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P770 Autologous regulatory T cell transfer in patients with refractory ulcerative colitis: Interim report of a phase 1, dose-escalation trial

Voskens, C.(1)*;Stoica, D.(1);Rosenberg, M.(1);Weidinger, C.(2);Vitali, F.(3);Zundler, S.(3);Ganslmayer, M.(3);Wiesinger, M.(1);Wunder, J.(3);Kummer, M.(1);Siegmund, B.(2);Schnoy, E.(4);Rath, T.(3);Hartmann, A.(5);Hackstein, H.(6);Schuler-Thurner, B.(1);Berking, C.(1);Schuler, G.(1);Atreya, R.(3);Neurath, M.F.(3);

(1)University Hospital Erlangen- Deutsches Zentrum für Immuntherapie DZI- Friedrich-Alexander University Erlangen-Nürnberg, Department of Dermatology, Erlangen, Germany;(2)Charité - Universitätsmedizin Berlin- corporate member of Freie Universität Berlin- Humboldt-Universität zu Berlin- Campus Benjamin Franklin, Medical Department- Division of Gastroenterology- Infectious Diseases and Rheumatology, Berlin, Germany;(3)University Hospital Erlangen- Deutsches Zentrum für Immuntherapie DZI- Friedrich-Alexander University Erlangen-Nürnberg, Department of Medicine 1, Erlangen, Germany;(4)University Hospital Augsburg, Department of Gastroenterology, Augsburg, Germany;(5)University Hospital Erlangen- Friedrich-Alexander University Erlangen- Nürnberg, Department of Pathology, Erlangen, Germany;(6)University Hospital Erlangen- Friedrich-Alexander University Erlangen- Nürnberg, Department of Transfusion Medicine, Erlangen, Germany;

Background

Ulcerative colitis (UC) is marked by impaired mucosal homeostasis with predominance of intestinal effector T cells and insufficient expansion of mucosal regulatory T cells (Tregs), thereby providing a scientific rationale for Treg-based immunotherapy in UC.

Methods

We developed a protocol to generate large numbers of autologous CD25+ cells under aegis of IL-2, rapamycin and anti-CD3/anti-CD28 expander beads ex vivo from CD25+ precursors derived from peripheral blood cells, intended for clinical use under good manufacturing practice (GMP) conditions. We initiated a single-centre, open-label, fast-track dose-escalation, phase-1 clinical trial with a single adoptive transfer of autologous ex vivo expanded CD4+CD25+CD127−/lo Tregs in patients with refractory UC. The primary objective of the trial was to define safety and the maximum tolerable dose of a single intravenous administration of autologous expanded Tregs according to the fast-track dosing principle. Adoptive transfer was escalated from the starting dose of 0.5×106 Tregs/kg body weight to the next dose level (1×106, 2×106, 5×106 and 10×106 Tregs/kg body weight) in each consecutive patient, respectively, if no dose-limiting toxicity occurred. We here report interim study data of the first 8 patients that received Treg transfer and were followed up over 12 weeks. There were no changes in concomitant medication during the study period.

Results

The 8 patients received 0.5 x106 (n=1), 1×106 (n=1), 2×106 (n=1), 2.8x106 (n=1), 5×106 (n=1) and 10×106 (n=3) Treg/kg body weight, respectively. The patients did not show any dose-limiting toxicity and there were no adverse events related to Treg transfer. 87.5% (7/8) of patients had previously received treatment with at least 2 different substance classes of advanced therapies, such as biologics and JAK inhibitors and the mean Mayo Score (MS) at baseline was 9.1±1.6. The mean modified MS (mMS) dropped significantly from 6.6±1.2 at baseline to 4.5±2.2 at week 4 (p=0.006) and 4.6±2.0 at week 12 (p=0.01). There was reduction of mean faecal Calprotectin levels from 1708±397 µg/g at baseline, to 1411±471 µg/g at week 4 and 919±332 µg/g at week 12. Clinical response was reached by 62.5% (5/8) of patients at week 4 and also week 12. Clinical response predominantly occurred in patients receiving the highest number of 10×106 Tregs/kg body weight. Clinical remission was achieved by 12.5% (1/8) of patients at week 4 and also week 12.

Conclusion

Autologous regulatory T cell transfer was well tolerated up to the maximal tested dose of 10×106 Tregs/kg body weight. Study results suggest that adoptively transferred polyclonal Tregs might be effective in refractory ulcerative colitis, warranting further clinical studies.