An investigation into the mechanisms of immune evasion in metastatic melanoma patients treated with molecular or immune checkpoint inhibitors.

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Summary

The aim of this project is to characterise the immune reaction and prevalence of immune inhibitory mechanisms present in metastatic melanoma patient tumours whilst on immune checkpoint and molecular inhibitors. Through this work we expect to uncover novel combinations of therapeutic treatment strategies for these patients.

Supervisor(s)

Professor Richard Scolyer, Professor Georgina Long

Research Location

Camperdown - Central Clinical School

Program Type

Masters/PHD

Synopsis

Since 2011, there has been a dramatic advance in the effectiveness of systemic therapies in the treatment of patients with metastatic melanoma. In 2009, it was discovered that up to 50% of cutaneous melanoma harboured a mutation to the BRAF gene, which results in the aberrant activation of the mitogen-activated protein kinase pathway (MAPK). Subsequently, targeted molecular inhibitors (BRAF and downstream MEK inhibitors) were developed, which are highly active and significantly increase patient survival. Similar advances have been made using immune checkpoint inhibitors, which have also proven to be extremely effective in the treatment of metastatic melanoma, these include antibodies specific to PD-1/L1 and CTLA-4 which block antigen binding that would otherwise stimulate T-cell exhaustion. Attention is now turning to identifying the most effective combination and timing of these treatments to improve response rates and survival.We have previously shown that BRAF inhibitors can induce a CD8+ cytotoxic T-cell infiltration into the tumours of BRAF mutant metastatic melanoma patient's tumours. We recently investigated this further by assessing changes in the levels of cytokine and chemokine in the serum of patients before and during treatment with MAPK inhibitors, finding significant increases early on treatment in cytokine that are indicative of a Th-1 T-cell mediated response (IFNγ, TNFα and CCL4). This is of particular interests when considering the combination with immunotherapies such as anti-PD1 as recently data suggests that a higher baseline expression of cytotoxic Th1 T-cell markers (CD8+, IFNg and Granzyme-A) correlates with improved response to the anti-PD1 therapy. Additionally, on treatment biopsies taken at baseline and at week 4 from anti-PD1 responding patients demonstrate an increase in Th1 T-cell markers (IFNγ, TNFα and others), while non-responders experience a decrease in T-cell activation over the same time point. Therefore MAPK inhibitors could provide a strong immunogenic sensitizer and drive the immunophenotype of the patient's disease into the high Th1 T-cell expression profile and enhance the response rate and duration to both therapies.However, to better understand how molecular and immunogenic therapies may interact we aim to assess changes in the oncogenic signalling of the tumours and characterise the anti-tumour immune response of patients whilst on treated with immune-checkpoint and MAPK inhibitors.

Techniques:
Multiplexed immunofluorescence staining
http://www.perkinelmer.com/catalog/category/id/opal-multiplex-tissue-staining

Spectral imaging and quantitative pathology
(http://www.perkinelmer.com/catalog/product/id/vectra)

Additionally, multiplexed protein assays will be used to assess the changes in chemokine in the serum and tumour microenvironment of patients on therapy. Finally, this data will be correlated with molecular (exome sequencing and RNA array) and clinical data to determine any association with response and survival.

Additional Information

Additional Supervisor: Dr James Wilmott

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Keywords

immunotherapy, Cancer, melanoma, targeted therapy, cancer biology

Opportunity ID

The opportunity ID for this research opportunity is: 118

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