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Identification of Candidate Biomarkers Associated with Response to Vedolizumab in Inflammatory Bowel Disease

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

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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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Correspondence to James D. Lord.

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Disclosures

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

Keywords

  • Anti-integrin
  • Biomarkers
  • Inflammatory bowel disease
  • Personalized medicine