title: Semliki forest virus vectors engineered to express higher IL-12 levels induce efficient elimination of murine colon adenocarcinomas.
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.
authors.affiliation: Division of Gene Therapy, School of Medicine, Center for Applied Medical Research, University of Navarra, Avenida Pio XII 55, 31008 Pamplona, Spain.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Rodriguez-Madoz
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Cristian
authors.initials: C
authors.lastname: Smerdou
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007111:Immunity, Cellular / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D012672:Semliki forest virus; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018664:Interleukin-12