Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis

Tew, Gaik W.; Hackney, Jason A.; Gibbons, Deena L.; Lamb, Christopher A; Luca, Diana; Egen, Jackson G.; Diehl, Lauri; Anderson, Jeff Eastham; Vermeire, Séverine; Mansfield, John C.; Feagan, Brian G.; Panés, Julián; Baumgart, Daniel C.; Schreiber, Stefan; Dotan, Iris; Sandborn, William J.; Kirby, John A.; Irving, Peter M; Hertogh, Gert De; Assche, Gert A. Van; Rutgeerts, Paul; O’Byrne, Sharon; Hayday, Adrian; Keir, Mary E.

doi:10.1053/j.gastro.2015.10.041

Cited by 134 publications

(98 citation statements)

References 36 publications

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“…Thus, it is very likely that αEβ7 + T cells communicate with the epithelium. Independent reports have recently shown that αEβ7 is enriched in pro-inflammatory T cell subsets (22, 35) and that αEβ7 + T cells express higher levels of granzyme A than αEβ7 − T cells (36). In vivo , this might result in deleterious effects of such αEβ7-expressing on epithelial cells, which is supported by some of our data showing correlations of changes in αEβ7 integrin with changes in clinical parameters that are indicative of intestinal epithelial barrier function.…”

Section: Discussionmentioning

confidence: 99%

Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles

et al. 2017

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BackgroundDespite large clinical success, deeper insights into the immunological effects of vedolizumab therapy for inflammatory bowel diseases are scarce. In particular, the reasons for differential clinical response in individual patients, the precise impact on the equilibrium of integrin-expressing T cell subsets, and possible associations between these issues are not clear.MethodsBlood samples from patients receiving clinical vedolizumab therapy were sequentially collected and analyzed for expression of integrins and chemokine receptors on T cells. Moreover, clinical and laboratory data from the patients were collected, and changes between homing marker expression and clinical parameters were analyzed for possible correlations.ResultsWhile no significant correlation of changes in integrin expression and changes in outcome parameters were identified in Crohn’s disease (CD), increasing α4β7 levels in ulcerative colitis (UC) seemed to be associated with favorable clinical development, whereas increasing α4β1 and αEβ7 correlated with negative changes in outcome parameters. Changes in α4β1 integrin expression after 6 weeks were significantly different in responders and non-responders to vedolizumab therapy as assessed after 16 weeks with a cutoff of +4.2% yielding 100% sensitivity and 100% specificity in receiver-operator-characteristic analysis.DiscussionOur data show that clinical response to vedolizumab therapy in UC but not in CD is associated with specific changes in integrin expression profiles opening novel avenues for mechanistic research and possibly prediction of response to therapy.

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Section: Discussionmentioning

confidence: 99%

Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles

et al. 2017

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“…These results are concordant with similar observations of lesser efficacy of vedolizumab among those with prior anti-TNF treatment. Additional analyses suggest that response to etrolizumab is associated with higher baseline gene expression of αE and with higher numbers of αE-expressing cells on colonic biopsy [31] . This finding, consistent with the anticipated mechanism of action, suggests that this agent may be more effectively targeted to specific subpopulations of patients to increase the likelihood of treatment success.…”

Section: Etrolizumabmentioning

confidence: 95%

Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions

Sands

2017

Dig Dis

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Background: In inflammatory bowel diseases (IBD), a pivotal step in the initiation and perpetuation of mucosal inflammation entails the recruitment of inflammatory leukocytes to the gut. Understanding the carefully coordinated series of molecular events that culminate in the recruitment of leukocytes to the gut has resulted in novel interventions with new capabilities in treating both Crohn's disease and ulcerative colitis. Key Messages: Natalizumab, an anti-α4 integrin antibody, was the first agent to demonstrate the efficacy of this approach for the induction and maintenance of response and remission in Crohn's disease. Widespread adoption was mitigated by the previously unknown risk of progressive multifocal leukoencephalopathy (PML) with this approach. Current approaches employ a more selective inhibition of adhesion molecules targeting the gut to avoid broad suppression of surveillance for JC virus, the causal pathogen of PML. Subsequently, vedolizumab, a humanized anti-α4β7 integrin antibody, has demonstrated efficacy in patients with IBD and has an excellent safety profile. To date, there have been no cases of PML in patients treated with vedolizumab, suggesting that this more selective agent does not have the same risk for PML as natalizumab. Other agents target β7 integrin (etrolizumab) and mucosal addressin cellular adhesion molecule-1, the endothelial ligand of α4β7 integrin. Efforts to inhibit the chemokine receptor CCR9 using the agent CCX282-B in Crohn's disease were not successful. An orally administered anti-α4 integrin compound showed some promise in a phase 2 trial but raises concern for PML. Finally, the S1P1 receptor agonist ozanimod showed promise in early trials in ulcerative colitis. Conclusions: In summary, anti-trafficking agents have the potential to provide safe and effective therapy for IBD, and are a burgeoning class of novel agents.

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“…Completed phase 1 and 2 and ongoing phase 3 clinical trials have shown that blockade of αEβ7 with etrolizumab is well tolerated, with rates of serious adverse events similar to those with placebo . In addition, both CD4 + αEβ7 + and CD8 + αEβ7 + cells are pro‐inflammatory in phenotype; CD4 + αEβ7 + demonstrating fewer markers associated with T reg cells including FoxP3 relative to CD4 + αEβ7 − lymphocytes …”

Section: Safety Of Anti‐integrin Therapiesmentioning

confidence: 99%

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Dotan

Allez

Danese

et al. 2019

Medicinal Research Reviews

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Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

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Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis

Cited by 134 publications

References 36 publications

Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles

Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles

Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

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