人脐带间充质干细胞剂量递增静脉输注治疗失代偿性肝硬化的安全性研究

Safety and escalation study of human mesenchymal stem cells for patients with decompensated liver cirrhosis

目的探索人脐带间充质干细胞(hUCMSCs)剂量递增外周静脉输注治疗失代偿性肝硬化的安全性和耐受性,并观察其疗效。方法采用开放、剂量递增的方法进行前瞻性的安全性研究,随访观察期1年。入组的肝硬化失代偿患者通过外周静脉输注hUCMSCs,输注剂量分为三个级别,即5×107个/次、1×108个/次和2×108个/次,从低剂量级开始,每个级别患者需接受3次同等剂量细胞的输注,按严格规定进行剂量升级。相关不良事件(AE)评价采用美国国立肿瘤研究所NCI-CTC AE4.0标准。干细胞制备有严格质控,每次输注的干细胞均可溯源。试验严格按照药物临床试验规范(GCP)进行观察和随访。结果 (1)共20例肝硬化失代偿患者纳入研究,显示静脉途径输注hUCMSCs有良好耐受性,最大耐受剂量为2×108个/次;(2)输注后患者生命体征、心电图、肾功能等均无异常;(3)20例患者共观察到516次AE,最常见与干细胞输注可能相关不良事件有发热、胆红素升高、PT延长、血小板降低等,AE的发生率不随细胞剂量升高而升高;(4)共观察到21起严重不良事件(SAE),仅1例SAE(PT延长)与hUCMSCs输注可能有关,且4 d内自行缓解,该患者至今存活;(4)多数患者生活质量改善明显(SF-36评分由基线109上升至127,P<0.05);(5)肝功能改善:前白蛋白由基线74.55 mg/L上升至104.61 mg/L(P<0.01);白蛋白由基线29.50 g/L上升至34.94 g/L(P<0.01);白球蛋白比由基线1.01上升至1.22(P<0.01);TBil由基线52.59μmol/L下降至40.02μmol/L;CTP评分由基线9.10下降至7.61(P<0.05);MELD评分由基线15.18下降至13.46。(6)1年生存率90%,随访至2年时无一例发生肿瘤。结论失代偿性肝硬化患者静脉途径输注hUCMSCs是安全的,并具有良好的耐受性。hUCMSCs在一定程度上可能改善患者临床表现。随访2年无肿瘤发生。

Objective To evaluate the safety and escaltion study of infusions of human umbilical cord mesenchymal stem cells（hUCMSCs）in patients with decompensated liver cirrhosis（DLC）.Methods It is an open,dose escalation study.Three doses of hUCMSCs are 5× 107 cells,1× 108 cells and 2 × 108 cells,respectively.The cells were administrated with IV infusion.Each patient received 3 times infusion every the fourth day,with a follow-up for 52 weeks. The criteria for Adverse Event（AE）was mainly in accordance to the NCI-CTCAE4.0version.The study was conducted on the principles of Good Clinical Practice（GCP）.Results Twenty patients were recruited（14 male and six female,mean age 54.2±5.9 years）.All patients were tolerant with the infusion.The frequency,grades and distributions of adverse events was not significantly different among the three cohorts.The total protein and albumin,total bilirubin,scores of Child-Pugh,Model for End-Stage Liver Disease and Quality of Life scale constant improved post-treatment in the three cohorts. Two patients died for complications after 6 months of the first infusion.The overall survival rate was 90%at week52.The most common AEs were fever,hyperbilirubinemia,decrease of platelet and prolonged prothrombin time（PT）.Only one SAE（prolonged PT）might be related to cells infusion according to the investigator＇s assessment,but the patient recovered soon,and survives well until now.The occurrence rate of AE doesn＇t increase with cell dose escalation.Meanwhile,the mean level of pre-albumin almost doubled after 12 months,and increased from74.55 to 104.61 g/L（P0.01）.Total protein,albumin（P 0.05）.The Child-Turcotte-Pugh（CTP）score and SF-36 questionnaire were also improved significantly at 6 and 12 months（P0.05）.Until now,no tumor occurrence was detected during 24 months after the first infusion.Conclusion It is safe and tolerant when the cells dose escalated to 2×108 cells/per infusion for DLC patients on the dose limiting toxicity（DLT）test.hUCMSCs could improve clinical outcomes at 52 weeks of follow-up for these patients.No tumor was detectecd after 24 months follow-up.