Mesenchymal Stromal Cell Therapy for Chronic Lung Allograft Dysfunction: Results of a First-in-Man Study

Abstract

Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long‐term survival after lung transplantation. Bone marrow‐derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single‐arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP‐compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow‐up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure‐related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p = .08). Two patients died at 152 and 270 days post‐MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow‐derived MSCs is feasible and safe even in patients with advanced CLAD. Stem Cells Translational Medicine 2017;6:1152–1157

Feasibility, Safety, and Tolerance of Mesenchymal Stem Cell Therapy for Obstructive Chronic Lung Allograft Dysfunction

“…Two of their patients died from progressive BOS at 152 and 270 days after the final infusion of MSCs, but the investigators did not believe these deaths were related to MSC infusion. They observed a reduction in the rate of decline in FEV 1 following MSC infusion, concluding that infusion of MSCs was feasible and safe in patients with advanced CLAD . Our study also used bone marrow‐derived MSCs with the primary purpose to improve lung function, or at least arrest the rate of decline in lung function, in patients with progressive BOS refractory to medical therapy.…”

“…Based on recent advances in ex vivo lung perfusion technology and the results of MSC infusion reported here and by Chambers et al , further studies into combining these therapies may be warranted. Donor lungs could be placed on ex vivo lung perfusion prior to transplantation, to infuse them with previously cultured autologous or allogeneic bone marrow‐derived MSCs, aiming to immunomodulate the donor lungs to reduce the incidence of primary graft dysfunction.…”

“…More recently, Chambers et al reported results of a phase I trial in which bone marrow‐derived MSCs from 5 donors were infused into 10 patients with either BOS grade 1 and added risk factors or BOS grade 2 or 3 showing rapid decline in FEV 1 despite medical therapy. Their protocol infused 2 million MSCs per kg twice a week for 2 weeks for a total of 8 million MSCs per kg.…”

“…Alveolar fluid clearance was increased to a normal level in lungs receiving MSCs, suggesting that this therapy can enhance the resolution of pulmonary edema in human lungs deemed unsuitable for transplantation [17]. More recently, Chambers et al [18] reported results of a phase I trial in which bone marrow-derived MSCs from 5 donors were infused into 10 patients with either BOS grade 1 and added risk factors or BOS grade 2 or 3 showing rapid decline in FEV 1 despite medical therapy. Their protocol infused 2 million MSCs per kg twice a week for 2 weeks for a total of 8 million MSCs per kg.…”

Stem cell manipulation, gene therapy and the risk of cancer stem cell emergence

“…Most of the clinical trials are now in phase I/II and so far, appear to be safe. For example, MSC therapies were recently used in the context of a retinal and optic nerve disease (74), for chronic lung allograft dysfunction (75). It was also used for the regeneration of durable articular cartilage in osteoarthritic knees where no cases of osteogenesis or tumorigenesis were observed after 7 years (76).…”