School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Queensland, Australia.
Stem Cells Transl Med. 2017 Apr;6(4):1152-1157. doi: 10.1002/sctm.16-0372. Epub 2017 Feb 1.
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 10 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.
慢性肺移植排斥反应（称为慢性肺移植物功能障碍[CLAD]）是肺移植后长期生存的主要障碍。骨髓间充质基质细胞（MSCs）因其相对的免疫特权、免疫抑制和耐受特性，在包括器官排斥在内的炎症性疾病的细胞治疗中具有吸引力。在闭塞性细支气管炎模型的临床前研究和移植物抗宿主病和肾移植的人类试验中，提示其在 CLAD 中具有潜在疗效。这项 1 期、单臂研究的目的是探索静脉输注同种异体 MSC 治疗晚期 CLAD 患者的可行性和安全性。来自无关供体的 MSC 从骨髓中分离出来，在符合 GMP 的设施中扩增和冷冻保存。患者 CLAD 恶化，且处于细支气管炎闭塞性（BOS）分级≥2 或分级 1 但有快速进展的风险因素。每周两次通过外周静脉输注 2 周，共 52 周随访。共 10 例患者（5 例男性，8 例双侧，中位[四分位间距]年龄 40[30-59]岁，3 例 BOS2，7 例 BOS3）参加了研究。MSC 治疗耐受性良好，所有患者均接受了完整的剂量方案，无任何与程序相关的严重不良事件。在 MSC 输注后，用力呼气量的下降速度减慢（输注前 120ml/月 vs. 输注后 30ml/月，p=0.08）。2 例患者在 MSC 治疗后 152 天和 270 天死亡，均死于进行性 CLAD。总之，即使在晚期 CLAD 患者中，输注同种异体骨髓来源的 MSC 也是可行和安全的。Stem Cells Translational Medicine 2017;6:1152-1157.
