¹Brain Tumor Center, University of Pittsburgh Cancer Institute and Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

²Brain Tumor Center, University of Pittsburgh Cancer Institute and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

³Brain Tumor Center, University of Pittsburgh Cancer Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁴Brain Tumor Center, University of Pittsburgh Cancer Institute and Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence to: H Okada, 208 Center for Biotechnology and Bioengineering, 300 Technology Drive, Pittsburgh, PA, 15219, USA

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon- (9L-IFN). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFN and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors. Gene Therapy (2001) 8, 1157-1166.

gliomas; gene therapy; cancer vaccine; cytokines