title: 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 106cells 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.
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chambers
authors.affiliation: Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Debra
authors.initials: D
authors.lastname: Enever
authors.affiliation: Western Australian Lung Transplant Program, Fiona Stanley Hospital, Perth, Western Australia, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lawrence
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Cell & Tissue Therapies Western Australia, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Sturm
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.|Cell & Tissue Therapies Western Australia, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Yerkovich
authors.affiliation: Western Australian Lung Transplant Program, Fiona Stanley Hospital, Perth, Western Australia, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Musk
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Hopkins
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005260:Female; D006084:Graft Rejection / Q000628:therapy; D006086:Graft vs Host Disease / Q000628:therapy; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D008875:Middle Aged
keywords: Cell- and tissue-based therapy; Clinical trial; Graft rejection; Lung transplantation; Mesenchymal stromal cells; Phase 1