Gastroenterology

Gastroenterology

Volume 143, Issue 5, November 2012, Pages 1207-1217.e2
Gastroenterology

Original Research
Clinical—Alimentary Tract
Safety and Efficacy of Antigen-Specific Regulatory T-Cell Therapy for Patients With Refractory Crohn's Disease

https://doi.org/10.1053/j.gastro.2012.07.116Get rights and content

Background & Aims

New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD.

Methods

We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin.

Results

Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 106 cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8.

Conclusions

Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44.

Section snippets

Patients

This phase 1/2a, exploratory, uncontrolled, and open-label clinical trial was conducted at 6 centers in France between 2008 and 2011. The study protocol and amendments were approved by the appropriate independent ethics committee and national regulatory authority (Eudract no. 2006-004712-44). The study was performed in accordance with Good Clinical Practice guidelines. An independent data safety monitoring board was appointed to independently evaluate the ethical aspect and ensure patients'

Patient Dispositions, Demographics, and Baseline Disease Characteristics

Of 36 patients screened, 29 were included in the study and had blood collected for ova-Treg production (Figure 1A). At the pre-entry visit, 9 patients no longer met the inclusion criteria and were excluded from the study. The remaining 20 patients were treated and evaluated for safety and efficacy assessments and represented the ITT population. The initial design considered 3 patients per cohort, with 9 subjects planned for the last cohort with the highest dose. This distribution was amended,

Discussion

The CATS1 study is the first-in-human study of antigen-specific Tregs, a somatic cell medicinal product in clinical development for the treatment of inflammatory bowel disease. This open-label, escalating-dose study was conducted in patients with active CD refractory to all available agents for whom the unmet medical need was the greatest. The present results showed good tolerability and potential signals of efficacy for ova-Tregs.

Several approaches for the treatment of CD are currently in

Acknowledgments

The authors thank all of the patients in the CATS1 study, and all medical and nursing staff at the participating centers for their help; the trial data safety monitoring board: Professor Philippe Marteau, Professor Bruno Quesnel, and the late Professor Dominique Emilie (chair); the late Professor Marc Lémann for his significant contribution during the conduct of the study as a friend and principal investigator at Hospital St Louis (Paris, France); and Professor Pierre Tiberghien and Dr Pascal

References (45)

  • M. Mandapathil et al.

    Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells

    J Biol Chem

    (2010)
  • M.J. Grainge et al.

    Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study

    Lancet

    (2010)
  • S.J. van Deventer et al.

    Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's diseaseCrohn's Disease Study Group

    Gastroenterology

    (1997)
  • F.S. Velayos et al.

    Positioning biologic therapy for Crohn's disease and ulcerative colitis

    Curr Gastroenterol Rep

    (2007)
  • A. Cassinotti et al.

    Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's disease

    Gut

    (2008)
  • J. Panes et al.

    Stem cell treatment for Crohn's disease

    Expert Rev Clin Immunol

    (2010)
  • P. Burra et al.

    Therapeutic application of stem cells in gastroenterology: an up-date

    World J Gastroenterol

    (2011)
  • M. Duijvestein et al.

    Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study

    Gut

    (2010)
  • Onken J, Gallup D, Hanson J, et al. Successful outpatient treatment of refractory Crohn's disease using adult...
  • S.E. Allan et al.

    CD4+ T-regulatory cells: toward therapy for human diseases

    Immunol Rev

    (2008)
  • M. Allez et al.

    Regulatory T cells: peace keepers in the gut

    Inflamm Bowel Dis

    (2004)
  • T.M. Brusko et al.

    Human regulatory T cells: role in autoimmune disease and therapeutic opportunities

    Immunol Rev

    (2008)
  • Cited by (308)

    • Regulatory T cells in dominant immunologic tolerance

      2024, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus

    Conflicts of interest The authors disclose the following: Pierre Desreumaux, Matthieu Allez, and Jean-Frédéric Colombel are consultants for TxCell, and Arnaud Foussat, Valérie Brun, Hervé Bastian, Nathalie Belmonte, Virginie Neveu, Nathalie Clerget-Chossat, and Miguel Forte are employed by TxCell. Laurent Beaugerie, Xavier Hébuterne, Yoram Bouhnik, Maria Nachury, Michel Ticchioni, Agnès Duchange, and Patricia Morel-Mandrino disclose no conflicts of interest.

    Funding Supported by TxCell SA.

    View full text