Skip to main content

Ex Vivo Cord Blood Manipulation: Methods, Data, and Challenges

  • Chapter
  • First Online:

Abstract

Low cell content of umbilical cord blood (UCB) graft contributes to high risk of graft rejection, delayed engraftment, and poor immune reconstitution, consequently leading to risk of relapse and infections after UCB transplantation (UCBT). With ex vivo UCB graft expansion techniques, cell dose can be augmented exponentially. Many of these novel methods demonstrated significantly faster time to neutrophil and platelet engraftment as compared with unmanipulated UCBT. Other innovative methods are focusing on improving the inherent bone marrow homing defect of UCB progenitor cells, without actual expansion of the graft. Not only this, graft engineering techniques allow for expansion of UCB natural killer cells, T cells, and regulatory T cells to prevent or treat infections, disease relapse, and graft-versus-host disease, which are the most common causes of morbidity and mortality after UCBT. Herein, we review various graft manipulation methods and their clinical outcomes.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Atsuta Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S et al (2009) Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood 113(8):1631–1638

    Article  PubMed  Google Scholar 

  • Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS et al (2005) Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105(3):1343–1347

    Article  CAS  PubMed  Google Scholar 

  • Barker JN, Fei M, Karanes C, Horwitz M, Devine S, Kindwall-Keller TL et al (2015) Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia. Br J Haematol 168(3):405–412

    Article  PubMed  Google Scholar 

  • Barrett AJ, Bollard CM (2015) The coming of age of adoptive T-cell therapy for viral infection after stem cell transplantation. Ann Transl Med 3(5):62

    PubMed  PubMed Central  Google Scholar 

  • Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA et al (2010) Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 116(22):4693–4699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3):1061–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE et al (2012) Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood 119(23):5591–5598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D et al (2016) Umbilical cord blood-derived T regulatory cells to prevent GvHD: kinetics, toxicity profile, and clinical effect. Blood 127(8):1044–1051

    Google Scholar 

  • Chen YB, Aldridge J, Kim HT, Ballen KK, Cutler C, Kao G et al (2012) Reduced-intensity conditioning stem cell transplantation: comparison of double umbilical cord blood and unrelated donor grafts. Biol Blood Marrow Transplant 18(5):805–812

    Article  PubMed  Google Scholar 

  • Christopherson KW 2nd, Hangoc G, Broxmeyer HE (2002) Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 169(12):7000–7008

    Google Scholar 

  • Christopherson KW 2nd, Hangoc G, Mantel CR, Broxmeyer HE (2004) Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 305(5686):1000–1003

    Article  CAS  PubMed  Google Scholar 

  • Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J et al (2013) Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122(17):3074–3081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M et al (2012) Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med 367(24):2305–2315

    Article  PubMed  PubMed Central  Google Scholar 

  • Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID (2010) Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 16(2):232–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL et al (2012) Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One 7(1):e30264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W et al (2010) Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 11(7):653–660

    Article  PubMed  PubMed Central  Google Scholar 

  • Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M, Khalil M et al (2009) Functionally active virus-specific T-cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood 114(9):1958–1967

    Google Scholar 

  • Hanley P, Leen A, Gee AP, Leung K, Martinez C, Krance RA et al (2013) Multi-virus-specific T-cell therapy for patients after hematopoietic stem cell and cord blood transplantation. Blood 122(21):140

    Google Scholar 

  • Hoggatt J, Singh P, Sampath J, Pelus LM (2009) Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 113(22):5444–5455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C et al (2014) Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 124(7):3121–3128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huls MH, Figliola MJ, Dawson MJ, Olivares S, Kebriaei P, Shpall EJ et al (2013) Clinical application of sleeping beauty and artificial antigen presenting cells to genetically modify T-cells from peripheral and umbilical cord blood. J Vis Exp 72:e50070

    Google Scholar 

  • Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA et al (2003) Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell system. Blood 101(12):5061–5067

    Article  CAS  PubMed  Google Scholar 

  • Kebriaei P, Huls H, Singh H, Olivares S, Figliola M, Kumar PR et al (2013) First clinical trials employing sleeping beauty gene transfer system and artificial antigen presenting cells to generate and infuse T-cells expressing CD19-specific chimeric antigen receptor. Blood 122(21):166

    Google Scholar 

  • Kindwall-Keller TL, Hegerfeldt Y, Meyerson HJ, Margevicius S, Fu P, van Heeckeren W et al (2012) Prospective study of one- vs two-unit umbilical cord blood transplantation following reduced intensity conditioning in adults with hematological malignancies. Bone Marrow Transplant 47(7):924–933

    Article  CAS  PubMed  Google Scholar 

  • Koller MR, Palsson MA, Manchel I, Palsson BO (1995) Long-term culture-initiating cell expansion is dependent on frequent medium exchange combined with stromal and other accessory cell effects. Blood 86(5):1784–1793

    CAS  PubMed  Google Scholar 

  • Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE et al (2004) Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351(22):2265–2275

    Article  CAS  PubMed  Google Scholar 

  • Le Bourgeois A, Mohr C, Guillaume T, Delaunay J, Malard F, Loirat M et al (2013) Comparison of outcomes after two standards-of-care reduced-intensity conditioning regimens and two different graft sources for allogeneic stem cell transplantation in adults with hematologic diseases: a single-center analysis. Biol Blood Marrow Transplant 19(6):934–939

    Article  PubMed  Google Scholar 

  • Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH et al (2013) Multicenter study of banked third-party virus-specific T-cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121(26):5113–5123

    Google Scholar 

  • Liu HL, Sun ZM, Geng LQ, Wang XB, Ding KY, Tong J et al (2014) Similar survival, but better quality of life after myeloablative transplantation using unrelated cord blood vs matched sibling donors in adults with hematologic malignancies. Bone Marrow Transplant 49(8):1063–1069

    Article  CAS  PubMed  Google Scholar 

  • Majhail NS, Brunstein CG, Tomblyn M, Thomas AJ, Miller JS, Arora M et al (2008) Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant 14(3):282–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majhail NS, Brunstein CG, Shanley R, Sandhu K, McClune B, Oran B et al (2012) Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors. Bone Marrow Transplant 47(4):494–498

    Article  CAS  PubMed  Google Scholar 

  • Micklethwaite KP, Savoldo B, Hanley PJ, Leen AM, Demmler-Harrison GJ, Cooper LJ et al (2010) Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. Blood 115(13):2695–2703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park KD, Marti L, Kurtzberg J, Szabolcs P (2006) In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T-cells from naive cord blood lymphocytes. Blood 108(5):1770–1773

    Google Scholar 

  • Parmar S, Robinson SN, Komanduri K, St John L, Decker W, Xing D et al (2006) Ex vivo expanded umbilical cord blood T-cells maintain naive phenotype and TCR diversity. Cytotherapy 8(2):149–157

    Google Scholar 

  • Pasquini MC, Zhu X (2015) Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2015. Available at: http://www.cibmtr.org

  • Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN et al (2015) IL-12-secreting CD19-targeted cord blood-derived T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29(2):415–422

    Google Scholar 

  • Peled T, Adi S, Peleg I, Rosenheimer NG, Daniely Y, Nagler A, et al. (2006) Nicotinamide modulates ex-vivo expansion of cord blood derived CD34+ cells cultured with cytokines and promotes their homing and engraftment in SCID mice. Blood;108(Abstract 725):Oral Session, ASH December 12, 2006

    Google Scholar 

  • Peled T, Shoham H, Aschengrau D, Yackoubov D, Frei G, Rosenheimer GN et al (2012) Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol 40(4):342–355. e1

    Article  CAS  PubMed  Google Scholar 

  • Popat U, Mehta RS, Rezvani K, Fox P, Kondo K, Marin D et al (2015) Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood 125(19):2885–2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson SN, Simmons PJ, Yang H, Alousi AM (2011) Marcos de lima J, Shpall EJ. Mesenchymal stem cells in ex vivo cord blood expansion. Best Pract Res Clin Haematol 24(1):83–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson SN, Simmons PJ, Thomas MW, Brouard N, Javni JA, Trilok S et al (2012) Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rgamma(null) mice. Exp Hematol 40(6):445–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson SN, Thomas MW, Simmons PJ, Lu J, Yang H, Parmar S et al (2014) Fucosylation with fucosyltransferase VI or fucosyltransferase VII improves cord blood engraftment. Cytotherapy 16(1):84–89

    Article  CAS  PubMed  Google Scholar 

  • Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A et al (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351(22):2276–2285

    Article  CAS  PubMed  Google Scholar 

  • Ruggeri A, Sanz G, Bittencourt H, Sanz J, Rambaldi A, Volt F et al (2014) Comparison of outcomes after single or double cord blood transplantation in adults with acute leukemia using different types of myeloablative conditioning regimen, a retrospective study on behalf of eurocord and the acute leukemia working party of EBMT. Leukemia 28(4):779–786

    Article  CAS  PubMed  Google Scholar 

  • Sanz J, Boluda JC, Martin C, Gonzalez M, Ferra C, Serrano D et al (2012) Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen. Bone Marrow Transplant 47(10):1287–1293

    Article  CAS  PubMed  Google Scholar 

  • Scaradavou A, Brunstein CG, Eapen M, Le-Rademacher J, Barker JN, Chao N et al (2013) Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood 121(5):752–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah N, Martin-Antonio B, Yang H, Ku S, Lee DA, Cooper LJ et al (2013) Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One 8(10):e76781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB et al (2002) Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 8(7):368–376

    Article  PubMed  Google Scholar 

  • Spanholtz J, Tordoir M, Eissens D, Preijers F, van der Meer A, Joosten I et al (2010) High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS One 5(2):e9221

    Article  PubMed  PubMed Central  Google Scholar 

  • Stiff P, Montesinos P, Peled T, Landau E, Rosenheimer N, Mandel J, Hasson N, et al (2013) 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 hematological malignancies. Blood 122:295; ASH annual Meeting Abstracts 2013

    Google Scholar 

  • Sun Q, Burton RL, Pollok KE, Emanuel DJ, Lucas KG (1999) CD4(+) Epstein-Barr virus-specific cytotoxic T-lymphocytes from human umbilical cord blood. Cell Immunol 195(2):81–88

    Google Scholar 

  • Takahashi S, Ooi J, Tomonari A, Konuma T, Tsukada N, Oiwa-Monna M et al (2007) Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 109(3):1322–1330

    Article  CAS  PubMed  Google Scholar 

  • Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH et al (2009) Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 114(19):4293–4299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA et al (2014) One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med 371(18):1685–1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner JE Jr, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D et al (2016) Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 18(1):144–155

    Article  CAS  PubMed  Google Scholar 

  • Weisdorf D, Eapen M, Ruggeri A, Zhang MJ, Zhong X, Brunstein C et al (2014) Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a center for international blood and marrow transplant research-eurocord analysis. Biol Blood Marrow Transplant 20(6):816–822

    Article  PubMed  PubMed Central  Google Scholar 

  • Xia L, McDaniel JM, Yago T, Doeden A, McEver RP (2004) Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood 104(10):3091–3096

    Article  CAS  PubMed  Google Scholar 

  • Xing D, Ramsay AG, Gribben JG, Decker WK, Burks JK, Munsell M et al (2010) Cord blood natural killer cells exhibit impaired lytic immunological synapse formation that is reversed with IL-2 exvivo expansion. J Immunother 33(7):684–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasmine van C, Goetgeluk G, Weening K, Verstichel G, Bonte S, Taghon T et al (2015) Chimeric antigen receptor transgenic, T-cell receptor/CD3 negative Monospecific T-cells generated from cord blood CD34 positive cells (abstract 3087). American Society of Hematology, San Diego

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rohtesh S. Mehta .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Mehta, R.S., Shpall, E.J. (2017). Ex Vivo Cord Blood Manipulation: Methods, Data, and Challenges. In: Horwitz, M., Chao, N. (eds) Cord Blood Transplantations. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-53628-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-53628-6_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-53627-9

  • Online ISBN: 978-3-319-53628-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics