Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis

TLDR

Characterizing the safety profile of mesenchymal stromal cells (MSCs) is essential as this novel therapy is increasingly evaluated in clinical trials for inflammatory conditions. This updated systematic review aimed to further characterize MSC safety by examining randomized controlled trials published between 2012 and 2019. The authors searched MEDLINE, EMBASE, Cochrane CENTRAL, and Web of Science up to May 2018, included adult RCTs comparing intravascular MSC delivery to controls, grouped adverse events into immediate, infection, thrombotic/embolic, and longer‑term categories, and performed inverse‑variance random‑effects meta‑analyses while summarizing efficacy endpoints descriptively. From 7,473 citations, 55 RCTs involving 2,696 patients were included; MSCs increased the risk of fever (RR = 2.48) but did not raise rates of acute infusion toxicity, infection, thrombotic/embolic events, death, or malignancy, and no trials were terminated early for safety reasons. Future trials should strengthen rigor and reporting of MSC characterization and adverse events, and the study was funded by the Stem Cell Network, Ontario Institute for Regenerative Medicine, and Ontario Research Fund.

Abstract

BackgroundCharacterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012–2019, we performed an updated systematic review to further characterize the MSC safety profile.MethodsMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively.Findings7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27–4·86; I2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70–1·91, 0·81–1·21, 0·67–1·95, 0·65–0·94, 0·60–1·45; I2 = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns.InterpretationsMSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events.FundingStem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund