Page 65 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 11 of 19

those in the placebo group at baseline, but mortality did many similarities with COVID-19. Chen and colleagues
not dif er signif cantly between groups. No patient expe- conducted an open-label clinical trial in 61 patients
rienced any BM-MSC-related hemodynamic or respira- infected with the H7N9 virus. All patients had moderate
tory adverse events. T e authors concluded that a single to severe ARDS. Seventeen patients consented to receive
dose of intravenous BM-MSCs was safe in patients with intravenous infusions of allogeneic menstrual blood
moderate to severe ARDS and larger trials were needed MSCs after failure to improve with standard treatment
to assess ef cacy. and, in some cases, invasive ventilation and extracor-
In a recent press release [238], Athersys announced poreal membrane oxygenation (ECMO). Patients were
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positive results of a randomized, placebo-controlled, infused with 1x10 MSCs/kg bw, three to four times.
Phase 2a study which aimed to test the safety and possi- No adverse MSC infusion-related events were noted
ble ef cacy of the adult BM-MSC investigational product in any of the patients. T e clinical outcomes were com-
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MultiStem in patients with ARDS. Within the prospec- pared with 44 patients matched with similar symptoms,
tively def ned group of patients with more severe ARDS, laboratory tests and other baseline characteristics. T ere
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MultiStem treatment was associated with a mark- was no signif cant dif erence in baseline data between
edly greater rate of survival and progression to func- the groups, except that the MSC treatment group had a
tional independence at 1 year. As measured at day-28, higher incidence of severe circulatory disturbances prior
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MultiStem treatment was associated with a higher mean to treatment. T e MSC treated group demonstrated a
ventilator-free day (VFD) score of 12.9 vs. 9.2 in the pla- signif cantly higher survival rate (82.4%) compared to the
cebo group, and a higher mean intensive care unit (ICU)- control group (45.5%). At discharge, signif cantly better
free day score of 10.3 vs. 8.1 in the placebo group. As laboratory test results (procalcitonin, creatinine, creatine
measured at day 28, among more severe ARDS patients, kinase, prothrombin time and D-dimer) were noted in
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mean VFD in the MultiStem subgroup was 14.6 vs. 8.0 the MSC infusion group. At the 1 year followup, chest
in placebo subgroup. Mean ICU-free days were 11.4 vs. CT scans of the patients showed signif cant improvement
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5.9 for MultiStem and placebo recipients, respectively. in the MSC treatment group. At f ve-year follow-up, all
Quality of Life outcomes, assessed by the EQ-5D, were tested survivors from the treatment group did not show
meaningfully better among all survivors who received any adverse ef ects of MSC treatment or decline in pul-
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MultiStem treatment compared to those who received monary function tests. T ese promising results support
placebo. Lower inf ammatory cytokine levels at day 7 the belief that MSCs reduce the inf ammatory ef ects
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in the MultiStem group relative to the placebo group, associated with viral infection, induced cytokine storm
including IFN-γ, IL-6 and IL-1b among others, sug- and severe respiratory distress. Future placebo-con-
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gest the potential for MultiStem treatment to abate the trolled, randomized clinical trials using a greater num-
severe inf ammatory response associated with ARDS. ber of patients are desperately needed to validate these
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MultiStem treatment was well tolerated in this very sick encouraging f ndings.
ARDS patient population, with no serious adverse events
related to administration through 1 year of follow-up. Human clinical trials of MSC therapy in COVID‑19
Multiple human clinical studies have reported that Despite the fact that COVID-19 was f rst reported only
MSC administration is safe in patients with severe pul- recently, several clinical studies on MSC therapy have
monary diseases, with little or no infusion reactions and been published. Liu and colleagues retrospectively ana-
only a few late adverse ef ects. However, due to the rela- lyzed the dif erences between 109 COVID-19 patients
tively small number of patients that have received MSC with and without ARDS. Patients had a mean of age
therapy thus far, further investigations are required to 55 years old with a median follow-up of 15 days. T e
determine safety and ef cacy. T e optimal cell origin, cell overall survival rate was 71.6%. Of all the patients, 48.6%
preparation, cell dose, route of administration and dosing developed ARDS. Compared to non-ARDS patients,
frequency have yet to be determined. ARDS patients were older and more likely to have coex-
istent morbidities. No signif cant ef ect on survival was
Human clinical trials of MSC therapy in infectious lung observed in these patients despite the use of antivirus,
diseases glucocorticoid, or immunoglobulin treatments [239].
Recently published evidence by Chen et al., demonstrated Liang and colleagues [240] reported the treatment of
promising safety and ef cacy data when MSCs were used a critically ill 65-year-old female infected with SARS-
to treat ARDS associated with Inf uenza A (H7N9) infec- CoV-2. On January 27, 2020 the patient presented with
tion [1]. During the spring of 2013, a novel avian-origin fatigue, fever and cough. T e following day she devel-
Inf uenza A (H7N9) virus emerged and spread among oped chest tightness, hypoxia and hypertension and
humans in China. T e disease caused by this virus shares tested positive for 2019 novel coronavirus. Radiographs