P0934The immunological response to gut-selective anti-α4β7 integrin therapy in anti-TNF–naïve and –exposed Crohn’s Disease patients using flow cytometry

Abstract Background Vedolizumab, a gut-selective monoclonal antibody targeting the α4β7 integrin has been shown to be effective in inducing and maintaining remission in Crohn’s disease. Its mechanism of action is thought to involve the inhibition of immune cell trafficking from the bloodstream into the intestinal tissue, thereby reducing local inflammation. Despite the observed benefits, a substantial proportion of patients fail to respond to vedolizumab, underscoring the unmet need for biomarkers that could facilitate personalized therapeutic strategies. Methods We conducted a study involving both anti-TNF–naïve and anti-TNF–experienced Crohn’s disease patients (trialcode: NL-004608 & NL-006475, n = 37) to investigate immunological mechanisms underlying vedolizumab (non-)response and to identify predictors of therapeutic efficacy. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to quantify T- and B-cell subsets and assess the expression of a variety of markers, including Ki-67, CCR9, and α4β1. Results Lower memory B cell percentages at baseline were associated with non-response across both patient groups. Although memory B cell frequencies differed between responders and non-responders, both groups showed increased IgA and CCR9 expression on memory B cells at week 20 post-treatment. Reduced expression of the proliferation marker Ki-67 on effector memory CD4+ T cells was associated with response in both anti-TNF-naïve and anti-TNF exposed patients, whereas decreased α4β1 expression at baseline and week 6 correlated with non-response. Increased expression of CCR9, a small intestinal homing marker, was detected on effector memory CD4+ T cells after treatment irrespective of response status or prior anti-TNF exposure but was significantly higher in non-responders than responders at week 6 in patients with ileal disease. Conclusion Vedolizumab response in Crohn’s disease is characterized by preserved memory B-cell frequencies, lower proliferative activity of effector memory CD4+ T cells, and higher baseline α4β1 expression, whereas non-response is linked to reduced memory B cells and altered integrin and homing profiles. These findings suggest that baseline integrin profiles and lymphocyte activation states may serve as useful biomarkers for predicting vedolizumab efficacy and highlight distinct immune trajectories in responders versus non-responders. Conflict of interest: Mx. Bakker, Sophie: My research regarding vedolizumab is supported by a grant from Takeda Pharmaceutical Company Limited. Kusters, Thom: - Dijkstra, Sarah: My research is supported by a grant from Takeda Pharmaceutical Company Limited. van Wijk, Femke: Prof. F. van Wijk has been a speaker and/or consultant for Janssen, Johnson & Johnson, and Takeda and has received grants from Regeneron Pharmaceuticals, Leo Pharma, Sanofi, BMS, Galapagos, and Takeda. Oldenburg, Bas: Unrestricted grants: Abbvie, Takeda, Pfizer, Galapagos Advisory boards: Abbvie, Takeda, Pfizer, Lilly, Galapagos, Janssen