Cell therapy for Acute Respiratory Distress Syndrome and COVID-19

Abstract

Acute Respiratory Distress Syndrome (ARDS) is characterised by acute hypoxaemic respiratory failure and bilateral infiltrates on chest imaging resulting from immune mediated destruction of the alveolar epithelial-endothelial barrier. Mesenchymal stromal cells (MSCs) are a potential therapeutic strategy due to their pleiotropic immunomodulatory, reparative and antimicrobial effects.

The aim of this thesis was to explore the role of MSCs in ARDS and COVID-19. Written under the ‘Thesis with Publications’ submission style, it includes reviews of ARDS and MSC therapy, and publications relating to the REALIST (Repair of ARDS with Stromal Cell Administration) trial.

REALIST investigated a novel MSC product (ORBCEL-CTM , a population of CD362 enriched allogeneic umbilical cord derived MSCs) in patients with moderate to severe ARDS defined by the Berlin criteria. Phase 1 investigated a single intravenous infusion of ORBCEL-CTM MSCs in a 3+3 open-label dose-escalation study (3 dose cohorts of 3 patients with ARDS receiving either 100, 200 or 400 million cells), establishing that 400 million cells was a safe dose for a phase 2 trial. Phase 2 recruited a cohort of patients with ARDS due to COVID-19. In this sixty-patient, randomised, triple blind placebo-controlled clinical trial a single intravenous infusion of 400 million ORBCEL-CTM MSCs was found to be safe (primary safety outcome serious adverse events up to day 90) but there was no difference in the primary efficacy outcome (oxygenation index at day 7) nor in a range of secondary surrogate outcomes of systemic and pulmonary organ function. Long term follow up to 2 years also found ORBCEL-CTM MSCs to be safe.

The final chapter in this thesis presents a critical appraisal of available evidence to explore 1) the feasibility of delivering cell-based therapy for critically ill patients within the UK national health service, 2) the safety and long-term outcomes of MSCs in ARDS and COVID-19, 3) efficacy of MSCs in ARDS and COVID-19, and 4) mechanistic insights regarding MSCs in ARDS and COVID-19.

Date of Award	2025
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Danny McAuley (Supervisor) & Cecilia O'Kane (Supervisor)