title: A Semliki forest virus vector engineered to express IFNα induces efficient elimination of established tumors.
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.
authors: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors: J I
authors: JI
authors: Quetglas
authors: J
authors: J
authors: Fioravanti
authors: N
authors: N
authors: Ardaiz
authors: J
authors: J
authors: Medina-Echeverz
authors: I
authors: I
authors: Baraibar
authors: J
authors: J
authors: Prieto
authors: C
authors: C
authors: Smerdou
authors: P
authors: P
authors: Berraondo
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D007111:Immunity, Cellular / Q000276:immunology; D007267:Injections; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D012672:Semliki forest virus / Q000235:genetics*
chemical_list: D016898:Interferon-alpha