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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

Nature Medicine volume 26, pages 1720–1725 (2020)Cite this article

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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 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 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 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.

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Fig. 1: Overview of the CYP-001 manufacturing process.
Fig. 2: Change in aGvHD status and best response in individual subjects by day 100.

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Data availability

All reasonable requests for raw and analyzed data that are not included in this manuscript or online content will be promptly reviewed by the senior authors to determine whether the request is subject to any intellectual property or confidentiality obligations. Patient-related data may be subject to patient confidentiality restrictions. Any data and materials that can be shared will be released via a material transfer agreement. All raw and analyzed global gene expression data can be found at the NCBI Gene Expression Archive (accession no. GSE150969).

References

  1. Kabat, M., Bobkov, I., Kumar, S. & Grumet, M. Trends in mesenchymal stem cell clinical trials 2004–2018: is efficacy optimal in a narrow dose range? Stem Cells Transl. Med. 9, 17–27 (2020).

    CAS  PubMed  Google Scholar 

  2. Elgaz, S. et al. Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfus. Med. Hemother. 46, 27–34 (2019).

    PubMed  PubMed Central  Google Scholar 

  3. Galipeau, J. The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15, 2–8 (2013).

    PubMed  Google Scholar 

  4. François, M. et al. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol. Ther. 20, 187–195 (2012).

    PubMed  Google Scholar 

  5. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  6. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  PubMed  Google Scholar 

  7. Galipeau, J. & Sensébé, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Harrell, C. R. et al. Mesenchymal stem cell–derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells 8, 1605 (2019).

    CAS  PubMed Central  Google Scholar 

  9. Galleu, A. et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med. 9, 7828 (2017).

    Google Scholar 

  10. Sharma, R. R. et al. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 54, 1418–1437 (2014).

    CAS  PubMed  Google Scholar 

  11. Wegmeyer, H. et al. Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev. 22, 2606–2618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Martin, I. et al. Challenges for mesenchymal stromal cell therapies. Sci. Transl. Med. 20, eaat2189 (2019).

    Google Scholar 

  13. Ketterl, N. et al. A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance. Stem Cell Res. Ther. 6, 236 (2015).

    PubMed  PubMed Central  Google Scholar 

  14. Siegel, G. et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 11, 146 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wagner, W. et al. Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS ONE 5, e2213 (2008).

    Google Scholar 

  16. von Bahr, L. et al. Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol. Blood Marrow Transplant. 18, 557–564 (2012).

    Google Scholar 

  17. Garnett, C. et al. Treatment and management of graft-versus-host disease: improving response and survival. Ther. Adv. Hematol. 4, 366–378 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).

    PubMed  Google Scholar 

  19. Ozay, E. I. et al. Cymerus™ iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of graft-vs-host disease. Stem Cell Res. 35, 101401 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Vodyanik, M. A. et al. A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell 7, 718–729 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Slukvin, I. I. & Kumar, A. The mesenchymoangioblast, mesodermal precursor for mesenchymal and endothelial cells. Cell. Mol. Life Sci. 75, 3507–3520 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen, G. et al. Chemically defined conditions for human iPS cell derivation and culture. Nat. Methods 8, 424–429 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Uenishi, G. et al. Tenascin C promotes hematoendothelial development and T lymphoid commitment from human pluripotent stem cells in chemically defined conditions. Stem Cell Rep. 3, 1073–1084 (2014).

    CAS  Google Scholar 

  24. Slukvin, I., Uenishi, G., Hei, D. & Drier, D. Colony forming medium and use thereof. Patent WO2017156580A1 (2017).

  25. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  26. Bader, P. et al. Effective treatment of steroid and therapy-refractory acute graft versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 53, 852–862 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kebriaei, P. et al. A phase 3 randomized study of remestemcel-L versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease. Biol. Blood Marrow Transplant. 26, 835–844 (2020).

    CAS  PubMed  Google Scholar 

  28. Zeiser, R. et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N. Engl. J. Med. 382, 1800–1810 (2020).

    PubMed  Google Scholar 

  29. Jagasia, M. et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 2 trial. Blood 135, 1739–1749 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Park, J. H. et al. Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation. Korean J. Intern. Med. 29, 630–636 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. De Jong, C. N. et al. Etanercept for steroid-refractory acute graft-versus-host disease: a single center experience. PLoS ONE 12, e0187184 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. Greinix, H. T. et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood 96, 2426–2431 (2000).

    CAS  PubMed  Google Scholar 

  33. Koch, J. M. et al. Mesenchymoangioblast-derived mesenchymal stromal cells inhibit cell damage, tissue damage and improve peripheral blood flow following hindlimb ischemic injury in mice. Cytotherapy 18, 219–228 (2016).

    CAS  PubMed  Google Scholar 

  34. Royce, S. G. et al. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. FASEB J. 31, 4168–4178 (2017).

    CAS  PubMed  Google Scholar 

  35. Royce, S. G. et al. iPSC- and mesenchymoangioblast-derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid. FASEB J. 33, 6402–6411 (2019).

    CAS  PubMed  Google Scholar 

  36. Khan, M. A. et al. iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants. Stem Cell Res. Ther. 10, 290 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. Millar, J. E. et al. Combined mesenchymal stromal cell therapy and ECMO in ARDS: a controlled experimental study in sheep. Am. J. Respir. Crit. Care Med. https://doi.org/10.1164/rccm.201911-2143OC (2020).

  38. Mandai, M., Kurimoto, Y. & Takahashi, M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 377, 792–793 (2017).

    PubMed  Google Scholar 

  39. Ylä-Herttuala, S. iPSC-derived cardiomyocytes taken to rescue infarcted heart muscle in coronary heart disease patients. Mol. Ther. 26, 2077 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. Stoddard-Bennett, T. & Reijo Pera, R. Treatment of Parkinson’s disease through personalized medicine and induced pluripotent stem cells. Cells 8, 26 (2019).

    CAS  PubMed Central  Google Scholar 

  41. Mack, A. A. et al. Generation of induced pluripotent stem cells from CD34+ cells across blood drawn from multiple donors with non-integrating episomal vectors. PLoS ONE 6, e27956 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Borowicz, S. et al. The soft agar colony formation assay. J. Vis. Exp. 92, e51998 (2014).

    Google Scholar 

  43. Przepiorka, D. et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 15, 825–828 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the University of Wisconsin Bioinformatics Resource Center for providing mRNA-seq analysis services, and all site investigators, coinvestigators, study coordinators, other study staff and study participants. Medical writer C. Markey, of Markey Medical Consulting Pty Ltd, assisted in the preparation of an earlier version of a draft manuscript describing this work. J.E.J.R. is supported by a National Health and Medical Research Council Investigator Grant (1177305) for ‘driving clinical cell and gene therapy in Australia’, as well as funding from Cure the Future, Therapeutic Innovation Australia and an anonymous foundation.

Author information

Authors and Affiliations

  1. Haematology & Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK

    Adrian J. C. Bloor & Amit Patel

  2. School of Medical Sciences, The University of Manchester, Manchester, UK

    Adrian J. C. Bloor

  3. Department of Bone Marrow Transplantation, University Hospitals Bristol NHS Foundation Trust, Bristol, UK

    James E. Griffin

  4. Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    Maria H. Gilleece

  5. Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK

    Rohini Radia

  6. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    David T. Yeung

  7. Royal Adelaide Hospital, Adelaide, South Australia, Australia

    David T. Yeung

  8. Waisman Biomanufacturing, University of Wisconsin–Madison, Madison, WI, USA

    Diana Drier & Laurie S. Larson

  9. Department of Cell and Regenerative Biology, University of Wisconsin–Madison, Madison, WI, USA

    Gene I. Uenishi & Igor Slukvin

  10. BlueRock Therapeutics, Cambridge, MA, USA

    Derek Hei

  11. Cynata Therapeutics Limited, Carlton, Victoria, Australia

    Kilian Kelly

  12. Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

    John E. J. Rasko

  13. Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Sydney, New South Wales, Australia

    John E. J. Rasko

  14. Central Clinical School, Faculty of Medicine & Health, University of Sydney, Sydney, New South Wales, Australia

    John E. J. Rasko

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Contributions

I.S., G.I.U., D.D. and D.H. developed and optimized the manufacturing process. I.S., D.D., D.H. and L.S.L. developed and optimized quality control assays and designed the experiment to verify that iPSCs do not survive M-CFM culture. K.K. designed the clinical trial and wrote the protocol. A.J.C.B., A.P., J.E.G., M.H.G., R.R., D.T.Y. and J.E.J.R. were principal investigators in the clinical trial. K.K. and J.E.J.R. prepared the first drafts of the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Adrian J. C. Bloor or John E. J. Rasko.

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Competing interests

Patent applications (some of which have been granted) covering aspects of the technology described in this manuscript have been filed by Wisconsin Alumni Research Foundation (which invests in the University of Wisconsin-Madison), Cellular Dynamics International (now FUJIFILM Cellular Dynamics) and Cynata Therapeutics. The patents with inventors including D.D., D.H., G.I.U., K.K. and I.S. cover the processes used to generate iPSCs and differentiate iPSCs into MSCs, as well as the residual undifferentiated iPSC assay. Cynata Therapeutics funded the work described in this manuscript. K.K. is an employee and shareholder of Cynata Therapeutics. I.S. is a cofounder, shareholder and scientific advisor of Cynata Therapeutics. L.S.L. and D.D. are employees of Waisman Biomanufacturing, University of Wisconsin-Madison, which provides contract manufacturing services to Cynata Therapeutics. D.H. is a former employee of both Waisman Biomanufacturing and Cellular Dynamics International. G.I.U. and J.E.J.R. have received travel grants from Cynata Therapeutics. A.J.C.B., A.P., J.E.G., M.H.G., R.R. and D.T.Y. declare no relevant competing interests.

Additional information

Peer review information Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 mRNAseq global gene expression analysis showing gene correlation and Pearson correlation coefficients.

mRNAseq global gene expression (transcriptome) analysis from three batches (CYN-IPSC-MSC-P5B-FP-001; CYN-IPSC-MSC-P5B-FP-002; CYN-IPSC-MSC-P5B-FP-003) showing gene correlation [log[2](TPM+1)] and Pearson correlation coefficients (R).

Extended Data Fig. 2 mRNAseq global gene expression analysis showing isoform correlation and Pearson correlation coefficients.

mRNAseq global gene expression (transcriptome) analysis from three batches (CYN-IPSC-MSC-P5B-FP-001; CYN-IPSC-MSC-P5B-FP-002; CYN-IPSC-MSC-P5B-FP-003) showing isoform correlation [log[2](TPM+1)] and Pearson correlation coefficients (R).

Extended Data Fig. 3 CONSORT diagram.

Clinical trial summary (CONSORT diagram).

Supplementary information

Supplementary Information

Supplementary Tables 1–11.

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Bloor, A.J.C., Patel, A., Griffin, J.E. et al. 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. Nat Med 26, 1720–1725 (2020). https://doi.org/10.1038/s41591-020-1050-x

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