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Unravelling the gut microbiome and IgA dynamics in immune-related adverse events to checkpoint blockade

Project Description

Immunotherapy with checkpoint inhibitors (CPI) has revolutionized the treatment of cancer over the last few years. Despite the effectiveness of these agents in improving long-term survival in different cancer cell types, treatment with CPIs can also lead to severe immune-related adverse events (irAE). These irAE have been postulated to be caused by non-specific activation of the immune system, which in turn lead to autoimmune phenotypes targeting several organs, including skin, gastrointestinal, hepatic and endocrine tissues. The mechanisms involved in irAE are not completely understood. Recently the composition of the gut microbiome has been shown to affect the efficacy of checkpoint inhibitors. However, very little is known about the crosstalk between microbial communities naturally present in the gut and immune surveillance, and how this crosstalk could influence gastrointestinal irAE. The aim of this 4 year PhD is to identify microbial species that interact with IgA-producing cells in the gut in patients presenting with irAE from CPI therapy. We hypothesise that specific species of bacteria are recognized by the immune system and preferentially coated with IgA in the gut, and that these are the species which are potentially causative agents of adverse events caused by CPI therapy via interaction with the immune system. The student will learn molecular biology methods (DNA extraction, Next-generation Sequencing), cellular and immunoassays and bioinformatics. The project will be supervised by Prof. Munir Pirmohamed and Dr. Vanessa Fontana (University of Liverpool, MRC Centre for Drug Safety Science) and Dr. Gregory Amos and Dr Sjoerd Rijpkema (The National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory agency). The student will be based in Liverpool during the first 12 months and the following 12 months at NIBSC. Placement thereafter will be determined by the needs of the project, but we anticipate that there will be a need for some flexibility for travelling between Liverpool and NIBSC.

About the Centre for Drug Safety Science (CDSS): Adverse drug reactions (ADRs) are a major public health concern because of their impact in the clinic and on the development of new medicines. There are very few centres worldwide with the integrated clinical, molecular and chemical expertise required to make major advances in this important aspect of human disease. The Centre for Drug Safety Science (CDSS) enhances drug safety through multi-disciplinary science centred around its state-of-the-art analytical facility. The main drive of the centre is to translate scientific discoveries in the laboratory to the clinic through the identification, evaluation and understanding of the mechanisms of adverse drug reactions. Our concept of drug safety science is that it is a dynamic science, which embraces Basic Pharmacology, Clinical Pharmacology and Toxicology, and through this contributes to the creative aspects of scientific endeavour and drug discovery.

About the National Institute for Biological Standards and Control (NIBSC): NIBSC is a centre of the Medicines and Healthcare products Regulatory Agency (MHRA) which enhances and improves the health of millions of people every day through the effective regulation of medicines and medical devices, underpinned by science and research. NIBSC has a major role in protecting and improving health globally through the production and distribution of International Standards and is the World Health Organization International Laboratory for Biological Standardisation. The studentship will be primarily based in the Microbiome Team at NIBSC. The microbiome team researches the development of novel microbiome therapeutics, investigates how changes in the microbiome may cause disease, and develops reference reagents (standards) for standardising common microbiome analytical pipelines. The microbiome team at NIBSC is led by Dr Gregory Amos and is part of the Enterics Group led by Dr Sjoerd Rijpkema, within the Division of Bacteriology.

To apply please send covering letter and CV for and .
For application enquires please contact Gregory Amos () or Vanessa Fontana ().

Funding Notes

The stipend for the studentship will be consistent with current Research Council Doctoral stipend levels. The indicative stipend for 2019 is £15,009. Fees for PhD registration and laboratory running costs will also be provided. The studentship will cover expenses for relocation between the University of Liverpool and NIBSC. Applications can only be from EU/UK applicants.

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