Cell Therapy News/Articles, page-12015

It was nice to see Remestemcel-L get a couple of mentions:

2. The Progress in the Clinical Translation of MSCs for Inflammatory Lung Disease

While earlier studies have not provided clear evidence of efficacy in phase 1/2 randomised controlled trials of MSCs in COPD [17] and ARDS [19,20] there are some reports of positive effects. A phase 2 trial enrolling 62 randomised patients with COPD, deemed the systemic administration of BM-MSC safe, although there were no differences in pulmonary function testing or with the 6-min walking test. However, a decrease in C-reactive protein was observed in comparison to elevated C-reactive protein (CRP) levels upon study entry (NCT00683722) [17]. In the context of the growing body of research suggesting the importance of the inflammatory lung profile of patients and its role in activating or licensing MSCs, a post-hoc analysis of the trial data was performed with stratification of COPD patients based on baseline levels of circulating inflammatory marker CRP. Interestingly, the data demonstrated that Remestemcel-L (BM-MSC) provided significant improvements in forced expiratory volume in one second, forced vital capacity and six-minute walk distance at 120 days post-infusion in patients with a higher baseline CRP [18]. In the context of ARDS, the findings from MSC clinical trials have not been clear-cut with respect to efficacy but studies have had favourable outcomes. Many of the current clinical trials investigating MSCs in lung inflammatory conditions are in COVID-19 ARDS and there is now a growing body of literature supportive of MSC efficacy in both non COVID-19 ARDS and in COVID-19 ARDS. A double-blinded randomised phase 2a safety trial investigating the use of allogeneic bone marrow derived-MSCs (BM-MSC) in severe ARDS patients showed there was no infusion-related haemodynamic or respiratory adverse events, proving their safety, although, the data could not support a claim for MSC efficacy in this trial and that may have been associated with reduced viability of the cell therapy product (NCT02097641). However, patients infused with BM-MSCs (with higher viability post-thaw) had lower concentrations of angiopoietin 2 (Ang-2) in their plasma after 6 h [19]. Interestingly, a nested cohort study within a phase 2a trial investigating BM-MSCs for moderate-to-severe ARDS, demonstrated that MSC treatment significantly reduced airspace total protein, Ang-2, IL-6 and soluble tumour necrosis factor (TNF) receptor-1 concentrations within a 48 h window following administration (NCT02097641) [33]. In addition, a phase 1 study of UC-MSCs in moderate-to-severe ARDS showed safety and reduction of circulating inflammatory biomarkers (ISRCTN52319075) [34].

Positive findings from the completed Athersys MUST-ARDS phase 1/2 randomised, double blind, placebo-controlled exploratory clinical study of MultiStem^® (BM derived human MSC-like cells) therapy in ARDS have been reported in a published conference abstract [35]. Interestingly, MultiStem® therapy enhanced ventilator-free days and ICU-free days and reduced mortality [35]. Ricordi and colleagues have also published the findings from their double-blind randomised control phase 1/2a trial of UC-MSCs in COVID-19 ARDS reporting significantly improved patient survival and significant decreases in pro-inflammatory cytokines in UC-MSC treated subjects at day 6 (NCT04355728) [21]. Similarly, a randomised controlled clinical trial investigating UC-MSCs reported improved survival rate, reduced length of stay and ventilator use as well as a decrease in IL-6 in patients who received UC-MSCs in COVID-19 ARDS (NCT04457609) [36]. Moreover, Mesoblast have reported positive initial findings from their phase 3 randomised, double-blind, placebo-controlled trial investigating Remestemcel-L in COVID-19 ARDS at international conferences (NCT04371393) [37]. Importantly, the work from Calfee and colleagues and others supports the idea of identifying phenotypes of ARDS [38,39] or treatable traits [40] and using that information to facilitate a personalised medicine approach. Together these studies suggest that patient stratification to identify disease phenotypes that might best respond to MSC therapy may increase the chance for MSC therapeutic efficacy.