Unravelling the immunopathophysiology of immune checkpoint inhibitor-induced gut inflammation in all areas

 Immune check point inhibitors (ICPi’s) are game changing immunotherapeutics that have revolutionized treatment paradigms for several cancers, including melanoma, lung and urological cancers. They block “checkpoint molecules”, such as CTLA-4 and PD-1, expressed by immune cells, instructing them to power down and switch off their inflammatory behaviour. Side-lining these inhibitory pathways amplifies immune activation and bolsters anti-tumour immunity, but risks triggering severe immune-mediated injury to non-cancer tissues including gastrointestinal toxicity. Diarrhoea/colitis affects up to 50% of ICPI-treated patients and is the most common cause of serious, life-threatening complications, and most common cause of discontinuation from life prolonging therapy. Our aim is to identify better treatment options informed by insights into mechanism driving ICPI-induced gut disease, with a view to improving quality of life and outcomes (reduced mortality/morbidity) for cancer patients. Potentially tractable therapeutic targets include proximal activating cytokines, which could be targeted by existing biological agents used in other indications, which would just require repurposing. 

We are working on understanding the pathophysiological mechanisms implicated in ICPi- colitis, using flow cytometry to analyse blood and colonic tissue, and human colonic organoids to interrogate pathways mediating inflammation. We are also working on identifying an immunological signature that may be able to predict onset of toxicity.