proof of concept study
Background
Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients.
Methods
Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters.
Findings
First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement.
Interpretation
Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects
The severity of the COVID-19 pandemic and the lack of effective proven therapies represents a formidable challenge and have stimulated multiple research groups on an urgent search for potentially useful therapeutic options. Multiple clinical trials are currently underway with a wide range of drugs (in the https://clinicaltrials.gov/hclinicaltrials.gov website accessed on May 1st are registered up to 600 clinical trials, almost half of which are already under recruitment). Furthermore, due to the therapeutic urgency many treatments are being used off-label through compassionate use programs.Here, we report the first series of COVID-19 patients requiring mechanical ventilation treated with AT-MSC, generating preliminary evidence of the absence of significant adverse events along with improvement in most of these patients. These results warrant conducting a multicenter randomized controlled trial already underway.
The outcome of COVID-19 patients admitted to the ICU is poor. In a recent series of 1581 Italian patients with COVID-19 ARDS admitted to ICU (88% requiring mechanical ventilation), with a median follow up of 9 days, 26% have died and only 16% had been discharged. In another series of patients with longer median follow-up (19 days), one third of them (31%) have been discharged from ICU and 23% have died. In our series, with a median follow-up of 16 days, mortality rate was 15%, while seven patients (53%) had been extubated and discharged from ICU and two additional patients were improving.
One of the most relevant findings of our work is the lack of adverse events associated with cell administration in these extremely critical patients with respiratory insufficiency, massive inflammation and prothrombotic risk. Safety of MSC treatments administered intravenously has been well demonstrated in multiple clinical trials for different conditions (e.g. Crohn's disease, graft-versus-host disease, etc.) as reported in two meta-analyses including almost 3000 patients. Pre-clinical evidence of the potential for MSCs in viral lung infections is still scarce and, in some cases, controversial. It is true that there are no preclinical studies in animal models of SARS-CoV-2 infection and that most preclinical evidence comes from influenza virus infection models, where the pathophysiology and systemic manifestations are different. Nevertheless, although results of these studies are not uniformly positive, no adverse events related to cell therapy in this setting has been reported. Stromal cells have been employed at the clinical level in other instances of severe pulmonary disease induced by viral infection. In this regard, menstrual-blood derived MSCs were administered in 17 Chinese patients H7N9-induced ARDS patients during the 2013–2014 outbreak, again with no associated toxicity and a better survival compared to a control group of 44 patients (82.4% versus 45.4%). However, cases of secondary concomitant or subsequent bacterial or fungal infection after cell administration merit further comment. Although in patients with COVID-19 under mechanical ventilation the risk of bacterial or fungal secondary infection has been described to be around 8% and its diagnosis is challenging theoretically an anti-inflammatory or immunomodulatory treatment such as MSC can potentially increase this risk and should be monitored and strictly assessed and followed in subsequent clinical trials.
The association between AT-MSC and a decrease in inflammatory parameters also support the hypothesis that cell administration may contribute to generate an inflammatory and immunomodulatory microenvironment. This fact is of particular relevance, since almost all the patients included in our series had received steroids as well as tocilizumab (some also with anakinra and/or siltuximab), without clinical response. Unlike monoclonal antibodies that act only by blocking the effect of a single interleukin (e.g. tocilizumab for IL-6 or anakinra for IL-1) AT-MSCs could act in the inflammatory microenvironment of endothelial and alveolar damage by interacting with various targets, releasing anti-inflammatory and anti-apoptotic molecules in a paracrine fashion, and modulating the action of the hyper-activated immune system, including macrophages, neutrophils and other cell types, and improving endothelial function.
Patients with COVID-19 pneumonia have been described to suffer from a pro-coagulant status and high levels of d-dimer have been associated to poor prognosis. Remarkably, we observed a reduction of d-dimer 5 days after the first AT-MSC dose in most patients, and none of the patients developed a thromboembolic event, although mesenchymal cells preferentially home to the pulmonary circulation after endovenous administration. Because of these pro-coagulant status patients with COVID-19 are routinely treated with low-molecular weight heparin. It is possible that receiving prophylactic anticoagulant therapy may have contributed to decrease the potential prothrombotic risk that might have been induced by MSCs, but due to the sample size this should be further evaluated in subsequent studies before making a definite recommendation for concomitant administration of low weight heparin in patients with COVID-19 receiving AT-MSC.
Finally, although the sample size does not allow definitive conclusions, our results suggest that treatment with AT-MSC early after mechanical intubation might improve the outcome. This is also a potentially useful fact to take into account for the design of randomized clinical trials such as our BALMYS-19 trial. In addition, we have not found differences in patients treated with thawed versus fresh cells due to the limited number of patients included. This issue, that has been widely debated in the MSC field should be also clarified in future trials.
Additional limitations of our study, besides the sample size, are related to the type of study (non-randomized case series) and to the variability inherent in the previous treatments, the different time of cell administration and the non-uniformity in the number of doses. The favorable response in many patients cannot be exclusively attributed to the effect of the cells, since other concomitant treatments were administered a few days before the cell administration and in a varied pattern. This proof-of-concept study, which constitutes the first case series of intubated COVID-19 patients treated with AT-MSC, has been used to design a randomized phase II clinical trial with a control arm that will provide better knowledge of the real scope of the potential of this therapeutic approach in this clinical setting.
In summary, our preliminary results, indicate that MSC derived from adipose tissue can be safely administered in critically ill patients with COVID-19 pneumonia and that administration of AT-MSC was followed by clinical improvement and changes in inflammatory and immune populations, which suggest a potential biological effect of the cells. These results have served as an initial proof of concept (especially taking into account the health emergency we are experiencing) for the design of a randomized, controlled phase 2 clinical trial of treatment with AT-MSCs in patients with COVID-19 requiring mechanical ventilation (BALMYS-19-“BAttLe against CO using MesenchYmal Stromal cells”-; EudraCT: 2020-001266-11; clinicaltrials.gov identifier NCT04348461). Our trial, as other potential randomized trials with a control arm consisting of standard treatment, will contribute to understanding the real potential of this cell-based therapeutic strategy
Reference & Source information: https://www.thelancet.com/
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