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

Gene Therapy volume 12, pages 1253–1263 (2005)Cite this article

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 (nonenhanced) 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.

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Acknowledgements

We thank Alex Whelan for assistance with histopathological studies, and Dorothy Mooney for assistance with laboratory protocols. Sareen Galbraith's advice and Christopher Logue's technical guidance contributed greatly to the project. We thank Peter Liljeström and colleagues at the Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm for provision of the SFV expression vectors. This work was supported by Cancer Research Ireland, the European Union and Science Foundation Ireland.

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Authors and Affiliations

  1. Department of Microbiology, Moyne Institute, Trinity College, Dublin, Ireland

    C P Chikkanna-Gowda, M N Fleeton & G J Atkins

  2. Department of Veterinary Pathology, Faculty of Veterinary Medicine, University College Dublin, Belfield, Dublin, Ireland

    B J Sheahan

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  1. C P Chikkanna-Gowda
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  3. M N Fleeton
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Chikkanna-Gowda, C., Sheahan, B., Fleeton, M. et al. Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12. Gene Ther 12, 1253–1263 (2005). https://doi.org/10.1038/sj.gt.3302561

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