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P363 Locally injected allogeneic bone marrow-derived mesenchymal stromal cells for the treatment of refractory proctitis: clinical results of a phase IIa trial

OuboterDrs., L.(1,2);Barnhoorn, M.(1);van Pel, M.(2,3);Zwaginga, J.J.(4);Hawinkels, L.(1);Maljaars, J.(1);Koning, F.(2);Verspaget, H.(1);van der Meulen - de de Jong, A.(1);

(1)Leiden University Medical Center, Department of Gastroenterology and Hepatology, Leiden, The Netherlands;(2)Leiden University Medical Center, Department of Immunology, Leiden, The Netherlands;(3)Netherlands Center for the Clinical Advancement of Stem Cell & Gene Therapies, nectsgen, Leiden, The Netherlands;(4)Leiden University Medical Center, Department of Internal Medicine, Leiden, The Netherlands

Background

Ulcerative proctitis (UP) can be refractory to treatment, which calls for development of new (local) therapies. Local injection of mesenchymal stromal cells (MSCs) has shown beneficial effects in patients with fistulizing Crohn’s disease and promising results have been obtained when MSCs were locally injected in the bowel of mice with experimental colitis. Our primary aim was to determine the safety, feasibility and tolerability of endoscopically injected allogeneic bone marrow-derived MSCs (bmMSCs) in UP patients.

Methods

UP patients with endoscopic Mayo score (EMS) 2 or 3, who failed on both rectal 5-ASA and corticosteroids for at least 4 weeks, were eligible for inclusion (EudraCT number 2017-003524-75). Rectal therapies were stopped 2 weeks prior to baseline, but other medication was kept stable until at least 6 weeks after MSC injection. MSCs were locally injected in 4 quadrants of the inflamed rectal submucosa if the inflammation was limited to 7 cm. If the length of inflammation was >7 cm, MSCs were injected in another 4 quadrants more proximally as well. Patients in the first cohort (n=7) were treated with 5*106 MSCs/spot and in the second cohort (n=6) with 10*106MSCs/spot. Adverse events, full Mayo score, fecal calprotectin (FCP), histologic activity (Geboes score [GS]) and quality of life (sIBDQ), were assessed at week 0, 2, 6, 12, and 24, and evaluated by non-parametric paired statistical analyses.

Results

All reported adverse events were minor, no patients required interventions and no feasibility issues were reported. Median[interquartile range (IQR)] full Mayo score was 11[9.5-12] at baseline, 9[8-11] at week 2 (p=0.003), 8[6-10] at week 6 (p=0.001), and 4[1.5-7] at week 24 (p<0.001). The FCP improved in 9/13 patients at week 2, in 6/13 patients at week 6 and in 11/13 patients at week 24 compared to baseline. The EMS at baseline was 3 (n=10 patients) and 2 (n=3 patients) and improved in some patients at week 2 and 6 (NS). At week 24 the EMS was 3 (n=2), 2 (n=4), 1 (n=5) and 0 (n=2)(p=0.002). The median[IQR] GS decreased after 6 weeks (7(6.5-12.5);p=0.09) and 24 weeks (4[2-8];p=0.01) compared to baseline (10[6.5-12.5]). Median[IQR] sIBDQ showed improvement during follow-up; week 2 (45[37.5-52];p=0.1), week 6 (47[42.50-55];p=0.02), week 12 (59[39.50-62];p=0.001) and week 24 (56[44.50-63.50];p=0.001) compared to baseline (41[34-49,50]). No dose-  response effects were observed in our study when comparing cohort 1 and 2.

Conclusion

Local administration of allogeneic bmMSCs appears safe, tolerable and feasible for the treatment of refractory UP, and shows encouraging indications of clinical efficacy. Further mechanistic and immunological analyses are currently being performed.

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