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Title: Cross-talk between the primary tumour and brain metastases enhances the efficacy of immune checkpoint inhibition
Author: Taggart, David John
ISNI:       0000 0004 6058 4570
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2016
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Melanoma brain metastases (MBrM) are devastating, occurring in up to 60% of melanoma patients and are increasing in incidence as systemic treatments improve. MBrM are notoriously difficult to treat and patients suffer from extremely poor survival rates, resulting in these patients being excluded from clinical trials testing new treatments, thus highlighting a need for research in this field. We developed a pre-clinical model where mice have simultaneous intracranial and extracranial B16 melanoma tumours to mimic the clinical setting. Notably, intracranial tumour growth was the survival-limiting factor, allowing the study of therapeutic effects specifically in the brain. Various combinations of anti-PD-1, anti-CTLA-4 and GM-CSF were investigated as potential therapies for MBrM. We found that the combination of anti-PD-1 and anti-CTLA-4 could prolong the survival of these mice; however, this was dependent on the presence of an extracranial tumour. Functional studies revealed that natural killer cells and cytotoxic T-cells were essential mediators of this therapy. Moreover, examination of the infiltrating immune cell populations demonstrated an increase in CD45+ immune cells in the intracranial tumours of mice also bearing a flank tumour and receiving the anti-PD-1 and anti-CTLA-4 therapy. This increase was found to be a result of the increase in infiltrating T-cells and macrophages/microglia and was reliant on the presence of an extracranial tumour. Analysis of cytotoxic T-cells revealed an increase in tumour antigen-specific cells in mice with an intracranial and extracranial tumour receiving treatment. Tumour antigen-specific T-cells within the blood showed an increased expression of homing receptors, which have been previously linked to an increase in T-cell infiltration into the brain. In conclusion, we have demonstrated that the combination of anti-PD-1 and anti-CTLA-4 can be an effective therapy for the treatment MBrM, while also identifying the main immune cell populations involved and a potential mechanism behind the therapeutic efficacy.
Supervisor: Lorger, Mihaela ; Melcher, Alan ; Ilett, Elizabeth Sponsor: Yorkshire Cancer Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available