First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline

Alexander Averyanov, Irina Koroleva, Mikhail Konoplyannikov, Veronika Revkova, Victor Lesnyak, Vladimir Kalsin, Olesya Danilevskaya, Alexey Nikitin, Anna Sotnikova, Svetlana Kotova, Vladimir Baklaushev, Alexander Averyanov, Irina Koroleva, Mikhail Konoplyannikov, Veronika Revkova, Victor Lesnyak, Vladimir Kalsin, Olesya Danilevskaya, Alexey Nikitin, Anna Sotnikova, Svetlana Kotova, Vladimir Baklaushev

Abstract

Previous phase I studies demonstrated safety and some beneficial effects of mesenchymal stem cells (MSCs) in patients with mild to moderate idiopathic pulmonary fibrosis (IPF). The aim of our study was to evaluate the safety, tolerability, and efficacy of a high cumulative dose of bone marrow MSCs in patients with rapid progressive course of severe to moderate IPF. Twenty patients with forced ventilation capacity (FVC) ≥40% and diffusing capacity of the lung for carbon monoxide (DLCO) ≥20% with a decline of both >10% over the previous 12 months were randomized into two groups: one group received two intravenous doses of allogeneic MSCs (2 × 108 cells) every 3 months, and the second group received a placebo. A total amount of 1.6 × 109 MSCs had been administered to each patient after the study completion. There were no significant adverse effects after administration of MSCs in any patients. In the group of MSC therapy, we observed significantly better improvement for the 6-minute walk distance in 13 weeks, for DLCO in 26 weeks, and for FVC in 39 weeks compared with placebo. FVC for 12 months in the MSCs therapy group increased by 7.8% from baseline, whereas it declined by 5.9% in the placebo group. We did not find differences between the groups in mortality (two patients died in each group) or any changes in the high-resolution computed tomography fibrosis score. In patients with IPF and a rapid pulmonary function decline, therapy with high doses of allogeneic MSCs is a safe and promising method to reduce disease progression.

Keywords: adult human bone marrow; adult stem cells; bone marrow stromal cells; cellular therapy; clinical trials; lung; stem cell transplantation; transplantation tolerance.

Conflict of interest statement

V.K. and V.B. declared researched funding from Federal Medical and Biological Agency, Order 20.001.13.800. The other authors indicated no potential conflict of interest.

© The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Characterization of cultured human bone marrow‐derived mesenchymal stem cell (MSCs; passage 4) before the transplantation. A, CD‐immunophenotyping of MSCs using flow cytometry. Red histograms represent isotype specific Ig control; blue histograms: fluorescein isothiocyanate/PE‐conjugated antihuman CD antibodies. B‐D, Differentiation analysis. MSCs were characterized by their differentiation potential by staining with Oil Red O—adipogenic lineage, B, Alcian blue—specific to sulfated GAGs, C, and alizarin red—osteogenic lineage, D. Magnification ×200, B‐D. E, Karyotype analysis of human MSCs, mFISH visualization method
Figure 2
Figure 2
CONSORT flow diagram
Figure 3
Figure 3
Secondary endpoints dynamics. A‐C, Differences (delta) of real values (y‐axis) of forced ventilation capacity (FVC; A), diffusing capacity of the lung for carbon monoxide, B, and 6MWD, C, from the baseline level, during the treatment period (median, minimum and maximum, 25% and 75% quartiles are shown). D, Change from the baseline in FVC median (% of predicted) during 12 months before the treatment and during the treatment (by week 52) in the main group and the control. In the legend, 3, 6, 9, and 12 mean the values after 3, 6, 9, and 12 months, respectively

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