A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019.

BACKGROUND AIMS: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. METHODS: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart. RESULTS: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. CONCLUSIONS: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.

GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis.

BACKGROUND: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD). OBJECTIVE: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD. METHODS: Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71. RESULTS: GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001). CONCLUSIONS: Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.