P0063Colonic imaging mass cytometry and tissue transcriptomics reveal B cell and plasma cell modulation as a key immune feature of response to the anti-integrin therapy etrolizumab in ulcerative colitis

Abstract Background Etrolizumab, a humanised anti-β7 integrin subunit monoclonal antibody, is proposed to selectively modulate leukocyte trafficking and retention in the gut1. Despite encouraging early phase clinical trials in ulcerative colitis (UC), a suite of Phase III studies demonstrated mixed results2. The cellular and molecular colonic immune landscape associated with response to etrolizumab in UC was evaluated utilising imaging mass cytometry (IMC) and bulk RNA sequencing (RNAseq). Methods Colonic biopsies pre- and post-etrolizumab treatment within the LAUREL Phase III clinical trial programme3 were analysed in 30 UC patients (15 responders and 15 non-responders) with moderate to severely active disease at baseline (Figure 1). Thirteen non-IBD control subjects with normal colonic mucosa were included. IMC was performed using a 37-marker panel and gene expression analysis was conducted via bulk RNAseq. Results Baseline UC tissue revealed increased immune infiltrates including B cells, plasma cells, neutrophils, CD11c+ mononuclear phagocytes and fibroblasts, with reduced NK cells, epithelial cells and myofibroblasts compared to healthy controls. IMC and bulk RNAseq demonstrated that response to etrolizumab was associated with significant reductions in B cell, plasma cell, neutrophil, Treg and fibroblast populations, alongside expansion of epithelial cells post-treatment (Figure 2A-C). Minimal cellular changes were seen in non-responders post-treatment. Tissue RNAseq identified 3,614 differentially expressed genes post-treatment in responders, and no differential gene expression in non-responders (Figure 2D). Conclusion Etrolizumab response in UC is associated with marked modulation of mucosal immune populations, particularly B cells and plasma cells. These findings highlight the importance of B cell biology in UC pathogenesis and treatment response and emphasise the importance of mechanistic evaluation of experimental medicines to guide future personalised therapeutic approaches. References: 1.Wyatt NJ, Speight RA, Stewart CJ, Kirby JA, Lamb CA. Targeting Leukocyte Trafficking in Inflammatory Bowel Disease. BioDrugs. 2021;35(5):473-503. doi:10.1007/s40259-021-00496-5 2.Sandborn WJ, Vermeire S, Tyrrell H, et al. Etrolizumab for the Treatment of Ulcerative Colitis and Crohn’s Disease: An Overview of the Phase 3 Clinical Program. Adv Ther. 2020;37(7):3417-3431. doi:10.1007/s12325-020-01366-2 3.Vermeire S, Lakatos PL, Ritter T, et al. Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study. Lancet Gastroenterol Hepatol. 2022;7(1):28-37. doi:10.1016/S2468-1253(21)00295-8 Conflict of interest: Ms. Doyle, Jennifer: No conflict of interest Tambourini, Fiona: Fiona Tambourini is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Wyatt, Nicola: No conflict of interest Hunter, Bethany: No conflict of interest Wittke, Maybeth: Maybeth Wittke is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Speight, Ally: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Lilly, Dr Falk Pharma Janssen Support for attending meetings and/or travel: AbbVie, Dr Falk Pharma Janssen, Tillott’s pharmaceuticals Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: BSG IBD Section Committee (unpaid) Hackney, Jason: Jason Hackney is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Eshghi, Shadi Toghi: Shadi Toghi Eshghi is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Au-Yeung, Amelia: Amelia Au-Yeung is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. McDonald, David: No conflict of interest Schiffman, Courtney: Courtney Schiffman is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Scherl, Alexis: Alexis Scherl is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. McBride, Jacqueline: Jacqueline McBride is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Keir, Mary: Mary Keir is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. O’Gorman, William: William O’Gorman is employed by Genentech Inc., a member of the Roche group and a for-profit company that produces and markets therapeutics. Filby, Andrew: No conflict of interest Lamb, Christopher Andrew: Grant: In the last 5 years I have undertaken research supported by grants from the following: Genentech, Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Roche, UCB Biopharma, Sanofi Aventis, Biogen IDEC, Orion OYJ and AstraZeneca. Personal Fees: In the last 5 years I have received honoraria for speaking at educational events from Takeda, Janssen, Dr Falk, Ferring and Nordic pharma. Other: The following companies were corporate sponsors of an educational event, IBD Newcastle 2023, I convened at Newcastle University on 29th November 2023 Amgen, Celltrion Healthcare, Janssen, Tillotts Pharma, Pharmacosmos, Dr Falk Pharma, Galapagos, Ferring, AbbVie, Takeda, Eli Lilly and Bristol Myers Squibb.