Effects of continuous localized infusion of granulocyte-macrophage colony-stimulating factor and inoculations of irradiated glioma cells on tumor regression

Object. Glioblastoma multiforme (GBM) is a malignant tumor of the central n ervous system that directly suppresses immunological defenses in vitro and in vivo. The authors used the peripheral delivery of continuously infused g ranulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence of irradiated tumor antigens as a tumor-specific stimulant to dendritic cells to initiate an immune response to GBM in rats. Methods. The 9L gliosarcoma tumors were established in the flanks of syngen eic Fischer 344 rots. Osmotic minipumps implanted in the animals' contralat eral flanks continuously delivered recombinant GM-CSF (0, 0.1, 1, or 10 ng/ day) for 28 days. Irradiated gliosarcoma cells were intermittently injected at the site of tho GM-CSF infusion. Animals in the saline control group 10 ng/day GM-CSF) died on Day 59 with average tumor volumes greater than 30,0 00 mm(3). This control group was significantly different from the GM-CSF-tr eated animals, which all survived with average tumor volumes that peaked on Day 23 and Inter regressed completely. Tumor growth as well as peak tumor volumes (5833 +/- 2284 mm(3), 3294 +/- 1632 mm(3). and 1979 +/- 1142 mm(3) for 0.1, 1, and 10 ng/day GM-CSF, respectively) in the different treatment groups reflected a significant dose-response relationship with the GM-CSF c oncentrations. All animals treated with GM-CSF and irradiated cells were re sistant to additional challenges of peripheral and intracerebral gliosarcom a, even when they were inoculated 8 months after initial immunotherapy. The colocalization of GM-CSF and inactivated tumor antigens was required to st imulate immunoprotection. To test the efficacy of a peripherally administer ed immunological therapy on intracerebral brain tumors the authors transpla nted 10(6) gliosarcoma cells into the striatum of treated and control anima ls. Subcutaneous pumps that released GM-CSF (10 ng/day) and irradiated glio sarcoma cells were placed in the treated animals. The control animals all d ied within 31 days after intracerebral tumor implantation. In contrast, 40% of the animals receiving GM-CSF-irradiated cell vaccinations survived beyo nd 300 days. Those long-term survivors showed no evidence of gliosarcoma at the injection site on evaluation by magnetic resonance imaging. Conclusions. These results suggest that the continuous localized delivery o f subcutaneous GM-CSF in conjunction with inactivated tumor antigens can in itiate a systemic response that leads to the regression of distant peripher al and intracerebral tumors. The success of this treatment illustrates the feasibility of tumor-specific peripheral immunological stimulation after tu mor resection to prevent the recurrence of malignant Drain tumors.