Baseline Peripheral Blood α4β7 Integrin Levels and Correlation With Response to Vedolizumab in Inflammatory Bowel Disease Patients Treated With Vedolizumab

Abstract

Precision medicine has the potential to tailor treatment regimens to patients most likely to respond positively to therapy. This patient selection approach based on individual patient biology provides patients with more effective treatment options and may deliver a better safety margin, ultimately leading to improved patient care. Unlike precision medicine, conventional drug therapy typically considers large patient populations to be relatively homogenous as a single group to be distinguished only by post treatment responses. This one-drug-fits-all approach has often failed to effectively treat disease, and more importantly, has delayed patients the opportunity to receive more effective treatment. Any given drug can be therapeutic in some patients but ineffective in others, and some experience adverse drug effects whereas others are unaffected. Although substantial progress has been made in the management of disorders such as inflammatory bowel disease (IBD), many patients still do not respond to the available treatment options. As a result, more research is needed to identify biomarkers predictive of drug response that could better manage treatment for patients with IBD. IBD with the main entities of Crohn’s Disease (CD) and Ulcerative Colitis (CD) are thought to arise from a complex pathogenesis that crucially involves pro-inflammatory lymphocytes (Danese et al., 2011). A multitude of molecules are involved in lymphocyte homing to sites of intestinal inflammation but only a few of them are responsible for mucosal specificity of the homing process. Important adhesion molecules in the homing of a specialized subset of lymphocytes, namely, T lymphocytes or T-cells, specifically to the intestines are the integrins alpha-4 beta-1 (α4β1) and alpha-4 beta-7 (α4β7) (Pedersen et al., 2014). Inflammation in IBD may also be regulated by the production of a variety of pro-inflammatory mediators, including cytokine tumor necrosis factor (TNF)-α (Pedersen et al., 2014), as well as environmental and genetic factors. This complex interaction between the immune system, microbiota and host genotype are thought to underlie the development of IBD. Several TNF-α inhibitors and other biologics directed against pathways involving cytokines, adhesion molecules or other mediator systems involved in the pathogenesis of IBD have been developed and tested in clinical trials (Pedersen et al., 2014). Although anti-TNF-α therapies have been highly effective in treating IBD, a significant proportion of IBD patients still do not respond or lose response to TNF-α inhibition and as a result, novel therapies are needed (Cheng et al., 2014). Unlike TNF-α inhibitors, the monoclonal anti- α4β7 integrin antibody vedolizumab (Entyvio®) acts by specifically binding to the α4β7 integrin heterodimer found on circulating immune cells. The binding of vedolizumab to cells expressing α4β7 integrin inhibits the interaction of α4β7 integrin to its primary ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thereby minimizing immune cell infiltration into the gastrointestinal tract (Neurath et al., 2014, and Soler et al., 2009). While vedolizumab has developed to a new mainstay in the therapy of IBD, deeper insights into the immunological effects of α4β7 blockade are still scarce. In particular, the reasons why some patients show no clinical response are still unclear. A potential explanation for the lack of response observed in vedolizumab treated patients could be due to insufficient level of target cells expressing α4β7 integrin, thus impacting the ability of pro-inflammatory lymphocytes that can be blocked from homing to the gut. My thesis will focus on addressing this point, specifically answering the question of whether baseline (pre-treatment) levels of α4β7 integrin expression on peripheral blood T-cells can be used as a predictor of non-response in patients who did not respond to vedolizumab treatment. This question will be addressed by using clinical data previously generated from two phase 3, randomized, placebo-controlled clinical trials aimed at determining the efficacy of vedolizumab in induction and maintenance of moderately to severely active UC (Takeda study C13006) and CD (Takeda study C13007). Although vedolizumab was more effective than placebo in both of these clinical studies, a proportion of patients did not respond to induction therapy or lost the response over time (Colombel et al., 2017, and Feagan et al., 2013). This observation was particularly evident in a subset of patients who had failed prior TNF-α therapy. As part of my thesis, baseline expression of α4β7 integrin in patients who failed or were intolerant of prior TNF-α therapy will also be investigated. The available α4β7 integrin data has been generated using a receptor occupancy flow cytometry based assay (deemed MAdCAM-1) that I developed at Takeda Pharmaceuticals (Wyant et al., 2016). This assay was subsequently validated and implemented in the aforementioned clinical trials. The thesis project will entail re-analyzing clinical data generated from this assay and correlating it with clinical parameters including response to therapy, clinical remission and clinical manifestations specific to each indication. Identifying patients most likely to respond to vedolizumab could lead to a precision medicine approach based on circulating peripheral blood α4β7 integrin expression levels.