Portal de Periódicos da CAPES

Sequential Immunotherapy by Vaccination With GM-CSF–expressing Glioma Cells and CTLA-4 Blockade Effectively Treats Established Murine Intracranial Tumors

2012; Lippincott Williams & Wilkins; Volume: 35; Issue: 5 Linguagem: Inglês

10.1097/cji.0b013e3182562d59

1537-4513

Pankaj K. Agarwalla, Zachary R. Barnard, Peter E. Fecci, Glenn Dranoff, William T. Curry,

CAR-T cell therapy research

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.