Bone Marrow-Derived Mesenchymal Stromal Cell Therapy in Severe COVID-19: Preliminary Results of a Phase I/II Clinical Trial

Céline Grégoire, Nathalie Layios, Bernard Lambermont, Chantal Lechanteur, Alexandra Briquet, Virginie Bettonville, Etienne Baudoux, Marie Thys, Nadia Dardenne, Benoît Misset, Yves Beguin, Céline Grégoire, Nathalie Layios, Bernard Lambermont, Chantal Lechanteur, Alexandra Briquet, Virginie Bettonville, Etienne Baudoux, Marie Thys, Nadia Dardenne, Benoît Misset, Yves Beguin

Abstract

Background: Treatment of acute respiratory distress syndrome (ARDS) associated with COronaVIrus Disease-2019 (COVID-19) currently relies on dexamethasone and supportive mechanical ventilation, and remains associated with high mortality. Given their ability to limit inflammation, induce immune cells into a regulatory phenotype and stimulate tissue repair, mesenchymal stromal cells (MSCs) represent a promising therapy for severe and critical COVID-19 disease, which is associated with an uncontrolled immune-mediated inflammatory response.

Methods: In this phase I-II trial, we aimed to evaluate the safety and efficacy of 3 intravenous infusions of bone marrow (BM)-derived MSCs at 3-day intervals in patients with severe COVID-19. All patients also received dexamethasone and standard supportive therapy. Between June 2020 and September 2021, 8 intensive care unit patients requiring supplemental oxygen (high-flow nasal oxygen in 7 patients, invasive mechanical ventilation in 1 patient) were treated with BM-MSCs. We retrospectively compared the outcomes of these MSC-treated patients with those of 24 matched control patients. Groups were compared by paired statistical tests.

Results: MSC infusions were well tolerated, and no adverse effect related to MSC infusions were reported (one patient had an ischemic stroke related to aortic endocarditis). Overall, 3 patients required invasive mechanical ventilation, including one who required extracorporeal membrane oxygenation, but all patients ultimately had a favorable outcome. Survival was significantly higher in the MSC group, both at 28 and 60 days (100% vs 79.2%, p = 0.025 and 100% vs 70.8%, p = 0.0082, respectively), while no significant difference was observed in the need for mechanical ventilation nor in the number of invasive ventilation-free days, high flow nasal oxygenation-free days, oxygen support-free days and ICU-free days. MSC-treated patients also had a significantly lower day-7 D-dimer value compared to control patients (median 821.0 µg/L [IQR 362.0-1305.0] vs 3553 µg/L [IQR 1155.0-6433.5], p = 0.0085).

Conclusions: BM-MSC therapy is safe and shows very promising efficacy in severe COVID-19, with a higher survival in our MSC cohort compared to matched control patients. These observations need to be confirmed in a randomized controlled trial designed to demonstrate the efficacy of BM-MSCs in COVID-19 ARDS.

Clinical trial registration: (www.ClinicalTrials.gov), identifier NCT04445454.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; cellular therapy; intensive care unit (ICU); mesenchymal stromal cells.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Grégoire, Layios, Lambermont, Lechanteur, Briquet, Bettonville, Baudoux, Thys, Dardenne, Misset and Beguin.

Figures

Figure 1
Figure 1
Evolution of oxygen support in patients treated with BM-MSCs. The bars represent the length of hospitalization (in days), and the left column indicates the day of the first positive PCR test, with day 0 being the day of hospital admission. The lines above the bars represent the length of ICU stay, and the “star” symbols represent MSC administrations. ECMO, extracorporeal membrane oxygenation; MSC, mesenchymal stromal cells; ICU, intensive care unit.
Figure 2
Figure 2
Survival curves in MSC and control groups. p-values refers to comparisons between the MSC and control groups at day 60 (using the Fisher test for non-matched analysis and Wilcoxon test for the matched analysis).
Figure 3
Figure 3
Day-0 and day-7 CRP and D-dimer values in the MSC and control groups. Boxes extend from the 25th to 75th percentiles, and the line in the box is plotted at the median, while whiskers represent minimum and maximum, and points represent individual values.

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