Effects of Irradiated Tumor Vaccine and Infusion of Granulocyte- Macrophage Colony-Stimulating Factor and Interleukin-12 on Established Gliomas in Rats

Purpose: We investigated granulocyte-macrophage colony- stimulating factor (GM-CSF) and interleukin-12 (IL-12) infused into the injection site of irradiated tumor vaccine( TV) as therapy for gliomas. Methods: Rats with subcutaneous RT-2 gliomas were treated with irradiated TV and/or subcutaneous infusion of GM-CSF and/or IL-12 via osmotic minipump 5 days after tumor-cell inoculation. Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity were analyzed to investigate immune responses. Rats with intracerebral gliomas were treated with irradiated TV and infused GM-CSF/IL-12 3 days after tumor-cell inoculation. Tumor growth rates and animal survival were followed. Survivors were re-challenged with wild-type RT-2 cells subcutaneously or intracerebrally to study long-term anti- tumor immunity. Results: Rats with subcutaneous gliomas treated with GM-CSF and IL-12 or TV plus GM-CSF or IL-12 did not have increased survival rate (P > 0.2), but did have prolonged survival time (P < 0.05); in contrast, rats treated with TV plus GM-CSF/IL-12 had increased survival rate (P < 0.05) and prolonged survival time (P < 0.05) compared with controls. These treatment strategies showed enhanced CTL and NK cell activities. Rats with intra- cerebral gliomas treated with TV plus GM-CSF/ IL-12 did not have increased survival rate (P=0.11), but did have prolonged survival time (P < 0.0001). Survivors in each group were re- challenged with wild-type RT-2 cells, and all had long-term survival. Conclusions: Irradiated TV plus continuous localized infusion of GM-CSF/IL -12 may induce a tumor-specific anti-tumor immune response on established subcutaneous or intra-cerebral gliomas, and such a treatment strategy deserves consideration as adjuvant treatment for glioma