Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells

To provide a means for comparing strategies for cytokine gene therapy again st intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transf ected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-ma crophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFN a lpha). To simulate direct and highly efficient cytokine gene delivery, cyto kine transfected 9L tumors were Implanted i.c. into syngeneic rats. i.c. in jection led to tumor-outgrowth in the brain and killed most animals, wherea s these cell lines were rejected following intradermal (i.d.) injection. Cy tokine-expressing i.c. 9L tumors, however, had a greater degree of infiltra tion by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis w as suppressed in cytokine-transfected tumors. Ina prophylaxis model, i.d. v accination with 9L-IL4 resulted in long-term survival of 90% of rats challe nged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFN alpha a nd 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 therapeuti c benefits as 43% of rats survived >100 days. These data indicate that peri pheral immunization with 9L-IL4 had the most potent therapeutic benefit amo ng various cytokines and approaches tested against established, i.c. 9L tum ors.