The Safety and Efficiency of Addressing ARDS Using Stem Cell Therapies in Clinical Trials

Rezoagli, Emanuele; Murphy, Emma J.; Laffey, John G.; O’Toole, Daniel

doi:10.1007/978-3-030-29403-8_12

Cited by 6 publications

(5 citation statements)

References 184 publications

(203 reference statements)

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“…Since 2014 until the COVID-19 pandemic, approximately 30 registered clinical trials have used MSCs for ARDS. Most of these trials have not begun or are currently recruiting patients and lack an update status [25]. From these trials, there are only three published final reports from phase 1-2 studies that focused on safety, tolerability, and feasibility of MSCs for ARDS [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

et al. 2021

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Background Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. Methods A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). Findings There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24–48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48–96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2–7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5–19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. Interpretation We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

et al. 2021

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“…This “cytokine storm” is responsible for early sepsis-related multiple organ failure and death [ 3 ]. Mesenchymal stromal cells (MSCs) are a promising therapeutic strategy for the treatment of sepsis due to their reported immunomodulatory properties [ 4 ] and have been shown to have a multimodal mechanism of action involving cytokine and other factor production, secretion of extracellular vesicles and even cell–cell contact-dependent processes [ 5 , 6 , 7 ]. Previous studies have shown the efficacy of these cells to improve the outcome of sepsis of different aetiologies [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Umbilical Cord-Derived CD362+ Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture

González

Keane

Masterson

et al. 2020

IJMS

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Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362+-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model. Surviving animals were assessed at 48 h post injury induction. MSCs improved human lung, colonic and kidney epithelial cell survival following cytokine activation. In severe systemic sepsis, MSCs administered at 30 min enhanced survival (Series 1), and reduced organ bacterial load. In moderate systemic sepsis (Series 2), MSCs were ineffective when delivered immediately or 24 h later. Of importance, MSCs delivered 4 h post induction of moderate sepsis (Series 3) were effective, improving serum lactate, enhancing bacterial clearance from tissues, reducing pro-inflammatory cytokine concentrations and increasing antimicrobial peptides in serum. While demonstrating benefit and immunomodulation in systemic sepsis, therapeutic efficacy may be limited to a specific point of disease onset, and repeat dosing, MSC enhancement or other contingencies may be necessary.

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“…It has been debated that the lung has limited regenerative capacities [ 64 , 74 ]. However, as we have set out above, therapies such as MSC secretome, exosomes and conditioned media can be produced and stored and still maintain their viability prior to administration.…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

“…However, the choice between the two strategies depends on the circumstance at hand. Preclinical trials have demonstrated that autologous cell therapy may not be the best option for chronic lung disease [ 64 ]. It may be challenging to isolate and expand cells from older patients due to their decreased biological activity, or from a patient that is severely ill due to their immune suppression properties and low immunogenicity, and the isolation and expansion of MSCs is a time-consuming process [ 65 ].…”

Section: Introductionmentioning

confidence: 99%

State of the Art Review of Cell Therapy in the Treatment of Lung Disease, and the Potential for Aerosol Delivery

Brave

MacLoughlin

2020

IJMS

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Respiratory and pulmonary diseases are among the leading causes of death globally. Despite tremendous advancements, there are no effective pharmacological therapies capable of curing diseases such as COPD (chronic obstructive pulmonary disease), ARDS (acute respiratory distress syndrome), and COVID-19. Novel and innovative therapies such as advanced therapy medicinal products (ATMPs) are still in early development. However, they have exhibited significant potential preclinically and clinically. There are several longitudinal studies published, primarily focusing on the use of cell therapies for respiratory diseases due to their anti-inflammatory and reparative properties, thereby hinting that they have the capability of reducing mortality and improving the quality of life for patients. The primary objective of this paper is to set out a state of the art review on the use of aerosolized MSCs and their potential to treat these incurable diseases. This review will examine selected respiratory and pulmonary diseases, present an overview of the therapeutic potential of cell therapy and finally provide insight into potential routes of administration, with a focus on aerosol-mediated ATMP delivery.

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The Safety and Efficiency of Addressing ARDS Using Stem Cell Therapies in Clinical Trials

Cited by 6 publications

References 184 publications

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

Umbilical Cord-Derived CD362+ Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture

State of the Art Review of Cell Therapy in the Treatment of Lung Disease, and the Potential for Aerosol Delivery

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