Autologous Ex Vivo Expanded Regulatory T Cells in Ulcerative Colitis

NCT04691232 | Completed Phase 1 DMC

• 1 other identifier: ER-TREG 01
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Together with Crohn's disease (CD), ulcerative colitis (UC) is one of the major forms of inflammatory bowel diseases (IBD).Currently, no curative therapy is available, since the pathophysiology of this disease is incompletely understood (1-3) and clinical practice demonstrates that current therapies induce remission in subgroups of patients only. Scientific evidence suggests that colitogenic immune responses can be controlled by increasing the number of circulating regulatory T cells (Treg) (4). The production of large numbers of autologous Treg is possible by isolation of CD25+ cells from the whole blood of a patient and subsequent ex vivo expansion in the presence of the immunomodulatory drug rapamycin, Interleukin-2 (IL-2) and CD3/CD28 expander beads (5). ER-TREG 01 is a single-center, open-label, fast-track phase I dose-escalation study designed to assess the safety profile and maximal tolerated dose (MTD) of a single infusion of ex vivo expanded autologous Treg in patients with active ulcerative colitis.

Conditions

Ulcerative Colitis; Autoimmune Diseases

Keywords

Ulcerative colitis; Regulatory T cells; Adoptive cell therapy

Outcome Measures

Primary Outcomes (1)

• Dose-finding

  To define the maximum tolerable dose (MTD) of one single infusion of autologous ex vivo expanded regulatory T cells in patients with ulcerative colitis

  Visit 5 (4 weeks after adoptive Treg transfer)

Secondary Outcomes (5)

• Assessment of safety of one single Infusion of regulatory T cells

  Visit 5 (4 weeks after adoptive Treg transfer)

• Assessment of inflammation in the gut

  Visit 5 (4 weeks after adoptive Treg transfer)

• Assessment of quality of life

  Visit 5 (4 weeks after adoptive Treg transfer)

• Assessment of Treg function in peripheral blood

  Visit 5 (4 weeks after adoptive Treg transfer)

• Assessment of Treg function in the gut

  Visit 5 (4 weeks after adoptive Treg transfer)

Study Arms (1)

Regulatory T cells

EXPERIMENTAL

Intravenous infusion of a single dose of 0.5x10e6, 1x10e6, 2x10e6, 5x10e6 or 10x10e6 Treg/kg body weight

Biological: Regulatory T cells

Interventions

Regulatory T cells BIOLOGICAL

Autologous, ex vivo expanded, regulatory T cells

Regulatory T cells

Eligibility Criteria

• Age: 18 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patients must have an established diagnosis of UC, with minimum time from diagnosis of ≥3 months
• Patients must be either in remission under the allowed concomitant therapy or must have received all the beneficial pharmacological treatment lines before enrollment and have moderate to severe disease activity (disease should extend 15 cm or more above the anal verge) determined by a modified Mayo score (excluding the friability at grade 1 for the endoscopic sub score) of 6 to 12 with an endoscopic subscore ≥ 2 and no other individual subscore \< 1.
• Patients must have a WHO performance status of 0, 1 or 2 and must be in stable medical condition.
• Patients must be between 18 and 75 years old and must be able and willing to give informed consent.
• Women of child-bearing age must have a negative pregnancy test at enrollment in the study, must be willing to undergo monthly pregnancy tests until at least 3 months after adoptive Treg transfer and must oblige to use effective contraception until at least 3 months after adoptive Treg transfer. A highly effective method of birth control is defined as one that results in a low failure rate (ie, less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or a vasectomized partner. For subjects using a hormonal contraceptive method, information regarding the product under evaluation and its potential effect on the contraceptive should be addressed.
• Male study patients, who are partners of women of child-bearing age must be willing to use effective contraception until at least 3 months after adoptive Treg transfer. A highly effective method of birth control is defined as one that results in a low failure rate (ie, less than 1 percent per year) when used consistently and correctly, such as sexual abstinence, or a vasectomy. The solely use of condoms is not considered as an effective method of birth control. Therefore, partners of child-bearing age from male study patients should be willing to use implants, injectables, combined oral contraceptives or intrauterine devices (IUDs) a highly effective method of birth control. Information regarding the product under evaluation and its potential effect on the contraceptive should be addressed.
• Patients must be willing to undergo a leukapheresis.
• Patients must be willing to get hospitalized for at least 24 hours following adoptive Treg transfer, and to cooperate for the whole period of the trial.
• Accomplishment of a washout phase for biological therapy of at least 8 weeks or no detectable serum trough levels prior to screening in case of a washout phase less than 8 weeks.

You may not qualify if:

• Impaired hematological function (on repeated testing) as indicated by Leukocyte Count ≤ 2,500 /mm3, or Neutrophils ≤ 1,000 / mm3, or Lymphocytes ≤ 700 / mm3, or Platelets ≤ 75,000 / mm3, or Hemoglobin ≤ 9 g / dl22
• Impaired hepatic or renal function as indicated by Serum creatinine ≥ 2.5 mg/100 ml, or Serum Bilirubin ≥ 2.0 mg/100 ml
• Any other major serious illness \[e.g. active systemic infections, immunodeficiency disease, clinically significant heart disease, respiratory disease, bleeding disorders, etc.\] or a contraindication to leukapheresis.
• Evidence for HIV-1, HIV -2, HTLV-1, TPHA, HBV, or HCV infection.
• Patients who have spent a cumulative period of 1 year or more in the UK between the beginning of 1980 and the end of 1996
• Patients who have a family history, which places them at risk of developing Creutzfeldt-Jacob disease
• Patients who have received a corneal or dura mater graft, or who have been treated in the past with medicines made from human pituitary glands
• Other active autoimmune diseases (such as but not limited to Lupus erythematosus, autoimmune thyroiditis or uveitis, multiple sclerosis).
• Previous splenectomy or radiation therapy to the spleen.
• Patients with organ allografts.
• Patients with celiac disease.
• Concomitant treatment with chemotherapy, immunotherapy, any investigational drug and paramedical substances.
• Existence or prior history of a malignant neoplasm.
• Organic brain syndrome or significant psychiatric abnormality which would preclude participation in the full protocol and follow up.
• Positive pregnancy test / Pregnancy or lactation. If pregnancy occurs during the course of the trial to female patients, the patient has to be excluded (not valid for partners of male patients treated).

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead

Study Sites (1)

University of Erlangen-Nürnberg Medical School

Erlangen, Bavaria, 91054, Germany

Location

Related Publications (24)

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• Mayne CG, Williams CB. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2013 Jul;19(8):1772-88. doi: 10.1097/MIB.0b013e318281f5a3.

  PMID: 23656897 BACKGROUND

• Wiesinger M, Stoica D, Roessner S, Lorenz C, Fischer A, Atreya R, Neufert CF, Atreya I, Scheffold A, Schuler-Thurner B, Neurath MF, Schuler G, Voskens CJ. Good Manufacturing Practice-Compliant Production and Lot-Release of Ex Vivo Expanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders. Front Immunol. 2017 Oct 26;8:1371. doi: 10.3389/fimmu.2017.01371. eCollection 2017.

  PMID: 29123521 BACKGROUND

• Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014 Jan;13(1):3-10. doi: 10.1016/j.autrev.2013.06.004. Epub 2013 Jun 15.

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• Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014 May;14(5):329-42. doi: 10.1038/nri3661. Epub 2014 Apr 22.

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• Iboshi Y, Nakamura K, Fukaura K, Iwasa T, Ogino H, Sumida Y, Ihara E, Akiho H, Harada N, Nakamuta M. Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis. J Gastroenterol. 2017 Mar;52(3):315-326. doi: 10.1007/s00535-016-1221-1. Epub 2016 May 13.

  PMID: 27178567 BACKGROUND

• Sujino T, Kanai T, Ono Y, Mikami Y, Hayashi A, Doi T, Matsuoka K, Hisamatsu T, Takaishi H, Ogata H, Yoshimura A, Littman DR, Hibi T. Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. Gastroenterology. 2011 Sep;141(3):1014-23. doi: 10.1053/j.gastro.2011.05.052. Epub 2011 Jun 7.

  PMID: 21699791 BACKGROUND

• Siddiqui KR, Powrie F. CD103+ GALT DCs promote Foxp3+ regulatory T cells. Mucosal Immunol. 2008 Nov;1 Suppl 1:S34-8. doi: 10.1038/mi.2008.43.

  PMID: 19079226 BACKGROUND

• Westendorf AM, Fleissner D, Groebe L, Jung S, Gruber AD, Hansen W, Buer J. CD4+Foxp3+ regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells. Gut. 2009 Feb;58(2):211-9. doi: 10.1136/gut.2008.151720. Epub 2008 Oct 2.

  PMID: 18832523 BACKGROUND

• Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, Muller W, Sparwasser T, Forster R, Pabst O. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011 Feb 25;34(2):237-46. doi: 10.1016/j.immuni.2011.01.016. Epub 2011 Feb 17.

  PMID: 21333554 BACKGROUND

• Coombes JL, Maloy KJ. Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin Immunol. 2007 Apr;19(2):116-26. doi: 10.1016/j.smim.2007.01.001. Epub 2007 Feb 21.

  PMID: 17320411 BACKGROUND

• Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007 Aug 6;204(8):1757-64. doi: 10.1084/jem.20070590. Epub 2007 Jul 9.

  PMID: 17620361 BACKGROUND

• Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med. 2010 Apr 12;207(4):699-709. doi: 10.1084/jem.20091618. Epub 2010 Apr 5.

  PMID: 20368580 BACKGROUND

• Pastille E, Bardini K, Fleissner D, Adamczyk A, Frede A, Wadwa M, von Smolinski D, Kasper S, Sparwasser T, Gruber AD, Schuler M, Sakaguchi S, Roers A, Muller W, Hansen W, Buer J, Westendorf AM. Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer Res. 2014 Aug 15;74(16):4258-69. doi: 10.1158/0008-5472.CAN-13-3065. Epub 2014 Jun 6.

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• Wang Z, Friedrich C, Hagemann SC, Korte WH, Goharani N, Cording S, Eberl G, Sparwasser T, Lochner M. Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium. Mucosal Immunol. 2014 Nov;7(6):1290-301. doi: 10.1038/mi.2014.17. Epub 2014 Mar 19.

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• Holmen N, Lundgren A, Lundin S, Bergin AM, Rudin A, Sjovall H, Ohman L. Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm Bowel Dis. 2006 Jun;12(6):447-56. doi: 10.1097/00054725-200606000-00003.

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  PMID: 16903919 BACKGROUND

• Ogino H, Nakamura K, Iwasa T, Ihara E, Akiho H, Motomura Y, Akahoshi K, Igarashi H, Kato M, Kotoh K, Ito T, Takayanagi R. Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J Gastroenterol. 2012 Apr;47(4):366-76. doi: 10.1007/s00535-011-0502-y. Epub 2011 Dec 22.

  PMID: 22189601 BACKGROUND

• Fantini MC, Becker C, Tubbe I, Nikolaev A, Lehr HA, Galle P, Neurath MF. Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut. 2006 May;55(5):671-80. doi: 10.1136/gut.2005.072801. Epub 2005 Sep 14.

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• Salas A, Panes J. IBD. Regulatory T cells for treatment of Crohn's disease. Nat Rev Gastroenterol Hepatol. 2015 Jun;12(6):315-6. doi: 10.1038/nrgastro.2015.68. Epub 2015 Apr 21.

  PMID: 25895817 BACKGROUND

• Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, Knott H, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF. Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis. Gut. 2023 Jan;72(1):49-53. doi: 10.1136/gutjnl-2022-327075. Epub 2022 Apr 15.

  PMID: 35428657 DERIVED

• Voskens CJ, Stoica D, Roessner S, Vitali F, Zundler S, Rosenberg M, Wiesinger M, Wunder J, Siegmund B, Schuler-Thurner B, Schuler G, Berking C, Atreya R, Neurath MF. Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial. BMJ Open. 2021 Dec 8;11(12):e049208. doi: 10.1136/bmjopen-2021-049208.

  PMID: 34880013 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative; Autoimmune Diseases

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases; Immune System Diseases

Study Officials

• Prof. Dr. med. Markus Neurath, MD

  University of Erlangen-Nürnberg Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2020
• First Posted: December 31, 2020
• Study Start: February 22, 2021
• Primary Completion: April 12, 2023
• Study Completion: May 22, 2023
• Last Updated: October 17, 2023

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)