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Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation

  • Stem Cell Transplantation (R Maziarz, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, delayed hematopoietic and immunologic recovery remains a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.

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References

  1. Sebrango A et al. Haematopoietic transplants combining a single unrelated cord blood unit and mobilized haematopoietic stem cells from an adult HLA-mismatched third party donor. Comparable results to transplants from HLA-identical related donors in adults with acute leukaemia and myelodysplastic syndromes. Best Pract Res Clin Haematol. 2010;23(2):259–74.

    Article  PubMed  Google Scholar 

  2. Liu H et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood. 2011;118(24):6438–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Peffault de Latour R et al. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. Biol Blood Marrow Transplant. 2013;19(9):1355–60.

    Article  PubMed  Google Scholar 

  4. Smith AR et al. Hematopoietic cell transplantation for children with acute lymphoblastic leukemia in second complete remission: similar outcomes in recipients of unrelated marrow and umbilical cord blood versus marrow from HLA matched sibling donors. Biol Blood Marrow Transplant. 2009;15(9):1086–93.

    Article  PubMed  Google Scholar 

  5. Jaroscak J et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell system. Blood. 2003;101(12):5061–7.

    Article  CAS  PubMed  Google Scholar 

  6. Scaradavou A et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013;121(5):752–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barker JN et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105(3):1343–7.

    Article  CAS  PubMed  Google Scholar 

  8. Milner LA et al. A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood. 1994;83(8):2057–62.

    CAS  PubMed  Google Scholar 

  9. Delaney C et al. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood. 2005;106(8):2693–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Delaney C et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16(2):232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gutman JA et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood. 2010;115(4):757–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moretta A et al. In vitro evaluation of graft-versus-graft alloreactivity as a tool to identify the predominant cord blood unit before double cord blood transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2012;18(7):1108–18.

    Article  Google Scholar 

  13. Delaney C. Infusion of Non-HLA matched, off-the-shelf ex vivo expanded cord blood progenitor cells in patients undergoing myeloablative cord blood transplantation is safe and decreases the time to neutrophil recovery. Biol Blood Marrow Transplant. 2012;18(2):S203.

    Article  Google Scholar 

  14. Peled T et al. Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice. Exp Hematol. 2004;32(6):547–55.

    Article  CAS  PubMed  Google Scholar 

  15. Peled T et al. Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine. Cytotherapy. 2004;6(4):344–55.

    Article  CAS  PubMed  Google Scholar 

  16. de Lima M et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant. 2008.

  17. Stiff PM et al. StemEx® (copper chelation based) ex vivo expanded Umbilical Cord Blood Stem Cell Transplantation (UCBT) accelerates engraftment and improves 100 day survival in myeloablated patients compared to a registry cohort undergoing double unit UCBT: results of a multicenter study of 101 patients with hematologic malignancies. Blood. 2013;122(295):3060.

    Google Scholar 

  18. Peled T et al. Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol. 2012;40(4):342–55.e1.

    Article  CAS  PubMed  Google Scholar 

  19. Horwitz ME et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. 2014;124(7):3121–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Briddell RA et al. Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential. Blood. 1993;82(6):1720–3.

    CAS  PubMed  Google Scholar 

  21. McNiece I et al. Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells. Cytotherapy. 2004;6(4):311–7.

    Article  CAS  PubMed  Google Scholar 

  22. de Lima M et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med. 2012;367(24):2305–15.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Boitano AE et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010;329(5997):1345–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wagner JE et al. StemRegenin-1 (SR1) Expansion Culture Abrogates the Engraftment Barrier Associated with Umbilical Cord Bood Transplantation. Abstract to be presented at the 56th American Society of Hematology Meeting and Exposition. 2014.

  25. North TE et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447(7147):1007–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cutler C et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013;122(17):3074–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ratajczak J et al. Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood. 2004;103(6):2071–8.

    Article  CAS  PubMed  Google Scholar 

  28. Reca R et al. Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. Blood. 2003;101(10):3784–93.

    Article  CAS  PubMed  Google Scholar 

  29. Brunstein CG et al. Complement fragment 3a priming of umbilical cord blood progenitors: safety profile. Biol Blood Marrow Transplant. 2013;19(10):1474–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hidalgo A et al. Functional selectin ligands mediating human CD34(+) cell interactions with bone marrow endothelium are enhanced postnatally. J Clin Invest. 2002;110(4):559–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Robinson SN et al. Fucosylation with fucosyltransferase VI or fucosyltransferase VII improves cord blood engraftment. Cytotherapy. 2014;16(1):84–9.

    Article  CAS  PubMed  Google Scholar 

  32. Xia L et al. Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood. 2004;104(10):3091–6.

    Article  CAS  PubMed  Google Scholar 

  33. Popat U et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood. 2015;125(19):2885–92.

    Article  CAS  PubMed  Google Scholar 

  34. Robinson SN et al. Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rgamma(null) mice. Exp Hematol. 2012;40(6):445–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Adult Blood and Marrow Transplant Program, Duke University School of Medicine, 2400 Pratt St. DUMC 3961, Durham, NC, 27710, USA

    Mitchell E. Horwitz

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  1. Mitchell E. Horwitz
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Correspondence to Mitchell E. Horwitz.

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Conflict of Interest

Mitchell Horwitz has received research support from and has served as a consultant for Gamida Cell Ltd.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Stem Cell Transplantation

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Horwitz, M.E. Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation. Curr Hematol Malig Rep 11, 12–18 (2016). https://doi.org/10.1007/s11899-015-0297-7

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  • DOI: https://doi.org/10.1007/s11899-015-0297-7

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