is fused with the C terminus of the adenovirus minor capsid protein IX. Propagation of a protein-IX (pIX)-gene-deleted human adenovirus 5 (HAdV-5) vector on cells that constitutively express the pIXscTCR fusion protein yielded viral particles with the pIXscTCR fusion protein incorporated in their capsid. Generated particles specifically transduced melanoma cell lines expressing the HLA-A1/MAGE-A1 target complex with at least 10-fold higher efficiency than control viruses. Whereas loading of HLA-A1-positive cells with MAGE-A1 peptides leads to enhanced transduction of the cells, the efficiency of virus transduction is strongly reduced if the HLA-A1 molecules are not accessible at the target cell. Taken together, these data provide proof of principle that pIXscTCR fusions can be used to target HAdV-5 vectors to tumor cells expressing intracellular CT antigens.

Original languageEnglish (US)
Pages (from-to)978-989
Number of pages12
JournalGene therapy
Volume15
Issue number13
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    de Vrij, J., Uil, T. G., van den Hengel, S. K., Cramer, S. J., Koppers-Lalic, D., Verweij, M. C., Wiertz, E. J. H. J., Vellinga, J., Willemsen, R. A., & Hoeben, R. C. (2008). Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX. Gene therapy, 15(13), 978-989. https://doi.org/10.1038/gt.2008.26