1. ¹Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine and Harper Hospital, Detroit, Michigan 48201, USA
2. ²Transgene SA, 11 Rue de Molsheim, Strasbourg 67085, France
3. ³Department of Pathology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine and Harper Hospital, Detroit, Michigan 48201, USA

Correspondence: Dr GG Hillman, Ph.D., Department of Radiation Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Hudson Weber Bldg, Room 515, 4100 John R., Detroit, MI 48201, USA. E-mail: hillmang@karmanos.org

Received 29 April 2003.

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- gene (Ad- IFN-) 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-, 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- 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- 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.