Exploring the interaction of gut microbiome, genetic and immunological factors in gastrointestinal toxicity of immune checkpoint inhibitors.

Cancer is a highly prevalent disease worldwide and it has been estimated that 1 in 2 people in the UK will get cancer in their lifetime. Despite the enormous investments in research to develop treatments to cure the disease, there are more than 200 different types of cancer and unfortunately there is no unique effective treatment to cure many cancer types. Recently, a new class of drugs, known as immune checkpoint inhibitors, have shown promising results in the treatment of some types of aggressive cancer, such as advanced melanoma and non-small cell lung carcinoma. These drugs act by facilitating the specialised immune cells, T cytotoxic lymphocytes, to attack and eliminate the cancer cells. However, some patients develop adverse reactions that vary from a mild skin rash or diarrhoea to more severe inflammation of intestine, liver, thyroid and other organs in the body. It can be explained, by hyperactivation of the immune cells and, therefore, T cells start attacking normal cells. Why some individuals have great benefit from these treatments, while others develop adverse and undesired effects is unknown. The aim of our project is to find out why some patients have severe gastrointestinal adverse reactions after treatment with these drugs while others do not. We expect our study to improve the understanding of the factors underlying gastrointestinal adverse reactions and, ultimately, deliver interventions to identify individuals at high risk of toxicity, and develop treatments to overcome the toxicity.

Monoclonal antibodies targeting regulatory immune checkpoint molecules that inhibit cytotoxic T cell activation, known as immune check-point inhibitors (ICI), are being widely used for the treatment of a range of cancer types. Despite their effectiveness in improving long-term survival, treatment with ICIs can lead to severe immune-mediated adverse drug reactions (ADRs). GI adverse effects are amongst the most frequently observed ADR in patients treated with ICI, and can be life-threatening. The aim of this study is to identify individual susceptibility factors and understand mechanisms that lead to immune-mediated gastrointestinal (GI) adverse reactions in patients treated with ICIs. Using both prospective longitudinal and cross-sectional study designs, we will identify patients with and without these ADRs after the initiation of the treatment with ICIs. We propose to investigate: 1) The composition of the intestinal microbiota in treatment-naïve individuals in faecal samples to compare the diversity and abundance of the microbes between cases and controls; 2) Genetic variants in CTLA-4, CD86, PD-1, PD-L1, HLA complex and other immune-related genes and any association with GI events; 3) Measure gene expression (mRNA and miRNA) in subpopulations of circulating immune cells before and after the treatment in cases and controls; 4) Obtain the cytokine profile in serum samples in cases and controls; 5) Characterise subpopulations of the cells infiltrating inflamed tissue obtained via colonic biopsies; 6) Use single-cell RNA sequencing of infiltrating T lymphocytes and colonic epithelial cells obtained from colonic biopsies. This work will reveal important regulatory mechanisms that determine self-tolerance vs. the development of immune-mediated adverse events affecting the lower GI tract after treatment with ICIs. The mechanistic understanding will allow us to develop novel interventional strategies to improve the benefit-risk ratio of these agents.