Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial

Abstract

Background: Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. Methods: REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 £ 10 6 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. Findings: Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 £ 10 6 ), three patients had died in cohort two (200 £ 10 6 ) and one patient had died in cohort three (400 £ 10 6 ). Overall day 28 mortality was 44% (n = 4/9). Interpretation: A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 £ 10 6 cells.

Clinical efficacy and mechanism of mesenchymal stromal cells in treatment of COVID-19

“…Several studies [ 23 – 27 ] have shown that MSCs can be safely infused intravenously or via the endobronchial route in humans, thus allowing MSCs to accumulate in the lungs to improve the lung microenvironment, protect alveolar epithelial cells, protect against pulmonary fibrosis, and improve lung function [ 28 – 30 ]. Although the specific molecular mechanisms underlying the effects of MSCs on COVID-19 treatment require further research, several studies have investigated possible processes, as summarized below.…”

Mesenchymal stem cell treatment for COVID-19

“…The safety of MSC treatment for patients with ARDS has been demonstrated in the studies listed in Table 1 . 71 , 72 , 73 , 74 , 75 , 76 In addition, MSCs simultaneously promote the restoration of pathological lung tissues. 77 Therefore, MSC therapy is considered an alternative option for patients with severe COVID-19.…”

“…Adverse events included apyrexia, non-sustained ventricular tachycardia, and deranged liver function. 76 MSCs, mesenchymal stem cells; AD-MSCs, adipose-derived MSCs; BM-MSCs, bone marrow autologous MSCs; UC-MSCs, umbilical cord-derived MSCs; IV, intravenous injection. …”

Current Status and Future Perspectives on Machine Perfusion: A Treatment Platform to Restore and Regenerate Injured Lungs Using Cell and Cytokine Adsorption Therapy

“…The meta-analysis found no correlation with acute infusional toxicity, organ complications, infection, death or malignancy, which led to the determination that MSC therapy was safe with the caveat of a need for larger scaled trials. In the phase 1 REALIST trial from 2021, a specific population of CD-362-enriched MSCs were again found to be well tolerated in moderate to severe ARDS, with doses of up to 400 × 10 6 cells per patient [ 24 ].…”

“…Others have refuted this point, pointing to increased proliferation with multilayering in cultures of umbilical cord-derived MSCs which does not occur in bone marrow-derived cells due to contact inhibition [ 37 , 38 ]. The implication of this would be the potential for malignant development, yet clinical trials have failed to replicate tumorigenic capacity [ 22 , 23 , 24 ].…”