CCCF Academy

Wolfe, Dianna1; Champagne, Josée1; Thompson, Mary1; Mei, Shirley H.J.7; Lalu, Manoj M.1,2; Fergusson, Dean1; Winston, Brent W.3; Marshall, John C.4; Walley, Keith5; English, Shane1,9; dos Santos, Claudia4; Granton, John6; Stewart, Duncan J.7,8; McIntyre, Lauralyn1,9; for the Canadian Critical Care Trials Group

1Ottawa Hospital Research Institute, Department of Epidemiology, Ottawa Methods Centre, Ottawa, Canada; 2Department of Anesthesiology, University of Ottawa, Ottawa, Canada; 3Department of Critical Care Medicine, University of Calgary, Calgary, Canada; 4Department of Surgery (Critical Care), University of Toronto, Toronto, Canada; 5Department of Medicine, University of British Columbia, Vancouver, Canada; 6Department of Medicine (Critical Care), University of Toronto, Toronto, Canada; 7Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada; 8Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Canada; 9Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, Canada

Introduction: Mesenchymal stromal cells (MSCs, “adult stem cells”) have been used in a variety of pre-clinical and clinical contexts. Evidence of the ability of MSC therapy to immune-modulate in pre-clinical models has led to interest in the possible therapeutic role for MSCs in a variety of acute and chronic inflammatory conditions. Characterization of the MSC safety profile is important as this novel therapeutic moves through the clinical experimental pipeline. A previous systematic review published in 2012 included 8 randomized controlled trials (RCTs) (n = 369 patients studied) and identified fever as the sole adverse event that was significantly associated with MSC therapy. Because of an increase in published MSC RCTs since that time, we performed an updated evaluation to further characterize the MSC safety profile.
Objectives: To perform an updated systematic review of the safety of MSCs as compared to controls by analyzing the current evidence from RCTs.
Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to February 2017) were searched. RCTs that used intravascular delivery of MSCs (intravenous or intra-arterial) in human adults were identified. Studies using differentiated MSCs or additional cell types were excluded. Adverse events, the primary outcome, were grouped according to time of manifestation: (1) immediate events (i.e., acute infusional toxicity and fever), which captured the potential for MSCs to embolize or cause hypersensitivity reactions; (2) infection events occurring at any time post-infusion, which capture the risk of immunomodulation as shown by pre-clinical models; and (3) long-term events including death and malignancy, the latter of which captured the theoretical risk that MSCs could engraft. Adverse events were both pooled across clinical indications and meta-analyzed by fitting inverse-variance weighted random effects models.
Results: 4464 citations were reviewed and 36 studies met inclusion criteria. A total of 1656 participants from a number of clinical indications, including cardiovascular diseases (11 trials(t)), neurological diseases (6t), hematological malignancies (4t), metabolic disorders (6t), immune-deficiency or chronic inflammatory diseases (3t), liver disease (3t), chronic obstructive pulmonary disease (1t), and critical illness (2t) were included. Mean sample size and follow-up duration was 46.8 (SD 25.6) patients and 16.8 (SD 15.2) months. Pooling across indications did not detect an increase in acute infusional toxicity (odds ratio (OR) = 1.68, 95% confidence interval (CI) = 0.62-4.54), infection (OR = 1.27, 95% CI = 0.84-1.98), death (OR = 0.59, 95% CI = 0.41-0.85) or malignancy (OR = 1.12, 95% CI = 0.40-3.15) for MSC therapy as compared to the control group. There was a significant increase in the odds of fever (OR = 9.20, 95% CI = 3.10-27.33). No serious adverse events were directly attributed to MSC therapy, and none of the included trials were ended prematurely due to safety concerns.
Conclusion: MSC therapy appears to be safe. However, rigorous reporting of immediate, short-, and longer-term adverse events in randomized clinical trials is needed to further define the MSC safety profile.