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EDITORIAL
Moving stem cell therapy to patients with idiopathic pulmonary fibrosis Key words: clinical trial, idiopathic pulmonary fibrosis, mesenchymal stem cell, placenta-derived stem cell. Abbreviations: IPF, idiopathic pulmonary fibrosis; MSCs, mesenchymal stem cells.
While stem cell treatments hold enormous therapeutic promise for many disease processes, rigorous clinical trials must be conducted to establish their safety and efficacy prior to widespread use. Because mesenchymal stem cells (MSCs) home to sites of injury, inhibit inflammation and contribute to epithelial tissue repair, their use has been contemplated as a novel treatment for idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited treatment options. In this issue, Chambers et al. publish the results of a phase 1b safety trial of placental-derived MSCs for the treatment of IPF. This single-centre, nonrandomized, dose escalation trial examined the safety of intravenous administration of placenta-derived mesenchymal stromal-type cells in patients with moderate to severe IPF.1 Eight patients were treated with a single dose of either 1 × 106 cells/kg (n = 4) or 2 × 106 cells/kg (n = 4). Patients were monitored throughout the infusion and then followed through 6 months for changes from baseline in lung function (forced vital capacity and diffusing capacity of carbon monoxide), gas exchange (partial pressure of oxygen in arterial blood), 6-min walk distance or lung fibrosis score as assessed by high-resolution computed tomography. Other than a transient and small decrease in arterial oxygen saturation, no infusionrelated adverse effects were noted. At 6 months, there was no change seen in lung function, gas exchange, 6-min walk distance or lung fibrosis score. Similarly, Tzouvelekis et al. found no adverse events after the endobronchial administration of adiposederived stromal cells-stromal vascular fraction to patients with mild to moderate IPF.2 Taken together, these studies suggest that the use of MSCs in patients with IPF is safe. While some preclinical studies suggested that MSCs might promote fibrosis, to date, no human studies have found a similar pro-fibrotic effect.3 These early clinical trials appropriately focus on safety, but they are based on the results of preclinical work suggesting that MSCs prevent fibrosis in the murine bleomycin model of IPF.4 The bleomycin model, the best characterized animal model of IPF, has been criticized as an inflammatory model in which the resulting fibrosis does not mimic the clinical course of patients with IPF. While the model is not perfect, significant concerns have been allayed by the recent © 2014 Asian Pacific Society of Respirology
finding that gene expression profiles from mice treated with bleomycin mirror those from patients with active IPF.5 Given the safety and ease of MSC administration in other patient populations, the promising results in preclinical models of IPF, and the major need for novel therapeutic options in this devastating disease, carefully designed clinical trials of MSCs for the treatment of patients with IPF are warranted. However, with the completion of these two trials, and a third in progress (Glassberg et al.), a number of questions arise. What is the most efficacious source of MSCs— placental tissue, adipose tissue, or bone marrow? Are allogeneic cells as safe as autologous MSCs? Are they more or less efficacious? Do MSCs retain efficacy after passage—how do we best handle them in the lab for optimal results? Are MSCs most effective in the lung when administered endobronchially, intravenously or by some other method? How many cells must be administered, how many times and how often? How can efficacy best be measured clinically and are there measureable biomarkers we might also use? Which patients should we focus on—those with early or late stage disease? How will treatment with pharmaceutical agents like pirfenidone and/or nintedanib (both of which were recently shown to have efficacy in the treatment of IPF) interact with stem cell treatments?6–8 These and many other questions will need to be addressed as we move forward. The results reported here by Chambers et al. are a necessary first step in this direction. As we gather more data, we will be better equipped to propose well-designed phase 3 trials. Assuming no new safety concerns arise, we may soon be in the position to consider larger multi-center efficacy trials of MSCs for the treatment of IPF. Marilyn K. Glassberg, MD1 and Rebecca L. Toonkel, MD2 1 Miller School of Medicine, University of Miami and 2 Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
REFERENCES 1 Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, Terkovich ST, Khalil D, Atkinson KM, Hopkins P. Stem cell therapy in IPF: a phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 2014. 19: 1013–8. 2 Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E, Oikonomou A, Zissimopoulos A, Boussios N, Dardzinski B, Respirology (2014) 19, 950–951 doi: 10.1111/resp.12364
Editorial Gritzalis D et al. A prospective, non-randomized, no placebocontrolled, 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. 3 Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. Proc. Am. Thorac. Soc. 2011; 8: 223–72. 4 Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am. J. Respir. Crit. Care Med. 2013; 188: 133–40. 5 Peng R, Sridhar S, Tyagi G, Phillips JE, Garrido R, Harris P, Burns L, Renteria L, Woods J, Chen L et al. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for ‘active’ disease. PLoS ONE 2013; 8: e59348.
© 2014 Asian Pacific Society of Respirology
951 6 King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L et al. ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2083–92. 7 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J et al. CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–9. 8 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y et al. INPULSIS Trial Investigators Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2071–82.
Respirology (2014) 19, 950–951
EDITORIAL
Moving stem cell therapy to patients with idiopathic pulmonary fibrosis Key words: clinical trial, idiopathic pulmonary fibrosis, mesenchymal stem cell, placenta-derived stem cell. Abbreviations: IPF, idiopathic pulmonary fibrosis; MSCs, mesenchymal stem cells.
While stem cell treatments hold enormous therapeutic promise for many disease processes, rigorous clinical trials must be conducted to establish their safety and efficacy prior to widespread use. Because mesenchymal stem cells (MSCs) home to sites of injury, inhibit inflammation and contribute to epithelial tissue repair, their use has been contemplated as a novel treatment for idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited treatment options. In this issue, Chambers et al. publish the results of a phase 1b safety trial of placental-derived MSCs for the treatment of IPF. This single-centre, nonrandomized, dose escalation trial examined the safety of intravenous administration of placenta-derived mesenchymal stromal-type cells in patients with moderate to severe IPF.1 Eight patients were treated with a single dose of either 1 × 106 cells/kg (n = 4) or 2 × 106 cells/kg (n = 4). Patients were monitored throughout the infusion and then followed through 6 months for changes from baseline in lung function (forced vital capacity and diffusing capacity of carbon monoxide), gas exchange (partial pressure of oxygen in arterial blood), 6-min walk distance or lung fibrosis score as assessed by high-resolution computed tomography. Other than a transient and small decrease in arterial oxygen saturation, no infusionrelated adverse effects were noted. At 6 months, there was no change seen in lung function, gas exchange, 6-min walk distance or lung fibrosis score. Similarly, Tzouvelekis et al. found no adverse events after the endobronchial administration of adiposederived stromal cells-stromal vascular fraction to patients with mild to moderate IPF.2 Taken together, these studies suggest that the use of MSCs in patients with IPF is safe. While some preclinical studies suggested that MSCs might promote fibrosis, to date, no human studies have found a similar pro-fibrotic effect.3 These early clinical trials appropriately focus on safety, but they are based on the results of preclinical work suggesting that MSCs prevent fibrosis in the murine bleomycin model of IPF.4 The bleomycin model, the best characterized animal model of IPF, has been criticized as an inflammatory model in which the resulting fibrosis does not mimic the clinical course of patients with IPF. While the model is not perfect, significant concerns have been allayed by the recent © 2014 Asian Pacific Society of Respirology
finding that gene expression profiles from mice treated with bleomycin mirror those from patients with active IPF.5 Given the safety and ease of MSC administration in other patient populations, the promising results in preclinical models of IPF, and the major need for novel therapeutic options in this devastating disease, carefully designed clinical trials of MSCs for the treatment of patients with IPF are warranted. However, with the completion of these two trials, and a third in progress (Glassberg et al.), a number of questions arise. What is the most efficacious source of MSCs— placental tissue, adipose tissue, or bone marrow? Are allogeneic cells as safe as autologous MSCs? Are they more or less efficacious? Do MSCs retain efficacy after passage—how do we best handle them in the lab for optimal results? Are MSCs most effective in the lung when administered endobronchially, intravenously or by some other method? How many cells must be administered, how many times and how often? How can efficacy best be measured clinically and are there measureable biomarkers we might also use? Which patients should we focus on—those with early or late stage disease? How will treatment with pharmaceutical agents like pirfenidone and/or nintedanib (both of which were recently shown to have efficacy in the treatment of IPF) interact with stem cell treatments?6–8 These and many other questions will need to be addressed as we move forward. The results reported here by Chambers et al. are a necessary first step in this direction. As we gather more data, we will be better equipped to propose well-designed phase 3 trials. Assuming no new safety concerns arise, we may soon be in the position to consider larger multi-center efficacy trials of MSCs for the treatment of IPF. Marilyn K. Glassberg, MD1 and Rebecca L. Toonkel, MD2 1 Miller School of Medicine, University of Miami and 2 Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
REFERENCES 1 Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, Terkovich ST, Khalil D, Atkinson KM, Hopkins P. Stem cell therapy in IPF: a phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 2014. 19: 1013–8. 2 Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E, Oikonomou A, Zissimopoulos A, Boussios N, Dardzinski B, Respirology (2014) 19, 950–951 doi: 10.1111/resp.12364
Editorial Gritzalis D et al. A prospective, non-randomized, no placebocontrolled, 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. 3 Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. Proc. Am. Thorac. Soc. 2011; 8: 223–72. 4 Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am. J. Respir. Crit. Care Med. 2013; 188: 133–40. 5 Peng R, Sridhar S, Tyagi G, Phillips JE, Garrido R, Harris P, Burns L, Renteria L, Woods J, Chen L et al. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for ‘active’ disease. PLoS ONE 2013; 8: e59348.
© 2014 Asian Pacific Society of Respirology
951 6 King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L et al. ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2083–92. 7 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J et al. CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–9. 8 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y et al. INPULSIS Trial Investigators Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2071–82.
Respirology (2014) 19, 950–951
