Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis
Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea E. van der Meulen – de Jong
Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea E. van der Meulen – de Jong
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Clinical Research and Public Health Clinical trials Inflammation

Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis

Abstract

BACKGROUND Due to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study that evaluated the impact of local MSC therapy on UP.METHODS Thirteen refractory UP patients, with an endoscopic Mayo score (EMS) of 2 or 3, were included. Seven patients received 20–40 million allogeneic MSCs (cohort 1), while 6 patients received 40–80 million MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and on weeks 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline and on weeks 2 and 6. Furthermore, we evaluated the engraftment of MSCs, the presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment.RESULTS No serious AEs were observed. The clinical Mayo score was significantly improved on weeks 2 and 6, and the EMS was significantly improved on week 6, compared with baseline. On week 6, donor MSCs were still detectable in rectal biopsies from 4 of 9 patients and DSAs against both HLA class I and class II were found. Mass cytometry showed a reduction in activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy.CONCLUSION Local administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials.TRIAL REGISTRATION EU Clinical Trials Register (EudraCT, 2017-003524-75) and the Dutch Trial Register (NTR7205).FUNDING ECCO grant 2020.

Authors

Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea E. van der Meulen – de Jong

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Figure 5

CD8+ T cells, γδ T cells and, innate lymphoid cells are decreased in case biopsies compared with control biopsies but do not change significantly upon local MSC injection.

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CD8+ T cells, γδ T cells and, innate lymphoid cells are decreased in cas...
(A) HSNE embedding showing 1.6 × 104 landmarks representing immune cells (3.4 × 106 cells) isolated from control biopsies at baseline (n = 12) and on week 6 (n = 7) and from case biopsies at baseline (n = 13) and on week 6 (n = 12). Colors represent the biopsies at different time points (left) and the other immune lineage clusters (right). (B) Frequencies of CD66b+ granulocyte cluster in control biopsies at baseline (n = 12), case biopsies at baseline (n = 13), and after 6 weeks (n = 12) as a percentage of total CD45+ cells. (C) Composition of the major immune lineages, CD66b+ granulocytes excluded, in individual patients (n = 13) in control biopsies (left), case biopsies (middle) at baseline, and case biopsies on week 6 (right), represented as vertical bars. The size of the colored segments represents the proportion of the cells as a percentage of total CD45+ cells in the samples. Colors are as in A. (D) Frequencies of the CD8+ T cells, γδ T cells, ILCs, and CD45+Lineage– cells from individual samples (n = 12) (control biopsies and case biopsies at baseline and case biopsies on week 6). Each dot represents an individual sample. Red dots are biopsies with mild endoscopic inflammation. NS, not significant. Wilcoxon’s signed-rank test was performed.