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

Caroline J Voskens, Diane Stoica, Susanne Roessner, Francesco Vitali, Sebastian Zundler, Marita Rosenberg, Manuel Wiesinger, Jutta Wunder, Britta Siegmund, Beatrice Schuler-Thurner, Gerold Schuler, Carola Berking, Raja Atreya, Markus F Neurath, Caroline J Voskens, Diane Stoica, Susanne Roessner, Francesco Vitali, Sebastian Zundler, Marita Rosenberg, Manuel Wiesinger, Jutta Wunder, Britta Siegmund, Beatrice Schuler-Thurner, Gerold Schuler, Carola Berking, Raja Atreya, Markus F Neurath

Abstract

Introduction: Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.

Methods and analysis: The study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×106, 1×106, 2×106, 5×106 or 10×106 autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa.

Ethics and dissemination: The study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media.

Trial registration number: NCT04691232.

Keywords: clinical trials; immunology; inflammatory bowel disease.

Conflict of interest statement

Competing interests: GS is inventor of granted patents related to the manuscript (publication number EP 1379625; CD4+CD25+ regulatory T cells from human blood).

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart of the ER-TREG 01 study. The initial starting dose is 0.5×106 Treg/kg bodyweight. Adoptive transfer is escalated to the next dose level (1×106 Treg/kg, 2×106 Treg/kg, 5×106/Treg/kg and 10×106 Treg/kg bodyweight), in a next patient, if no dose-limiting toxicity (DLT) occurs. Consecutive patients will be treated at least 4 weeks apart to monitor acute severe adverse advents. If a DLT is noted, three additional patients will receive the same dose level. If two patients among a cohort of four patients experience a DLT, dose de-escalation to the highest previously tolerated dose-level will follow. DSMB, data safety monitoring board.

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Source: PubMed

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