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Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial

https://doi.org/10.1016/S2213-2600(14)70291-7Get rights and content

Summary

Background

No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.

Methods

The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.

Findings

No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.

Interpretation

A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.

Funding

The National Heart, Lung, and Blood Institute.

Introduction

Despite advances in our understanding of the pathogenesis of acute respiratory distress syndrome (ARDS), no drug has reduced mortality in ARDS.1 Treatment remains primarily supportive, with lung-protective ventilation and a fluid conservative strategy, as well as early neuromuscular blockade and prone positioning in more severe cases.2, 3, 4, 5, 6, 7 Mortality of ARDS has declined modestly with improved ventilator and fluid management, but remains high (between 20% and 40% in clinical studies).1, 8

Treatment with allogeneic bone marrow-derived human mesenchymal stem (stromal) cells (MSCs) is attractive as a potential new treatment for ARDS for several reasons. MSCs are multipotent cells with low immunogenicity that secrete multiple paracrine factors including endothelial and epithelial growth factors, anti-inflammatory cytokines, and antimicrobial peptides.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 They are also capable of transferring mitochondria to injured epithelial cells.21 These characteristics are directly relevant to the main abnormalities that underlie lung injury in patients with ARDS.1

Preclinical studies in small animal (mouse and rat) and large animal (sheep) experiments, as well as in an ex-vivo perfused human lung model, showed potential efficacy and safety of MSC administration for the treatment of ARDS.9, 10, 12, 13, 15, 22, 23, 24 In April, 2014, Zheng and colleagues25 published the results of a single-centre trial testing a single dose of 1 million cells/kg adipose-derived human MSCs in 12 patients with moderate-to-severe ARDS and reported no infusion-related adverse events. Additionally, MSCs have been tested in more than 2000 human patients for a variety of conditions, with no apparent major adverse effects.19 Based on these studies, we aimed to assess the safety of bone marrow-derived human MSCs for the treatment of moderate-to-severe ARDS and to determine the maximum tolerated MSC dose up to a dose of 10 million cells/kg predicted bodyweight (PBW).

Section snippets

Study design and participants

The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by (1) the acute onset of the need for positive pressure ventilation by an endotracheal

Results

As planned, nine patients were enrolled: three patients received the low dose (1 million cells/kg PBW), three patients received the intermediate dose (5 million cells/kg PBW), and three patients received the high dose (10 million cells/kg PBW) MSCs. Baseline characteristics of each patient are shown in table 1. Most patients (seven of nine) had pneumonia or aspiration as the primary cause of ARDS. Although several patients met criteria for severe ARDS when first identified by the study team,

Discussion

Intravenous administration of a single dose of bone marrow-derived human MSCs was well tolerated in this phase 1 trial in nine patients with moderate to severe ARDS, with no evidence of prespecified infusion-associated adverse events, immediate clinical instability, or dose-limiting toxicity at any of the doses tested (panel 3). Based on external review by the SRC and DSMB, none of the severe adverse events reported in our trial were related to MSC infusion. Thus, the primary outcomes suggest

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