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Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy — Achieving global consensus and visibility for cellular host-directed therapies

Open AccessPublished:May 17, 2020DOI:https://doi.org/10.1016/j.ijid.2020.05.040

      Abstract

      As of May 17th 2020, the novel coronavirus disease 2019 (COVID-19) pandemic has caused 307,395 deaths worldwide, out of 3,917,366 cases reported to the World Health Organization. No specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and/or vaccines are found. In search of effective treatments, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical trials on a range of antiviral drug regimens and repurposed drugs in various combinations. A paradigm shift is underway from the current focus of drug development targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2 and high COVID-19 mortality rates. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for treatment of COVID-19. MSCs should also be trialed for treatment of other circulating WHO priority Blueprint pathogens such as MERS-CoV which causes upto 34% mortality rates. It’s about time funding agencies invested more into development MSCs per se, and also for a range of other HDTs, in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 death rates and preventing long-term functional disability in those who survive disease.

      Introduction — Cornavirus-2019 Disease (COVID-19) — a global pandemic

      Since early January 2020, the world has witnessed unprecedented global scientific and political attention focused on the devastating coronavirus disease 2019 (COVID-19) pandemic, caused by the novel, highly contagious zoonotic pathogen, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (
      • Hui D.S.
      • I Azhar E.
      • Madani T.A.
      • et al.
      The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China.
      ,
      • Chen N.
      • Zhou M.
      • Dong X.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study [published online ahead of print, 2020 Jan 30].
      ). By May 17th, 2020, there have been 307,395 deaths worldwide out of 3,917,366 (7% case fatality) confirmed COVID-19 cases reported from all continents to the World Health Organization (). As with the two other novel coronavirus zoonotic diseases of humans, SARS and MERS, no specific treatments for reducing mortality or morbidity are yet available (
      • Memish Z.A.
      • Perlman S.
      • Van Kerkhove M.D.
      • Zumla A.
      Middle East respiratory syndrome.
      ,
      • Hui D.S.
      • I Azhar E.
      • Madani T.A.
      • et al.
      The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China.
      ,
      • Hui D.S.C.
      • Zumla A.
      Severe acute respiratory syndrome: historical, epidemiologic, and clinical features.
      ). The management of COVID-19 patients remains largely symptomatic and supportive with organ support for severely ill patients (
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Guan W.J.
      • Liang W.H.
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      • Liang H.R.
      • Chen Z.S.
      • Li Y.M.
      • Liu X.Q.
      • et al.
      Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis.
      ). Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and vaccines are found.

      Clinical trials of therapeutic interventions

      With no specific treatments being available for treating COVID-19 patients, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 related trials (https://clinicaltrials.gov/ct2/who_table). These clinical trials have been fast-tracked by ethical committees worldwide and a range of therapeutic interventions registered on clinical trials.gov are taking forward phase 1, 2 and 3 trials of antiviral drug regimens, biologics, repurposed drugs in various combinations, herbal remedies, nutritional supplements, and cellular therapies. A paradigm shift is underway from the current focus of drug treatment combinations targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses, which underlie the pathogenesis of SARS-CoV-2 and the high COVID-19 death rates. This is an area, which has been eclipsed by the current emphasis the huge number of trials evaluating new anti-viral drugs, repurposed drugs and combinations thereof. We thus focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. A paradigm shift is underway from the current focus of drug treatment combinations targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) (
      • Zumla A.
      • Azhar E.I.
      • Arabi Y.
      • et al.
      Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections.
      ,
      • Zumla A.
      • Hui D.S.
      • Azhar E.I.
      • Memish Z.A.
      • Maeurer M.
      Reducing mortality from 2019-nCoV: host-directed therapies should be an option.
      ) for tackling the aberrant host immune and inflammatory responses, which underlie the pathogenesis of SARS-CoV-2 and the high COVID-19 death rates. This is an area, which has been eclipsed by the current emphasis the huge number of trials evaluating new anti-viral drugs, repurposed drugs and combinations thereof. We thus focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease.

      Pathology and Autopsy studies of COVID-19 deaths

      Defining the underlying pathogenesis and pathology of COVID-19 disease for developing appropriate therapeutic interventions may prevent end organ damage and long-term functional disability in those who survive severe disease. Autopsy and minimally invasive biopsy studies indicate that COVID-19 is a multi-system disease. The lungs in particular manifest significant pathological lesions, such as alveolar exudative inflammation and interstitial inflammation, alveolar epithelium proliferation and hyaline membrane formation (
      • Menter T.
      • Haslbauer J.D.
      • Nienhold R.
      • et al.
      Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4].
      ,
      • Tian S.
      • Xiong Y.
      • Liu H.
      • et al.
      Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
      ). Significant proliferation of type II alveolar epithelia and focal desquamation of alveolar and bronchial epithelia and hyaline membrane formation are seen (
      • Xu Z.
      • Shi L.
      • Wang Y.
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ); with predominantly macrophage and monocyte immune cell infiltration in alveoli with multinucleated giant cells; lymphocytes (mostly CD4-positive T cells), and some eosinophils and neutrophils. The blood vessels of alveolar septum were congested, edematous and widened, with modest infiltration of monocytes and lymphocytes. Hyaline thrombi in microvessels and focal hemorrhage in lung tissue, organization of exudates, and pulmonary interstitial fibrosis have been observed. Furthermore, degeneration and necrosis of parenchymal cells and formation of hyaline thrombus in small vessels were observed in other organs and tissues (
      • Menter T.
      • Haslbauer J.D.
      • Nienhold R.
      • et al.
      Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4].
      ,
      • Tian S.
      • Xiong Y.
      • Liu H.
      • et al.
      Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
      ). Immunohistochemical staining showed alveolar epithelia and macrophages positive for SARS-CoV-2 antigen. Evidence of SARS-CoV-2 antigens in other organs and tissues has been detected which suggests that host immune responses evoked by SARS-CoV-2 infection are involved in the pathogenesis of multi-organ injury (
      • Yao X.H.
      • Li T.Y.
      • He Z.C.
      • Ping Y.F.
      • Liu H.W.
      • Yu S.C.
      • et al.
      A pathological report of three COVID-19 cases by minimally invasive autopsies.
      ).

      COVID-19 Pathogenesis and aberrant immune responses

      SARS-CoV-2 enters the host cells via the cell surface angiotensin converting enzyme 2 (ACE2) receptor on the target cell surface (
      • Zhang H.
      • Penninger J.M.
      • Li Y.
      • Zhong N.
      • Slutsky A.S.
      Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.
      ). ACE2 as a cardio-regulator, so there are numerous cells with ACE2 receptors in blood vessels, alveolar type II cells (AT2) in the lungs and several other organs, such as heart, kidneys. It appears that all three lethal zoonotic coronaviruses, MERS-CoV, SARS-CoV and SARS-CoV-2 seem to induce excessive and aberrant host immune responses which are associated with severe lung pathology leading to acute respiratory distress syndrome (ARDS) (
      • Memish Z.A.
      • Perlman S.
      • Van Kerkhove M.D.
      • Zumla A.
      Middle East respiratory syndrome.
      ,
      • Liu J.
      • Li S.
      • Liu J.
      • et al.
      Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients.
      ,
      • Li G.
      • Fan Y.
      • Lai Y.
      • et al.
      Coronavirus infections and immune responses [published online ahead of print, 2020 Jan 25].
      ,
      • Li H.
      • Liu L.
      • Zhang D.
      • et al.
      SARS-CoV-2 and viral sepsis: observations and hypotheses.
      ). Characteristic findings on chest imaging in COVID 19 include bilateral ground glass and consolidative changes (
      • Shi H.
      • Han X.
      • Jiang N.
      • Cao Y.
      • Alwalid O.
      • Gu J.
      • et al.
      Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
      ). An associated cytokine storm may play a role in pathogenesis. Elevated proinflammatory cytokines and chemokines including tumour necrosis factor (TNF)α, interleukin 1β (IL-1β), IL-6, granulocyte-colony stimulating factor, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory proteins 1-α were significantly elevated in COVID-19 patients. (
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published online ahead of print, 2020 Jan 24] [published correction appears in Lancet. 2020 Jan 30].
      ,
      • Liu J.
      • Li S.
      • Liu J.
      • et al.
      Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients.
      ,
      • Ye Q.
      • Wang B.
      • Mao J.
      The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ). Patients with evidence of hyperinflammation have an increased risk of mortality (
      • Mehta McAuley
      • et al.
      COVID – 19: consider cytokine storm syndromes and immunosuppression.
      ,
      • Ruan Q.
      • Yang K.
      • Wang W.
      • Jiang L.
      • Song J.
      Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.
      ). In those who survive intensive care, the consequences of these aberrant and excessive immune responses may lead to long term pulmonary damage and fibrosis, with functional disability and reduction of quality of life (Batwai et al., 2019). It is important that therapeutic interventions which can dampen the excess inflammation, thus preventing end organ damage and long-term functional disability in those who survive severe disease.

      Cellular based therapies to reduce excessive inflammation and immune-mediated tissue damage

      For the past decade the medical and pharma communities have focused on developing therapeutics targeting the pathogen rather than on the role of underlying host factors (
      • Zumla A.
      • Azhar E.I.
      • Arabi Y.
      • et al.
      Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections.
      ,
      • Zumla A.
      • Hui D.S.
      • Azhar E.I.
      • Memish Z.A.
      • Maeurer M.
      Reducing mortality from 2019-nCoV: host-directed therapies should be an option.
      ). Human immune defenses are dependent on a complex array of mechanical, innate and acquired immune mechanisms and any disturbance of this internal lung milieu results in serious and fatal consequences. Improved understanding of inflammatory and immune pathways governing protective or deleterious outcomes, provide novel opportunities to target specific pathways that mediate immune pathology (Figure 1). Advances in host-directed therapies (HDTs) now provide a range of options to enhance immune responses or reduce excessive inflammation A range of HDTS with different mechanisms of action are under consideration from cellular therapy with mesenchymal stromal (stem) cells (MSCs), biologics, and repurposed drugs with HDT potential (
      • Lérias J.R.
      • Paraschoudi G.
      • de Sousa E.
      • et al.
      Microbes as master immunomodulators: immunopathology, cancer and personalized immunotherapies.
      ,
      • Hui D.S.
      • I Azhar E.
      • Madani T.A.
      • et al.
      The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China.
      ).
      Figure 1
      Figure 1Overview of mechanisms of Action of Mesenchymal Stromal cells.
      Viable MSCs rescue injured cells by mitochondrial transfer and produce a broad array of immuno-modulatory cytokines. MSCs may be taken up by phagocytic cells – that may prolong and augment their biological effect after intravenous delivery. Risks include generally reduced immune – competence including anti-viral/bacterial/fungal activity, as well as potential pro-tumorigenic effects. Beneficial reduction of pro-inflammatory cytokines, increased Treg and IL-10 production.

      Mesenchymal Stromal (Stem) Cells (MSCs)

      Mesenchymal stromal cells (MSCs) are being widely used in basic research and clinical application (
      • Pittinger
      • et al.
      Mesenchymal stem cell perspective: cell biology to clinical progress: npj regenerative medicine.
      ,
      • Galipeau J.
      • Sensebe L.
      Mesenchymal stromal cells: clinical challenges and therapeutic opportunities.
      ,
      • Yip
      • et al.
      Human umbilical cord-derived mesenchymal stem cells for acute respiratory distress syndrome.
      ). MSCs are non haemopoetic cells which are derived from bone marrow, adipose tissue, lung, umbilical cord tissue, dental pulp, and placenta. MSCs express certain markers such as CD73, CD90 and CD105 and test negative for CD14 (monocytes), CD19 (B-cells), CD34 (stem cells), CD11b (expressed on leukocytes including monocytes, neutrophils, natural killer cells, granulocytes and macrophages).and CD45 expressed on all leucocytes (
      • Ullah I.
      • Subbarao R.B.
      • Rho G.J.
      Human mesenchymal stem cells - current trends and future prospective.
      ,
      • Dominici M.
      • Le Blanc K.
      • Mueller I.
      • Slaper-Cortenbach I.
      • Marini F.
      • Krause D.
      • et al.
      Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement.
      ,
      • Hoogduijn M.J.
      Are mesenchymal stromal cells immune cells?.
      ). They appear to exert anti-inflammatory and immunoregulatory functions, promote the regeneration of damaged tissues and inhibit tissue fibrosis. The immunomodulatory effects of MSCs involve direct and indirect effects on the host immune cells (
      • Le Blanc
      • Mougiakakos D.
      Multipotent mesenchymal stromal cells and the innate immune system.
      ). The use of MSCs have been approved as Advanced Therapy Medical Products (ATMP) and the guidelines from the Food and Drug Administration (FDA) require MSCs to be produced under good manufacturing Practice (GMP) with quality control measures, reproducibility and (
      • Torre M.L.
      • Lucarelli E.
      • Guidi S.
      • et al.
      Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application.
      ,
      • Codinach M.
      • Blanco M.
      • Ortega I.
      • et al.
      Design and validation of a consistent and reproducible manufacture process for the production of clinical-grade bone marrow-derived multipotent mesenchymal stromal cells.
      ). There have been FDA Regenerative Medicine Advanced Therapy (RMAT) designation to 42 products as of 6 May 2020, and 4/42 products are Mesenchymal stromal cells (MCS) (https://ipscell.com/rmat-list). In 2018 the first allogeneic MSC product received marketing approval in the European Union. Since some commercial stem cell clinics are marketing dubious therapies for cardiovascular disease and cancer (
      • Sissung T.M.
      • Figg W.D.
      Stem cell clinics: risk of proliferation.
      ) there are FDA and CDC cautions regarding their use (https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies) (https://www.cdc.gov/hai/outbreaks/stem-cell-products.html).

      Mechanism of action of Mesenchymal Stromal Cells

      Mesenchymal stromal cells interact with most of the cell types of the innate and acquired immune system, including B cells, T cells, dendritic cells (DCs), natural killer (NK) cells, neutrophils, and macrophages, moderating their response to pathogens (
      • deWitte S.F.H.
      • Luk F.
      • Sierra Parraga J.M.
      • Gargesha M.
      • Merino A.
      • Korevaar S.S.
      • et al.
      Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells.
      ,
      • Dominici M.
      • Le Blanc K.
      • Mueller I.
      • Slaper-Cortenbach I.
      • Marini F.
      • Krause D.
      • et al.
      Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement.
      ,
      • Hoogdujin M.J.
      • Lombardo E.
      Mesenchymal stromal cells anno 2019: dawn of the therapeutic era? concise review.
      ; Jiang et al., 2020;
      • Le Blanc
      • Mougiakakos D.
      Multipotent mesenchymal stromal cells and the innate immune system.
      ). MSCs also play a role in the control of tissue inflammation (Jiang et al., 2004). The therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, and some of the effects may be mediated through host phagocytic cells which clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function (
      • Weiss A.R.R.
      • Dahlke M.H.
      Immunomodulation by Mesenchymal Stem Cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs.
      ;
      • Walter J.
      • Ware L.B.
      • Matthay M.A.
      Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis.
      ;
      • Wang M.
      • Yuan Q.
      • Xie L.
      Mesenchymal stem cell-based immunomodulation: properties and clinical application.
      ). In response to inflammatory factors such as Interferon (IFNγ) and Tumour Necrosis Factor (TNFα) secreted by activated immune cells and tissue cells, MSCs can adopt an immunoregulatory phenotype (
      • Ankrum J.A.
      • Ong J.F.
      • Karp J.M.
      Mesenchymal stem cells: immune evasive, not immune privileged.
      ). They increase the expression of anti-inflammatory factors including programmed death ligand 1 and prostaglandin E2 and inhibit immune cell activity and proliferation through metabolic regulation, such as via indolamine 2,3-dioxygenase-dependent catabolism of tryptophan (
      • Weiss A.R.R.
      • Dahlke M.H.
      Immunomodulation by Mesenchymal Stem Cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs.
      ). MSCs also express ATPases and possess ecto-nucleotidase activity through CD73 expression, through which they have the capacity to deplete ATP. The immunomodulatory effects of MSCs may also be triggered further by the activation of TLR receptor in MSCs, which is stimulated by pathogen-associated molecules such as LPS Importantly, MSCs do not have an ACE2 receptor, which makes them immune to SARS-CoV-2.

      Human therapeutic Trials of Mesenchymal stromal cells- safety, efficacy and regulatory approval

      Whilst generally regarded as safe (
      • Editorial
      Safety, efficacy and mechanisms of action of mesenchymal stem cell therapies.
      ), MSCs are not immunologically inert as previously thought (
      • Lohan P.
      • Treacy O.
      • Griffin M.D.
      • Ritter T.
      • Ryan A.E.
      Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning?.
      ,
      • Ankrum J.A.
      • Ong J.F.
      • Karp J.M.
      Mesenchymal stem cells: immune evasive, not immune privileged.
      ). A recent systematic review and meta-analysis of intravascular MSC therapy reviewed 55 randomised controlled trials of MSC therapy compared to controls (
      • Thompson M.
      • Mei S.H.J.
      • Wolfe D.
      • et al.
      Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: an updated systematic review and meta-analysis.
      ), MSCs compared to controls were associated with an increased risk of fever but not non-fever acute infusional toxicity, infection, thrombotic/embolic events or malignancy.
      In ARDS, MSCs have been evaluated in several Phase 1 and Phase 2 trials.
      • Wilson J.G.
      • Liu K.D.
      • Zhuo N.J.
      • Caballero L.
      • McMillan M.
      • Fang X.H.
      • et al.
      Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.
      reported the results of the phase-I Stem cells for ARDS Treatment (START) study. Patients with moderate-to-severe ARDS received a single intravenous administration of allogeneic bone marrow derived MSCs at either a low-dose [10e6 MSCs/kg predicted body weight (PBW)], intermediate-dose (5 × 10e6 MSCs/kg PBW), or high-dose (10e7 MSCs/kg PBW) (n = 3/dose). No adverse events or toxicity was observed at any of the doses tested. High-dose MSCs improved daily SOFA score compared to lower doses. In the Phase 2 START trial, a randomized placebo controlled evaluating a single intravenous infusion of allogeneic bone marrow derived MSCs (107 cells/PBW) compared with placebo (2:1 ratio), with primary outcome of safety and secondary clinical outcomes including all-cause mortality at day 28 and day 60, no adverse respiratory or haemodynamic events were observed (
      • Matthay M.A.
      • Calfee C.S.
      • Zhuo H.
      • et al.
      Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
      ). The ‘MUST-ARDS’ clinical trial (https://clinicaltrials.gov/ct2/show/NCT02611609) tested safety of MultiStem (multi-potent adult progenitor cells, related to MSCs) cells in patients with ARDS. The results have been published in abstract form (
      • Bellingan G.
      • Jacono F.
      • Bennard-Smith J.
      • et al.
      Primary analysis of a phase 1/2 study to assess MultiStem® cell therapy, a regenerative advanced therapy medicinal product (ATMP), in acute respiratory distress syndrome (MUST-ARDS).
      ) and results of 1 year followup are awaited. 30 patients with moderate to severe ARDS were recruited: 20 randomised to MultiStem cell therapy (at a dose of 900 million cells) and 10 to placebo. The therapy was well tolerated, and the authors reported trends to improvement in mortality in the MultiStem treated group, although the study was not powered for mortality.
      Additionally Phase 1 studies of MSCs in ARDS have been conducted by investigators in China and Taiwan.
      • Zheng
      • et al.
      Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study.
      investigated allogeneic adipose derived MSCs in a randomized, placebo-controlled study (total recruitment n = 12, randomized 1:1). No serious adverse events related to MSC administration were reported. Yip et al. investigated UC derived MSCs in a dose escalation study (1, 5 and 10 × 106 cells/kg) recruiting a total of 9 patients (3 patients per dose cohort). MSC infusion was associated with mild adverse reactions in 3 patients however no serious treatment related adverse events were identified.

      The use of MSCs for treatment of COVID-19 patients

      MSCs are now being used as a potential therapy for treating COVID-19 patients in order to reduce mortality. Although the use of MSCs has been found to be safe when used for treatment of other diseases, it is important to evaluate whether they are safe to use specifically in COVID-19 patients. There have been reports of early Phase studies in COVID-19 patients from China (NCT04252118 and NCT04288102).
      • Leng Zikuan
      • Rongjia Zhu
      • Wei Hou
      • et al.
      Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia [J].
      investigated the use of MSCs in hospitalized patients with COVID 19 who were not improving despite standard therapy. Seven patients were administered intravenous MSCs at a dose of 1 × 106 cells per kg. MSC infusion was well tolerated in all patients with no acute infusion related reactions. A study published in Aging and Disease claimed the effectiveness of MSCs therapy was safe and attributed the recovery of all 7 patients who were administered MSCs. This was led by researchers from Shanghai University and Peking Union Medical College (PUMC) and Chinese Academy of Medical Sciences (CAMS). Seven COVID-19 patients aged between 45 to 65 (four severe cases, one critically severe case) received with allogenic MSC therapy and three were in the control group. Since the study had several limitations, no conclusions on efficacy can be drawn. It was a small study with 7 patients with no blinding or randomization, and the control group of 3 patients was selected after all MSC patients were treated. The Chinese Medical Association has issued guidelines to standardize stem cell treatment for COVID-19. On April 5, 2020, the US-FDA approved MSC treatment for use in seriously ill COVID-19 patients under what is known as ‘expanded access compassionate use’.

      Ongoing trials of Mesenchymal stromal (stem) Cell Therapies for COVID-19

      The excessive host response seen in patients with COVID-19 appears to have induced a paradigm shift in longstanding focus of drug treatment interventions targeting the pathogen (SARS-CoV-2 in this case) to targeting the host response. Currently, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs and their products for treatment or prevention of COVID-19.
      Table 1 lists clinical trials of MSCs or their products which have been registered on clinicaltrials.gov. Not all of the registered trials will be pursued and in recent weeks, five trials registered on the Chinese Clinical Trial Register (“ChiCTR”) and one trial registered on ClinicalTrials.gov have been marked as “Cancelled by the Investigator”.
      Table 1Mesenchymal stromal (Stem) cell trials registered on ClinicalTrials.Gov related to treatment of COVID-19 Disease – Trial number, source of MSCs, Dose, route of administration and Primary endpoints.
      Trial ID NoResponsible institutionPatient populationSource of MSCsDose of MSCsRoute of administration Number of treatmentsPrimary endpoint(s)
      NCT04315987Azidus BrasilCOVID 19 pneumoniaNestCell ®2 × 107 cells/doseIV

      3/4 (days 1, 3, 5; day 7 optional)
      Change in clinical condition (WHO ordinal scale) (day 10)
      NCT04288102Beijing 302 HospitalCOVID 19 pneumoniaHuman MSCs4 × 107 cells/doseIV

      3 (days 0, 3 and 6)
      Size of lesion area and severity of pulmonary fibrosis by chest CT (day 6, 10, 14, 28 and 90)
      NCT04313322Stem Cells ArabiaCOVID 19Wharton's Jelly-MSCs1 × 106 cells/kg/doseIV

      3 (3 days apart from each other)
      Clinical Outcome

      CT Scan changes

      RT-PCR results

      (All at 3 weeks)
      NCT04336254Renmin Hospital of Wuhan UniversityCOVID 19 pneumoniaAllogeneic Human Dental Pulp MSCs3 × 107 cells/doseIV

      3 (days 1, 4 and 7)
      Time to Clinical Improvement (day 1 to 28)
      NCT04302519CAR-T (Shanghai) Biotechnology Co., Ltd.COVID 19 pneumoniaDental Pulp MSCs1 × 106 cells/kg/doseIV

      3 (days 1, 3 and 7)
      Disappearance time of ground-glass shadow in the lungs (day 14)
      NCT04339660Puren Hospital Affiliated to Wuhan University of Science and TechnologyCOVID 19 pneumoniaUmbilical cord derived MSCs1 × 106 cells/kg/doseIV

      1/2 (Second infusion after 1 week optional)
      Immune function (TNF-α, IL-1β, IL-6, TGF-β, IL-8, PCT, CRP) (within 4 weeks)

      Blood oxygen saturation (within 4 weeks)
      NCT04252118Beijing 302 HospitalCOVID 19 pneumoniaHuman MSCs3 × 107 cells/doseIV

      3 (Days 0, 3 and 6).
      Size of lesion area by chest radiograph or CT (day 3, 6, 10, 14, 21 and 28)

      Side effects in the MSCs treatment group (indicated by treatment related adverse events) (day 3, 6, 10, 14, 21, 28, 90 and 180)
      NCT04333368

      STROMA-CoV2
      Assistance Publique - Hôpitaux de ParisCOVID 19 -ARDSUmbilical Cord-Wharton's Jelly derived MSCs1 × 106 cells/kg/doseIV

      3 (Days 1, 3 and 5)
      PaO2/FiO2 ratio (baseline to day 7)
      NCT04273646Wuhan Union Hospital, ChinaCOVID 19 pneumoniaUmbilical Cord-derived MSCs0.5 × 106 cells/kg/doseIV

      4 (Days 1, 3, 5 and 7)
      Pneumonia severity index (baseline to week 12)

      Oxygenation index (PaO2/FiO2) (baseline to week 12)
      NCT04341610

      ASC COVID-19
      Rigshospitalet, DenmarkCOVID 19 pneumoniaAdipose derived MSCs100 × 106 cells/doseIV

      1
      Changes in clinical critical treatment index (at day 7)
      NCT04269525Zhongnan HospitalCOVID 19 pneumonia in ICUUmbilical Cord-derived MSCs9.9 × 107 cells/doseIV

      4 (days 1, 3, 5 and 7)
      Oxygenation index (PaO2/FIO2) (day 14)
      NCT04299152Tianhe Stem Cell Biotechnologies Inc.Symptomatic COVID 19 patients‘Educated’ autologous immune cellsSCE therapy circulates a patient's blood through a blood cell separator, briefly cocultures the patient's immune cells with adherent cord-blood stem cells (CB-SC) in vitro, and returns the "educated" autologous immune cells to the patient's circulation.Determine the number of Covid-19 patients who were unable to complete SCE Therapy
      NCT04276987Ruijin HospitalCOVID 19 pneumoniaExosomes Derived from Allogenic Adipose MSCs2 × 108 nano vesicles/3 mLInhalational

      5 (days 1, 2, 3, 4 and 5)
      Adverse reaction and severe adverse reaction (day 28)

      Time to clinical improvement (day 28)
      NCT03042143

      COVID 19 REALIST
      Belfast Health and Social Care TrustCOVID 19 - ARDSREALIST Orbcel-C Human umbilical cord derived CD362 enriched MSCs400 × 106 cells/doseIV

      1
      Oxygenation index at day 7

      (defined as (Mean Airway Pressure*FiO2*100)/PaO2)

      Incidence of Serious Adverse Events (day 28)
      NCT04345601Baylor College of MedicineCOVID 19 ARDSBone marrow derived MSCs1 × 108 cells/doseIV

      1
      Incidence of unexpected adverse events (day 28)

      Improved oxygen saturations ≥93% (day 7)
      NCT04362189Hope BiosciencesHospitalised COVID 19Allogeneic Adipose derived MSCs100 × 106/doseIV

      Day 0, 3, 7, and 10.
      Mortality rate (day 28)

      Need for Invasive mechanical ventilation (day 0, 3, 7, 10 and 28)
      NCT04371393Icahn School of Medicine at Mount SinaiCOVID 19 ARDSMesoblast

      Remestemcel-L

      Bone marrow derived MSCs
      2 × 106 cells/kg/doseIV

      2 (day 1 and 4 days following first infusion ± 1 day)
      All-cause mortality (day 30)
      NCT04371601Fuzhou General HospitalCOVID 19 pneumoniaUmbilical cord derived MSCs10 × 106 cells/kg/doseIV

      4 (once every 4 days)
      Oxygenation index (PaO2/FiO2) (12 months)
      NCT04377334University Hospital TuebingenCOVID 19 ARDSAllogeneic bone marrow derived MSCsNot specifiedNot specifiedLung injury score (day 10)
      NCT04355728University of MiamiCOVID 19 ARDSUmbilical cord derived MSCs100 × 106 cells/doseIV

      2 (day 1 and 3)
      Incidence of pre-specified infusion associated adverse events (day 5)

      Incidence of Severe Adverse Events (day 90)
      NCT04349631Hope BiosciencesRisk of occupational exposure COVID 19 No signs or symptoms of COVID 19Autologous Adipose derived MSCsNot specifiedIV

      5 (time points not specified)
      Incidence of hospitalization for COVID-19 (week 26)

      Incidence of symptoms for COVID-19 (week 26)
      NCT04348435Hope BiosciencesRisk of occupational exposure COVID 19 No signs or symptoms of COVID 19Allogeneic Adipose derived MSCs50, 100 or 200 × 106 cells/doseIV

      5 (0, 2, 6, 10 and 14 weeks)
      Incidence of hospitalization for COVID-19 (week 26)

      Incidence of symptoms associated with COVID-19 (week 26)
      NCT04366063Royan InstituteCOVID 19 ARDSMSCs (source not specified)

      MSC derived extracellular vesicles
      MSCs – 100 × 106 cells/dose

      EVs – dose not specified
      IV

      2 (days 0 and 2)

      ± 2 EV infusions (on day 4 and 6)
      Adverse events assessment (day 28)

      Blood oxygen saturation (day 14)
      NCT04346368Guangzhou Institute of Respiratory DiseaseCOVID 19 pneumoniaBone marrow derived MSCs1 × 106 cells/kg/doseIV

      1
      Oxygenation index (PaO2/FiO2) (baseline, 6 h, Day 1 and 3, Week 1, 2, 4 and 6 months)

      Side effects (treatment related adverse events) (6 months)
      NCT04348461Instituto de Investigación Sanitaria de la Fundación Jiménez DíazCOVID 19 ARDSAllogeneic Adipose derived MSCs1.5 × 106 cells/kg/doseIV

      2
      Survival rate (day 28)

      Adverse event rate (day 28)
      NCT04366271

      MESCEl-COVID19
      Hospital Infantil Universitario Niño Jesús, Madrid, SpainCOVID 19 pneumoniaUmbilical cord derived MSCsNot specifiedIV

      1
      Mortality rate (day 28)
      NCT04361942Red de Terapia CelularCOVID 19 pneumonia in ICUAllogeneic MSCs (source not specified)1 × 106/kg/doseIV

      1
      Proportion of patients who have achieved withdrawal of invasive mechanical ventilation (day 7)

      Mortality rate (day 28)
      NCT04366323Andalusian Network for Design and Translation of Advanced TherapiesCOVID 19 pneumoniaAllogeneic Adipose derived MSCs80 × 106 cells/doseIV

      2
      Adverse Event Rate (12 months)

      Survival Rate (day 28)
      NCT04352803Regeneris MedicalHospitalized COVID 19Autologous Adipose derived MSCs0.5 × 106 cells/kg/doseIV

      1
      Incidence of unexpected adverse events (day 28)

      Progression to mechanical ventilation (day 28)

      Length of mechanical ventilation (day 28)

      Length of weaning of mechanical ventilation (day 28)

      Length of hospital stay (day 28)

      Mortality rate (day 28)
      The registered trials are different in design, have different sources of MSCs, different dose administration schedules, selection of patients and primary outcomes highlighting the need for standardizing protocols through a global consortium network. There is an urgent need for reaching global consensus on advancing Mesenchymal Stromal Cell and Cellular therapies for COVID-19 and other infectious diseases.

      Advancing MSC therapeutics and achieving global consensus and visibility for cellular host-directed therapies

      Table 2 highlights the priority needs for advancing Mesenchymal Stromal Cell and Cellular therapies for COVID-19 and other infectious diseases. We have created an international consortium between clinical cancer and infectious disease research investigators (Website: https://www.fchampalimaud.org/covid19/aci) is open to any interested parties to join us to help define optimal MSC therapy regimens and change the course of COVID-19 and sustain the growing portfolio of cellular therapies for a range of acute and chronic infectious diseases.
      Table 2Priority needs for advancing Mesenchymal Stromal Cell and Cellular therapies for COVID-19 and other infectious diseases.
      • 1
        Taking forward the Global Network for Cellular and other Host-Directed Therapies: Advancing an international multidisciplinary, multi-continental consortium between clinical infectious disease and cancer research investigators with interested stakeholders for proactively defining the landscape, priorities for R&D, developing common protocols, and having regular ‘out of the box’ thinking exchanges'. (Website: https://fchampalimaud.org/covid19/aci). This consortium network is open to any interested party to join and help take forward the growing portfolio of cellular therapies for improving treatment outcomes for a range of acute and chronic infectious diseases. Current focus of the consortium is on HDTs for COVID-19.
      • 2
        Opportunities for conduct of common scientific studies and defining unanswered questions regarding MSC therapy:
      • 2
        Omics approach: RNAseq data/Proteomics shared or centrally conducted from MSCs products for better definition of: cellular products; differences in gene expression/proteomics in freshly prepared versus cryopreserved and subsequently thawed MSCs; microRNAs in MSCs; Investigator – initiated studies and commercial products; use different tissue origins and culture methods that may lead to different MSC phenotypes and gene expression patterns; difference of ‘edited’, e.g. cytokine-edited MSCs
      • 3
        Host responses: RNAseq expression pattern, immuno-phenotyping and functional T-cells assays gauging immuno-competence (e.g. anti-CMV responses) in longitudinally sampled blood prior and after MSC infusion to gauge for systemic MSC effects
      • 4
        Measuring CMV DNA in patients prior to MSC delivery and in the clinical followup after MSC infusion. Gauges immune-competence using CMV control as a biological readout.
      • 5
        Tagging or barcoding MSCs. Better understanding of MSC-MoA, e.g. phagocytosis of MSCs by macrophages and systemic effects.
      • 6
        Differences in Dendritic Cells and Macrophage responses in vitro and ex vivo using viable MSC or MSC-derived products (e.g. exosomes, apoptotic bodies). Gauging the most suitable and safest MSC profile for COVID-19 treatment.
      • 3
        Better definition of MSC delivery and dosing
        • a
          Smart clinical studies to address different modes of MSC delivery, e.g. single or repeated doses, escalating dosing? Improved clinical efficacy by repeated infusions? Role of identical MSC donor in repeated dosing? Increased efficacy and safety if MSCs are used from different donors in the case of repeated infusions?
        • b
          *Conditioning' patients prior to MSCs delivery. Can MSC-associated effects be improved by using repurposed drugs or biologicals that would augment the desired MSCs effects, e.g. decreasing damaging inflammation, while preserving pathogen directed immune responses?
      • 4
        Better definition of selection of patients receiving MSCs
      • 5
        Concise study design considering COVID pathophysiology. Which patients benefit most from MSC treatment? Concise clinical documentation needed concerning patients with COVID-19 that allows comparison of trials. Differences associated with MSC products (viable, MSC – apoptotic bodies, exosomes), (COVID-19), disease status or the patients ‘inflammatory phenotype’ (e.g. high IL-6 or IL-17 levels)? Role of lymphopenia in response to MSCs? Smarter patient selection associated with pathophysiology may aid to offer improved treatment modalities.
      • 5
        Attracting pharma and funder attention: Convincing donors that cellular therapies are viable options for the adjunct treatment of patients with COVID-19 and other lethal infectious diseases
      • 7
        Adverse events monitoring and analysis: short term and long-term folllowup of patients, e.g. short term analysis of general immuno-competence (e.g. anti-CMV and anti-SARS-CoV-2 humoral and cellular responses, long term observation concerning infectious complications, increased premalignant or malignant diseases?
      • 8
        Creation of Biobanks and Access to biological material from patients with COVID-19 infection: Creating repository of samples obtained during MSC trials e.g. blood samples (or BAL) for unbiased gene expression analysis, proteomics and molecular analysis of T-cell responses, e.g. defined by deep TCR sequencing to gauge for MSC effects, different reactivity and biology of neutrophils, macrophages and dendritic cells from patients with COVID-19 as compared to non-Covid-19 patients? Synoptic view with other, complementary assays gauging pulmonary recovery, immuno-competence and capacity to mount long-term anti-SARS-CoV immune responses.
      • 9
        Advancing HDT trial activities to application of MSCs or MSC-associated products with identical biological readouts, for other infectious diseases where the host response underlies end organ damage causing death or long term functional disability. e.g. MERS, MDR-TB.

      Conclusions

      Despite intense research and pharma activity on developing effective antiviral drug and biologics treatments for the two previous novel lethal coronavirus infections of humans, SARS-CoV-1 and MERS-CoV, all efforts have been fruitless. Novel treatments which can save lives and prevent long-term functional disability in those who survive are urgently required. The COVID-19 pandemic has provided an opportunity for a paradigm shift in focus from targeting the pathogen to the tackling host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2. The increasing interest in therapeutic use of MSCs is a promising sign that COVID-19 pandemic and the year 2020 may be the dawn of the new therapeutic era of MSCs treatment for lethal infectious and inflammatory diseases. MSCs should also be advanced and trialed for treatment of severe cases of MERS, where mortality rates are up to 34% since MERS-CoV remains a WHO priority Blueprint pathogen (
      • Memish Z.A.
      • Perlman S.
      • Van Kerkhove M.D.
      • Zumla A.
      Middle East respiratory syndrome.
      ,
      • Zumla A.
      • Azhar E.I.
      • Arabi Y.
      • et al.
      Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections.
      ,
      • Azhar E.I.
      • Lanini S.
      • Ippolito G.
      • Zumla A.
      The Middle East respiratory syndrome coronavirus - a continuing risk to global health security.
      ). It’s about time funding agencies now invested more into accelerate trailing of MSC per se, and combinations of MSCs with other therapeutics. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 and MERS death rates.

      Author declarations

      All authors have a special interest in Host-Directed Therapies and are members of an International consortium involved in MSC trials for COVID-19, other infectious diseases and cancer.
      Professor Fu-Sheng Wang and Professor Danny McAuley are PIs of clinical trials of MSCs in Covid-19 patients.
      All authors are members of the Global Cancer and Infectious Diseases consortium for Host-directed therapies: Weblink: https://www.fchampalimaud.org/covid19/aci/.

      Acknowledgements

      Sir Zumla and Prof Ippolito are members of the Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET – https://www.pandora-id.net/) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme for Research and Innovation. Sir Zumla is in receipt of a National Institutes of Health Research senior investigator award. Professor Ippolito and Dr Vairo are supported by the Italian Ministry of Health (Ricerca Corrente Linea 1). Prof Maeurer is funded by the Champalimaud Foundation and member of the innate immunity advisory group of the Bill and Melinda Gates Foundation. We are indebted to Dr. Joana Lerias, Fundacao Champalimaud for creating and updating the clinical trial information for MSCs.

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