Title: The gut microbiome as a biomarker and modulator of checkpoint inhibitor immunotherapy
Funder: Cancer Research UK

Abstract: Background: Our CRUK proposal will focus on the first ever large-scale, high-resolution analysis (i.e. to bacterial strain level) of cancer patient stool and oral microbiomes (two proxies of the gastrointestinal microbiome) to determine biomarker potential and to generate the future rationale for patient management and stratification and to potentially manipulate a patient’s gastrointestinal microbiome to enhance treatment tolerance and efficacy. Aims: 1. To successfully collate a bank of oral and stool microbiome and peripheral blood cells (buffy coat) samples from melanoma and renal cancer patients receiving both single agent immune checkpoint inhibitors and combination regimens; to validate our preliminary stool culture and sequencing findings (outlined above and Figures 2 & 3) in large-scale prospective clinical trial cohorts with well annotated patient data. 2. To perform precision high-resolution taxonomic analysis from oral and stool samples from cancer patients and healthy controls and to link these microbiome profiles to clinical outcomes in terms of treatment toxicity and host responses. To correlate these microbiome profiles to relevant patient factors such as blood transcriptomes, BMI/obesity, PPI use and NSAID/antibiotic use to delineate key microbial, immune and clinical parameters impacting patient outcome. 3. To perform discovery science on cancer patient microbiomes to identify and define translation opportunities. We will explore the potential use of cancer microbiome profiles for patient management, and using pre-clinical models, test and pilot combinations of beneficial commensals aimed at improving outcomes associated with checkpoint inhibitor therapy. Methods: High resolution DNA sequencing and bacterial culture of material from patients in immunotherapy clinical trials. We have three specific hypotheses: 1. Specific pathogenic bacterial species/strains pre-exist in most patients who develop toxicities to immunotherapies (Aim 2). These microbes can be identified before treatment to predict, and therefore potentially prevent, severe IrAEs. Thus, a personalized microbiome profile represents a potential tool for improving patient care (Aim 3). 2. Some exceptional responders carry specific beneficial bacterial species/strains before treatment that provoke the immune system (Aim 2) that could be predictive of response. These bacteria or bacterial mixes, can be isolated and used as adjuvants to immunotherapy to increase the likelihood of patient response (Aim 3). Deep profiling of the microbiome is critical for defining these organisms. 3. Co-morbidities such as obesity and auto-immune diseases and common treatments (NSAIDs, antibiotics and PPIs) shape the microbiome of cancer patients and these factors influence clinical response to immunotherapy (Aims 2 and 3).

Lay abstract: Background: Our CRUK proposal will focus on the first ever large-scale, high-resolution analysis (i.e. to bacterial strain level) of cancer patient stool and oral microbiomes (two proxies of the gastrointestinal microbiome) to determine biomarker potential and to generate the future rationale for patient management and stratification and to potentially manipulate a patient’s gastrointestinal microbiome to enhance treatment tolerance and efficacy. Aims: 1. To successfully collate a bank of oral and stool microbiome and peripheral blood cells (buffy coat) samples from melanoma and renal cancer patients receiving both single agent immune checkpoint inhibitors and combination regimens; to validate our preliminary stool culture and sequencing findings (outlined above and Figures 2 & 3) in large-scale prospective clinical trial cohorts with well annotated patient data. 2. To perform precision high-resolution taxonomic analysis from oral and stool samples from cancer patients and healthy controls and to link these microbiome profiles to clinical outcomes in terms of treatment toxicity and host responses. To correlate these microbiome profiles to relevant patient factors such as blood transcriptomes, BMI/obesity, PPI use and NSAID/antibiotic use to delineate key microbial, immune and clinical parameters impacting patient outcome. 3. To perform discovery science on cancer patient microbiomes to identify and define translation opportunities. We will explore the potential use of cancer microbiome profiles for patient management, and using pre-clinical models, test and pilot combinations of beneficial commensals aimed at improving outcomes associated with checkpoint inhibitor therapy. Methods: High resolution DNA sequencing and bacterial culture of material from patients in immunotherapy clinical trials. We have three specific hypotheses: 1. Specific pathogenic bacterial species/strains pre-exist in most patients who develop toxicities to immunotherapies (Aim 2). These microbes can be identified before treatment to predict, and therefore potentially prevent, severe IrAEs. Thus, a personalized microbiome profile represents a potential tool for improving patient care (Aim 3). 2. Some exceptional responders carry specific beneficial bacterial species/strains before treatment that provoke the immune system (Aim 2) that could be predictive of response. These bacteria or bacterial mixes, can be isolated and used as adjuvants to immunotherapy to increase the likelihood of patient response (Aim 3). Deep profiling of the microbiome is critical for defining these organisms. 3. Co-morbidities such as obesity and auto-immune diseases and common treatments (NSAIDs, antibiotics and PPIs) shape the microbiome of cancer patients and these factors influence clinical response to immunotherapy (Aims 2 and 3).

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS