Semliki forest virus vectors engineered to express higher IL-12 levels induce efficient elimination of murine colon adenocarcinomas

Mol Ther. 2005 Jul;12(1):153-63. doi: 10.1016/j.ymthe.2005.02.011.

Abstract

To evaluate the use of alphavirus vectors for tumor treatment we have constructed and compared two Semliki Forest virus (SFV) vectors expressing different levels of IL-12. SFV-IL-12 expresses both IL-12 subunits from a single subgenomic promoter, while in SFV-enhIL-12 each IL-12 subunit is expressed from an independent subgenomic promoter fused to the SFV capsid translation enhancer. This latter strategy provided an eightfold increase of IL-12 expression. We chose the poorly immunogenic MC38 colon adenocarcinoma model to evaluate the therapeutic potential of SFV vectors. A single intratumoral injection of 10(8) viral particles of SFV-IL-12 or SFV-enh-IL-12 induced>or=80% complete tumor regressions with long-term tumor-free survival. However, lower doses of SFV-enhIL-12 were more efficient than SFV-IL-12 in inducing antitumoral responses, indicating a positive correlation between the IL-12 expression level and the therapeutic effect. Moreover, repeated intratumoral injections of suboptimal doses of SFV-enhIL-12 increased the antitumoral response. In all cases SFV vectors were more efficient at eliminating tumors than a first-generation adenovirus vector expressing IL-12. In addition, the antitumoral effect of SFV vectors was only moderately affected by preimmunization of animals with high doses of SFV vectors. This antitumoral effect was produced, at least partially, by a potent CTL-mediated immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / prevention & control
  • Adenocarcinoma / therapy*
  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / prevention & control
  • Colonic Neoplasms / therapy*
  • Genetic Therapy*
  • Genetic Vectors*
  • Immunity, Cellular / immunology
  • Interleukin-12 / genetics*
  • Interleukin-12 / metabolism
  • Mice
  • Semliki forest virus*
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Interleukin-12