The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Allogeneic clonal mesenchymal stem cell therapy for refractory graft-versus-host disease to standard treatment: a phase I study

  • Yi, Hyeon Gyu (Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine) ;
  • Yahng, Seung-Ah (Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea) ;
  • Kim, Inho (Department of Internal Medicine, Seoul National University Hospital, Seoul National University School of Medicine) ;
  • Lee, Je-Hwan (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Min, Chang-Ki (Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Kim, Jun Hyung (Translational Research Center, Inha University School of Medicine and SCM Lifescience Co., Ltd.) ;
  • Kim, Chul Soo (Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine) ;
  • Song, Sun U. (Translational Research Center, Inha University School of Medicine and SCM Lifescience Co., Ltd.)
  • Received : 2015.07.24
  • Accepted : 2015.09.11
  • Published : 2016.01.01
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Abstract

Severe graft-versus-host disease (GVHD) is an often lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). The safety of clinical-grade mesenchymal stem cells (MSCs) has been validated, but mixed results have been obtained due to heterogeneity of the MSCs. In this phase I study, the safety of bone marrow-derived homogeneous clonal MSCs (cMSCs) isolated by a new subfractionation culturing method was evaluated. cMSCs were produced in a GMP facility and intravenously administered to patients who had refractory GVHD to standard treatment resulting after allogeneic HSCT for hematologic malignancies. After administration of a single dose ($1{\times}10^6cells/kg$), 11 patients were evaluated for cMSC treatment safety and efficacy. During the trial, nine patients had 85 total adverse events and the rate of serious adverse events was 27.3% (3/11 patients). The only one adverse drug reaction related to cMSC administration was grade 2 myalgia in one patient. Treatment response was observed in four patients: one with acute GVHD (partial response) and three with chronic GVHD. The other chronic patients maintained stable disease during the observation period. This study demonstrates single cMSC infusion to have an acceptable safety profile and promising efficacy, suggesting that we can proceed with the next stage of the clinical trial.

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References

  1. Garnett C, Apperley JF, Pavlu J. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol. 2013;4:366-378. https://doi.org/10.1177/2040620713489842
  2. Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant. 2012;18:982-988. https://doi.org/10.1016/j.bbmt.2012.04.006
  3. Sellar RS, Peggs KS. Recent progress in managing graft-versus-host disease and viral infections following allogeneic stem cell transplantation. Future Oncol. 2012;8:1549-1565. https://doi.org/10.2217/fon.12.153
  4. Battiwalla M, Hematti P. Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy. 2009;11:503-515. https://doi.org/10.1080/14653240903193806
  5. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579-1586. https://doi.org/10.1016/S0140-6736(08)60690-X
  6. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-1441. https://doi.org/10.1016/S0140-6736(04)16104-7
  7. Herrmann R, Sturm M, Shaw K, Purtill D, Cooney J, Wright M, Phillips M, Cannell P. Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study. Int J Hematol. 2012;95:182-188. https://doi.org/10.1007/s12185-011-0989-2
  8. Muroi K, Miyamura K, Ohashi K, Murata M, Eto T, Kobayashi N, Taniguchi S, Imamura M, Ando K, Kato S, Mori T, Teshima T, Mori M, Ozawa K. Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study. Int J Hematol. 2013;98:206-213. https://doi.org/10.1007/s12185-013-1399-4
  9. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559. https://doi.org/10.1371/journal.pone.0047559
  10. Bernardo ME, Fibbe WE. Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders. Ann N Y Acad Sci. 2012;1266:107-117. https://doi.org/10.1111/j.1749-6632.2012.06667.x
  11. Song SU, Kim CS, Yoon SP, Kim SK, Lee MH, Kang JS, Choi GS, Moon SH, Choi MS, Cho YK, Son BK. Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion. Stem Cells Dev. 2008;17:451-461. https://doi.org/10.1089/scd.2007.0167
  12. Lim JH, Lee MH, Yi HG, Kim CS, Kim JH, Song SU. Mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease: a report of two cases. Int J Hematol. 2010;92:204-207. https://doi.org/10.1007/s12185-010-0606-9
  13. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828.
  14. Pavletic SZ, Lee SJ, Socie G, Vogelsang G. Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow Transplant. 2006;38:645-651. https://doi.org/10.1038/sj.bmt.1705490
  15. Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, Koc ON. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant. 2004;33:597-604. https://doi.org/10.1038/sj.bmt.1704400
  16. Tian Y, Deng YB, Huang YJ, Na XD, Li Y, Ye MH. Role of bone marrow-derived mesenchymal stem cells in reduction of graft-versus-host disease by effecting CD4+CD25+ regulatory T cells in rats. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006;14:1210-1214.
  17. Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006;24:2582-2591. https://doi.org/10.1634/stemcells.2006-0228

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