Enhanced Dendritic Cell Immunology for Glioblastoma

Glioblastoma Multiforme(GBM) is a highly malignant brain tumour with many patients surviving less that a year. Even with maximum surgery, chemotherapy and radiotherapy less than half of patients will survive 2 years and only 6% will be alive at 5 years. Therefore there is an urgent need for new treatments. Boosting the immune system's natural ability to fight cancer using dendritic cells has shown promise in some patients. Dendritic cells (DC) are particular white cells which mobilise other immune cells (killer T-cells) to recognise and kill cancer cells. DC can be made in a laboratory using a patient's own white cells (monocyte derived DC, moDC) and then stimulated with the patient's own cancer removed at surgery. These DCs are injected back into the patients to boost the immune system (DC Vaccination). Phase I/II trials have shown this approach is very useful in some patients, allowing patients to live significantly longer than predicted, but for many the effect is limited. More research is needed to make these promising treatments more effective in more patients. Our proposal aims is to increase the effectiveness of current DC vaccines, to test potentially even more effective DC approaches and examine combinations with other treatments that boost the immune system. We will do this this by: 1. Enhancing the function of DC by blocking specific signalling pathways: Cancer is able to suppress the immune system, and in particular can suppress the important functions of DCs. We and other have found specific signalling pathways within the DC by which cancer can do this and have shown that specific drugs can block these and restore DC function. We will apply this knowledge to improve current DC therapy against GBM. Using DC from healthy donors and GBM patients and using GBM cell lines and tumour removed at operation, we will test how well the pathway blocking drugs enhance DC function. 2. Compare circulating DC populations with the current laboratory generated moDC and test feasibility for use in vaccines: DCs circulating naturally in the blood have favourable characteristics compared to moDC, generated in the laboratory, and are potentially more potent as DC vaccines. I will test this in relation to GBM and will test whether these can be enhanced in the same way as moDC. In preliminary experiments I have shown that circulating DC are reduced in GBM patients compared to healthy people, however modern techniques allow isolation of small numbers of cells for use as vaccines. In this proposal I will test whether one can actually prepare a vaccine from circulating DCs in GBM. This is very important because, in addition to potentially being better vaccines, these DC do not need culture in a specialised laboratory and so treatments may be more accessible to more patients. 3. Combine DC therapy and Checkpoint blockade: A new class of anti cancer drugs, that 'release the brakes' on the immune system (checkpoint blockade) have shown very promising results in a range of cancers. Using experimental systems already established in our laboratories, we will combine our enhanced DCs, which 'turn on' T cells and checkpoint blockade drugs which 'take the brakes off' the T cell, and test if we can produce even more effective anti-cancer T-cells. If our experiments are successful, we expect these finding to be incorporated very quickly into the next generation of clinical trials and so potentially giving patient benefit over the next five years. This will be facilitated by our collaborators who have on going DC vaccine clinical programmes. Our aim being a treatment which prolongs survival, with little toxicity and improved quality of life for GBM patients. The ability to target DC function and so modify immnue responses has implications for other areas of immunology such as autoimmunity and infectious diseases. We also envisage that our finding can be extrapolated to other cancers with similar benefits.