(F1306) GENETICALLY ENHANCED MESENCHYMAL STEM CELLS SIGNIFICANTLY IMPROVED SURVIVAL OF SEPSIS IN ANIMALS AND APPEARED WELL TOLERATED IN A PHASE 1 SAFETY TRIAL OF SEPTIC SHOCK PATIENTS
Investigator Ottawa Hospital Research Institute, Ontario, Canada
Abstract: Sepsis is a disease of organ dysfunction, caused by a dysregulated host immune response to infection. Despite >1000 clinical trials, no new product has been approved. It is a global health priority as sepsis is a leading cause of morbidity and mortality in these critically ill patients. Our novel approach is based on genetically engineering immunomodulatory mesenchymal stem/stromal cells (MSCs) to express vascular protective angiopoietin-1 (ANGPT1) and the Gram-negative bacteria-targeting protein acyloxyacyl hydrolase (AOAH), which were tested to show proof of concept efficacy in improving mice survival in two sepsis models (p=0.002 in E. coli peritonitis, p=0.01 in polymicrobial sepsis, compared to vehicle). A first-in-human, dose-escalation phase 1 safety trial (AMETHYST: Advanced Mesenchymal Enhanced cell THerapY for SepTic, NCT04961658) was designed to determine the safety and maximum feasible tolerated dose (MFTD) in adult septic shock patients. A cryopreserved, allogeneic, genetically enhanced MSC therapy product (GEM00220) was manufactured at a GMP facility, with an established stability of 24 months in liquid nitrogen. Products were thawed at the bedside of intensive care units (ICU) and given at 4 ascending dose levels: A - 15 million cells, B - 60 million cells, C - 150 million cells, and D - 300 million cells given as two doses of 150 million cells, separated by 24 hours. Safety and tolerability were also assessed by monitoring adverse events up to 28 days, with day 28, day 90, and 1-year survival assessment. Eleven participants (3 each in cohort A-C; and 2 in cohort D) were enrolled with a median age of 58 years old (range: 28 to 81); median SOFA score of 15 (range 5 to 18) with a median predicted mortality risk of 80% (range: < 10% to >90%). In patients treated with GEM00220, twenty-eight-day mortality was 36% in all cohorts, with no death in cohorts C and D. Infusion for all doses was well tolerated. No stopping rule criteria were met for any dose cohort. In conclusion, infusing cryopreserved GEM00220, up to 300 million cells, into patients with septic shock seemed safe and feasible. This easy-to-use MSC therapy, engineered to express ANGPT1 and AOAH, represents a novel approach to the treatment of sepsis, independent of microbial identity or antibiotic resistance.
