Abstract
The Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) that occur in individuals immunosuppressed by solid organ transplant (SOT) or T cell-depleted stem cell transplantation (SCT) are unequivocally a result of T cell dysfunction. Reconstitution of “at-risk” patients with EBV-specific cytotoxic T lymphocyte (CTL) lines that have been reactivated and expanded in vitro, should prevent the development of post-transplant lymphoprohferative disease or treat pre-existing disease. We have provided over 125 infusions of donor-derived EBV-specific CTL to 60 recipients of T cell-depleted stem cells. As prophylaxis, infusions were safe and effective, as no patient developed EBV-LPD, in contrast to 11.5% of controls who did not receive CTL. The CTL-reconstituted cellular immune responses to EBV, persisted for up to 80 months following infusion and reduced the high virus load seen in about 12% of patients. CTL were also effective in two of three patients who received CTL as treatment for fulminant disease. SOT recipients are also good candidates for CTL therapy, but present problems not seen in bone marrow transplant recipients. First the CTL product must be autologous, since the majority of tumors are recipient-derived and allogeneic CTL are unlikely to survive in vivo. Second most patients continue to receive immunosuppressive drugs, which may compromise the function of infused CTL. Third, unlike SCT recipients SOT recipients do not have an empty niche for EBV-specific CTL. Finally, standard protocols are not effective in generating CTL from seronegative recipients of EBV-carrying organs. who are the patients most at risk for the development of EBV-LPD. For CTL to be an option for the management of EBV in these patients, a sensitive and specific assay for the prediction of high-risk patients is required as well as an effective method for the generation of EBV-specific CTL from seronegative recipients.
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References
Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, Heslop HE (1994) Early identification of Epstein-Barr virus-associated post-transplant lymphoproliferative disease. Br J Haematol 89:98–103
Savoie A, Perpete C, Carpentier L, Joncas J, Alfieri C (1994) Direct correla-tion between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease. Blood 83:2715–2722
Riddler SA, Breinig MC, McKnight JLC (1994) Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood 84:972–984
Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG (2000) Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95:807–814
Green M, Bueno J, Rowe D, Mazariegos G, Qu L, Abu-Almagd K, Reyes J (2000) Predictive negative value of persistent low Epstein-Barr virus viral load after intestinal transplantation in children. Transplantation 70:593–596
Cook RC, Connors JM, Gascoyne RD, Fradet G, Levy RD (1999) Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation [letter]. Lancet 354:1698–1699
Kuehnle I, Huls MH, Liu Z, Semmelmann M, Krance RA, Brenner MK, Rooney CM, Heslop HE (2000) CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95:1502–1505
Milpied N, Vasseur B, Parquet N, Garnier JL, Antoine C, Quartier P, Carret AS, Bouscary D, Faye A, Bourbigot B, Reguerre Y, Stoppa AM, Bourquard P, Hurault de Ligny B, Dubief F, Mathieu-Boue A, Leblond V (2000) Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lympho-proliferative disorder: a retrospective analysis on 32 patients. Ann Oncol 11 (Suppl 1):113–116
Miller G, Lipman M (1973) Release of infectious Epstein-Barr virus by transformed marmoset leukocytes. Proc Naü Acad Sci USA 70:190–194
Smith CA, Ng CYC, Heslop HE, HoUaday MS, Richardson S, Turner EV, Loftin SK, Li C, Brenner MK, Rooney CM (1995) Production of genetically modified EBV-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J Hematother 4:73–79
Heslop HE, Rooney CM (1997) Adoptive immunotherapy of EBV lymphoproliferative diseases. Immunol Rev 157:217–222
Heslop HE, Ng CYC, Li C, Smith CA, Loftin SK, Krance RA, Brenner MK, Rooney CM (1996) Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nature Med 2:551–555
Rooney CM, Smith CA, Ng C, Loftin SK, Li C, Krance RA, Brenner MK, Heslop HE (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lympho proliferation. Lancet 345:9–13
Rooney CM, Smith CA, Ng CYC, Loftin SK, Sixbey JW, Gan Y-J, Srivastava D-K, Bowman LC, Krance RA, Brenner MK, Heslop HE (1998) Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92:1549–1555
Lucas K, Small T, Heller G, Dupont B, O’Reilly RJ (1996) The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood 87:2594–2603
Gottschalk S, Ng CYC, Smith CA, Perez M, Sample C, Brenner MK, Heslop HE, Rooney CM (2001) An Epstein-Barr virus deletion mutant that causes fatal lymphoproliferative disease unresponsive to virus-specific T cell therapy. Blood 97:835–843
Gratama JW, Oosterveer MAP, Zwaan EE, Lepoutre J, Klein G, Ernberg I (1988) Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency. Proc Natl Acad Sci USA 85:8693–8696
Hale G, Waldmann H, for CAMPATH users (1998) Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants. Blood 91:3079–3083
Khanna R, Bell S, Sherritt M, Galbraith A, Burrows SR, Rafter L, Clarke B, Slaughter R, Falk MC, Douglass J, Williams T, Elliott SL, Moss DJ (1999) Acti-vation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease. Proc Natl Acad Sci USA 96:10391–10396
Savoldo B, Goss J, Liu Z, Huls H, Doster S, Gee AP Brenner MK, Heslop HE, Rooney CM (2001) Generation of autologous Epstein Barr virus (EBV)-speeific cytotoxic T cells (CTL) for adoptive immunotherapy in solid organ transplant recipients. Transplantation (in press)
Nair SK, Boczkowski D, Morse M, Cumming RI, Lyerly HK, Gilboa E (1998) Induction of primary carcino embryo nie antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nature Biotechnol 16:364–369
Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N (2000) Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells [see comments]. J Exp Med 191:423–434
Kern F, Faulhaber N, Khatamzas E, Frommel C, Ewert R, Prosch S, Volk H, Reinke P (1999) Measurement of anti-human cytomegalovirus T cell reactivity in transplant recipients and its potential clinical use: a mini-review. Intervirology 42:322–324
Poppema S, Potters M, Visser L, van den Berg AM (1998) Immune escape mechanisms in Hodgkin’s disease. Ann Oncol 9 [Suppl 5]:S21–S24
Kapp U, Yeh WC, Patterson B, Elia AL Kagi D, Ho A, Hessel A, Tipsword M, WilEams A, Mirtsos C, Itie A, Moyle M, Mak TW (1999) Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 189:1939–1946
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Liu, Z. et al. (2002). Epstein-Barr Virus (EBV)-Specific Cytotoxic T Lymphocytes for the Prevention and Treatment of EBV-Associated Post-Transplant Lymphomas. In: Oertel, S.H., Riess, H. (eds) Immunosurveillance, Immunodeficiencies and Lymphoproliferations. Recent Results in Cancer Research, vol 159. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56352-2_15
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DOI: https://doi.org/10.1007/978-3-642-56352-2_15
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