• Kenny Schlosser, Jia-Pey Wang, Claudia Dos Santos, Keith R Walley, John Marshall, Dean A Fergusson, Brent W Winston, John Granton, Irene Watpool, Duncan J Stewart, Lauralyn A McIntyre, Mei Shirley H J SHJ Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada., and Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group.
• Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
• Crit. Care Med. 2019 Jul 1; 47 (7): 918-925.

ObjectivesCellular Immunotherapy for Septic Shock is the first-in-human clinical trial evaluating allogeneic mesenchymal stem/stromal cells in septic shock patients. Here, we sought to determine whether plasma cytokine profiles may provide further information into the safety and biological effects of mesenchymal stem/stromal cell treatment, as no previous study has conducted a comprehensive analysis of circulating cytokine levels in critically ill patients treated with mesenchymal stem/stromal cells.DesignPhase 1 dose-escalation trial.PatientsThe interventional cohort (n = 9) of septic shock patients received a single dose of 0.3, 1.0, or 3.0 million mesenchymal stem/stromal cells/kg body weight (n = 3 per dose). The observational cohort received no mesenchymal stem/stromal cells (n = 21).InterventionsAllogeneic bone marrow-derived mesenchymal stem/stromal cells.Measurements And Main ResultsSerial plasma samples were collected at study baseline prior to mesenchymal stem/stromal cell infusion (0 hr), 1 hour, 4 hours, 12 hours, 24 hours, and 72 hours after mesenchymal stem/stromal cell infusion/trial enrollment. Forty-nine analytes comprised mostly of cytokines along with several biomarkers were measured. We detected no significant elevations in a broad range of pro-inflammatory cytokines and biomarkers between the interventional and observational cohorts. Stratification of the interventional cohort by mesenchymal stem/stromal cell dose further revealed patient-specific and dose-dependent perturbations in cytokines, including an early but transient dampening of pro-inflammatory cytokines (e.g., interleukin-1β, interleukin-2, interleukin-6, interleukin-8, and monocyte chemoattractant protein 1), suggesting that mesenchymal stem/stromal cell treatment may alter innate immune responses and underlying sepsis biology.ConclusionsA single infusion of up to 3 million cells/kg of allogeneic mesenchymal stem/stromal cells did not exacerbate elevated cytokine levels in plasma of septic shock patients, consistent with a safe response. These data also offer insight into potential biological mechanisms of mesenchymal stem/stromal cell treatment and support further investigation in larger randomized controlled trials.

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