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Immunological influence of serum-free manufactured umbilical cord-derived mesenchymal stromal cells for steroid-resistant acute graft-versus-host disease

Abstract

This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr).

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Data availability statement

Deidentified individual participant data that underlie the reported results will be made available 3 months after publication for a period of 5 years after the publication date. Requests should be sent to tokikoni@ims.u-tokyo.ac.jp.

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Acknowledgements

We thank Yamamoto Y. and Miharu Y. at the Institute of Medical Science, University of Tokyo (IMSUT) for manufacturing products, performing quality management, and providing technical support. We thank Saito Y. at IMSUT Hospital for clinical trial preparations. We thank Tsunoda H., Sugita M., Satoh N., and the staff at NTT Medical Center Hospital (Tokyo), and Yamaguchi S. and the staff at Yamaguchi Hospital, for performing UC tissue and CB collection after obtaining informed consent. We thank the clinical coordinators and nurses at IMSUT Hospital, Komagome Hospital, and Toranomon Hospital for their continuous support during the clinical trial and Dr. Hanaoka and all staff at the Clinical Research Center of Chiba University Hospital. We thank Dr. Narita M at the School of Health Sciences, Faculty of Medicine, Niigata University, for providing PMDC05 cell line.

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) (Project number: 17bk0104070h0001/18bk0104070h0002/19bk0104070h0003/20bk01041h0001/21bk0104109h0002). AMED No. 21be0804004h0001 supports the stable delivery of the source of somatic stem cells to researchers and companies as cord blood and UC-MSC medical product.

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Correspondence to Tokiko Nagamura-Inoue.

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Conflict of interest

The study was partially supported by the joint research study of the University of Tokyo with Rohto Pharmaceutical Co. Ltd. in the development of culture medium and processing (December 2014, December to March 2020) and the joint study of the University of Tokyo with Human Life Cord Japan Inc. in the development of banking and clinical application (September 2017–). Nagamura-Inoue is the senior medical advisor of Human Life Cord Japan Inc.

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Nagamura-Inoue, T., Kato, S., Najima, Y. et al. Immunological influence of serum-free manufactured umbilical cord-derived mesenchymal stromal cells for steroid-resistant acute graft-versus-host disease. Int J Hematol (2022). https://doi.org/10.1007/s12185-022-03408-7

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  • DOI: https://doi.org/10.1007/s12185-022-03408-7

Keywords

  • Mesenchymal stromal cell
  • Umbilical cord
  • Acute GVHD
  • Clinical trial
  • Umbilical cord-derived mesenchymal stromal cells (UC-MSCs)