Predicting Response to Immunotherapy for Melanoma With Gut Microbiome and Metabolomics

Study Overview
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Brief Summary
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This study will investigate the effects of gut microbiome diversity (richness in terms of many bacterial species in the gut) on responses and side effects of immunotherapy in advanced melanoma patients. Immunotherapy for melanoma is especially damaging for the gut with colitis which can lead to death and significant morbidity with repeated hospital admissions. The richness of the microbiome in the gut may be protective against colitis and other side effects but this needs to be confirmed. There is also some preliminary evidence that the gut microbiome diversity can enhance responses to immunotherapy in cancer but this has been shown in small numbers of melanoma patients.

Detailed Description
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This pilot project will assess the gut microbiome with metagenome sequencing before and after starting immunotherapy in stage 3 and 4 melanoma patients. The project will assess the impact of the gut microbiome on treatment response rates and side effects induced by immunotherapy. 200 stage 4 and 250 stage 3 melanoma patients naive to immunotherapy will be recruited from melanoma clinics. Stool samples will be donated pre-treatment and at follow-up visits throughout treatment. An additional sample will also be requested in the event of disease progression or toxicity necessitating treatment delay or discontinuation. An accompanying stool sample questionnaire will be completed at each sampling time point with the optional completion of a 24-hour recall food diary. Blood samples will also be taken before and after starting immunotherapy treatment, with gastrointestinal, food frequency, quality of life questionnaires administered at baseline. An optional tumour biopsy if safe and accessible, is requested from patients in the stage 4 cohort before and after starting immunotherapy. Microbiome data from melanoma patients will be compared with the TwinsUK healthy control gut microbiome data on more than 3000 healthy adults. This analysis will help us assess if there are major differences between the microbiome composition in the melanoma cases prior to therapy compared to the control gut microbiome data from TwinsUK.

Official Title
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Predicting Response to Immunotherapy for Melanoma With Gut Microbiome and Metabolomics

Conditions
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Melanoma (Skin)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patients aged over the age of 18 years with advanced melanoma due to receive first line systemic treatment with immunotherapy with a checkpoint inhibitor alone or in combination. Exclusion Criteria: Patients who have had systemic anti-cancer treatment for locally advanced or metastatic disease. Patients unable to consent because of language barrier or inability to consent. Patients unable to collect or send the stool samples for geographical, social or psychological reasons. Persons benefitting from protection system of adults (including guardianship and curatorship) Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort A<br>Patients with stage 4 melanoma due to commence immunotherapy. Patients should be naïve to immunotherapy. | |
| Cohort B<br>Patients with stage 3 melanoma who are naïve to immunotherapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut microbiome diversity via measurement of bacterial species in stool samples | Gut microbiome diversity and peripheral blood mononuclear cells immunophenotyping in relation to responses to treatment and side effects in patients with stage 3 or stage 4 melanoma receiving immunotherapy | 3-5 years | 
| Peripheral blood monocyte measurements to determine the characterisation of peripheral blood mononuclear cells (immunophenotyping) and inflammatory markers before and after starting immunotherapy treatment. | Gut microbiome diversity and peripheral blood mononuclear cells immunophenotyping in relation to responses to treatment and side effects in patients with stage 3 or stage 4 melanoma receiving immunotherapy. | 3-5 years | 
| Side effects as determined by CTCAE scale Common Toxicity Criteria for Adverse Events v5.03 | Gut microbiome diversity and peripheral blood mononuclear cells immunophenotyping in relation to responses to treatment and side effects in patients with stage 3 or stage 4 melanoma receiving immunotherapy. | 3-5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of optional punch biopsy samples before and after commencing immunotherapy treatment in patients with stage 4 melanoma | Exploratory analysis to examine the association between the gut microbiome and the presence of tumour infiltrates and regulatory environments. | 3-5 years |