Lauralyn A McIntyre1,2,3, Duncan J Stewart4,3, Shirley H J Mei3,5, David Courtman3,5, Irene Watpool3, John Granton6, John Marshall7, Claudia Dos Santos7, Keith R Walley8, Brent W Winston9, Kenny Schlosser3,5, Dean A Fergusson2,3. 1. 1 Division of Critical Care, Department of Medicine. 2. 3 Department of Epidemiology and Community Medicine, and. 3. 2 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 4. 4 Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. 5. 5 Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 6. 6 Department of Medicine and. 7. 7 Department of Surgery and Critical Care Medicine, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 8. 8 Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; and. 9. 9 Department of Critical Care Medicine, Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Abstract
RATIONALE: In septic animal models mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance tissue repair and pathogen clearance, and reduce death. OBJECTIVES: To conduct a phase I dose escalation trial of MSCs in septic shock with the primary objective of examining the safety and tolerability of MSCs. METHODS: We enrolled nine participants within 24 hours of admission to the ICU. A control cohort of 21 participants was enrolled before starting the MSC interventional cohort to characterize expected adverse events (AEs) and to serve as a comparator for the intervention cohort. Three separate MSC dose cohorts, with three participants per cohort, received a single intravenous dose of 0.3, 1.0, and 3.0 × 106 cells/kg. A prespecified safety plan monitored participants for the occurrence of AEs; cytokines were collected at prespecified time points. MEASUREMENTS AND MAIN RESULTS: Ages of participants in the interventional versus observational cohorts were median of 71 (range, 38-91) and 61 (range, 23-95). Acute Physiology and Chronic Health Evaluation scores were median of 25 (range, 11-28) and 26 (range, 17-32). MSC doses ranged from 19 to 250 million cells. There were no prespecified MSC infusion-associated or serious unexpected AEs, nor any safety or efficacy signals for the expected AEs or the measured cytokines between the interventional and observational cohorts. CONCLUSIONS: The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).
RATIONALE: In septic animal models mesenchymal stem (stromal) cells (MSCs) modulate inflammation, enhance tissue repair and pathogen clearance, and reduce death. OBJECTIVES: To conduct a phase I dose escalation trial of MSCs in septic shock with the primary objective of examining the safety and tolerability of MSCs. METHODS: We enrolled nine participants within 24 hours of admission to the ICU. A control cohort of 21 participants was enrolled before starting the MSC interventional cohort to characterize expected adverse events (AEs) and to serve as a comparator for the intervention cohort. Three separate MSC dose cohorts, with three participants per cohort, received a single intravenous dose of 0.3, 1.0, and 3.0 × 106 cells/kg. A prespecified safety plan monitored participants for the occurrence of AEs; cytokines were collected at prespecified time points. MEASUREMENTS AND MAIN RESULTS: Ages of participants in the interventional versus observational cohorts were median of 71 (range, 38-91) and 61 (range, 23-95). Acute Physiology and Chronic Health Evaluation scores were median of 25 (range, 11-28) and 26 (range, 17-32). MSC doses ranged from 19 to 250 million cells. There were no prespecified MSC infusion-associated or serious unexpected AEs, nor any safety or efficacy signals for the expected AEs or the measured cytokines between the interventional and observational cohorts. CONCLUSIONS: The infusion of freshly cultured allogenic bone marrow-derived MSCs, up to a dose of 3 million cells/kg (250 million cells), into participants with septic shock seems safe. Clinical trial registered with www.clinicaltrials.gov (NCT02421484).
Entities:
Keywords:
allogeneic; bone marrow; mesenchymal stem cells; phase I clinical trial; septic shock
Authors: Min-Young Kwon; Sailaja Ghanta; Julie Ng; Konstantin Tsoyi; James A Lederer; Roderick T Bronson; Souheil El-Chemaly; Su Wol Chung; Xiaoli Liu; Mark A Perrella Journal: Crit Care Med Date: 2020-05 Impact factor: 7.598
Authors: Swantje Voller; H Rob Taal; Serife Kurul; Kinga Fiebig; Robert B Flint; Irwin K M Reiss; Helmut Küster; Sinno H P Simons Journal: Pediatr Res Date: 2021-09-08 Impact factor: 3.756
Authors: Jonathan E Millar; Nicole Bartnikowski; Margaret R Passmore; Nchafatso G Obonyo; Maximillian V Malfertheiner; Viktor von Bahr; Meredith A Redd; Louise See Hoe; Katrina K Ki; Sanne Pedersen; Andrew J Boyle; J Kenneth Baillie; Kiran Shekar; Nathan Palpant; Jacky Y Suen; Michael A Matthay; Daniel F McAuley; John F Fraser Journal: Am J Respir Crit Care Med Date: 2020-08-01 Impact factor: 21.405