Original article
Alimentary tract
A Phase 2 Study of Allogeneic Mesenchymal Stromal Cells for Luminal Crohn's Disease Refractory to Biologic Therapy

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Background & Aims

Transplantation of peripheral blood stem cells has been successful therapy for small numbers of patients with Crohn's disease (CD), but requires prior myeloconditioning. Mesenchymal stromal cells (MSCs) escape immune recognition, so myeloconditioning is not required before their administration. We investigated the efficacy of allogeneic MSCs in patients with luminal CD.

Methods

Our phase 2, open-label, multicenter study included 16 patients (21-55 y old; 6 men) with infliximab- or adalimumab-refractory, endoscopically confirmed, active luminal CD (CD activity index [CDAI], >250). Subjects were given intravenous infusions of allogeneic MSCs (2 × 106 cells/kg body weight) weekly for 4 weeks. The primary end point was clinical response (decrease in CDAI >100 points) 42 days after the first MSC administration; secondary end points were clinical remission (CDAI, <150), endoscopic improvement (a CD endoscopic index of severity [CDEIS] value, <3 or a decrease by >5), quality of life, level of C-reactive protein, and safety.

Results

Among the 15 patients who completed the study, the mean CDAI score was reduced from 370 (median, 327; range, 256-603) to 203 (median, 129) at day 42 (P < .0001). The mean CDAI scores decreased after each MSC infusion (370 before administration, 269 on day 7, 240 on day 14, 209 on day 21, 182 on day 28, and 203 on day 42). Twelve patients had a clinical response (80%; 95% confidence interval, 72%-88%; mean reduction in CDAI, 211; range 102-367), 8 had clinical remission (53%; range, 43%-64%; mean CDAI at day 42, 94; range, 44-130). Seven patients had endoscopic improvement (47%), for whom the mean CDEIS scores decreased from 21.5 (range, 3.3-33) to 11.0 (range, 0.3-18.5). One patient had a serious adverse event (2 dysplasia-associated lesions), but this probably was not caused by MSCs.

Conclusions

In a phase 2 study, administration of allogeneic MSCs reduced CDAI and CDEIS scores in patients with luminal CD refractory to biologic therapy. ClinicalTrials.gov number, NCT01090817.

Section snippets

Study Overview

This phase II study was an open-label, multicenter, Australian, nonrandomized evaluation of subjects with active luminal CD (CD activity index [CDAI], >250) who had failed anti-tumor necrosis factor therapy. Subjects received 4 MSC infusions (2 × 106 cell/kg body weight) each 1 week apart (Figure 1). The primary outcome measure was clinical response (CDAI reduction, >100 points) at day 42; secondary outcome measures at day 42 were clinical remission (CDAI, <150), endoscopic improvement (CD

Demographics

This study included 16 patients, aged 21 to 55 years (7 men), with a mean CDAI of 371 (range, 256-603). Thirteen patients had Crohn's colitis, 2 patients had ileocolitis, and 1 patient had ileal disease alone (Table 1). Three patients had primary failure of a single biologic; the remainder failed both infliximab and adalimumab. The most recently administered biologic was between 4 and 8 weeks before MSC administration in 11 patients (adalimumab, n = 10; infliximab, n = 1), and between 8 weeks

Discussion

This phase II study suggests efficacy of intravenous allogeneic MSCs in luminal CD. In 15 patients with moderate to severe active disease, refractory to anti-tumor necrosis factor therapy, 4 infusions of 2 × 106 cell/kg at weekly intervals led to clinical response in 12 patients (80%), clinical remission in 8 patients (53%), and endoscopic improvement in 7 patients (47%). Quality of life improved, in parallel with improvement in CDAI.12 Locally injected allogeneic MSCs are effective in perianal

Acknowledgments

The authors acknowledge and thank the following: Janina Pawlik, Janice Fogarty, Kath Shaw, Lisa Kaminskis, Adrian Pannekoek, and the staff of the Department of Haematology at The Alfred Hospital.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Broad Medical Research Program of The Broad Foundation, and Therapeutic Innovation Australia (formerly Research Infrastructure Support Services, Inc).

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