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Human cytotoxic T lymphocytes specific for a single minor histocompatibility antigen HA-1 are effective against human lymphoblastic leukaemia in NOD/scid mice

Leukemia volume 20, pages 371–374 (2006)Cite this article

Donor lymphocyte infusions (DLIs) after human leukocyte antigen (HLA)-matched allogeneic stem cell transplantation (SCT) can induce curative graft-versus-leukaemia (GvL) effects.1 Cytotoxic T lymphocytes (CTLs) recognising minor histocompatibility antigens (mHags) HA-1 and HA-2 on the recipient's haematopoietic cells coincide with leukaemia remissions after DLI.2 This indicates, that therapeutic boosting of only those CTLs that recognise the haematopoiesis restricted mHags HA-1 and HA-2 (HA-1 and HA-2 CTLs) might increase the GvL effect. The risk of graft-versus-host disease (GvHD) will be low because nonhaematopoietic cells will not be recognized.3 The efficacy of this therapeutic concept is unclear, since a causal relationship between mHag CTL appearance and clinical responses could not yet be made. In vitro assays that show HA-1 and HA-2 CTLs killing leukaemic cells and inhibiting leukaemic progenitor cell outgrowth3 support the role of mHag CTLs as mediators of the GvL activity. The predictive value of these in vitro assays for the in vivo efficacy of human CTLs is, however, unknown. Compared to the in vitro situation, different cytotoxic mechanisms might be relevant, the accumulation of toxic soluble factors may be different and the time and chance of CTL – target cell interaction might be lower in vivo. Recently, a nonobese diabetic/severe combined immune deficiency (NOD/scid) human leukaemia model has been used to show the antileukaemic efficacy of T-cell therapy in vivo.4 Allo-HLA T-cell lines served as model for T-cell therapy, but are, due to a high risk of GvHD, clinically not applicable. Here, we used the same NOD/scid mouse leukaemia model to confine the postulated in vivo antileukaemic efficacy of CTLs recognising only a single HLA ligand, the mHag HA-1.

To evaluate the in vivo antileukaemic efficacy of HA-1 CTLs, NOD/scid mice were inoculated with 107 OF leukaemia cells. After 3 days, when the mice were still in a status of minimal disease, 3 × 107 HA-1 CTLs or as control CMV CTLs or PBS were administered intravenously. The mice received interleukin 2 (IL-2) intraperitoneally daily and leukaemia and T cells were monitored in peripheral blood samples weekly as described earlier.4

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References

  1. Kolb H, Schattenberg A, Goldman J, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  2. Marijt W, Heemskerk M, Kloosterboer F, Goulmy E, Kester M, van der Horn M et al. Hematopoiesis-restricted minor histocompatibilty antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–2747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hambach L, Goulmy E . Immunotherapy of cancer through targeting of minor histocompatibility antigens. Curr Opin Immunol 2005; 17: 202–210.

    Article  CAS  PubMed  Google Scholar 

  4. Nijmeijer B, Willemze R, Falkenburg J . An animal model for human cellular immunotherapy: specific eradication of human acute lymphoblastic leukemia by cytotoxic T lymphocytes. Blood 2002; 100: 654–660.

    Article  CAS  PubMed  Google Scholar 

  5. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E . Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. Blood 1999; 93: 2336–2341.

    CAS  PubMed  Google Scholar 

  6. Bonnet D, Warren E, Greenberg P, Dick J, Riddell S . CD8+ minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells. Proc Natl Acad Sci USA 1999; 96: 8639–8644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Verra N, Jorritsma A, Weijer K, Ruizendaal J, Voordouw A, Weder P et al. Human telomerase reverse transcriptase transduced human cytotoxic T cells suppress the growth of human melanoma in immunodeficient mice. Cancer Res 2004; 64: 2153–2161.

    Article  CAS  PubMed  Google Scholar 

  8. Yee C, Thompson J, Byrd D, Riddell S, Roche P, Celis E et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 2002; 99: 16168–16173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Mr M Kester for tetramer synthesis, Dr WN van Wieringen for statistical analysis and Dr R Offringa for critical reading of the manuscript. This work was in part supported by the Dutch Cancer Society and the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Department of Immunohaematology and Blood Transfusion, E3Q, Leiden University Medical Centre, RC Leiden, The Netherlands

    L Hambach, Z Aghai, M H M Wauben & E Goulmy

  2. Department of Haematology, Leiden University Medical Centre, Leiden, The Netherlands

    B A Nijmeijer, M L J van Schie & J H F Falkenburg

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  1. L Hambach
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  2. B A Nijmeijer
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  3. Z Aghai
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  7. E Goulmy
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Hambach, L., Nijmeijer, B., Aghai, Z. et al. Human cytotoxic T lymphocytes specific for a single minor histocompatibility antigen HA-1 are effective against human lymphoblastic leukaemia in NOD/scid mice. Leukemia 20, 371–374 (2006). https://doi.org/10.1038/sj.leu.2404056

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