First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline
Authors: Averyanov Alexander , Koroleva Irina , Konoplyannikov Mikhail , Revkova Veronika , Lesnyak Victor , Kalsin Vladimir , Danilevskaya Olesya , Nikitin Alexey , Sotnikova Anna , Kotova Svetlana , Baklaushev Vladimir 
Published: October 2019

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 &gt;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.

Lessons learned The primary objective was the evaluation of the safety and tolerability of repeated infusions of high doses of bone marrow-derived MSCs up to the total cumulative dose of 2 billion cells in subjects with rapidly progressing idiopathic pulmonary fibrosis. The evaluation was based on the number and severity of AEs related to the infusion during 52 weeks of follow-up. The secondary objective was evaluation of the main lung function parameters, such as forced ventilation capacity and diffusing capacity of the lung for carbon monoxide. The stem cell treatment has been found safe and well tolerable. Patients in the main group had their lung function increased, as compared to the placebo group, in which the continued decline of the lung function was observed. These findings allow us to conclude that such stem cell therapy is effective for the treatment of rapidly progressing idiopathic pulmonary fibrosis. Significance statementThe results of this first-in-human clinical trial revealed that a high cumulative dose of mesenchymal stem cells (MSCs) is safe and well tolerated by patients with idiopathic pulmonary fibrosis with a rapid lung function decline. During the treatment period, the patients in the main group experienced increased lung function; however, the patients in the placebo group experienced a continued decline in lung function. Thus, this study shows the safety, tolerability, and potential benefits of greater doses of MSCs than those used earlier in patients with idiopathic pulmonary fibrosis, and these findings might move future trials toward a new step in stem cells transplantation.