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Review
. 2023 Jun;40(6):2626-2692.
doi: 10.1007/s12325-023-02507-z. Epub 2023 Apr 17.

Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives

Sabrina Mattoli  1   2 , Matthias Schmidt  3   4
Affiliations
Review

Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives

Sabrina Mattoli et al. Adv Ther. 2023 Jun.

Abstract

Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.

Keywords: Acute respiratory distress syndrome; Add-on therapy; COVID-19; Cell-based therapy; Clinical trial; Exosome; Extracellular vesicle; Influenza; Mesenchymal stem cell; Mesenchymal stromal cell.

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Conflict of interest statement

Sabrina Mattoli is consultant to the European Commission and to the Eureka Association and is shareholder in Novartis Pharma AG and Pfizer Inc. Matthias Schmidt is named as co-inventor on a submitted patent application concerning the generation of engineered exosomes for targeted delivery of biologics to the lungs.

Figures

Fig. 1
Fig. 1
Immunomodulatory properties of mesenchymal stem/stromal cells. Copyright 2021 Müller, Tunger, Wobus, von Bonin, Towers, Bornhäuser, Dazzi, Wehner, and Schmitz [54], Figure reproduced without changes under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors(s) and the copyright owner(s) are credited, the original publication is cited, the link to the license is given, and it is indicated if changes were made. CD cluster of differentiation, CTL cytotoxic T lymphocytes, EVs extracellular vesicles, FasL Fas ligand, HGF hepatocyte growth factor, IDO indoleamine 2,3-dioxygenase, IFN interferon, IL interleukin, IL1-RA interleukin 1 receptor antagonist, MHC major histocompatibility complex, M-CSF macrophage colony-stimulating factor, miRNA microRNA, OX40L OX40 ligand, PD-L1 programmed death-ligand 1, PGE2 prostaglandin 2, Th T helper lymphocyte, TGF transforming growth factor, TNF tumor necrosis factor, Treg T regulatory lymphocyte, TSG tumor necrosis factor-stimulated gene
Fig. 2
Fig. 2
Mechanistic rationale for investigating the clinical use of mesenchymal stem/stromal cells and their products as adjunctive therapy for the management of severe and critical coronavirus disease 2019 and influenza. The pathological mechanisms leading to alveolar damage, hypoxemia, and systemic inflammation are highlighted in red, and the counteracting effects of intravenously injected allogeneic mesenchymal stem/stromal cells that have been induced to express an antiinflammatory/immunosuppressive phenotype systemically and in the inflamed alveoli are highlighted in green. In severe and critical coronavirus disease 2019, virus replication, the proliferation of effector T lymphocytes, the release of proinflammatory cytokines, and the recruitment of leukocytes from the peripheral blood are inhibited by the recommended treatment with antivirals and the glucocorticoid dexamethasone in combination with a Janus kinase inhibitor of the JAK1/JAK2 subtype, such as baricitinib, or with the humanized antibody against the interleukin-6 receptor tocilizumab. This combination also reduces the systemic effects of viral replication and excessive inflammation, but in abolishing the acute-phase response and the IL-6 mediated enhancement of bacterial phagocytosis, the combination of antiinflammatory agents concurs to render the host more vulnerable to pulmonary and systemic infections. Key adjunctive effects of mesenchymal stem/stromal cells are the following: reestablishment of the regulatory function of subpopulations of T and B lymphocytes (Treg and Breg cells) that normally suppress excessive and deleterious immunological/inflammatory responses; activation of the mechanisms involved in the repair of the alveolar-capillary barrier via the release of soluble factors (Ang-1, HGF, and KGF) and extracellular vesicles delivering microRNAs; enhancement of the viability of alveolar epithelial cells through the transfer of healthy mitochondria by intercellular communication; prevention of the development of secondary bacterial infections by producing antimicrobial peptides and by enhancing the phagocytic activity of neutrophils and macrophages through the release of prostaglandin E2. In severe and critical influenza, where a combination of antivirals and antiinflammatory or immunoregulators is not allowed, most of the biological effects of mesenchymal stem/stromal cells highlighted in this figure would be desirable. Generated using in part ScienceSlides graphics from VisiScience Corp., licensed use. AEC alveolar epithelial cell, AMPs antimicrobial peptides, Ang angiopoietin, Breg B regulatory lymphocytes, CRP C-reactive protein, CoV coronavirus, COX cyclooxygenase, CTL cytotoxic T lymphocytes, EVs extracellular vesicles, FGF fibroblast growth factor, GCs glucocorticoids, HGF hepatocyte growth factor, IAV influenza virus, IDO indoleamine 2,3-dioxygenase, IFN interferon, IL interleukin, IL1-RA interleukin 1 receptor antagonist, IL-6R interleukin-6 receptor, ISGs interferon-stimulated genes, JAKis Janus kinase inhibitors, KGF keratinocyte growth factor, miRNA microRNA, NK natural killer, PGE2 prostaglandin 2, RLR retinoic acid-inducible gene-1-like receptor, TCR T cell receptor, TGF transforming growth factor, Th T helper lymphocyte, TLR toll-like receptor, TNF tumor necrosis factor, Treg T regulatory lymphocyte, TSG tumor necrosis factor-stimulated gene
Fig. 3
Fig. 3
Potential future integration of investigational therapy into the recommended therapeutic management of hospitalized adult patients with severe and critical COVID-19 or influenza, which is based on published international guidelines [19, 35, 90]. The arrows indicate potential sequential treatment strategies, where allogeneic mesenchymal stem/stromal cells or their products are administered intravenously as an adjunctive or alternative add-on therapy to prevent further disease progression and death in patients not responding to the recommended first-line treatment with dexamethasone, while receiving adequate respiratory support and the required critical care management. The asterisk indicates the allowed addition of the antiviral remdesivir in immunocompromised patients with severe coronavirus disease 2019 who require oxygen through a high-flow device or noninvasive ventilation and are receiving dexamethasone. ANI antiviral neuraminidase inhibitor, COVID-19 coronavirus disease 2019, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, IL-6 interleukin-6, IMV invasive mechanical ventilation, IV intravenous, MSC mesenchymal stem/stromal cells, NIV noninvasive ventilation, WHO CPS World Health Organization Clinical Progression Scale
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