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Editorial |

Safety of IV Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis FREE TO VIEW

Andrew H. Limper, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN

CORRESPONDENCE TO: Andrew H. Limper, MD, FCCP, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Gonda Bldg 18 S, Rochester, MN, 55905


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(5):951-952. doi:10.1016/j.chest.2016.12.015
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Published online

Idiopathic pulmonary fibrosis (IPF) remains an inexorably progressive and fatal disorder, with an overall incidence of roughly 94 cases per 100,000 person-years in the United States. The disease is characterized by ongoing lung injury with insidious deposition of extracellular matrix material leading to progressive distortion of lung architecture and subsequent loss of respiratory function. Traditional antiinflammatory therapies are well documented as having no efficacy for treating this condition and may, in fact, be associated with worse outcomes., The disease manifests as a relentless reduction in respiratory function, with interspersed episodes of rapidly progressive deterioration known as acute exacerbations. Despite the recent availability of two US Food and Drug Administration-approved antifibrotic agents for treating this disorder, no current medical therapies are known to be curative., In this light, continued investigation is desperately needed to develop new therapies to address this extremely devastating illness. Cell-based therapies, including the use of human mesenchymal stem cells (hMSCs) have been postulated as one such novel approach to treat IPF. Stem cells are proposed to target sites of ongoing tissue injury, to foster tissue regeneration and modulate lung remodeling, and to regulate pulmonary inflammation. The desperate nature of IPF and the promise of cell-based therapies have driven patients to seek out such treatment approaches even outside the confines of carefully controlled clinical studies, at times resulting in unfavorable outcomes. Accordingly, it remains imperative that the application of cell-based therapies for IPF be conducted only in carefully controlled clinical trial settings.

FOR RELATED ARTICLE SEE PAGE 971

In the current issue of CHEST, Glassberg et al report a well-performed phase I dose-escalation safety study using a single IV infusion of hMSCs in patients with mild to moderate IPF. They describe the results of the Allogeneic Human Mesenchymal Stem Cells in Patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) study, which uses an absolute dose of hMSCs derived from unrelated male donors. Three cohorts were dosed with 20, 100, or 200 × 106 human bone marrow-derived hMSCs at a single time point. They observed no treatment emergent side effects within the first month following infusion. Of the nine patients studied, there were two deaths at longer follow-up intervals, one related to acute exacerbation of IPF and one related to progression of the disease. However, these events occurred beyond the initial 30-day time point that was used to define treatment emergent side effects. Of note, these two individuals received the highest dose of hMSCs but were also found to have the most severe degrees of fibrosis at the time of enrollment. The study was not designed, nor was it powered, to evaluate the efficacy of this intervention. However, over the 60-week time frame of the study, the mean decline in the percent predicted FVC was only 3% and the mean decline of the percent predicted diffusing capacity of lung for carbon monoxide was only 5.4%. The authors nicely discuss the limitations of the study, which include the small sample size (nine patients), the lack of randomization, and the absence of a placebo control arm for comparison.

The study is consistent with prior studies using other cell-based therapies in patients with IPF., Chambers et al reported the use of placenta-derived mesenchymal stromal cells administered by IV infusion in patients with IPF. These cells were well tolerated, with only minor and transient acute adverse side effects, including a minor transient fall in oxygen saturation, without changes in hemodynamics. These patients were followed for 6 months with little change in FVC, diffusing capacity of lung for carbon monoxide, 6-min walking distance, and CT fibrosis score. An additional study by Tzouvelekis et al evaluated the administration of three endobronchial infusions of autologous adipose-derived stromal cells/stromal vascular fraction in 14 patients with mild to moderate IPF. They observed no serious or clinically significant adverse effects related to the intervention, including no evidence of short-term, infusion-related toxicities or long-term ectopic tissue formation. The efficacy of these cell-based treatments on IPF disease progression was also not a primary end point in either of these prior studies. The current AETHER study reported by Glassberg et al extends this safety profile by demonstrating for the first time that a single IV infusion of hMSCs is well tolerated, with no appreciable worsening of respiratory function during infusion and with no other treatment emergent side effects over the first month. Treatment-unrelated adverse events following the hMSC infusions were observed in most patients over the 60-week observation period and included bronchitis, common colds, and sinusitis.

The AETHER study provides an important first step in the evaluation of hMSCs in the treatment of IPF. However, additional information and studies are clearly needed. The tolerability of this approach may well need to be evaluated in the setting of multiple successive infusions of hMSCs. In addition, it will be important to discern whether such interventions are appropriate for patients with more severe respiratory limitation during IPF. In light of the two reported fatalities in the current study that occurred in patients with more advanced disease, appropriate caution will be needed in further clinical trials. In addition, appropriate patient selection criteria must also be defined. All such information will be essential prior to large-scale randomized placebo-controlled trials to determine the efficacy of hMSC therapy in patients with idiopathic primary fibrosis. It should be also be noted that earlier animal experiments suggested that under certain circumstances, MSC therapy may actually be associated with worsening lung fibrosis. Fortunately, this has not been borne out in the early available literature of stem cell studies in humans, nor was there any indication from the current study that IV hMSC therapy worsened lung fibrosis following a single IV infusion. In that light, the study by Glassberg et al provides an important first step in our understanding of this potentially exciting therapy for patients with this intractable lung disease. It will be essential as we move forward that such studies are conducted in carefully controlled clinical trial settings, with an ongoing focus on the safety as well as the potential efficacy of these innovative new therapies.

References

Raghu G. .Chen S.Y. .Yeh W.S. .et al Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2:566-572 [PubMed]journal. [CrossRef] [PubMed]
 
Collard H.R. .Ryu J.H. .Douglas W.W. .et al Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004;125:2169-2174 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Anstrom K.J. .King T.E. Jr.. Idiopathic Pulmonary Fibrosis Clinical Research Networket al Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .Costabel U. .Selman M. .et al Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079-1087 [PubMed]journal. [CrossRef] [PubMed]
 
Ortiz L.A. .Gambelli F. .McBride C. .et al Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407-8411 [PubMed]journal. [CrossRef] [PubMed]
 
Glassberg M.K. .Minkiewicz J. .Toonkel R.L. .et al Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I, safety, clinical trial. Chest. 2017;151:971-981 [PubMed]journal
 
Chambers D.C. .Enever D. .Ilic N. .et al A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19:1013-1018 [PubMed]journal. [CrossRef] [PubMed]
 
Tzouvelekis A. .Paspaliaris V. .Koliakos G. .et al A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171- [PubMed]journal. [CrossRef] [PubMed]
 
Lama V.N. .Phan S.H. . The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am Thorac Soc. 2006;3:373-376 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Raghu G. .Chen S.Y. .Yeh W.S. .et al Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2:566-572 [PubMed]journal. [CrossRef] [PubMed]
 
Collard H.R. .Ryu J.H. .Douglas W.W. .et al Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 2004;125:2169-2174 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Anstrom K.J. .King T.E. Jr.. Idiopathic Pulmonary Fibrosis Clinical Research Networket al Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .Costabel U. .Selman M. .et al Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079-1087 [PubMed]journal. [CrossRef] [PubMed]
 
Ortiz L.A. .Gambelli F. .McBride C. .et al Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407-8411 [PubMed]journal. [CrossRef] [PubMed]
 
Glassberg M.K. .Minkiewicz J. .Toonkel R.L. .et al Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I, safety, clinical trial. Chest. 2017;151:971-981 [PubMed]journal
 
Chambers D.C. .Enever D. .Ilic N. .et al A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19:1013-1018 [PubMed]journal. [CrossRef] [PubMed]
 
Tzouvelekis A. .Paspaliaris V. .Koliakos G. .et al A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171- [PubMed]journal. [CrossRef] [PubMed]
 
Lama V.N. .Phan S.H. . The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am Thorac Soc. 2006;3:373-376 [PubMed]journal. [CrossRef] [PubMed]
 
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