Biomarker analyses reveals anti-inflammatory mechanism of action of Mesenchymal Stromal Cells (MSCs) in Osteoarthritis patients with improvements to pain and symptoms

Chahal, Jaskarndip (1,2,3,4), Chaboureau, Amélie (1,3,5), Bhatt, Shashank (1,3,5), Fazio, Antonietta (1,3), Gómez-Aristizábal, Alejandro (1,3,5), Sussman, Marshall (6,7,8), Chisholm, Jolene (1,3,5), Weston, Amanda (1,3), Kapoor, Mohit (1,2,3,9), Keating, Armand (1,3,5,10,11,12), Ogilvie-Harris, Darrell (1,2,3,4), Mahomed, Nizar (1,2,3,13), Gandhi, Rajiv (1,2,3,9), Marshall, K. Wayne (1,2,3), Syed, Khalid (1,2), Naraghi, Ali (6,7), and Viswanathan, Sowmya (1,3,5,10,11)

1 Arthritis Program, University Health Network ; 2 Division of Orthopaedic Surgery, University of Toronto ; 3 Krembil Research Institute, University Health Network ; 4 University of Toronto Orthopaedic Sports Medicine Program, University of Toronto ; 5 Cell Therapy Program, University Health Network ; 6 Department of Medical Imaging, University of Toronto ; 7 Joint Department of Medical Imaging, University Health Network ; 8 Toronto General Hospital Research Institute, University Health Network ; 9 Department of Laboratory Medicine and Pathobiology, University of Toronto ; 10 Faculty of Medicine, University of Toronto ; 11 Institute of Biomaterials and Biomedical Engineering, University of Toronto ; 12 Princess Margaret Cancer Centre, University Health Network ; 13 Institute of Health Policy, Management and Evaluation, University of Toronto

We initiated the first Canadian clinical trial using autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) to treat 12 patients with Kellgren-Lawrence III/IV knee osteoarthritis. Patients (mean age 56; range 46–65; 7/12 male) received 1, 10 or 50 million MSCs in a single intra-articular injection without any adverse events. Overall, patients had improved disease-specific Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores, standardized clinical indices at 12 months relative to baseline (p=0.023, 0.007, 0.042, 0.012, 0.092 for KOOS pain, symptoms, function in daily living, quality of life, and sports/recreation, respectively; and p=0.042, 0.013 and 0.003 for WOMAC function, pain, and stiffness, respectively). Individual analyses show that 8/12 patients had a Minimal Clinically Important change of 10 points relative to baseline in KOOS pain and symptom at 12 months. This clinical improvement appears to correlate with interim MRI analysis of resolution of synovial inflammation suggestive of anti-inflammatory mechanism of action of MSCs (full analyses pending). There was a decrease in levels of pro-inflammatory monocytes/macrophages in the synovial fluid post-MSC injection relative to baseline, concomitant with increased levels of PGE2 and decreased levels of IL12p40, suggestive of MSC-mediated inflammation resolution. Analyses of 12 patient-specific MSCs showed elevated gene and protein expression of anti-inflammatory markers that correlated with clinical patient responses suggesting that donor heterogeneity is partially responsible for the observed clinical differences. Autologous BM-MSCs result in significant improvements in overall KOOS and WOMAC scores at 12 months with patients in the 50 million dose cohort reporting clinically significant improvements in scores. For the first time, we show that MSC injection resulted in less inflammatory synovial environment, which correlated with improved patient reported outcomes.