A phase I study for intravenous autologous mesenchymal stromal cell administration to patients with severe emphysema

Stolk, Jan; Broekman, Winifred; Mauad, Thaís; Zwaginga, Jaap Jan; Roelofs, Helene; Fibbe, W. E.; Oostendorp, Jaap; Bajema, Ingeborg M.; Versteegh, Michel I.M.; Taube, Christian; Hiemstra, Pieter S.

doi:10.1093/qjmed/hcw001

Cited by 93 publications

(105 citation statements)

References 18 publications

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“…As most results were attributed to cell therapy, but patients were not compared with a control group, outcomes may in fact have been due to LVRS and not necessarily due to effects of cell therapy. Thus, its results should be interpreted with caution 30.…”

Section: Discussionmentioning

confidence: 99%

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

Oliveira

Cruz

Antunes

et al. 2016

Stem Cells Translational Medicine

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One‐way endobronchial valves (EBV) insertion to reduce pulmonary air trapping has been used as therapy for chronic obstructive pulmonary disease (COPD) patients. However, local inflammation may result and can contribute to worsening of clinical status in these patients. We hypothesized that combined EBV insertion and intrabronchial administration of mesenchymal stromal cells (MSCs) would decrease the inflammatory process, thus mitigating EBV complications in severe COPD patients. This initial study sought to investigate the safety of this approach. For this purpose, a phase I, prospective, patient‐blinded, randomized, placebo‐controlled design was used. Heterogeneous advanced emphysema (Global Initiative for Chronic Lung Disease [GOLD] III or IV) patients randomly received either allogeneic bone marrow‐derived MSCs (108 cells, EBV+MSC) or 0.9% saline solution (EBV) (n = 5 per group), bronchoscopically, just before insertion of one‐way EBVs. Patients were evaluated 1, 7, 30, and 90 days after therapy. All patients completed the study protocol and 90‐day follow‐up. MSC delivery did not result in acute administration‐related toxicity, serious adverse events, or death. No significant between‐group differences were observed in overall number of adverse events, frequency of COPD exacerbations, or worsening of disease. Additionally, there were no significant differences in blood tests, lung function, or radiological outcomes. However, quality‐of‐life indicators were higher in EBV + MSC compared with EBV. EBV + MSC patients presented decreased levels of circulating C‐reactive protein at 30 and 90 days, as well as BODE (Body mass index, airway Obstruction, Dyspnea, and Exercise index) and MMRC (Modified Medical Research Council) scores. Thus, combined use of EBV and MSCs appears to be safe in patients with severe COPD, providing a basis for subsequent investigations using MSCs as concomitant therapy. Stem Cells Translational Medicine 2017;6:962–969

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Section: Discussionmentioning

confidence: 99%

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

Oliveira

Cruz

Antunes

et al. 2016

Stem Cells Translational Medicine

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“…This trial clarified the possibility of administering repeated doses of large numbers of MSCs to an older sicker cohort of patients with severe lung disease. Another clinical trial demonstrated the safety and feasibility of administration of autologous MSC to patients with very severe emphysema undergoing lung volume reduction surgery for severe emphysema (8). Increased expression of the endothelial marker CD31 was observed in tissue from patients after infusion, but this study awaits confirmation in a placebo-controlled study.…”

Section: Mesenchymal Stromal Cells In Clinical Trials: Implications Fmentioning

confidence: 95%

“…Moreover, one major limitation of COPD studies is that a very long treatment period is needed before any functional improvements can be observed. To overcome this limitation, one recent study (8) has been looking at histological markers of improvements in COPD patients after MSC treatment, and showed that CD31 expression in lung tissue is increased following MSC treatment in patients with severe emphysema undergoing lung volume reduction surgery (8).…”

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confidence: 99%

Best of Milan 2017—repair of the emphysematous lung: mesenchymal stromal cell and matrix

Polverino

2017

J. Thorac. Dis.

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“…The authors proposed that this study forms an important basis for future research; however, overall the clinical results were not very promising, with only a mild systemic anti-inflammatory effect. In a more recent phase I clinical trial, 8 severe emphysema patients received 60–140 × 10 6 autologous BM-MSCs [40]. This treatment was similarly well tolerated and a 3-fold increase in the platelet and endothelial marker CD31 was found within the alveolar septa 3 weeks after infusion.…”

Section: Msc Administration In Human Emphysemamentioning

confidence: 99%

Mesenchymal Stromal Cells to Regenerate Emphysema: On the Horizon?

et al. 2018

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Mesenchymal stem or stromal cells (MSCs) are multipotent cells that play a pivotal role in various phases of lung development and lung homeostasis, and potentially also lung regeneration. MSCs do not only self-renew and differentiate into renew tissues, but also have anti-inflammatory and paracrine properties to reduce damage and to support tissue regeneration, constituting a promising cell-based treatment strategy for the repair of damaged alveolar tissue in emphysema. This review discusses the current state of the art regarding the potential of MSCs for the treatment of emphysema. The optimism regarding this treatment strategy is supported by promising results from animal models. Still, there are considerable challenges before effective stem cell treatment can be realized in emphysema patients. It is difficult to draw definitive conclusions from the available animal studies, as different models, dosage protocols, administration routes, and sources of MSCs have been used with different measures of effectiveness. Moreover, the regrowth potential of differentiated tissues and organs differs between species. Essential questions about MSC engraftment, retention, and survival have not been sufficiently addressed in a systematic manner. Few human studies have investigated MSC treatment for chronic obstructive pulmonary disease, demonstrating short-term safety but no convincing benefits on clinical outcomes. Possible explanations for the lack of beneficial effects on clinical outcomes could be the source (bone marrow), route, dosage, frequency of administration, and delivery (lack of a bioactive scaffold). This review will provide a comprehensive overview of the (pre)clinical studies on MSC effects in emphysema and discuss the current challenges regarding the optimal use of MSCs for cell-based therapies.

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A phase I study for intravenous autologous mesenchymal stromal cell administration to patients with severe emphysema

Abstract: Autologous MSC treatment in severe emphysema is feasible and safe. The increase in CD31 expression after LVRS and MSC treatment suggests responsiveness of microvascular endothelial cells in the most severely affected parts of the lung.

Cited by 93 publications

References 18 publications

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

Best of Milan 2017—repair of the emphysematous lung: mesenchymal stromal cell and matrix

Mesenchymal Stromal Cells to Regenerate Emphysema: On the Horizon?

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