Effects of Mesenchymal Stem Cell Treatment on Systemic Cytokine Levels in a Phase 1 Dose Escalation Safety Trial of Septic Shock Patients

Objectives: Cellular 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. Design: Phase 1 dose-escalation trial. Patients: The 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). Interventions: Allogeneic bone marrow-derived mesenchymal stem/stromal cells. Measurements and Main Results: Serial 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. Conclusions: A 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. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Stewart, McIntyre, and Mei are co-senior authors. Drs. Schlosser, Stewart, McIntyre, and Mei, and Ms. Wang designed and did the study concept. Ms. Wang performed measurements for data acquisition. Drs. Schlosser, Stewart, McIntyre, and Mei, and Ms. Wang analyzed and interpreted the data. Dr. Schlosser drafted the initial article. All authors were involved in critical revisions of the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://bit.ly/29S62lw). Drs. McIntyre’s and Mei’s institutions received funding from Ontario Institute of Regenerative Medicine (OIRM) Disease Team Grant (to Dr. Mei) and from the Canadian Institutes of Health Research (CIHR) Operating Grant (to Dr. McIntyre). Dr. Walley disclosed he was a founder and shareholder of Cyon Therapeutics. Dr. Fergusson’s institution received funding from CIHR. Dr. Granton received other funding from Actelion, Bayer, and Bellepheron as a member of steering or adjudication committees for clinical trials in pulmonary hypertension and from Actelion and Bayer for support of pulmonary hypertension research. Dr. Granton disclosed off-label product use of stem cells. Dr. Stewart holds a patent for mesenchymal stem/stromal cell (MSC) therapy for the treatment of acute lung injury. Dr. Mei has received personal fees from Northern Therapeutics that are outside of this submitted work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: smei@ohri.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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