Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma.
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.
Hillman
Gilda G
GG
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
Slos
Philippe
P
Wang
Yu
Y
Wright
Jennifer L
JL
Layer
Andrey
A
De Meyer
Micael
M
Yudelev
Mark
M
Che
Mingxin
M
Forman
Jeffrey D
JD
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
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D007371:Interferon-gamma