Advertisement

Safety, Efficacy, and Regulation of Mesenchymal Stromal/Stem Cells

  • Mimmi PatrikoskiEmail author
  • Kristiina Rajala
  • Susanna Miettinen
Chapter

Abstract

The scientific progress during the last decades has led to the development of cell therapy and tissue-engineered products that are moving rapidly into clinical application. Cranio-maxillofacial applications have paved the way for cell therapy and especially for tissue-engineered products. Cell-based medicinal products (CBMP) differ from conventional drug products, as they are often more complex and variable and less comprehensively characterizable. In addition, they often have complex mechanisms of action that remain incompletely understood. The overall risk/benefit to the proposed indication in certain patient population is evaluated with respect to the available data on quality, safety, and efficacy on a case-by-case basis. In this chapter, safety and efficacy of CBMP, especially mesenchymal stromal/stem cells (MSC)-based products, are discussed. The demonstration of quality, safety, efficacy, and comparability between production batches may be demanding for CBMP. Thus, a well-established and controlled manufacturing process is needed in order to produce a qualified product to guarantee reproducible data from nonclinical and clinical studies. In this chapter, we will also provide an overview of the regulation of CBMP in the European Union (EU) and the United States of America (US).

Keywords

Mesenchymal stromal/stem cells MSC Cell-based medicinal products Advanced medicinal products Safety Efficacy Cell therapy Clinical trials Regulation 

Notes

Acknowledgment

Permission to reproduce extracts from British Standards is granted by BSI Standards Limited (BSI). No other use of this material is permitted. British Standards can be obtained in PDF or hard copy format from the BSI online shop: www.bsigroup.com/Shop.

References

  1. 1.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Gimble JM, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003;5(5):362–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Mattar P, Bieback K. Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells. Front Immunol. 2015;6:560.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Berebichez-Fridman R, Montero-Olvera PR. Sources and clinical applications of mesenchymal stem cells: state-of-the-art review. Sultan Qaboos Univ Med J. 2018;18(3):e264–77.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Sandor GK, Numminen J, Wolff J, Thesleff T, Miettinen A, Tuovinen VJ, et al. Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. Stem Cells Transl Med. 2014;3(4):530–40.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Talaat WM, Ghoneim MM, Salah O, Adly OA. Autologous bone marrow concentrates and concentrated growth factors accelerate bone regeneration after enucleation of mandibular pathologic lesions. J Craniofac Surg. 2018;29(4):992–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Katagiri W, Osugi M, Kawai T, Hibi H. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med. 2016;12:5.  https://doi.org/10.1186/s13005-016-0101-5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Khojasteh A, Kheiri L, Behnia H, Tehranchi A, Nazeman P, Nadjmi N, et al. Lateral ramus cortical bone plate in alveolar cleft osteoplasty with concomitant use of buccal fat pad derived cells and autogenous bone: phase I clinical trial. Biomed Res Int. 2017;2017:6560234.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Baba S, Yamada Y, Komuro A, Yotsui Y, Umeda M, Shimuzutani K, et al. Phase I/II trial of autologous bone marrow stem cell transplantation with a three-dimensional woven-fabric scaffold for periodontitis. Stem Cells Int. 2016;2016:6205910.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Semont A, Francois S, Mouiseddine M, Francois A, Sache A, Frick J, et al. Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol. 2006;585:19–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Eterno V, Zambelli A, Pavesi L, Villani L, Zanini V, Petrolo G, et al. Adipose-derived mesenchymal stem cells (ASCs) may favour breast cancer recurrence via HGF/c-Met signaling. Oncotarget. 2014;5(3):613–33.PubMedCrossRefGoogle Scholar
  12. 12.
    Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–84.CrossRefGoogle Scholar
  13. 13.
    Mesimaki K, Lindroos B, Tornwall J, Mauno J, Lindqvist C, Kontio R, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009;38(3):201–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102(10):3837–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD. Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie. 2013;95(12):2235–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Fritz V, Jorgensen C. Mesenchymal stem cells: an emerging tool for cancer targeting and therapy. Curr Stem Cell Res Ther. 2008;3(1):32–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Karnoub AE, Weinberg RA. Chemokine networks and breast cancer metastasis. Breast Dis. 2006-2007;26:75–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Yu JL, Rak JW. Host microenvironment in breast cancer development: inflammatory and immune cells in tumour angiogenesis and arteriogenesis. Breast Cancer Res. 2003;5(2):83–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Delay E, Garson S, Tousson G, Sinna R. Fat injection to the breast: technique, results, and indications based on 880 procedures over 10 years. Aesthet Surg J. 2009;29(5):360–76.PubMedCrossRefGoogle Scholar
  21. 21.
    Kolle SF, Fischer-Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, Glovinski PV, et al. Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. Lancet. 2013;382(9898):1113–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Rigotti G, Marchi A, Stringhini P, Baroni G, Galie M, Molino AM, et al. Determining the oncological risk of autologous lipoaspirate grafting for post-mastectomy breast reconstruction. Aesthetic Plast Surg. 2010;34(4):475–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Rubio D, Garcia S, Paz MF, De la Cueva T, Lopez-Fernandez LA, Lloyd AC, et al. Molecular characterization of spontaneous mesenchymal stem cell transformation. PLoS One. 2008;3(1):e1398.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, et al. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65(8):3035–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Torsvik A, Rosland GV, Svendsen A, Molven A, Immervoll H, McCormack E, et al. Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track - letter. Cancer Res. 2010;70(15):6393–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Garcia S, Bernad A, Martin MC, Cigudosa JC, Garcia-Castro J, de la Fuente R. Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. Exp Cell Res. 2010;316(9):1648–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Grimes BR, Steiner CM, Merfeld-Clauss S, Traktuev DO, Smith D, Reese A, et al. Interphase FISH demonstrates that human adipose stromal cells maintain a high level of genomic stability in long-term culture. Stem Cells Dev. 2009;18(5):717–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Meza-Zepeda LA, Noer A, Dahl JA, Micci F, Myklebost O, Collas P. High-resolution analysis of genetic stability of human adipose tissue stem cells cultured to senescence. J Cell Mol Med. 2008;12(2):553–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Patrikoski M, Juntunen M, Boucher S, Campbell A, Vemuri MC, Mannerstrom B, et al. Development of fully defined xeno-free culture system for the preparation and propagation of cell therapy-compliant human adipose stem cells. Stem Cell Res Ther. 2013;4(2):27.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Blazquez-Prunera A, Diez JM, Gajardo R, Grancha S. Human mesenchymal stem cells maintain their phenotype, multipotentiality, and genetic stability when cultured using a defined xeno-free human plasma fraction. Stem Cell Res Ther. 2017;8(1):103.  https://doi.org/10.1186/s13287-017-0552-z.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chase LG, Yang S, Zachar V, Yang Z, Lakshmipathy U, Bradford J, et al. Development and characterization of a clinically compliant xeno-free culture medium in good manufacturing practice for human multipotent mesenchymal stem cells. Stem Cells Transl Med. 2012;1(10):750–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Haack-Sorensen M, Juhl M, Follin B, Harary Sondergaard R, Kirchhoff M, Kastrup J, et al. Development of large-scale manufacturing of adipose-derived stromal cells for clinical applications using bioreactors and human platelet lysate. Scand J Clin Lab Invest. 2018;78(4):293–300.PubMedCrossRefGoogle Scholar
  33. 33.
    Berger M, Muraro M, Fagioli F, Ferrari S. Osteosarcoma derived from donor stem cells carrying the Norrie’s disease gene. N Engl J Med. 2008;359(23):2502–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Bielack SS, Rerin JS, Dickerhoff R, Dilloo D, Kremens B, von Stackelberg A, et al. Osteosarcoma after allogeneic bone marrow transplantation. A report of four cases from the Cooperative Osteosarcoma Study Group (COSS). Bone Marrow Transplant. 2003;31(5):353–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Abarrategi A, Tornin J, Martinez-Cruzado L, Hamilton A, Martinez-Campos E, Rodrigo JP, et al. Osteosarcoma: cells-of-origin, cancer stem cells, and targeted therapies. Stem Cells Int. 2016;2016:3631764.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007;67(19):9142–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Choumerianou DM, Dimitriou H, Perdikogianni C, Martimianaki G, Riminucci M, Kalmanti M. Study of oncogenic transformation in ex vivo expanded mesenchymal cells, from paediatric bone marrow. Cell Prolif. 2008;41(6):909–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Xiao W, Mohseny AB, Hogendoorn PC, Cleton-Jansen AM. Mesenchymal stem cell transformation and sarcoma genesis. Clin Sarcoma Res. 2013;3(1):10.  https://doi.org/10.1186/2045-3329-3-10.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Guo CJ, Gao Y, Hou D, Shi DY, Tong XM, Shen D, et al. Preclinical transplantation and safety of HS/PCs expanded from human umbilical cord blood. World J Stem Cells. 2011;3(5):43–52.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: joint ASH and AABB educational session in transfusion medicine. Hematology Am Soc Hematol Educ Program. 2003:575–89.CrossRefGoogle Scholar
  41. 41.
    Galvez P, Clares B, Bermejo M, Hmadcha A, Soria B. Standard requirement of a microbiological quality control program for the manufacture of human mesenchymal stem cells for clinical use. Stem Cells Dev. 2014;23(10):1074–83.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Fennrich S, Hennig U, Toliashvili L, Schlensak C, Wendel HP, Stoppelkamp S. More than 70 years of pyrogen detection: current state and future perspectives. Altern Lab Anim. 2016;44(3):239–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Stormer M, Wood EM, Schurig U, Karo O, Spreitzer I, McDonald CP, et al. Bacterial safety of cell-based therapeutic preparations, focusing on haematopoietic progenitor cells. Vox Sang. 2014;106(4):285–96.PubMedCrossRefGoogle Scholar
  44. 44.
    European Medicines Agency (EMA). Guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011). Available at European Medicines Agency (EMA). Guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011). www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf. Accessed 7 Jan 2019.
  45. 45.
    Brennan MA, Renaud A, Guilloton F, Mebarki M, Trichet V, Sensebe L, et al. Inferior in vivo osteogenesis and superior angiogeneis of human adipose tissue: a comparison with bone marrow-derived stromal stem cells cultured in xeno-free conditions. Stem Cells Transl Med. 2017;6(12):2160–72.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov. 2013;12(8):569.PubMedCrossRefGoogle Scholar
  47. 47.
    Johal KS, Lees VC, Reid AJ. Adipose-derived stem cells: selecting for translational success. Regen Med. 2015;10(1):79–96.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    McGovern JA, Griffin M, Hutmacher DW. Animal models for bone tissue engineering and modelling disease. Dis Model Mech. 2018;11(4)  https://doi.org/10.1242/dmm.033084.CrossRefGoogle Scholar
  49. 49.
    Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507–12.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Correction for Takao and Miyakawa, Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2015;112(10):E1163-7.Google Scholar
  51. 51.
    Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2015;112(4):1167–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Skardal A, Shupe T, Atala A. Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. Drug Discov Today. 2016;21(9):1399-11.  https://doi.org/10.1016/j.drudis.2016.07.003.PubMedCrossRefGoogle Scholar
  53. 53.
    Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007;100(9):1249–60.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25(5):829–48.PubMedCrossRefGoogle Scholar
  55. 55.
    Gjerde C, Mustafa K, Hellem S, Rojewski M, Gjengedal H, Yassin MA, et al. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther. 2018;9(1):213.  https://doi.org/10.1186/s13287-018-0951-9.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Katagiri W, Watanabe J, Toyama N, Osugi M, Sakaguchi K, Hibi H. Clinical study of bone regeneration by conditioned medium from mesenchymal stem cells after maxillary sinus floor elevation. Implant Dent. 2017;26(4):607–12.PubMedCrossRefGoogle Scholar
  57. 57.
    Bajestan MN, Rajan A, Edwards SP, Aronovich S, Cevidanes LHS, Polymeri A, et al. Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: a randomized controlled, clinical trial. Clin Implant Dent Relat Res. 2017;19(5):793–801.PubMedCrossRefGoogle Scholar
  58. 58.
    Prins HJ, Schulten EA, Ten Bruggenkate CM, Klein-Nulend J, Helder MN. Bone regeneration using the freshly isolated autologous stromal vascular fraction of adipose tissue in combination with calcium phosphate ceramics. Stem Cells Transl Med. 2016;5(10):1362–74.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rickert D, Vissink A, Slot WJ, Sauerbier S, Meijer HJ, Raghoebar GM. Maxillary sinus floor elevation surgery with BioOss(R) mixed with a bone marrow concentrate or autogenous bone: test of principle on implant survival and clinical performance. Int J Oral Maxillofac Surg. 2014;43(2):243–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Heberer S, Wustlich A, Lage H, Nelson JJ, Nelson K. Osteogenic potential of mesenchymal cells embedded in the provisional matrix after a 6-week healing period in augmented and non-augmented extraction sockets: an immunohistochemical prospective pilot study in humans. Clin Oral Implants Res. 2012;23(1):19–27.PubMedCrossRefGoogle Scholar
  61. 61.
    Behnia H, Khojasteh A, Soleimani M, Tehranchi A, Atashi A. Repair of alveolar cleft defect with mesenchymal stem cells and platelet derived growth factors: a preliminary report. J Craniomaxillofac Surg. 2012;40(1):2–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM. Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res. 2011;22(3):251–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Hematti P. Characterization of mesenchymal stromal cells: potency assay development. Transfusion. 2016;56(4):32S–5S.PubMedCrossRefGoogle Scholar
  64. 64.
    Galipeau J, Krampera M, Barrett J, Dazzi F, Deans RJ, DeBruijn J, et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy. 2016;18(2):151–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Salmikangas P, Menezes-Ferreira M, Reischl I, Tsiftsoglou A, Kyselovic J, Borg JJ, et al. Manufacturing, characterization and control of cell-based medicinal products: challenging paradigms toward commercial use. Regen Med. 2015;10(1):65–78.PubMedCrossRefGoogle Scholar
  66. 66.
    Boran T, Menezes-Ferreira M, Reischl I, Celis P, Ferry N, Gansbacher B, et al. Clinical development and commercialization of advanced therapy medicinal products in the European Union: how are the product pipeline and regulatory framework evolving? Hum Gene Ther Clin Dev. 2017;28(3):126–35.PubMedCrossRefGoogle Scholar
  67. 67.
    Kassim SH, Somerville RP. From lipoproteins to chondrocytes: a brief summary of the European Medicines Agency’s regulatory guidelines for advanced therapy medicinal products. Hum Gene Ther. 2013;24(6):568–70.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bedford P, Jy J, Collins L, Keizer S. Considering cell therapy product “Good Manufacturing Practice” status. Front Med (Lausanne). 2018;5:118.CrossRefGoogle Scholar
  69. 69.
    Fink DW Jr. FDA regulation of stem cell-based products. Science. 2009;324(5935):1662–3.PubMedCrossRefGoogle Scholar
  70. 70.
    Knoepfler PS. From bench to FDA to bedside: US regulatory trends for new stem cell therapies. Adv Drug Deliv Rev. 2015;82–83:192–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mimmi Patrikoski
    • 1
    • 2
    • 3
    Email author
  • Kristiina Rajala
    • 1
    • 2
  • Susanna Miettinen
    • 1
    • 2
  1. 1.Adult Stem Cell Group, Faculty of Medicine and Health TechnologyTampere UniversityTampereFinland
  2. 2.Research, Development and Innovation CentreTampere University HospitalTampereFinland
  3. 3.Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland

Personalised recommendations