Understanding the pathogenesis of Epstein-Barr virus-associated complications arising in patients treated with immune checkpoint regulators

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Immune checkpoint regulators (iCR) are a revolutionary new class of treatment which manipulate the immune system to fight cancer. Whilst iCR regimens have yielded improved outcomes for patients with cancer, they are associated with a number of autoimmune complications termed 'immune-related adverse events' (irAE). One of the commonest irAE to affect patients is immune related colitis (irColitis), which in approximately 1-5% of patients, will result in severe inflammation of the bowel and perforation. Colonic perforation is a serious and life threatening emergency which has potential long term implications for patients. It is known that bacteria can modulate the effects and complications of immune checkpoint therapy. Nothing is known about the effect of viruses on outcome following iCR.In a small retrospective study of diagnostic tissue specimens, we found a proportion of iCR treated patients with irCol showed multiple ulcerations along the course of their gastrointestinal tract. On further investigation, these ulcerations contained immune cells infected with the Epstein-Barr virus (EBV). This entity is called EBV mucocutaneous ulcer (EBVMCU). Critically, the 4 of 13 cases which showed EBVMCU were all associated with severe inflammation and perforation.The findings suggest the either iCR, or the anti-immune drugs used to treat colitis, affects the way the immune system control EBV, which is latently present in 95% of the population. This is the first ever example of a link between viruses and complications related to iCR treatment. As new iCR drugs are developed, it is possible that such interactions will become ever more important to how iCRs are used clinically. The aim of this study is to: 1. Characterise the clinical course and pathological features of iCR associated EBVMCU. 2. Study the changes in the immune system in blood and tissue that occur upon commencement if iCR therapy, development of irColitis.PlanPart 1: We will characterise the features of EBVMCU that occur in patients treated on iCR therapy. We will examine surplus diagnostic tissue from patients who have suffered bowel perforated following irColitis. We will perform the following tests:i. EBV: Test for the presence of EBV.ii. Genes: we will see if variations in the CTLA-4 gene, the target of some iCR, effect EBVMCU development in iCR.iii. We will examine the cellular composition and the immune cells of the EBVMCU lesions.This will enable us to establish the incidenece of EBVMCU in irColitis and provide insight into how these lesions develop. Part 2: We will follow 50 patients started on iCR therapy and measure a the effect iCR has on the immune system, specifically, the control of EBV. This will provide new information on the effects of iCRs on human viruses and the immune responses that is essential for controlling them. The study will provide a valuable insight into the regulation of EBV immunity and could have clinical consequences as to how irAE are managed.