Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12

Gene Ther. 2005 Aug;12(16):1253-63. doi: 10.1038/sj.gt.3302561.

Abstract

The Semliki Forest virus (SFV) vector is an RNA-based suicide expression vector that has been used experimentally for tumour therapy. Recently, a new enhanced vector pSFV10-E has been developed that expresses foreign genes at levels up to 10 times higher than the original vector. Interleukin-12 (IL-12), an immunomodulatory cytokine, plays a key role in the induction of T-helper1 responses. The two IL-12 gene subunits were cloned from mouse splenocytes and inserted into the pSFV10-E and pSFV10 (non-enhanced) vectors. Both constructs expressed and secreted biologically active murine IL-12. Administration of high titre rSFV10-E-IL12 particles intratumourally to treat implanted K-BALB tumours in BALB/c mice demonstrated complete tumour regression in comparison to control or rSFV10-IL12 treated groups. High titre rSFV10-E-IL12 particles were also effective in the CT26 tumour model. Histological and immunohistochemical studies revealed tumour necrosis in addition to aggressive influx of CD4+ and CD8+ T cells and other immune cells. Furthermore, inhibition of primary tumour growth and lung metastases of a metastatic (4T1) tumour model indicated the potential of high titres of rSFV10-E-IL12 particles as an efficient antitumour therapeutic agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / blood
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cell Line, Tumor
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy*
  • Combined Modality Therapy
  • Female
  • Gene Expression
  • Genetic Therapy / methods*
  • Immunohistochemistry / methods
  • Immunotherapy / methods*
  • Interleukin-12 / analysis
  • Interleukin-12 / genetics*
  • Interleukin-12 / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental
  • Neovascularization, Pathologic
  • Semliki forest virus / genetics
  • Transduction, Genetic / methods

Substances

  • Biomarkers, Tumor
  • Interleukin-12