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A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

Gene Therapy volume 19, pages 271–278 (2012)Cite this article

Abstract

Semliki Forest virus (SFV) represents a promising gene therapy vector for tumor treatment, because it produces high levels of recombinant therapeutic proteins while inducing apoptosis in infected cells. In this study, we constructed a SFV vector expressing murine interferon alpha (IFNα). IFNα displays antitumor activity mainly by enhancing an antitumor immune response, as well as by a direct antiproliferative effect. In spite of the antiviral activity of IFNα, SFV–IFN could be produced in BHK cells at high titers. This vector was able to infect TC-1 cells, a tumor cell line expressing E6 and E7 proteins of human papillomavirus, leading to high production of IFNα both in vitro and in vivo. When injected into subcutaneous TC-1 tumors implanted in mice, SFV–IFN was able to induce an E7-specific cytotoxic T lymphocyte response, and to modify tumor infiltrating immune cells, reducing the percentage of T regulatory cells and activating myeloid cells. As a consequence, SFV–IFN was able to eradicate 58% of established tumors treated 21 days after implantation with long-term tumor-free survival and very low toxicity. SFV–IFN was also able to induce significant antitumor responses in a subcutaneous tumor model of murine colon adenocarcimoma. These data suggest that local production of IFNα by intratumoral injection of recombinant SFV–IFN could represent a potent new strategy to treat tumors in patients.

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Acknowledgements

This work was supported by the agreement between FIMA and the ‘UTE project CIMA’ and grants from the Spanish Health Ministry (FIS-PI081660), the Government of Navarra (GNE-VECTORES ALFAVIRUS), Fundación Pedro Barrié de la Maza, Condesa de Fenosa and Red de Inmunoterapia INMUNONET-SOE1/P1/E014. JIQ was the recipient of a Torres Quevedo contract. JF and JM-E were supported by a fellowship of Spanish Fondo de Investigación Sanitaria. PB was supported by a Miguel Servet contract from Instituto de Salud Carlos III, FIS.

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Author notes

  1. J I Quetglas and J Fioravanti: These authors contributed equally to this work.

  2. C Smerdou and P Berraondo: These authors share senior authorship.

Authors and Affiliations

  1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain

    J I Quetglas, J Fioravanti, N Ardaiz, J Medina-Echeverz, I Baraibar, J Prieto, C Smerdou & P Berraondo

  2. Liver Unit, Clínica Universitaria, CIBER-EHD, Pamplona, Navarra, Spain

    J Prieto

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  1. J I Quetglas
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Correspondence to C Smerdou or P Berraondo.

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Quetglas, J., Fioravanti, J., Ardaiz, N. et al. A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors. Gene Ther 19, 271–278 (2012). https://doi.org/10.1038/gt.2011.99

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