Cellular Immunotherapy for Septic Shock (CISS): A Phase I trial
CCCF ePoster library. McIntyre L. Oct 4, 2017; 198145; 92
Lauralyn McIntyre
Lauralyn McIntyre
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Cellular Immunotherapy for Septic Shock (CISS): A Phase I trial

McIntyre, Lauralyn A. 1,2,3, Stewart, Duncan J. 2,4, Mei, Shirley H. J.2,5,, Courtman, David2,5, Watpool, Irene2, Granton, John6, Marshall, John7, dos Santos, Claudia7, Walley, Keith R.8, Winston, Brent W.9, Fergusson, Dean A.2,3, For the Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group



1Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, Canada; 2The Ottawa Hospital Research Institute, Ottawa, Canada; 3Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada;

4Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Canada; 5Department of Regenerative Medicine, University of Ottawa, Ottawa, Canada; 6Department of Medicine, University of Toronto, Toronto, Canada; 7Department of Surgery and Critical Care Medicine, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, The University of Toronto, Toronto, Canada; 8Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; 9Department of Critical Care Medicine, Biochemistry and Molecular Biology, Cumming School of Medicine, Univeristy of Calgary, Calgary, Canada


INTRODUCTION: Septic shock is common and devastating with a mortality rate of 20-40%, and an economic burden of 24 billion dollars annually in the USA alone1-3. Sepsis is characterized by activation of an innate immune response that results in microcirculatory and endothelial cell dysfunction, leading ultimately to multi-organ dysfunction, which is the most common cause of death4,5. The current mainstays of treatment for septic shock include early identification and fluid resuscitation, prompt institution of antibiotic therapy and source control, circulatory support and lung protective mechanical ventilation strategies for those who develop severe respiratory failure6.  Several decades of research targeting the inflammatory cascade have not yet identified an efficacious therapy7

OBJECTIVE: Mesenchymal stem cells (MSCs) represent a promising new therapeutic for septic shock and have been shown to modulate inflammation, enhance tissue repair and pathogen clearance, and improve survival in septic animal models. We conducted an open label single-centre Phase I dose-escalation trial of freshly cultured adult allogenic bone marrow-derived MSCs in patients with septic shock to examine the safety and tolerability of MSCs in this clinical setting.

METHODS: Eligible septic patients were enrolled within 24 hours of the first admission to the intensive care unit. A control group of 21 participants who met the same eligibility criteria but did not receive MSCs were prospectively enrolled in advance of initiation of the MSC interventional group of the trial to characterize the incidence of expected adverse events (AEs) and to serve as a comparator for the intervention group. In the MSC interventional group there were three separate MSC dose cohorts, with 3 participants per cohort who received doses of 0.3, 1.0 and 3.0 x 106/kilogram to a maximum of 300 million MSCs. Participants were monitored for the occurrence of pre-specified MSC transfusion associated AEs and serious unexpected AEs for 1 year post MSC transfusion.

RESULTS: Participants in the interventional versus observational groups were of similar median age (71 yrs, range: 38-91; and 61 yrs, 23-95, respectively) and exhibited similar acute physiology and chronic health median scores (25, range: 11 to 28; and 26, range: 17 to 32). All participants were ventilated and on vasoactive agents at baseline. The lung and abdomen were the 2 most common sources of infection (66% (n=6) and 67% (n=14)). MSC doses ranged from 19 to 250 million cells. There were no pre-specified MSC transfusion associated AEs, serious unexpected AEs that were considered related to the study product, or significant differences related to pre-specified expected AEs between the MSC and control groups (see Table 1).

CONCLUSIONS: We conclude that infusion of freshly cultured allogenic MSCs into participants with septic shock up to a dose of 3 million cells per kg (250 million cells) appear safe and justify proceeding to a multi-centre, concealed, randomized controlled trial to examine efficacy of MSCs in septic shock.

 

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