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

adult human bone marrow adult stem cells bone marrow stromal cells cellular therapy clinical trials lung stem cell transplantation transplantation tolerance

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#1 Engadin

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Posted 16 October 2019 - 05:29 PM


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F U L L   T E X T   S O U R C E :    Stem Cell Journal

 

 

 

 

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 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‐min 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.
 
 
Significance statement
 
The results of this first‐in‐human clinical trial revealed that high cumulative dose of mesenchymal stem cells (MSCs) is safe and well tolerated by patients' idiopathic pulmonary fibrosis with a rapid lung function decline. During the treatment period, the 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. Thus, this study states 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.
 
1. INTRODUCTION
 
Idiopathic pulmonary fibrosis (IPF) is the most common of the interstitial lung diseases, a progressing chronic disease with unknown origin characterized by the development of fibrotic transformation of the lung parenchyma, predominantly in the older population.1 The prevalence of IPF appears to be increasing, potentially explained by population aging.2 The survival median of patients with IPF is 3 to 5 years; at the same time, the individual survival of patients may be extremely variable.3-5 Conventionally, the IPF clinical course can be categorized into three types based on the rate of the forced ventilation capacity (FVC) decline: slow deterioration (less than 10% decline in FVC over 6 months or no changes in the disease indicators for many months), intermittent deterioration with episodes of exacerbations and rapid deterioration (more than 10% decline in FVC for 6 months).3, 6, 7 For the last type, before the era of antifibrotic medications, the life expectancy of patients did not usually exceed 2 years from the time of diagnosis.6-8 Besides acute exacerbations, a poor prognosis might be suspected in patients with IPF with such predictors as low values of FVC and diffusing capacity of the lung for carbon monoxide (DLCO), old age, and a high rate of pulmonary function decline.3, 9 The majority of clinical studies on the drug therapy of IPF did not evaluate the pretreatment functional reduction rate10, 11; therefore, it is difficult to judge its efficiency in patients with a fast lung function decline.
 
After a large number of successful preclinical studies, a treatment with mesenchymal stem cells (MSCs) is considered a potential new direction for lung fibrosis therapy.12, 13 The potential effects of MSCs in pulmonary fibrosis are related to their ability to produce a large number of biologically active substances with anti‐inflammatory, immunosuppressive, and angiogenic properties.12 The results of the published clinical trials on the cell therapy for IPF confirmed the safety of MSCs; however, all of these studies included patients with mild to moderate impairment of lung function, without taking into account the rate of their preceding decline. Also, the total dose of administered cells did not exceed 2 × 108.14-16 We performed the first clinical trial in this field in patients who had a fast lung function decline, using a significantly more intensive intervention with respect to both the individual MSCs dose and the frequency of dose administration.
 
 
 
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3. RESULTS
 
3.1 MSCs characterization
 
The results from the flow cytometric analysis revealed that the standardized culture of human MSCs in vitro resulted in stable expression of the surface markers following a serial passage. The flow cytometry analysis showed that the cultured MSCs had a CD29+ CD44+ CD73+ CD90+ CD105+ CD34− CD45− phenotype, the one characteristic of adult human MSCs (Figure 1A). The differentiation potential of MSCs was identified by their osteogenic, adipogenic, and chondrogenic differentiation and demonstrated by positive staining with alizarin red, Oil Red O, and Alcian blue, respectively (Figure 1B–D). A normal diploid karyotype with 46 chromosomes and no abnormal changes in the chromosome structure was observed by the analysis of 30 metaphase cells by mFISH visualization method (Figure 1E).
 
 
sct312605-fig-0001-m.jpg
 
 
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
 
 
sct312605-fig-0002-m.jpg
 
 
FIGURE 2
CONSORT flow diagram
 
 
sct312605-fig-0003-m.jpg
 
 
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
 
 
Thus, the characterization of cells prior to administration revealed that we obtained three potent MSCs with normal diploid karyotype and a high level of expression of MSC‐specific surface markers.
 
 
 
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Also tagged with one or more of these keywords: adult human bone marrow, adult stem cells, bone marrow stromal cells, cellular therapy, clinical trials, lung, stem cell transplantation, transplantation tolerance

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