Safety of Allogeneic Mesenchymal Stromal Cell Therapy Across Human Clinical Indications: A Systematic Review of Landmark Clinical Trials and Published Safety Evidence
Abstract
Kirk Sanford, Felix Porras, Fergie Martinez, Hugo Ramos, Janine Zamitiz, Carlos Green and Edward Ramsay
Background: Allogeneic mesenchymal stromal cells (MSCs) have emerged as an off-the-shelf regenerative medicine platform across cardiovascular, pulmonary, musculoskeletal, autoimmune, gastrointestinal, and renal indications. Although individual clinical trials frequently describe favorable tolerability, safety reporting remains heterogeneous across studies, and the adverse event profile of allogeneic MSC administration has not been consistently synthesized with emphasis on treatment-related serious toxicity. Landmark MSC safety meta-analyses have generally concluded that MSC therapy appears safe, with transient fever representing the most reproducible treatment-associated event.
Objective: To evaluate the safety profile of allogeneic mesenchymal stromal cell therapy across human clinical indications, with emphasis on treatment-related serious adverse events, immediate administration-related toxicity, and clinically important long-term safety signals.
Methods: A systematic review framework was developed in accordance with PRISMA 2020 guidance. The review focused on human clinical studies of allogeneic MSC administration, prioritizing landmark randomized controlled trials, controlled prospective studies, and high-yield safety meta-analyses. Primary outcome emphasis was placed on treatment-related serious adverse events. Secondary outcomes included any adverse event, infusion or injection reactions, transient fever, infection, death, immunologic reactions, malignancy, and ectopic tissue formation. Evidence was synthesized qualitatively across landmark trials and interpreted in the context of prior MSC safety meta-analyses.
Results: Across landmark allogeneic MSC trials in acute myocardial infarction, ischemic cardiomyopathy, dilated cardiomyopathy, acute respiratory distress syndrome, COVID-19 ARDS, Crohn’s disease, systemic lupus erythematosus, diabetic kidney disease, and knee osteoarthritis, no reproducible signal of frequent treatment-related serious adverse toxicity was identified. Acute myocardial infarction studies concluded intravenous allogeneic MSCs were safe. The POSEIDON randomized trial supported comparative safety of allogeneic transendocardial MSC delivery in ischemic cardiomyopathy. The START phase 2a ARDS trial established safety in critically ill patients. The phase 3 ADMIRE-CD trial supported safety of locally administered allogeneic adipose-derived MSCs in complex perianal fistulizing Crohn’s disease. Across previously published pooled safety evidence, MSC therapy was not associated with increased serious adverse events, death, infection, arrhythmia, vascular complications, or malignancy, while transient fever was the main event consistently increased.
Conclusion: Current human clinical evidence supports a favorable safety profile for allogeneic mesenchymal stromal cell therapy across multiple therapeutic indications and routes of administration. Treatment-related serious adverse events appear uncommon, and no consistent signal of infection excess, thromboembolic toxicity, organ toxicity, or mortality attributable to MSC administration has emerged from landmark trials or prior pooled safety analyses. Importantly, the clinical MSC literature has not demonstrated evidence of tumorigenicity. No confirmed cases of tumors derived from administered MSCs have been reported in human clinical trials, and pooled safety analyses have not identified increased malignancy risk among MSC-treated patients. These findings support the continued clinical development of allogeneic MSC therapy as a scalable and generally well-tolerated regenerative medicine platform.