title: Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors.
abstract: Malignant glioma is an incurable disease with a relatively short median survival. Several clinical trials have demonstrated that immunotherapy with vaccination is a safe and possibly effective way of prolonging survival. Antibody-based blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) ligation on T lymphocytes is associated with enhanced antitumor immunity in animal models of cancer and in patients with advanced melanoma. We hypothesized that sequential therapy with granulocyte-macrophage-colony-stimulating factor (GM-CSF)-expressing whole-glioma-cell vaccination and CTLA-4 blockade is an effective strategy for treating established intracranial gliomas. GL261 glioma cells were injected into the right frontal lobes of syngeneic C57/BL6 mice. At days 3, 6, and 9 after tumor implantation, mice were treated with subcutaneous injection of irradiated GM-CSF-expressing GL261 cells. Mice were also treated with intraperitoneal injection of anti-CTLA-4 monoclonal antibodies (mAbs), either at days 3, 6, and 9 or days 12, 15, and 18. Animals were followed for survival. Splenocytes were harvested at day 22 for use in enzyme-linked immunosorbent spot assays. Early treatment of established intracranial gliomas with high-dose CTLA-4 blockade was associated with increased survival in GL261-bearing mice. Later treatment with anti-CTLA-4 monoclonal antibodies did not significantly improve survival compared with control-treated mice. Early vaccination followed by subsequent CTLA-4 blockade was associated with significantly improved survival versus either treatment alone and intensified tumor-specific immunity as measured by interferon-γ enzyme-linked immunosorbent spot assay. Sequential immunotherapy with GM-CSF-expressing irradiated glioma cells and CTLA-4 blockade synergistically prolongs survival in mice bearing established intracranial gliomas.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Agarwalla
authors.forename: Zachary
authors.initials: Z
authors.lastname: Barnard
authors.forename: Peter
authors.initials: P
authors.lastname: Fecci
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000517:prevention & control* / Q000628:therapy; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D005720:Gamma Rays; D005910:Glioma / Q000276:immunology / Q000401:mortality / Q000517:prevention & control* / Q000628:therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007167:Immunotherapy; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor