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:

Graft-Versus-Tumor Effects

Rapid and massive expansion of cord blood-derived cytokine-induced killer cells: an innovative proposal for the treatment of leukemia relapse after cord blood transplantation

Bone Marrow Transplantation volume 38, pages 621–627 (2006)Cite this article

Abstract

We have used a standardized 21-day expansion protocol to produce cytokine-induced killer (CIK) cells starting from very small amounts of nucleated cells (approximately 15 × 106 cells) isolated from cord blood. Mononuclear cells are stimulated with anti CD3 (OKT3) and IFNγ and then expanded with IL-2. Moreover, we show that washouts of cord blood units bags (at the end of the infusion) may be sufficient to yield almost 500 × 106 CIK by the same expansion protocol. CIK cells show strong cytotoxic activity against a variety of tumor target cell lines including B and T lymphomas and myeloid leukemias. More importantly, expanded cord blood-derived CIK cells are cytotoxic against fresh leukemic blasts and express perforin, granzyme and NKG2D molecule at high levels. The same in vitro protocol has already been used to expand CIK cells from peripheral blood of adult donors under GMP conditions and therefore these observations open up the possibility of imagining a future clinical application of leukemia relapse following cord blood transplantation with CIK cells obtained from the same cord blood unit.

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
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Tse W, Laughlin MJ . Umbilical cord blood transplantation: a new alternative option. Hematology (Am Soc Hematol Educ Program) 2005, 377–383.

    Article  Google Scholar 

  2. Sanz MA . Cord-blood transplantation in patients with leukemia – a real alternative for adults. N Engl J Med 2004; 351: 2328–2330.

    Article  CAS  Google Scholar 

  3. Bradley MB, Cairo MS . Cord blood immunology and stem cell transplantation. Hum Immunol 2005; 66: 431–446.

    Article  CAS  Google Scholar 

  4. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE 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  Google Scholar 

  5. 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  Google Scholar 

  6. Lu PH, Negrin RS . A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 1994; 153: 1687–1696.

    CAS  PubMed  Google Scholar 

  7. Hoyle C, Bangs CD, Chang P, Kamel O, Mehta B, Negrin RS et al. Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. Blood 1998; 92: 3318–3327.

    CAS  PubMed  Google Scholar 

  8. Alvarnas JC, Linn YC, Hope EG, Negrin RS . Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2001; 7: 216–222.

    Article  CAS  Google Scholar 

  9. Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL . Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 1991; 174: 139–149.

    Article  CAS  Google Scholar 

  10. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS . Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001; 97: 2923–2931.

    Article  CAS  Google Scholar 

  11. Schmidt-Wolf IG, Lefterova P, Mehta BA, Fernandez LP, Huhn D, Blume KG et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 1993; 21: 1673–1679.

    CAS  Google Scholar 

  12. Linn YC, Lau LC, Hui KM . Generation of cytokine-induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous and allogeneic leukaemic blasts. Br J Haematol 2002; 116: 78–86.

    Article  CAS  Google Scholar 

  13. Sconocchia G, Lau M, Provenzano M, Rezvani K, Wongsena W, Fujiwara H et al. The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions. Blood 2005; 106: 3666–3672.

    Article  CAS  Google Scholar 

  14. Verneris MR, Ito M, Baker J, Arshi A, Negrin RS, Shizuru JA et al. Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant 2001; 7: 532–542.

    Article  CAS  Google Scholar 

  15. Edinger M, Cao YA, Verneris MR, Bachmann MH, Contag CH, Negrin RS et al. Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood 2003; 101: 640–648.

    Article  CAS  Google Scholar 

  16. Sweeney TJ, Mailander V, Tucker AA, Olomu AB, Zhang W, Cao Y et al. Visualizing the kinetics of tumor-cell clearance in living animals. Proc Natl Acad Sci USA 1999; 96: 12044–12049.

    Article  CAS  Google Scholar 

  17. Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin RS . A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant 2005; 11: 181–187.

    Article  Google Scholar 

  18. Wang FS, Liu MX, Zhang B, Shi M, Lei ZY, Sun WB et al. Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo. World J Gastroenterol 2002; 8: 464–468.

    Article  CAS  Google Scholar 

  19. Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, Feng YY et al. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 2004; 10: 1146–1151.

    Article  CAS  Google Scholar 

  20. Derzic S, Slone V, Sender L . IL-2-activated cord blood mononuclear cells. Cytotherapy 2005; 7: 408–416.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Tomizawa D, Aoki Y, Nagasawa M, Morio T, Kajiwara M, Sekine T et al. Novel adopted immunotherapy for mixed chimerism after unrelated cord blood transplantation in Omenn syndrome. Eur J Haematol 2005; 75: 441–444.

    Article  Google Scholar 

  23. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS . Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004; 103: 3065–3072.

    Article  CAS  Google Scholar 

  24. Introna M, Barbui AM, Golay J, Rambaldi A . Innovative cell-based therapies in onco-hematology: what are the clinical facts? Haematologica 2004; 89: 1253–1260.

    PubMed  Google Scholar 

  25. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  Google Scholar 

  26. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E et al. Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 2001; 97: 63–72.

    Article  CAS  Google Scholar 

  27. Burt RK, Drobyski WR, Seregina T, Traynor A, Oyama Y, Keever-Taylor C et al. Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions. Exp Hematol 2003; 31: 903–910.

    Article  CAS  Google Scholar 

  28. Mesel-Lemoine M, Cherai M, Le Gouvello S, Guillot M, Leclercq V, Klatzmann D et al. Initial depletion of regulatory T cells: the missing solution to preserve the immune functions of T lymphocytes designed for cell therapy. Blood 2006; 107: 381–388.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was partially supported by the Italian Association for Cancer Research (AIRC, to MI, AR), the ‘Associazione Italiana contro le leucemie, linfomi e mieloma (AIL) Bergamo, sezione Paolo Belli and by a generous personal donation from Dr EC.

Author information

Authors and Affiliations

  1. Division of Hematology, Laboratory of Cellular and Gene Therapy ‘G. Lanzani’, Ospedali Riuniti di Bergamo, Bergamo, Italy

    M Introna, M Franceschetti, A Ciocca, G Borleri, E Conti, J Golay & A Rambaldi

Authors
  1. M Introna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Franceschetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Ciocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Borleri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Conti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Golay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Rambaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Introna.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Introna, M., Franceschetti, M., Ciocca, A. et al. Rapid and massive expansion of cord blood-derived cytokine-induced killer cells: an innovative proposal for the treatment of leukemia relapse after cord blood transplantation. Bone Marrow Transplant 38, 621–627 (2006). https://doi.org/10.1038/sj.bmt.1705503

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705503

Keywords

This article is cited by

Search

Advanced search

Quick links