Effect of the α4β7 integrin blocking antibody vedolizumab on the clinical and host immune response in patients with inflammatory bowel disease

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Judge, Ciaran
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University College Cork
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Background: Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting condition affecting the gastrointestinal tract. Development of IBD is thought to arise from a complex interplay of genetic susceptibility, environmental contributors, and disordered immune responses to host microbial components. Improvements in our understanding of these interactions have identified novel therapeutic targets and therapeutic interventions which will address unmet clinical need and the therapeutic gap in IBD. However, currently, response and remission rates remain static, reflecting the need and potential for future developments. Vedolizumab (VDZ) is a humanised monoclonal anti-integrin targeting the α4β7 molecule. It is designed to have gut-specific anti-inflammatory effects by blocking the interaction between α4β7+ lymphocytes and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) on gut endothelial cells. It is thought that this may reduce lymphocyte trafficking specifically into inflamed gut tissue in IBD. Despite advances in our understanding of its clinical efficacy and its proposed mechanism of action the exact mechanism of action of this drug remains uncertain. Aim: The aim of this MD thesis is to characterise the effect of treatment with VDZ on patients with IBD at the clinical and immune system level over three studies, to determine if there are clinical or immune features that may predict or enhance response to therapy, or that may create new opportunities for treating this challenging group of conditions. Methods: Study One was a cohort study evaluating the clinical outcomes of patients with IBD treated with VDZ from 9 Irish hospitals. Study Two was designed as a prospective cohort study to assess the impact of VDZ monotherapy on the gut mucosal immune response. Mucosal biopsies were obtained from patients about to start VDZ therapy for active IBD and isolated cells from tissue were analyzed by flow cytometry to assess both mucosal α4β7+ macrophages (CD45, CD11c, CD14, CD163, CD64, CD66b, HLA DR, SIRPa, CD103, α4β7) and α4β7+ lymphocytes (CD3, CD4, CD8, CCR7, CD45 RA, αEβ7, α4β7). Study Three took a similar approach to investigate potential differences in the gut mucosal immune response of patients already established on a combination therapy (CBT) of VDZ with another anti-TNF biological therapy (e.g. VDZ + infliximab, or VDZ + adalimumab) for treatment-refractory IBD, versus those established on VDZ-monotherapy, or patients who were VDZ-naïve. Results: Analysis of 129 patients in Study One supported the clinical efficacy and safety of VDZ in IBD, with 6-month corticosteroid-free clinical remission rates of 31% and 48% in patients with ulcerative colitis (UC) and Crohn’s disease (CD), respectively; and adverse event rates of 1% and 11%, respectively. Study Two, although limited by effects of Covid-19 pandemic in Ireland, revealed that there were more α4β7+ monocytes and lymphocytes in inflamed vs non-inflamed GI mucosa, and more α4β7+ lymphocytes in mucosal samples from patients with CD vs UC. Small numbers of CD64+α4β7+ monocytes were also identified in the inflamed tissue. Study Three revealed a significant ongoing trend towards a higher percentage of α4β7+ T cells in those treated with VDZ-CBT in comparison to both other groups, in addition to an overall increase in the number of αEβ7+ cells in both CD4+ and CD8+ compartments in those treated with VDZ-CBT. Conclusion: Study One demonstrated the clinical utility of VDZ in the treatment of IBD in an Irish cohort of patients, providing valuable real-world data in line with international studies. Study Two supports reports that α4β7+ lymphocytes are more prevalent in inflamed tissue in IBD, and suggests that α4β7+ monocytes may play a role in mucosal inflammation. Study Three demonstrates ongoing presence of α4β7+ cells despite combination biologic therapy, perhaps due to a more refractory inflammatory phenotype, or the ‘re-wiring’ of inflammatory pathways. This project provides valuable information on the clinical utility of VDZ in the treatment of IBD, in addition to novel insight into the cellular and immunological effects of this important medication.
Inflammatory bowel disease , Microbiome , Host clinical response , Vedolizumab , Integrin , Combination biologic , Crohn's , Ulcerative colitis , Etrolizumab , α4β7
Judge, C. 2021. Effect of the α4β7 integrin blocking antibody vedolizumab on the clinical and host immune response in patients with inflammatory bowel disease. MD Thesis, University College Cork.