Mesenchymal stromal cell therapy for coronavirus disease 2019: which? when? and how much?

Abstract

Mesenchymal Stromal Cells (MSCs) are under active consideration as a treatment strategy to control the hyperinflammation and slow disease progression in COVID-19. The possible mechanism of protection through their immunoregulatory and paracrine action has been reviewed extensively. However, the importance of process control to achieve a consistent cell quality, maximum safety and efficacy - for which the three key questions are of ‘which’, ‘when’ and ‘how much’ - remain unaddressed. Any commonality, if exists, in the ongoing clinical trials is yet to be analysed and reviewed. In this review, we have therefore compiled and discussed study design data from ongoing clinical trials to address the key questions of ‘which’ tissue source, donor profile, isolation technique, culture conditions, long-term culture and cryopreservation for MSCs; the question of ‘when’ with regard to defining the transplantation window, by identifying and staging of patients based on their pro-inflammatory profile; and finally that of ‘how much’ with respect to the number of cells in a single administration, the number of doses and route of transplantation. To homogenize MSC therapy for COVID-19 on a global scale and to make it readily available in large numbers, a shared understanding and uniform agreement on these fundamental issues is essential.

Updated Living Systematic Review and Meta-analysis of Controlled Trials of Mesenchymal Stromal Cells to Treat COVID-19: A Framework for Accelerated Synthesis of Trial Evidence for Rapid Approval—FASTER Approval

“…The optimal timing of MSC administration to patients with COVID-19 remains uncertain. 41 , 72 With their potential to attenuate the cytokine storm early in COVID-19 disease progression, some suggest administering MSCs at the onset of hypoxia to avoid intubation or mechanical ventilation. 41 , 72 Concern regarding potential exacerbation of a hypercoagulable state, however, has been expressed 73 given that MSCs from certain tissue sources are rich in tissue factor (TF/CD142).…”

“… 41 , 72 With their potential to attenuate the cytokine storm early in COVID-19 disease progression, some suggest administering MSCs at the onset of hypoxia to avoid intubation or mechanical ventilation. 41 , 72 Concern regarding potential exacerbation of a hypercoagulable state, however, has been expressed 73 given that MSCs from certain tissue sources are rich in tissue factor (TF/CD142). 73 Future subgroup analysis examining the clinical outcomes and occurrence of adverse events in patients administered MSCs at different stages of COVID-19 disease would be informative and may help in the design of an optimized dosing schedule.…”

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome

“… 1 In severe cases, COVID-19 leads to acute respiratory distress syndrome (ARDS), thought to be due to direct injury to the lung and hyperinflammatory response. 2 Treatment recommendations for COVID-19-related-ARDS (COVID-ARDS) have evolved to include remdesivir, dexamethasone, and immunomodulatory therapies; however, there remains no effective treatment for ARDS, resulting in many patients dying from sepsis or multi organ failure. 3 , 4 The use of mesenchymal stromal cells (MSC) offers a unique therapeutic option for patients with COVID-ARDS that might shorten time to lung injury resolution.…”

Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia

“…Moreover, these therapies were not effective to treat severe infection of SARS-CoV-2 due to these treatments potentially inducing the robust cytokine storm 3,4 . A previous study demonstrated that there is a correlation between disease severity and the release of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-6, IL-1B, IL-4, IFN-γ, IFN-γ-induced protein 10 (IP10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1a (MIP-1a), and granulocyte-colony stimulating factor (G-CSF) 5 . This finding was confirmed by the high plasma cytokines found in the most severe COVID-19 patients associated with extensive lung damage 6,7 .…”