臨床研究揭示iPSC衍生MSCs在難治性急性移植物抗宿主病患者中的應用
作者：
小柯機器人發布時間：2020/9/17 15:08:41
澳大利亞皇家阿爾弗雷德王子醫院John E. J. Rasko和英國Christie NHS基金會Adrian J. C. Bloor小組合作取得一項新成果。他們在類固醇難治性急性移植物抗宿主病（SR-aGvHD）患者中對iPSC衍生間質基質細胞的產生、安全性和有效性進行了I期、多中心、開放性、劑量遞增研究。2020年9月14日的《自然-醫學》發表了這項成果。
CYP-001（誘導多能幹細胞（iPSC）衍生的間充質基質細胞（MSCs））是由經過優化、符合生產規範（GMP）的方法產生的。研究人員在SR-aGvHD受試者中進行了一項1期、開放性的臨床試驗（No. NCT02923375）。他們篩選了16名受試者，並依次分配到A或組B（每組n = 8）。B組中的一名受試者在接受CYP-001之前退出並被排除在分析之外。其他所有受試者在第0天和第7天接受CYP-001靜脈輸注，注射劑量為每公斤體重1×106個細胞，每次最大輸注量為1×108個細胞（A組），或2×106個細胞每千克體重，最大劑量為每次輸注2×108個細胞（B組）。
該研究的主要目標是評估CYP-001的安全性和耐受性，而次要目標是基於此方法顯示出完全緩解（CR）、總體緩解（OR）和總體生存期（OS）參與者的比例來評估療效時間28/100。CYP-001安全且耐受良好。沒有與CYP-001相關的嚴重不良事件發生。到第100天，CR、OR和OS率分別為86.7、53.3和86.7％。現在可以在多種炎症和免疫疾病中探究iPSC來源MSC的治療潛能。
據悉，已有研究證明了供體來源的MSCs在多種疾病治療中的潛力，包括SR-aGvHD。但是，傳統MSCs產生方法受到可擴展性和供體間可變性的阻礙，臨床試驗結果顯示出不一致性。iPSC具有克服這些困難的潛力，因為它們具有多系分化和無限增殖的能力。儘管如此，以前尚未有iPSC衍生細胞的人體臨床試驗。
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