Safety Of Cell Therapy With Mesenchymal Stromal Cells (MSCs): A Systematic Review

Abstract

BACKGROUND: Recent preclinical studies suggest that mesenchymal stromal cells (MSCs) may markedly improve outcome from critical illness, specifically septic shock and acute respiratory distress syndrome. Before considering a human clinical trial of MSC immunomodulatory cell therapy for the critically ill, we performed a systematic review of all clinical studies to examine the safety of MSCs in adults. We focused on serious adverse events that could affect the cardiovascular, pulmonary, renal, neurological, and hematological systems. METHODS: Electronic databases were searched from 1950 to 2009 (MEDLINE, EMBASE, Cochrane Central Registry of Controlled Trials); conference proceedings and grey literature were also searched from 2004 to 2009. All prospective clinical trials (randomized controlled trials (RCT), prospective cohort studies, and case series) that examined safety of MSCs in adult populations were identified. Only trials that exclusively used MSCs with no other concomitant experimental therapy were included. No restrictions were placed for language or publication type. RESULTS: Of the 1885 citations reviewed, 24 studies were included. A total of 652 patients with conditions including ischemic stroke, spinal cord injury, Crohn's disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eleven studies included a control group for comparison (191 MSC treated patients, 250 control) ten were RCTs. No study stopped MSCs administration due to immediate adverse reactions. Of eleven trials with a control group, death was reported in five and was less frequent in the MSC as compared to the control group (7/102 (6.8%) vs. 20/112 (17.8%), p<0.05); four reported arrhythmias which occurred less frequently in the MSC group (3/96 (3.1%) vs. 13/98 (13.2%), p<0.05). Self-limited fever was described in two trials and was more common following intrathecal administration of MSCs versus control (13/22 (59.1%) vs. 0/31 (0.0%), p<0.05). One trial noted more pulmonary edema following intracoronary injection of MSCs as compared to control (3/24 (12.5%) vs. 0/24 (0%), p<0.05). One study noted pinpoint ischemic areas of the brain by computed tomography scan (without neurological deficits) following carotid intraarterial MSC administration. There were no reports of pulmonary hypertension or emboli, hemodynamic instability, hematological issues, or renal insufficiency. Follow-up for the studies ranged from 2 weeks to 30 months. Longer term safety data is currently unavailable. CONCLUSIONS: Results from this systematic review suggests that MSC administration appears to be safe based on the available evidence. Longer term follow up studies will help further define the safety profile of MSCs in different patient populations.