Autologous Ex Vivo Expanded Regulatory T Cells in Ulcerative Colitis

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.

Timeline

Start

2021-02-22

Primary completion

2023-04-12

Completion

2023-05-22

Publications

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• Background Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011 Nov 3;365(18):1713-25. doi: 10.1056/NEJMra1102942. No abstract available.
• Background 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.
• 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.
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• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Background 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.
• Background 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.
• Background Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006 Aug;212:256-71. doi: 10.1111/j.0105-2896.2006.00423.x.
• 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.
• 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.
• Background 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.
• 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.
• 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.

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