title: Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma.
abstract: To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-gamma gene (Ad- IFN-gamma) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or Ad- IFN-gamma, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-gamma intratumoral gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-gamma was less pronounced and did not lead to tumor immunity. Histological observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response.
authors.affiliation: Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine and Harper Hospital, Detroit, Michigan 48201, USA. hillmang@karmanos.org
authors.forename: Gilda G
authors.initials: GG
authors.lastname: Hillman
authors.forename: Philippe
authors.initials: P
authors.lastname: Slos
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wright
authors.forename: Andrey
authors.initials: A
authors.lastname: Layer
authors.forename: Micael
authors.initials: M
authors.lastname: De Meyer
authors.forename: Mark
authors.initials: M
authors.lastname: Yudelev
authors.forename: Mingxin
authors.initials: M
authors.lastname: Che
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Forman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D007371:Interferon-gamma