Skip to main content

Advertisement

SpringerLink
Log in

Infusions of Epstein–Barr virus-specific cytotoxic T lymphocytes as post-remission therapy in high-risk post-transplant lymphoproliferative disorder patients: report of two cases

  • Case Report
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Conventional therapeutic approaches to post-transplant lymphoproliferative disorder (PTLD) occurring after solid-organ transplantation have shown only limited success in achieving durable response. Key factors driving the pathogenesis of PTLD include Epstein–Barr virus (EBV) reactivation and impaired immune surveillance due to prolonged immune suppression. Thus, EBV-specific cytotoxic T lymphocytes (EBV-CTLs) have emerged as an alternative therapeutic approach for the treatment of EBV-associated PTLD by enhancing EBV-specific immunity. We evaluated the safety and efficacy of EBV latent membrane proteins (LMP)-1- and 2-specific CTLs in two PTLD patients at high risk for relapse. Following diagnosis, patients were initially treated with a combination of chemotherapy and/or radiotherapy. Patients then received a total of eight doses of 2 × 107 EBV-CTLs/m2. Following initial therapy, both patients achieved complete remission confirmed by FDG-PET/CT imaging. Post-remission therapy using adoptive transfer of EBV-CTLs was safe without immediate or late toxicities. Infusion of EBV-CTLs led to an overall reduction in plasma EBV levels in the peripheral blood, which was associated with long-term remission of both patients during a follow-up of more than 65 months. Further prospective studies with larger number of patients will be needed to confirm the role of EBV-CTLs as post-remission therapy in high-risk PTLD.

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. Jacobson CA, LaCasce AS. Lymphoma: risk and response after solid organ transplant. Oncology. 2010;24(10):936–44.

    PubMed  Google Scholar 

  2. Young LS, Rickinson AB. Epstein–Barr virus: 40 years on. Nat Rev Cancer. 2004;4(10):757–68.

    Article  CAS  PubMed  Google Scholar 

  3. Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S, et al. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder (bigstar). Am J Transplant. 2011;11(2):336–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984;1(8377):583–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Vary M, Babel N, et al. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005;5(12):2901–6.

    Article  CAS  PubMed  Google Scholar 

  6. Choquet S, Leblond V, Herbrecht R, Socie G, Stoppa AM, Vandenberghe P, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood. 2006;107(8):3053–7.

    Article  CAS  PubMed  Google Scholar 

  7. Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 2010;28(6):1038–46.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Trappe RU, Choquet S, Dierickx D, Mollee P, Zaucha JM, Dreyling MH, et al. International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial. Am J Transplant. 2015;15(4):1091–100.

    Article  CAS  PubMed  Google Scholar 

  9. Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27(20):3354–62.

    Article  PubMed  Google Scholar 

  10. Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23(30):7574–82.

    Article  PubMed  Google Scholar 

  11. Balduzzi A, Lucchini G, Hirsch HH, Basso S, Cioni M, Rovelli A, et al. Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplant. 2011;46(7):987–92.

    Article  CAS  PubMed  Google Scholar 

  12. Merlo A, Turrini R, Dolcetti R, Zanovello P, Amadori A, Rosato A. Adoptive cell therapy against EBV-related malignancies: a survey of clinical results. ‎Expert Opin Biol Ther. 2008;8(9):1265–94.

    Article  CAS  PubMed  Google Scholar 

  13. Gottschalk S, Heslop HE, Rooney CM. Adoptive immunotherapy for EBV-associated malignancies. Leuk Lymphoma. 2005;46(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  14. Cho SG, Kim N, Sohn HJ, Lee SK, Oh ST, Lee HJ, et al. Long-term outcome of extranodal NK/T cell lymphoma patients treated with postremission therapy using EBV LMP1 and LMP2a-specific CTLs. Mol Ther. 2015;23(8):1401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoon JH, Lee S, Kim HJ, Lee JW, Min WS, Chung BH, et al. Comparative analysis of post-transplant lymphoproliferative disorder after kidney transplantation versus hematopoietic stem cell transplantation. Transplant Int. 2014;27(7):721–32.

    Article  Google Scholar 

  16. Caillard S, Porcher R, Provot F, Dantal J, Choquet S, Durrbach A, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol. 2013;31(10):1302–9.

    Article  PubMed  Google Scholar 

  17. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4(2):222–30.

    Article  PubMed  Google Scholar 

  18. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80(9):1233–43.

    Article  CAS  PubMed  Google Scholar 

  19. Khedmat H, Taheri S. Late onset post transplantation lymphoproliferative disorders: analysis of international data from 5 studies. Anna Transplant. 2009;14(4):80–5.

    Google Scholar 

  20. Khedmat H, Taheri S. Very late onset lymphoproliferative disorders occurring over 10 years post-renal transplantation: PTLD. Int. Survey. Hematol Oncol Stem Cell Ther. 2011;4(2):73–80.

    Article  PubMed  Google Scholar 

  21. Blyth E, Clancy L, Simms R, Ma CK, Burgess J, Deo S, et al. Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. Blood. 2013;121(18):3745–58.

    Article  CAS  PubMed  Google Scholar 

  22. Comoli P, Labirio M, Basso S, Baldanti F, Grossi P, Furione M, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood. 2002;99(7):2592–8.

    Article  CAS  PubMed  Google Scholar 

  23. Haque T, Amlot PL, Helling N, Thomas JA, Sweny P, Rolles K, et al. Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients. J Immunol. 1998;160(12):6204–9.

    CAS  PubMed  Google Scholar 

  24. Comoli P, Maccario R, Locatelli F, Valente U, Basso S, Garaventa A, et al. Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells. Am J Transplan. 2005;5(6):1415–22.

    Article  Google Scholar 

  25. Haque T, Taylor C, Wilkie GM, Murad P, Amlot PL, Beath S, et al. Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation. 2001;72(8):1399–402.

    Article  CAS  PubMed  Google Scholar 

  26. Sun Q, Burton R, Reddy V, Lucas KG. Safety of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for patients with refractory EBV-related lymphoma. Br J Haematol. 2002;118(3):799–808.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (H12C0718), a Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea, and from the Catholic Institute of Cell Therapy, The Catholic University of Korea.

Author information

Authors and Affiliations

  1. Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, South Korea

    Nayoun Kim, Young-Woo Jeon & Seok-Goo Cho

  2. Catholic Institute of Cell Therapy, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Nayoun Kim & Seok-Goo Cho

  3. Catholic Hematopoietic Stem Cell Bank, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 137-701, South Korea

    Hyun-Jung Sohn, Hyun-Joo Lee & Tai-Gyu Kim

  4. Department of Nuclear Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Joo Hyun Oh

  5. Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Young-Woo Jeon & Seok-Goo Cho

  6. Cancer Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Hyun-Il Cho

  7. Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea

    Byung Ha Chung & Chul-Woo Yang

Authors
  1. Nayoun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun-Jung Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joo Hyun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young-Woo Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyun-Joo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyun-Il Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Byung Ha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chul-Woo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tai-Gyu Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seok-Goo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tai-Gyu Kim or Seok-Goo Cho.

Ethics declarations

Conflicts of interest

The authors declare that there are no conflicts of interest.

Additional information

Tai-Gyu Kim and Seok-Goo Cho contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, N., Sohn, HJ., Oh, J.H. et al. Infusions of Epstein–Barr virus-specific cytotoxic T lymphocytes as post-remission therapy in high-risk post-transplant lymphoproliferative disorder patients: report of two cases. Int J Hematol 107, 596–603 (2018). https://doi.org/10.1007/s12185-017-2381-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-017-2381-3

Keywords

Search

Navigation