INTERLEUKIN-12-BASED IMMUNOTHERAPY AGAINST RAT 9L GLIOMA

OBJECTIVE: Interleukin-12 (IL-12) may be useful for immunotherapy agai nst gliomas because it can reverse the glioma-induced suppression of T -cell proliferation and interferon-gamma production. We postulated tha t peripheral infusion of IL-12 along with irradiated tumor cells can l ead to immunological rejection of 9L glioma. METHODS: 9L gliosarcoma f lank tumors were established in syngeneic Fischer 344 rats. Osmotic mi nipumps delivered IL-12 subcutaneously, and irradiated 9L cells were i njected on Days 0, 3, 7, 14, and 21. Tumor volumes were measured by a blinded observer. For tumor rechallenge, animals initially cured of 9L flank tumors received either another implantation of flank tumor or a stereotactic injection of 10(6) 9L cells into the right striatum. Del ayed-type hypersensitivity was measured after injecting 10(6) irradiat ed 9L tumor cells into the right pinnae. RESULTS: Tumor growth curves were significantly different between treated and control animals. Amon g the animals that received 1 ng per day of IL-12, 40% did not develop any measurable tumors at all. A combination of irradiated 9L cells an d IL-12 was necessary for optimal effect. Cured animals rejected futur e flank tumors. All animals rechallenged with intraparenchymal brain t umors survived, whereas control animals all died by Day 22. Delayed-ty pe hypersensitivity measurements showed a specific and long-lasting re sponse against 9L cells. CONCLUSION: Continuous administration of the lymphokine IL-12, in the presence of irradiated tumor cells for antige n presentation, circumvents the need for gene transfection for generat ing tumor cell vaccines. We have demonstrated that the combination of IL-12 and irradiated tumor cells can lead to regression of 9L flank tu mors and resistance to future flank and central nervous system tumor c hallenges.