Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Conditioning Regimens

Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial

Bone Marrow Transplantation volume 41, pages 771–778 (2008)Cite this article

Abstract

The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 × 107 total nucleated cells (TNCs) per kilogram pre-expansion. All donor–recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2–620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 × 107/kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16–46) and 48 (range, 35–105) days. There were no cases of grades 3–4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. de Lima M, Shpall E . Cord blood transplantation. Curr Opin Organ Transpl 2002; 7: 286–293.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Rubinstein P, Stevens C . An Empirical Analysis of the Probability of Finding a Well-matched Cord Blood Unit with Adequate Cell Dose [Abstract]. Fourth Annual Cord Blood Transplantation Symposia, Los Angeles; 2006.

  5. Wagner JE, Barker JN, Defor TE, Baker K, Blazar B, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618.

    CAS  PubMed  Google Scholar 

  6. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 373–381.

    Article  CAS  PubMed  Google Scholar 

  7. Laughlin MJ, Barker J, Bambach B, Koc O, Rizzieri D, Wagner J et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344: 1815–1822.

    Article  CAS  PubMed  Google Scholar 

  8. Barker JN, Weisdorf D, Wagner J . Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors. N Engl J Med 2001; 344: 1871.

    Article  Google Scholar 

  9. Magro E, Regidor C, Cabrera R, Sanjuan I, Fores R, Garcia-Marco J et al. Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor. Haematologica 2006; 91: 640–648.

    PubMed  Google Scholar 

  10. Peled T, Landau E, Prus E, Treves A, Nagler A, Fibach E . Cellular copper content modulates differentiation and self-renewal in cultures of cord blood-derived CD34+ cells. Br J Haematol 2002; 116: 655–661.

    Article  CAS  PubMed  Google Scholar 

  11. Peled T, Gluckman E, Hasson N, Adi S, Assor H, Yudin D et al. Chelatable cellular copper modulates differentiation and self-renewal of cord blood-derived hematopoietic progenitor cells. Exp Hematol 2005; 33: 1092–1100.

    Article  CAS  PubMed  Google Scholar 

  12. Peled T, Mandel JL, Goudsmid R, Landor C, Hasson N, Harati 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: 344–355.

    Article  CAS  PubMed  Google Scholar 

  13. Peled T, Landau E, Mandel J, Glukhman E, Goudsmid N, Nagler A 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: 547–555.

    Article  CAS  PubMed  Google Scholar 

  14. Przepiorka D, Weisdorf D, Martin P, Klingemann H, Beatty P, Hows J et al. 1994 Consensus Conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  15. NCI. National Cancer Institute Common Toxicity Criteria version 3 2007. http://www.ctep.cancer.gov/reporting/ctc.html.

  16. Przepiorka D, Ippoliti C, Khouri I, Woo M, Mehra R, Le Bhers D et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. Blood 1996; 88: 4383–4389.

    CAS  PubMed  Google Scholar 

  17. Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 2003; 101: 2137–2143.

    Article  CAS  PubMed  Google Scholar 

  18. Rubinstein P, Stevens CE . Placental blood for bone marrow replacement: the New York Blood Center's program and clinical results. Baillieres Best Pract Res Clin Haematol 2000; 13: 565–584.

    Article  CAS  PubMed  Google Scholar 

  19. Cornetta K, Laughlin M, Carter S, Wall D, Weinthal J, Delaney C et al. Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT). Biol Blood Marrow Transplant 2005; 11: 149–160.

    Article  PubMed  Google Scholar 

  20. Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin P, Driscoll T et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the Aastrom Replicell System. Blood 2003; 101: 5061–5067.

    Article  CAS  PubMed  Google Scholar 

  21. Shpall E, Quinones R, Giller R, Zeng C, Baron A, Jones R et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002; 8: 376.

    Article  Google Scholar 

  22. Lekakis L, Giralt S, Couriel D, Shpall E, Hosing C, Khouri I et al. Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies. Bone Marrow Transplant 2006; 38: 421–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was partially supported by RO1-CA061508-15 (EJS).

Author information

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cell Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M de Lima, J McMannis, K Komanduri, D Couriel, B S Andersson, C Hosing, I Khouri, R Jones, R Champlin, S Karandish, T Sadeghi & E J Shpall

  2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    A Gee

  3. Gamida Cell Ltd, Jerusalem, Israel

    T Peled, F Grynspan & Y Daniely

  4. Chaim Sheba Medical Center, Tel Hashomer, Israel

    A Nagler

Authors
  1. M de Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J McMannis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Gee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Komanduri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Couriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B S Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Hosing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I Khouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Champlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Karandish
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T Sadeghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Peled
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F Grynspan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Daniely
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. A Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. E J Shpall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M de Lima.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Lima, M., McMannis, J., Gee, A. et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 41, 771–778 (2008). https://doi.org/10.1038/sj.bmt.1705979

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705979

Keywords

This article is cited by

Search

Advanced search

Quick links