Efficient gene transfer of CD40 ligand into ovarian carcinoma cells with a recombinant adeno-associated virus vector

Int J Oncol. 2005 Jan;26(1):95-101.

Abstract

Recombinant adeno-associated virus type 2 (rAAV) has many properties of an ideal vector for gene therapy: broad spectrum of susceptible cells, efficient gene transfer, persistent transgene expression in vivo, and no indiction of vector-related toxicity. Ovarian carcinoma cell lines, however, were previously reported to be quite resistant to rAAV transduction. Using an optimized adenovirus-free packaging system, highly purified rAAV vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and for mCD40 ligand (AAV/CD40L) were generated. Their transduction efficiency in ovarian carcinoma cell lines was assessed with and without irradiation prior to infection. As measured by flow cytometry, transgene expression in up to 92% of cells was achieved with AAV/EGFP. gamma-irradiation (20 Gy) significantly increased the transduction rates up to 3.5-fold in cell lines with low susceptibility to AAV infection. The aquired capability of AAV/CD40L transduced tumor cells to activate dendritic cells was demonstrated in a second step. Dendritic cells were generated from human peripheral blood monocytes and maturized by stimulation with IL-4 and GM-CSF. Co-cultivation of mCD40L transgenic tumor cells with these dendritic cells resulted in strong ELISA-determined expression of IL-12 as an indicator of dendritic cell activation. We conclude that transduction of tumor cells with rAAV encoding mCD40L is a promising strategy for tumor immunotherapy which may be further developed to a vaccination approach with transgenic ovarian carcinoma cells generated by ex vivo transduction.

MeSH terms

  • Animals
  • CD40 Ligand / genetics*
  • CD40 Ligand / physiology
  • Carcinoma / genetics
  • Carcinoma / immunology*
  • Carcinoma / therapy
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dependovirus / genetics*
  • Female
  • Gamma Rays
  • Genetic Therapy / methods
  • Genetic Vectors* / genetics
  • Green Fluorescent Proteins / analysis
  • Green Fluorescent Proteins / genetics
  • Humans
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Mice
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / therapy
  • Transduction, Genetic* / methods

Substances

  • enhanced green fluorescent protein
  • CD40 Ligand
  • Green Fluorescent Proteins
  • Interleukin-12