title: Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat.
abstract: Cytokines play a major role in the regulation of the immune system. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate dendritic cells to present tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies have shown that each of these cytokines alone can induce the regression of tumor cells. In the present study we postulated that peripheral infusion of GM-CSF along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased survival from 9L brain tumors. 9L gliosarcoma cells (10(6)) were implanted in the brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12. Irradiated 9L cells were injected subcutaneously at various time points during treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis were used to further characterize the anti-tumor response. Treatment with GM-CSF and irradiated tumor cells led to an increase in survival rate in rats with intracranial 9L tumors when compared to untreated animals. The addition of IL-2 or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These results suggest that the combined infusion of GM-CSF and other cytokines may be effective adjuvants in treating brain tumors.
authors.affiliation: Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Jean
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spellman
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Wallenfriedman
authors.forename: Christine T
authors.initials: CT
authors.lastname: Flores
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kurtz
authors.forename: Walter A
authors.initials: WA
authors.lastname: Hall
authors.forename: Walter C
authors.initials: WC
authors.lastname: Low
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D005260:Female; D018316:Gliosarcoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006968:Hypersensitivity, Delayed / Q000503:physiopathology; D007150:Immunohistochemistry; D007156:Immunologic Memory; D007167:Immunotherapy; D018664:Interleukin-12 / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D009367:Neoplasm Staging; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis
chemical_list: D000943:Antigens, Differentiation; D007376:Interleukin-2; C459465:OX-62 antigen, rat; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor