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

Frontiers in Immunology - Tập 13
Céline Gregoire1,2, Nathalie Layios3,4, Bernard Lambermont3,5, Chantal Lechanteur6, Alexandra Briquet6, Virginie Bettonville6, Étienne Baudoux6, Marie Thys7, Nadia Dardenne8, Benoît Misset3, Yves Béguin1,2,6
1Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
2Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée - Infection, Immunité & Inflammation (GIGA-I3), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA) Institute, University of Liège, Liège, Belgium
3Department of Intensive Care, University Hospital Center of Liège, Liège, Belgium
4Laboratory of Cardiology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA) Institute, University of Liège, Liège, Belgium
5Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-In silico Medicine, University of Liège, Liège, Belgium
6Laboratory of Cell and Gene Therapy, University Hospital Center of Liège and University of Liège, Liège, Belgium
7Department of Medico-Economic Information, University Hospital Center of Liège, Liège, Belgium
8University Hospital Center of Biostatistics, Faculty of Medicine, University of Liège, Liège, Belgium

Tóm tắt

BackgroundTreatment 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.MethodsIn 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.ResultsMSC 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).ConclusionsBM-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

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Tài liệu tham khảo

2021, Clinical Characteristics and Day-90 Outcomes of 4244 Critically Ill Adults With COVID-19: A Prospective Cohort Study, Intensive Care Med, 47, 60, 10.1007/s00134-020-06294-x

Hoffmann, 2020, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, 181, 271, 10.1016/j.cell.2020.02.052

Osuchowski, 2021, The COVID-19 Puzzle: Deciphering Pathophysiology and Phenotypes of a New Disease Entity, Lancet Respir Med, 9, 10.1016/S2213-2600(21)00218-6

Grifoni, 2020, Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans With COVID-19 Disease and Unexposed Individuals, Cell, 181, 1489, 10.1016/j.cell.2020.05.015

Liao, 2020, Single-Cell Landscape of Bronchoalveolar Immune Cells in Patients With COVID-19, Nat Med, 26, 10.1038/s41591-020-0901-9

Robbiani, 2020, Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals, Nature, 584, 10.1038/s41586-020-2456-9

Laing, 2020, A Dynamic COVID-19 Immune Signature Includes Associations With Poor Prognosis, Nat Med, 26, 10.1038/s41591-020-1038-6

Bermejo-Martin, 2020, Viral RNA Load in Plasma is Associated With Critical Illness and a Dysregulated Host Response in COVID-19, Crit Care, 24, 691, 10.1186/s13054-020-03398-0

De Biasi, 2020, Marked T Cell Activation, Senescence, Exhaustion and Skewing Towards TH17 in Patients With COVID-19 Pneumonia, Nat Commun, 11, 3434, 10.21203/rs.3.rs-23957/v1

Mathew, 2020, Deep Immune Profiling of COVID-19 Patients Reveals Distinct Immunotypes With Therapeutic Implications, Science, 369, 10.1126/science.abc8511

Grasselli, 2020, Pathophysiology of COVID-19-Associated Acute Respiratory Distress Syndrome: A Multicentre Prospective Observational Study, Lancet Respir Med, 8, 10.1016/S2213-2600(20)30370-2

Ader, 2022, Remdesivir Plus Standard of Care Versus Standard of Care Alone for the Treatment of Patients Admitted to Hospital With COVID-19 (DisCoVeRy): A Phase 3, Randomised, Controlled, Open-Label Trial, Lancet Infect Dis, 22, 10.1016/S1473-3099(21)00485-0

Pan, 2021, Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results, N Engl J Med, 384, 497, 10.1056/NEJMoa2023184

Horby, 2021, Dexamethasone in Hospitalized Patients With Covid-19, N Engl J Med, 384, 693, 10.1056/NEJMoa2021436

2021, Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-Analysis, JAMA, 326, 499, 10.1001/jama.2021.11330

Ely, 2022, Efficacy and Safety of Baricitinib Plus Standard of Care for the Treatment of Critically Ill Hospitalised Adults With COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: An Exploratory, Randomised, Placebo-Controlled Trial, Lancet Respir Med, 10, 10.1016/S2213-2600(22)00006-6

Lambermont, 2021, Outcome Improvement Between the First Two Waves of the Coronavirus Disease 2019 Pandemic in a Single Tertiary-Care Hospital in Belgium, Crit Care Explor, 3, 10.1097/CCE.0000000000000438

Le Blanc, 2012, Multipotent Mesenchymal Stromal Cells and the Innate Immune System, Nat Rev Immunol, 12, 10.1038/nri3209

Rohban, 2017, Mesenchymal Stem and Progenitor Cells in Regeneration: Tissue Specificity and Regenerative Potential, Stem Cells Int, 2017, 5173732, 10.1155/2017/5173732

Servais, 2016, Multipotent Mesenchymal Stromal Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease After Allogeneic Stem Cell Transplantation, Belgian J Hematol, 7

Grégoire, 2017, Review Article: Mesenchymal Stromal Cell Therapy for Inflammatory Bowel Diseases, Aliment Pharmacol Ther, 45, 10.1111/apt.13864

Ren, 2008, Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide, Cell Stem Cell, 2, 10.1016/j.stem.2007.11.014

Hung, 2007, Short-Term Exposure of Multipotent Stromal Cells to Low Oxygen Increases Their Expression of CX3CR1 and CXCR4 and Their Engraftment In Vivo, PloS One, 2, e416, 10.1371/journal.pone.0000416

Hung, 2007, Angiogenic Effects of Human Multipotent Stromal Cell Conditioned Medium Activate the PI3K-Akt Pathway in Hypoxic Endothelial Cells to Inhibit Apoptosis, Increase Survival, and Stimulate Angiogenesis, Stem Cells, 25, 10.1634/stemcells.2006-0686

Leng, 2020, Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients With COVID-19 Pneumonia, Aging Dis, 11, 10.14336/AD.2020.0228

Atluri, 2020, Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use, Pain Phys, 23

Lechanteur, 2016, Clinical-Scale Expansion of Mesenchymal Stromal Cells: A Large Banking Experience, J Trans Med, 14, 10.1186/s12967-016-0892-y

Lechanteur, 2021, MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process, Cells, 10, 1320, 10.3390/cells10061320

2020, A Minimal Common Outcome Measure Set for COVID-19 Clinical Research, Lancet Infect Dis, 20, 10.1016/S1473-3099(20)30483-7

Lim, 2021, Case Fatality Rates for Patients With COVID-19 Requiring Invasive Mechanical Ventilation. A Meta-Analysis, Am J Respir Crit Care Med, 203, 54, 10.1164/rccm.202006-2405OC

Aranda, 2021, Long-Term Impact of COVID-19 Associated Acute Respiratory Distress Syndrome, J Infect, 83, 10.1016/j.jinf.2021.08.018

Rousseau, 2021, Post-Intensive Care Syndrome After a Critical COVID-19: Cohort Study From a Belgian Follow-Up Clinic, Ann Intensive Care, 11, 118, 10.1186/s13613-021-00910-9

Boucher, 2022, The Cost of ARDS: A Systematic Review, Chest, 161, 10.1016/j.chest.2021.08.057

Galleu, 2017, Apoptosis in Mesenchymal Stromal Cells Induces In Vivo Recipient-Mediated Immunomodulation, Sci Trans Med, 9, 10.1126/scitranslmed.aam7828

Lee, 2009, Intravenous hMSCs Improve Myocardial Infarction in Mice Because Cells Embolized in Lung are Activated to Secrete the Anti-Inflammatory Protein TSG-6, Cell Stem Cell, 5, 54, 10.1016/j.stem.2009.05.003

Lopes-Pacheco, 2020, Current Understanding of the Therapeutic Benefits of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome, Cell Biol Toxicol, 36, 83, 10.1007/s10565-019-09493-5

Zheng, 2014, Treatment of Acute Respiratory Distress Syndrome With Allogeneic Adipose-Derived Mesenchymal Stem Cells: A Randomized, Placebo-Controlled Pilot Study, Respir Res, 15, 39, 10.1186/1465-9921-15-39

Wilson, 2015, Mesenchymal Stem (Stromal) Cells for Treatment of ARDS: A Phase 1 Clinical Trial, Lancet Respir Med, 3, 24, 10.1016/S2213-2600(14)70291-7

Matthay, 2019, Treatment With Allogeneic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome (START Study): A Randomised Phase 2a Safety Trial, Lancet Respir Med, 7, 10.1016/S2213-2600(18)30418-1

Ringdén, 2022, Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome, Front Immunol, 13, 10.3389/fimmu.2022.839844

Meng, 2020, Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy in Patients With COVID-19: A Phase 1 Clinical Trial, Signal Transduct Target Ther, 5, 172, 10.1038/s41392-020-00286-5

Guo, 2020, Administration of Umbilical Cord Mesenchymal Stem Cells in Patients With Severe COVID-19 Pneumonia, Crit Care, 24, 420, 10.1186/s13054-020-03142-8

Xu, 2021, Evaluation of the Safety and Efficacy of Using Human Menstrual Blood-Derived Mesenchymal Stromal Cells in Treating Severe and Critically Ill COVID-19 Patients: An Exploratory Clinical Trial, Clin Transl Med, 11, e297, 10.1002/ctm2.297

Hashemian, 2021, Mesenchymal Stem Cells Derived From Perinatal Tissues for Treatment of Critically Ill COVID-19-Induced ARDS Patients: A Case Series, Stem Cell Res Ther, 12, 91, 10.1186/s13287-021-02165-4

Iglesias, 2021, Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19, Aging Dis, 12, 10.14336/AD.2020.1218

Häberle, 2021, Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS, J Intensive Care Med, 36, 10.1177/0885066621997365

Ercelen, 2021, Clinical Experience on Umbilical Cord Mesenchymal Stem Cell Treatment in 210 Severe and Critical COVID-19 Cases in Turkey, Stem Cell Rev Rep, 17, 10.1007/s12015-021-10214-x

Lanzoni, 2021, Umbilical Cord Mesenchymal Stem Cells for COVID-19 Acute Respiratory Distress Syndrome: A Double-Blind, Phase 1/2a, Randomized Controlled Trial, Stem Cells Transl Med, 10.1002/sctm.20-0472

Monsel, 2022, Treatment of COVID-19-Associated ARDS With Mesenchymal Stromal Cells: A Multicenter Randomized Double-Blind Trial, Crit Care, 26, 48, 10.1186/s13054-022-03930-4

Shi, 2021, Effect of Human Umbilical Cord-Derived Mesenchymal Stem Cells on Lung Damage in Severe COVID-19 Patients: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial, Signal Transduct Target Ther, 6, 58, 10.1038/s41392-021-00488-5

Dilogo, 2021, Umbilical Cord Mesenchymal Stromal Cells as Critical COVID-19 Adjuvant Therapy: A Randomized Controlled Trial, Stem Cells Transl Med, 10, 10.1002/sctm.21-0046

Shu, 2020, Treatment of Severe COVID-19 With Human Umbilical Cord Mesenchymal Stem Cells, Stem Cell Res Ther, 11, 361, 10.1186/s13287-020-01875-5

Bikdeli, 2020, COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-Of-the-Art Review, J Am Coll Cardiol, 75, 10.1016/j.jacc.2020.04.031

Grégoire, 2019, Comparison of Mesenchymal Stromal Cells From Different Origins for the Treatment of Graft-Vs.-Host-Disease in a Humanized Mouse Model, Front Immunol, 10, 10.3389/fimmu.2019.00619

Moll, 2015, Different Procoagulant Activity of Therapeutic Mesenchymal Stromal Cells Derived From Bone Marrow and Placental Decidua, Stem Cells Dev, 24, 10.1089/scd.2015.0120

Moll, 2020, MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy, Front Immunol, 11, 10.3389/fimmu.2020.01091

Wiersinga, 2020, Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review, JAMA, 324, 10.1001/jama.2020.12839

Moll, 2022, Improved MSC Minimal Criteria to Maximize Patient Safety: A Call to Embrace Tissue Factor and Hemocompatibility Assessment of MSC Products, Stem Cells Trans Med, 11, 2, 10.1093/stcltm/szab005

Pires, 2016, Unveiling the Differences of Secretome of Human Bone Marrow Mesenchymal Stem Cells, Adipose Tissue-Derived Stem Cells, and Human Umbilical Cord Perivascular Cells: A Proteomic Analysis, Stem Cells Dev, 25, 10.1089/scd.2016.0048

Cottle, 2022, Impact of Cryopreservation and Freeze-Thawing on Therapeutic Properties of Mesenchymal Stromal/Stem Cells and Other Common Cellular Therapeutics, Curr Stem Cell Rep, 8, 72, 10.1007/s40778-022-00212-1

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Frontiers in Immunology

Tập 13

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