Abstract
Background/Aims
Vedolizumab is an anti-α4β7 monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). This exploratory study aimed to identify biomarkers associated with vedolizumab response.
Methods
Twenty-six IBD patients (15 with Crohn’s, 11 with ulcerative or indeterminate colitis) initiating vedolizumab at a single center between 2014 and 2016 underwent sampling of serum and peripheral blood mononuclear cells (PBMCs) before and during vedolizumab therapy. Response was defined as steroid-free improvement in endoscopic score or Harvey–Bradshaw index/simple clinical colitis activity index (reduction greater than 3 or total less than 3). PBMCs were evaluated for immunophenotype and expression of α4β7 integrin on lymphocytes before and during vedolizumab therapy. Serum vedolizumab levels and α4β7 saturation were measured serially after induction.
Results
Fourteen out of 26 (54%) patients treated with vedolizumab responded to therapy. Pretreatment α4β7 expression was higher in responders on multiple subsets of T, B, and NK cells, with terminal effector memory (p = .0009 for CD4 and .0043 for CD8) and NK cells (p = .0047) best discriminating between responders and nonresponders. During therapy, log10 serum vedolizumab levels at trough were higher in responders than nonresponders (p = .0007). Conversely, the percentage of effector memory T cells with free α4β7 at trough was lower in responders than nonresponders (p < .0001). However, loss of α4β7 saturation with vedolizumab was more sensitive to low serum vedolizumab in nonresponders.
Conclusions
Pretreatment α4β7 expression and α4β7 receptor saturation during maintenance therapy were identified as candidate biomarkers for vedolizumab response.
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Abbreviations
- IBD:
-
Inflammatory bowel disease
- UC:
-
Ulcerative colitis
- CD:
-
Crohn’s disease
- IC:
-
Indeterminate colitis
- MAdCAM-1:
-
Mucosal addressin cell adhesion molecule
- PBMC:
-
Peripheral blood mononuclear cell
- NK:
-
Natural killer
- HBI:
-
Harvey–Bradshaw index
- SCCAI:
-
Simple clinical colitis activity index
- APC:
-
Allophycocyanin
- Tregs:
-
Regulatory T cells
- IC50:
-
Half maximal inhibitory concentration
- IQR:
-
Interquartile range
- MFI:
-
Mean fluorescence intensity
- TEM :
-
T effector memory
- TEMRA :
-
Terminal effector memory T cells
- AUC:
-
Area under the curve
- tTreg:
-
Thymically derived Treg
- pTreg:
-
Peripherally derived Treg
- MAIT:
-
Mucosal-associated invariant T cells
- TFH :
-
T follicular helper
References
Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol. 1994;15:517–528.
Pérez-Villar JJ, Zapata JM, Melero I, Postigo A, Sánchez-Madrid E, López-Botet M. Expression and function of alpha 4/beta 7 integrin on human natural killer cells. Immunology. 1996;89:96–104.
Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol. 1994;1:3282–3293.
Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;22:699–710.
Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;22:711–721.
Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147:618–627.e3.
Colombel J-F, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2016. https://doi.org/10.1136/gutjnl-2015-311079.
Jin Y, Lin Y, Lin L-J, Zheng C-Q. Meta-analysis of the effectiveness and safety of vedolizumab for ulcerative colitis. World J Gastroenterol. 2015;28:6352–6360.
Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–927.
Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13:522–530.e2.
Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E, Ringler DJ. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol. 1997;1:2099–2106.
Mora JR, Bono MR, Manjunath N, et al. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature. 2003;3:88–93.
Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song S-Y. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21:527–538.
Kreher CR, Dittrich MT, Guerkov R, Boehm BO, Tary-Lehmann M. CD4+ and CD8+ cells in cryopreserved human PBMC maintain full functionality in cytokine ELISPOT assays. J Immunol Methods. 2003;278:79–93.
Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;8:514.
Walmsley RS, Ayres RC, Pounder RE, Allan RN. A simple clinical colitis activity index. Gut. 1998;43:29–32.
Rodriguez MW, Paquet AC, Yang YH, Erle DJ. Differential gene expression by integrin beta 7+ and beta 7− memory T helper cells. BMC Immunol. 2004;5:5–13.
Erle DJ, Brown T, Christian D, Aris R. Lung epithelial lining fluid T cell subsets defined by distinct patterns of beta 7 and beta 1 integrin expression. Am J Respir Cell Mol Biol. 1994;10:237–244.
Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. 2012;18:1470–1479.
Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;20:188–202.
Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–646.
Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–1254.
Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2009;10:49–54.
Van Moerkercke W, Ackaert C, Compernolle G, et al. 405 high infliximab trough levels are associated with mucosal healing in Crohn’s disease. Gastroenterology. 2010;138:S–60.
Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008;6:1370–1377.
Rosario M, Wyant T, Leach T, et al. Vedolizumab pharmacokinetics, pharmacodynamics, safety, and tolerability following administration of a single, ascending, intravenous dose to healthy volunteers. Clin Drug Investig. 2016;36:913–923.
Ladd AHM, Scott FI, Grace R, Bownik H, Lichtenstein GR. Sa1086 dose escalation of vedolizumab from every 8 weeks to every 4 or 6 weeks enables patients with inflammatory bowel disease to recapture response. Gastroenterology. 2016;150:S235–S236.
Acknowledgments
We would like to thank Kassidy Benoscek for subject consent, phlebotomy, and coordination, Katherine Schwedhelm with flow cytometer management, and Samuel Skinner for biostatistical review of the manuscript. This work was supported by a grant from the Digestive Disease Institute at Virginia Mason Medical Center.
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JDL has received research funding from Takeda Pharmaceuticals for an alternative investigator-initiated project. MVC is a site principal investigator, and JDL and EKB are site sub-investigators for Takeda-funded clinical trials.
Author’s contribution
JDL contributed to study concept. EKB and JDL helped in study design. EKB, MVC, and JDL participated in clinical care and subject recruitment. EKB contributed to clinical data acquisition. DMS and JDL contributed to scientific data acquisition. EKB, DMS, and JDL involved in data analysis and interpretation. EKB and JDL drafted the manuscript and made critical revision for important intellectual content. All authors contributed to the critical revision of the manuscript and have read and approved the final version of this manuscript.
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Boden, E.K., Shows, D.M., Chiorean, M.V. et al. Identification of Candidate Biomarkers Associated with Response to Vedolizumab in Inflammatory Bowel Disease. Dig Dis Sci 63, 2419–2429 (2018). https://doi.org/10.1007/s10620-018-4924-8
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DOI: https://doi.org/10.1007/s10620-018-4924-8