Skip to main content

Advertisement

SpringerLink
Log in

Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

An Erratum to this article was published on 11 September 2015

Abstract

The infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene (TK-cells) is a promising strategy for the treatment of hematologic malignancies relapsing after allogeneic hematopoietic stem cell transplantation. Here we report the results of a phase I clinical trial designed to examine the feasibility, safety, and efficacy of donor lymphocyte infusion (DLI) of TK-cells. Three patients (two with malignant lymphomas, one with acute myeloid leukemia) were enrolled in the trial and received a single DLI of 1 × 107 or 5 × 107 TK-cells/kg. No local or systemic toxicity related to the gene-transfer procedure was observed. Two patients achieved stable disease. No patient had severe graft-versus-host disease requiring systemic steroid and/or ganciclovir administration. TK-cells were detected in the peripheral blood of all three patients by PCR, but did not persist longer than 28 days. Analysis of cytotoxic T lymphocyte activity detected no immune response against TK-cells by the recipient’s own T cells. Flow cytometric analysis showed low proliferative activity and cytotoxic function of TK-cells. In conclusion, DLI of TK-cells was safely performed in all three patients. Our analysis suggests the probable cause of rapid disappearance of TK-cells to be insufficient in vivo expansion of TK-cells in these patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658–66.

    Article  CAS  PubMed  Google Scholar 

  2. Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–44.

    PubMed  Google Scholar 

  3. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76:2462–5.

    CAS  PubMed  Google Scholar 

  4. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev. 2010;36:528–38.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–50.

    CAS  PubMed  Google Scholar 

  6. Carlens S, Remberger M, Aschan J, Ringden O. The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse. Biol Blood Marrow Transplant. 2001;7:31–8.

    Article  CAS  PubMed  Google Scholar 

  7. Barrett AJ. Understanding and harnessing the graft-versus-leukaemia effect. Br J Haematol. 2008;142:877–88.

    Article  CAS  PubMed  Google Scholar 

  8. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112:4371–83.

    Article  CAS  PubMed  Google Scholar 

  9. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science. 1997;276:1719–24.

    Article  CAS  PubMed  Google Scholar 

  10. Borchers S, Provasi E, Silvani A, Radrizzani M, Benati C, et al. Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation. Hum Gene Ther. 2011;22:829–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Burt RK, Drobyski WR, Seregina T, Traynor A, Oyama Y, et al. Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions. Exp Hematol. 2003;31:903–10.

    Article  CAS  PubMed  Google Scholar 

  12. Ciceri F, Bonini C, Gallo-Stampino C, Bordignon C. Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation. Cytotherapy. 2005;7:144–9.

    Article  CAS  PubMed  Google Scholar 

  13. Ciceri F, Bonini C, Marktel S, Zappone E, Servida P, et al. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood. 2007;109:4698–707.

    Article  CAS  PubMed  Google Scholar 

  14. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study. Lancet Oncol. 2009;10:489–500.

    Article  PubMed  Google Scholar 

  15. Onodera M. Gene and cell therapy for relapsed leukemia after allo-stem cell transplantation. Front Biosci. 2008;13:3408–14.

    Article  CAS  PubMed  Google Scholar 

  16. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, 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  PubMed  Google Scholar 

  17. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  PubMed  Google Scholar 

  18. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–9.

    Article  PubMed  Google Scholar 

  19. Verzeletti S, Bonini C, Marktel S, Nobili N, Ciceri F, et al. Herpes simplex virus thymidine kinase gene transfer for controlled graft-versus-host disease and graft-versus-leukemia: clinical follow-up and improved new vectors. Hum Gene Ther. 1998;9:2243–51.

    Article  CAS  PubMed  Google Scholar 

  20. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 1986;46:5276–81.

    CAS  PubMed  Google Scholar 

  21. St Clair MH, Lambe CU, Furman PA. Inhibition by ganciclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information. Antimicrob Agents Chemother. 1987;31:844–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Bonini C, Grez M, Traversari C, Ciceri F, Marktel S, et al. Safety of retroviral gene marking with a truncated NGF receptor. Nat Med. 2003;9:367–9.

    Article  CAS  PubMed  Google Scholar 

  23. Mavilio F, Ferrari G, Rossini S, Nobili N, Bonini C, et al. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood. 1994;83:1988–97.

    CAS  PubMed  Google Scholar 

  24. Choi YW, Kotzin B, Herron L, Callahan J, Marrack P, et al. Interaction of Staphylococcus aureus toxin “superantigens” with human T cells. Proc Natl Acad Sci USA. 1989;86:8941–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Labrecque N, McGrath H, Subramanyam M, Huber BT, Sekaly RP. Human T cells respond to mouse mammary tumor virus-encoded superantigen: V beta restriction and conserved evolutionary features. J Exp Med. 1993;177:1735–43.

    Article  CAS  PubMed  Google Scholar 

  26. Depil S, Deconinck E, Milpied N, Sutton L, Witz F, et al. Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome. Bone Marrow Transplant. 2004;33:531–4.

    Article  CAS  PubMed  Google Scholar 

  27. Zeng W, Nakao S, Takamatsu H, Yachie A, Takami A, et al. Characterization of T-cell repertoire of the bone marrow in immune-mediated aplastic anemia: evidence for the involvement of antigen-driven T-cell response in cyclosporine-dependent aplastic anemia. Blood. 1999;93:3008–16.

    CAS  PubMed  Google Scholar 

  28. Yatabe Y, Hida T, Horio Y, Kosaka T, Takahashi T, et al. A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer. J Mol Diagn. 2006;8:335–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Marktel S, Magnani Z, Ciceri F, Cazzaniga S, Riddell SR, et al. Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation. Blood. 2003;101:1290–8.

    Article  CAS  PubMed  Google Scholar 

  30. Berger C, Flowers ME, Warren EH, Riddell SR. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood. 2006;107:2294–302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Mercier-Letondal P, Deschamps M, Sauce D, Certoux JM, Milpied N, et al. Early immune response against retrovirally transduced herpes simplex virus thymidine kinase-expressing gene-modified T cells coinfused with a T cell-depleted marrow graft: an altered immune response? Hum Gene Ther. 2008;19:937–50.

    Article  CAS  PubMed  Google Scholar 

  32. Traversari C, Marktel S, Magnani Z, Mangia P, Russo V, et al. The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood. 2007;109:4708–15.

    Article  CAS  PubMed  Google Scholar 

  33. Mailly L, Leboeuf C, Tiberghien P, Baumert T, Robinet E. Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD. Curr Opin Investig Drugs. 2010;11:559–70.

    CAS  PubMed  Google Scholar 

  34. Nicholson E, Ghorashian S, Stauss H. Improving TCR gene therapy for treatment of haematological malignancies. Adv Hematol. 2012;2012:404081.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Japanese Ministry of Health, Labour and Welfare and the National Cancer Research and Development Fund. We further thank our strategic partner and the developer of TK, MolMed S.p.A., for all of the support, advice, and technical information provided to us that has allowed progress in this work.

Conflict of interest

This study was technologically supported by Takara Bio Inc. Daisuke Tomura and Ikuei Nukaya are employees, and Junichi Mineno and Kazutoh Takesako are employees/directors of Takara Bio Inc. The other authors have no competing interests.

Author information

Authors and Affiliations

  1. Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hisayoshi Hashimoto & Ryosuke Ueda

  2. Division of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Shigehisa Kitano

  3. Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Shigehisa Kitano & Kohei Tada

  4. Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Ayumu Ito, Kohei Tada, Shigeo Fuji, Takuya Yamashita & Takahiro Fukuda

  5. Center for Cell and Gene Therapy, Takara Bio Inc, Seta 3-4-1, Otsu, Shiga, 520-2193, Japan

    Daisuke Tomura, Ikuei Nukaya & Junichi Mineno

  6. Division of Hematology and Oncology, St. Luke’s International Hospital, 9-1 Akashi-cho, Chou-ku, Tokyo, 104-8560, Japan

    Shinichiro Mori

  7. Research Planning and Management Department, St. Luke’s International Hospital, 9-1 Akashi-cho, Chou-ku, Tokyo, 104-8560, Japan

    Yoichi Takaue

  8. Immunotherapy and Cell Therapy Service, St. Luke’s International University and Hospital, 9-1 Akashi-cho, Chou-ku, Tokyo, 104-8560, Japan

    Yuji Heike

Authors
  1. Hisayoshi Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigehisa Kitano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryosuke Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayumu Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kohei Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeo Fuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takuya Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daisuke Tomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ikuei Nukaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junichi Mineno
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takahiro Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shinichiro Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yoichi Takaue
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuji Heike
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Heike.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 191 kb)

Supplementary material 2 (PPTX 223 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashimoto, H., Kitano, S., Ueda, R. et al. Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Int J Hematol 102, 101–110 (2015). https://doi.org/10.1007/s12185-015-1801-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1801-5

Keywords

Search

Navigation