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

• Published in: Nature medicine Vol. 26; no. 11; pp. 1720 - 1725
• Main Authors: Bloor, Adrian J. C., Patel, Amit, Griffin, James E., Gilleece, Maria H., Radia, Rohini, Yeung, David T., Drier, Diana, Larson, Laurie S., Uenishi, Gene I., Hei, Derek, Kelly, Kilian, Slukvin, Igor, Rasko, John E. J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/532/2064/2158; 631/532/2118/2074; 692/699/249/1529; Adolescent; Adult; Aged; Biomedical and Life Sciences; Biomedicine; Body weight; Cancer Research; Care and treatment; Clinical trials; Disease; Dosage; Drug Resistance; Female; Good Manufacturing Practice; Graft versus host reaction; Graft vs Host Disease - pathology; Graft vs Host Disease - therapy; Grafting; Humans; Induced Pluripotent Stem Cells - transplantation; Infectious Diseases; Intravenous administration; Letter; Male; Manufacturing; Manufacturing industry; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchyme; Metabolic Diseases; Middle Aged; Molecular Medicine; Neurosciences; Pluripotency; Remission Induction - methods; Safety; Stem cells; Steroids; Steroids - adverse effects; Steroids - therapeutic use; Stromal cells; Survival Rate; Testing; Young Adult; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-020-1050-x

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases 1 , 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 outcomes 3 , 4 . Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation 5 , 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 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 6 cells per kg body weight, to a maximum of 1 × 10 8 cells per infusion (cohort A), or 2 × 10 6 cells per kg body weight, to a maximum dose of 2 × 10 8 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. A GMP-compliant process for generating human iPSC-derived mesenchymal stromal cells tested in a phase 1 trial is safe and well tolerated in subjects with acute steroid-resistant graft versus host disease.