title: Live attenuated Salmonella as a vector for oral cytokine gene therapy in melanoma.
abstract: Systemic administration of cytokines has shown therapeutic benefits in cancer patients; however, serious adverse effects associated with direct protein administration prevent the wide use of this approach. We have assessed the capacity of live attenuated Salmonella to act as a vector for oral cytokine-gene therapy. Salmonella orally administered to melanoma-bearing mice was found to accumulate within the tumor, reaching up to 10(5) bacteria per gram of tumor by day 21 after bacterial inoculation. Numbers of bacteria recovered from tumor did not differ from those recovered from liver or spleen at any time point. Recombinant bacteria carrying eukaryotic expression vectors encoding the murine IL-4 or IL-18 genes were administered to groups of mice with established subcutaneous melanoma tumors. We found that a single oral dose of Salmonella carrying any of the cytokine-encoding plasmids resulted in significantly increased survival time, as compared with mice that received Salmonella carrying the parental plasmid or PBS. Increased levels of IFNgamma were found in sera of animals receiving either of the cytokine-encoding bacteria, but not in mice receiving Salmonella alone or PBS. Co-administration of both recombinant bacteria maximized the production of IFNgamma. Overall these results suggest that cytokine-encoding Salmonella can be an effective and safer alternative to systemic administration of cytokines for immunotherapy of cancer.
authors.affiliation: Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Av. Navarro 3051, Montevideo, Uruguay.
authors.forename: Caroline
authors.initials: C
authors.lastname: Agorio
authors.forename: Fernanda
authors.initials: F
authors.lastname: Schreiber
authors.forename: Mark
authors.initials: M
authors.lastname: Sheppard
authors.forename: Piero
authors.initials: P
authors.lastname: Mastroeni
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martinez
authors.forename: Jose Alejandro
authors.initials: JA
authors.lastname: Chabalgoity
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D016207:Cytokines / Q000008:administration & dosage*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000032:analysis; D020382:Interleukin-18 / Q000008:administration & dosage / Q000235:genetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D012475:Salmonella / Q000235:genetics*; D015996:Survival Rate; D014613:Vaccines, Attenuated
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D020382:Interleukin-18; D014613:Vaccines, Attenuated; D015847:Interleukin-4; D007371:Interferon-gamma