Glioblastoma Multiforme (GBM) is highly malignant brain tumour and the most common occurring brain cancer in adults. The average survival rate of GBM patients is only 15 months, despite aggressive standard treatment involving surgery, radiotherapy and chemotherapy. Due to this bleak diagnosis, approaches which activate the immune system are now being explored. We have a cancer vaccine which can activate the immune system. However, this vaccine is ineffective as a lone therapy because the immune system has “off” switches which are expressed either early or late during an immune response. To improve the vaccine, we can combine it with drugs which hide the “off” switches, allowing more robust immune responses. Here, we show that by hiding the early “off” switch, we can stimulate a powerful immune response which is capable of clearing brain tumours, resulting in 80% long term survival. This is because the early “off” switch controls many of the survival and growth factors needed for cells of the immune system to survive. However, if we hide the late “off” switch, mice succumb to brain tumours. On the other hand, if the tumour is implanted under the skin, it can be easily eradicated by hiding the late “off” switch. This is because the drugs that hide the late “off” switch are able to enter the tumours beneath the skin, but are unable to enter the brain to ensure the late immune responses are not inhibited. These results have direct clinical relevance and suggest that a one size fits all approach does not apply when harnessing the immune system to treat tumours in different locations of the body.