Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis

Li, Allen Cheng-Wei; Dong, Chen; Tay, Soon-Tzeh; Ananthakrishnan, Ashwin N.

doi:10.3389/fimmu.2022.1025350

Cited by 7 publications

(6 citation statements)

References 46 publications

(52 reference statements)

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“…Preventing T cell trafficking to the gut is beneficial for GVHD prophylaxis, and it is already being investigated using vedolizumab, a monoclonal antibody targeting integrin α4β7 and therefore inhibiting its interaction with mucosal addressin cell adhesion molecule 1 (MADCAM1) expressed by intestinal endothelial cells 54 . For a possible therapeutic intervention targeting CXCL11, it is important to consider that its expression might be limited to specific time frames during intestinal inflammation and disrupting the CXCL11/CXCR3 axis may only be necessary for a relatively brief period in such a therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Cutilli,

Jansen,

Paolucci

et al. 2024

Preprint

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The cytokine interferon-gamma (IFNγ) plays a multifaceted role in intestinal immune responses ranging from anti-to pro-inflammatory depending on the setting. Here, using a 3D co-culture system based on human intestinal epithelial organoids, we explore the capacity of IFNγ-exposure to reprogram intestinal epithelia and thereby directly modulate lymphocyte responses. IFNγ treatment of organoids led to transcriptional reprogramming, marked by a switch to a pro-inflammatory gene expression profile, including transcriptional upregulation of the chemokines CXCL9, CXCL10, and CXCL11. Proteomic analysis of organoid-conditioned medium post-treatment confirmed chemokine secretion. Furthermore, IFNγ-treatment of organoids led to enhanced T cell migration in a CXCL11-dependent manner without affecting T cell activation status. Taken together, our results suggest a specific role for CXCL11 in T cell recruitment that can be targeted to prevent T cell trafficking to the inflamed intestine.

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Section: Discussionmentioning

confidence: 99%

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Cutilli,

Jansen,

Paolucci

et al. 2024

Preprint

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“…Another monoclonal antibody, vedolizumab, that inhibits T-cell trafficking to the GI tract by selectively binding the α4β7 heterodimer, has shown inconsistent results as a treatment for GVHD, 13 , 14 , 33 , 34 , 35 although a recent meta-analysis suggested that vedolizumab may be efficacious for corticosteroid-resistant GI GVHD. 36 It is possible that blockade of recirculating T cells between the secondary lymphoid organs and the GI tract may be more effective if used to prevent GVHD. A phase 1b study that investigated GVHD prevention with vedolizumab reported encouraging results 37 and this strategy is under further investigation in a randomized, placebo-controlled trial (NCT03657160).…”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease

Malki

London²,

Baez

et al. 2023

Blood Advances

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Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker–based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.

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“…There are several regimens of other mechanisms that were not involved in included trials, such as the anti-α4β7 integrins monoclonal antibody vedolizumab and the anti-interleukin-6 receptor (IL-6R) monoclonal antibody tocilizumab. A systematic review and meta-analysis have evaluated the efficacy of vedolizumab in the treatment of gastrointestinal aGVHD and obtained a pooled long-term ORR higher than 70% ( 56 ). As for steroid-refractory gastrointestinal aGVHD, several retrospective studies of small sample size were published and the reported ORR ranges from 45% to 79% ( 57 – 59 ).…”

Section: Discussionmentioning

confidence: 99%

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials

Luo,

Huang,

Wei

et al. 2023

Front. Immunol.

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ObjectiveSteroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens.MethodsLiterature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method.ResultsEight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01–1.32, P = 0.04), especially in patients with severe (grade III–IV or grade C–D) aGVHD (RR = 1.26, 95% CI = 1.04–1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05–1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy.ConclusionsAdding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

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Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis

Cited by 7 publications

References 46 publications

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials

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