Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

Abstract

Acute respiratory distress syndrome (ARDS) in COVID‐19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti‐inflammatory effects and could yield beneficial effects in COVID‐19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC‐MSC) infusions in subjects with COVID‐19 ARDS. A double‐blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty‐four subjects were randomized 1:1 to either UC‐MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC‐MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC‐MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion‐associated AEs. No serious adverse events (SAEs) were observed related to UC‐MSC infusions. UC‐MSC infusions in COVID‐19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC‐MSC‐treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE‐free survival (P = .008), and time to recovery (P = .03). UC‐MSC infusions are safe and could be beneficial in treating subjects with COVID‐19 ARDS.

Human umbilical cord-derived mesenchymal stem/stromal cells: a promising candidate for the development of advanced therapy medicinal products

“…UC-MSCs infusion normalized lymphocytes levels and increased migration of DC to the inflammatory site [44]. Moreover, the plasma levels of C-reactive protein and pro-inflammatory cytokines, such as TNF-α and IL-6, were decreased after UC-MSCs treatment while anti-inflammatory factors such as IL-10 was increased [42][43][44].…”

“…They showed a decrease of disease progression from severe to critical phase in the UC-MSCs group comparing to the SOC. More recently, Lanzoni et al showed a significant improvement in patient survival with 91% in UC-MSCs group versus 42% in the control group [43]. Indeed, UC-MSCs can reduce the cytokine storm in COVID-19 patients, owing to their anti-inflammatory and immunomodulatory functions, which may be a crucial step in the treatment of this pathology.…”

Anticipated Impact of Stem Cell and Other Cellular Medicine Clinical Trials for COVID-19

“…Dozens of articles on cellular therapies for COVID-19 continue to be published, but they consist mostly of review or perspectives pieces and case reports. A randomized, double-blinded, placebo-controlled study reporting indications of potential efficacy of umbilical cord cells for COVID-19 has generated attention recently [ 3 ], but it has some important limitations including small size (24 participants in total), which produced difficultly in balancing baseline characteristics of the control and interventional groups. Another more recently published umbilical cord MSC clinical trial for COVID-19 using a larger group of participants did not produce clear signals on safety and efficacy [ 19 ].…”

“…Dozens of new trials of cell therapies for COVID-19 have generated major attention and valuable resources are being devoted to these clinical studies, but at present the potential for meaningful impact from this line of clinical research is unclear. Although publications in 2020 and early 2021 on small clinical studies or case reports [ 2 , 3 ] generated some early optimism, there is relatively little rigorous data so far to support the widespread adoption of clinical use of any cellular therapies and more specifically stem cell-based interventions for COVID-19. There has been concern that because of the urgent nature of the pandemic that COVID-19 trial standards overall and those of cellular COVID-19 therapies specifically could be lowered, as compared with nonpandemic-related trials [ 4 , 5 ].…”

The Centrality of Obesity in the Course of Severe COVID-19

“…A study involving 41 patients showed that the administration of MSCs has favorable effects in COVID-19 patients, including a faster time for the oxygenation index and lymphocyte count to return to within the normal range and reduced lung inflammation (86). A randomized controlled trial conducted by the University of Miami Miller School of Medicine found that umbilical cord mesenchymal stem cell (UC-MSC) infusions can increase patient survival to more than double (91% vs 42%) in subjects with COVID-19-related ARDS without serious adverse events (87). Obesity-associated factors can disrupt the functions of MSCs with regard to tissue regeneration, antiinflammation, and immune modulation (88).…”