Haematology & Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK.
School of Medical Sciences, The University of Manchester, Manchester, UK.
Nat Med. 2020 Nov;26(11):1720-1725. doi: 10.1038/s41591-020-1050-x. Epub 2020 Sep 14.
The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases, including steroid-resistant acute graft versus host disease (SR-aGvHD). However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation. 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 phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 10 cells per kg body weight, to a maximum of 1 × 10 cells per infusion (cohort A), or 2 × 10 cells per kg body weight, to a maximum dose of 2 × 10 cells per infusion (cohort B). 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 days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 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.
供体来源间充质基质细胞（MSCs）的治疗潜力已在多种疾病中得到研究，包括类固醇耐药性急性移植物抗宿主病（SR-aGvHD）。然而，传统的制造方法受到可扩展性和供体间变异性的挑战，临床试验显示结果不一致。诱导多能干细胞（iPSCs）由于其多能性分化和无限增殖的能力，有可能克服这些挑战。尽管如此，以前尚未完成 iPSC 衍生细胞的人体临床试验。CYP-001（iPSC 衍生的 MSCs）是使用优化的、符合良好生产规范（GMP）的制造工艺生产的。我们在患有 SR-aGvHD 的受试者中进行了一项 1 期、开放标签临床试验（编号 NCT02923375）。16 名受试者被筛选并顺序分配到队列 A 或队列 B（每组 8 名）。队列 B 中的 1 名受试者在接受 CYP-001 治疗前退出，被排除在分析之外。所有其他受试者在第 0 天和第 7 天接受 CYP-001 的静脉输注，剂量水平为每公斤体重 1×10 个细胞，最大剂量为每输注 1×10 个细胞（队列 A），或每公斤体重 2×10 个细胞，最大剂量为每输注 2×10 个细胞（队列 B）。主要目的是评估 CYP-001 的安全性和耐受性，次要目的是根据接受 CYP-001 治疗的参与者中完全缓解（CR）、总体缓解（OR）和总体生存（OS）的比例评估疗效，到第 28/100 天。CYP-001 安全且耐受良好。没有评估与 CYP-001 相关的严重不良事件。到第 100 天的 OR、CR 和 OS 率分别为 86.7%、53.3%和 86.7%。iPSC 衍生的 MSCs 的治疗应用现在可以在多种炎症和免疫介导的疾病中进行探索。
