Glioblastoma Multiforme (GBM) is highly malignant brain tumour and the most common occurring brain cancer in adults. The median survival rate of GBM patients is only 15 months, despite aggressive standard treatment involving surgical resection, radiotherapy and concurrent chemotherapy with temozolomide. Owing to this bleak diagnosis, immunotherapeutic approaches are now being investigated. We have shown that prophylactic administration of a vaccine comprised of irradiated glioma cells loaded with a-galactosylceramide (a-GalCer), a compound that stimulates “invariant” Natural Killer T Cells, provides an adaptive immune response that can limit tumour growth in a murine glioma model. Vaccination in a therapeutic setting however, is insufficient to bestow long-term survival unless suppressive mechanisms are overcome. Recent advances in monoclonal antibody checkpoint blockade have shown promise in clinical trials for melanoma. Here we show that antibody blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4), combined with immunotherapeutic vaccination results in a predominantly CD4+ T cell mediated response, characterised by production of Th1 cytokines IFN-g and TNF-a. Importantly, therapeutic vaccination in combination with CTLA-4 blockade provided significant protection against intracranial tumours, with 80% of animals surviving past day sixty. No significant survival benefit was observed following administration of a-CTLA-4 alone. Conversely, vaccination combined with blockade of programmed death-1 (PD-1) was unable to provide a survival advantage in an intracranial setting but was highly effective in eradication of subcutaneous tumours. These results demonstrate that checkpoint blockade targeting the priming or effector phase of the immune response can result in distinct survival outcomes, and the anatomical location of tumours should be considered when combining immunotherapeutic approaches with checkpoint inhibitors.