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临床研究揭示iPSC衍生MSCs在难治性急性移植物抗宿主病患者中的应用

植物病虫害 时间:2021-05-12 10:25:00 作者:莫敖坤
【http://www.globalcon.cn - 中国农业科技网】

本期文章:《自然—医学》:Online/在线发表

澳大利亚皇家阿尔弗雷德王子医院John E. J. Rasko和英国Christie NHS基金会Adrian J. C. Bloor小组合作取得一项新成果。他们在类固醇难治性急性移植物抗宿主病(SR-aGvHD)患者中对iPSC衍生间质基质细胞的产生、安全性和有效性进行了I期、多中心、开放性、剂量递增研究。2020年9月14日的《自然-医学》发表了这项成果。

CYP-001(诱导多能干细胞(iPSC)衍生的间充质基质细胞(MSCs))是由经过优化、符合生产规范(GMP)的方法产生的。研究人员在SR-aGvHD受试者中进行了一项1期、开放性的临床试验(No. NCT02923375)。他们筛选了16名受试者,并依次分配到A或组B(每组n = 8)。B组中的一名受试者在接受CYP-001之前退出并被排除在分析之外。其他所有受试者在第0天和第7天接受CYP-001静脉输注,注射剂量为每公斤体重1×106个细胞,每次最大输注量为1×108个细胞(A组),或2×106个细胞每千克体重,最大剂量为每次输注2×108个细胞(B组)。

该研究的主要目标是评估CYP-001的安全性和耐受性,而次要目标是基于此方法显示出完全缓解(CR)、总体缓解(OR)和总体生存期(OS)参与者的比例来评估疗效时间28/100。CYP-001安全且耐受良好。没有与CYP-001相关的严重不良事件发生。到第100天,CR、OR和OS率分别为86.7、53.3和86.7%。现在可以在多种炎症和免疫疾病中探究iPSC来源MSC的治疗潜能。

据悉,已有研究证明了供体来源的MSCs在多种疾病治疗中的潜力,包括SR-aGvHD。但是,传统MSCs产生方法受到可扩展性和供体间可变性的阻碍,临床试验结果显示出不一致性。iPSC具有克服这些困难的潜力,因为它们具有多系分化和无限增殖的能力。尽管如此,以前尚未有iPSC衍生细胞的人体临床试验。

附:英文原文

Title: Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study

Author: Adrian J. C. Bloor, Amit Patel, James E. Griffin, Maria H. Gilleece, Rohini Radia, David T. Yeung, Diana Drier, Laurie S. Larson, Gene I. Uenishi, Derek Hei, Kilian Kelly, Igor Slukvin, John E. J. Rasko

Issue&Volume: 2020-09-14

Abstract: The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohortA or cohortB (n=8 per group). One subject in cohortB withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days0 and 7, at a dose level of either 1×106 cells per kg body weight, to a maximum of 1×108 cells per infusion (cohortA), or 2×106 cells per kg body weight, to a maximum dose of 2×108 cells per infusion (cohortB). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.

DOI: 10.1038/s41591-020-1050-x

Source: https://www.nature.com/articles/s41591-020-1050-x

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex

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