Current Treatment Options in Oncology

, Volume 14, Issue 2, pp 224–236

EBV-Related Lymphomas: New Approaches to Treatment

Lymphoma (LI Gordon, Section Editor)

Opinion statement

In the treatment of Epstein-Barr virus (EBV)-related lymphomas, there are few therapies specifically targeted against the latent virus within these tumors; in most cases the treatment approach is not different than the approach to EBV-negative lymphomas. Nonetheless, current and emerging therapies focused on exploiting aspects of EBV biology may offer more targeted strategies for EBV-positive lymphomas in the future. Conceptually, EBV-specific approaches include bolstering the antiviral/antitumor immune response with vaccines or EBV-specific cytotoxic T-lymphocytes, activating lytic viral genes to render the tumor cells susceptible to antiviral therapies, and inhibiting the downstream prosurvival or antiapoptotic pathways that may be activated by latent EBV proteins. EBV-specific cytotoxic T-cell infusions have proven effective in EBV-related posttransplantation lymphoproliferative disorder (EBV-PTLD) and expanding such adoptive immunotherapies to other EBV-related malignancies is an area of active research. However, other EBV-related lymphomas typically have more restricted, less immunogenic arrays of viral antigens to therapeutically target with adoptive immunotherapy compared with EBV-PTLD. Furthermore, the malignant EBV-positive tumor cells of Hodgkin lymphoma are scattered amid a dense infiltrate of regulatory T-cells, macrophages, and other cells that may dampen the antitumor efficacy of adoptive immunotherapy. Strategies to overcome these obstacles are areas of ongoing preclinical and clinical investigations. Some emerging approaches to EBV-related lymphomas include the coupling of agents that induce lytic viral replication with antiherpesvirus agents, or the use of small molecule inhibitors that block signaling pathways that are constitutively activated by EBV. EBV vaccines seem most promising for the treatment or prevention of EBV-related malignancies, rather than the prevention of primary EBV infection. EBV vaccine trials in patients with residual or low-bulk EBV-related malignancies or for the prevention of EBV-PTLD in EBV-seronegative patients awaiting solid organ transplantation are ongoing.

Keywords

Epstein-Barr virus Hodgkin lymphoma Burkitt lymphoma Non-Hodgkin lymphoma Posttransplantation lymphoproliferative disorder HIV-associated lymphomas Immunodeficiency Adoptive T-cell therapy Epstein-Barr virus-specific cytotoxic T cells Rituximab Viral latency Epstein-Barr virus-DNA 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Levin LI, Chang ET, Ambinder RF, et al. Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. Blood. 2012;120:3750–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Jones K, Nourse JP, Keane C, et al. Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. Am J Hematol. 2012;87:258–65.PubMedCrossRefGoogle Scholar
  3. 3.•
    Wang ZY, Liu QF, Wang H, et al. Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy. Blood. 2012;120:2003–10. Elevated pre-treatment EBV-DNA copy number in plasma is associated with inferior survival outcomes in extranodal NK/T-cell lymphoma.PubMedCrossRefGoogle Scholar
  4. 4.
    Gandhi MK, Lambley E, Burrows J, et al. Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin's lymphoma. Clin Cancer Res. 2006;12:460–4.PubMedCrossRefGoogle Scholar
  5. 5.•
    Kanakry JA, Li H, Gellert LL, et al. Plasma Epstein-Barr virus DNA as a marker of tumor response in Hodgkin lymphoma. 2012: Abstract #8003. Plasma EBV-DNA correlates well with EBV tumor status and pre-treatment plasma EBV-DNA positivity is an independent prognostic marker of inferior progression-free survival in Hodgkin lymphoma.Google Scholar
  6. 6.•
    Hohaus S, Santangelo R, Giachelia M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17:2885–92. High plasma EBV-DNA correlates with tumor-infiltrating macrophages in Hodgkin lymphoma.PubMedCrossRefGoogle Scholar
  7. 7.
    Styczynski J, Reusser P, Einsele H, et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43:757–70.PubMedCrossRefGoogle Scholar
  8. 8.•
    Ito Y, Kimura H, Maeda Y, et al. Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type. Clin Cancer Res. 2012;18:4183–90. Plasma EBV-DNA copy number predicts response to chemotherapy and grade 4 toxicity for patients with extranodal NK/T-cell lymphoma.PubMedCrossRefGoogle Scholar
  9. 9.
    Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119:4129–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transpl Infect Dis. 2009;11:383–92.PubMedCrossRefGoogle Scholar
  11. 11.•
    Kim JH, Kim WS, Park C. Epstein-Barr virus latent membrane protein-1 protects B-cell lymphoma from rituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1. Leuk Lymphoma. 2012;53:1586–91. Role of Akt pathway in LMP-1-mediated rituximab resistance in EBV-positive lymphomas.PubMedCrossRefGoogle Scholar
  12. 12.•
    Nelson BP, Wolniak KL, Evens A, Chenn A, Maddalozzo J, Proytcheva M. Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation. Am J Clin Pathol. 2012;138:568–78. mTOR activation in EBV-PTLD.PubMedCrossRefGoogle Scholar
  13. 13.
    El-Salem M, Raghunath PN, Marzec M, et al. Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders. Lab Invest. 2007;87:29–39.PubMedCrossRefGoogle Scholar
  14. 14.
    Gibelli NE, Tannuri U, Pinho-Apezzato ML, et al. Sirolimus in pediatric liver transplantation: a single-center experience. Transplant Proc. 2009;41:901–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Garcia VD, Bonamigo Filho JL, Neumann J, et al. Rituximab in association with rapamycin for post-transplant lymphoproliferative disease treatment. Transpl Int. 2003;16:202–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Vaysberg M, Balatoni CE, Nepomuceno RR, Krams SM, Martinez OM. Rapamycin inhibits proliferation of Epstein-Barr virus-positive B-cell lymphomas through modulation of cell-cycle protein expression. Transplantation. 2007;83:1114–21.PubMedCrossRefGoogle Scholar
  17. 17.••
    Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115:925–35. Long-term outcomes of EBV-specific CTL therapy for the prevention and treatment of EBV-PTLD.PubMedCrossRefGoogle Scholar
  18. 18.
    Rooney CM, Smith CA, Ng CYC, et al. Use of Gene-Modified Virus-Specific T-Lymphocytes to Control Epstein-Barr-Virus-Related Lymphoproliferation. Lancet. 1995;345:9–13.PubMedCrossRefGoogle Scholar
  19. 19.••
    Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol. 2012;9:510–9. Review of EBV-CTL therapies.PubMedCrossRefGoogle Scholar
  20. 20.•
    Doubrovina E, Oflaz-Sozmen B, Prockop SE, et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood. 2012;119:2644–56. Comparison of clinical outcomes following donor lymphocyte infusion versus EBV-CTL therapy for post-HSCT EBV-PTLD.PubMedCrossRefGoogle Scholar
  21. 21.
    Haque T, Wilkie GM, Jones MM, et al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007;110:1123–31.PubMedCrossRefGoogle Scholar
  22. 22.•
    Icheva V, Kayser S, Wolff D, et al. Adoptive transfer of Epstein-Barr Virus (EBV) nuclear antigen 1-specific T cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation. J Clin Oncol 2012. Interferon-gamma capture technique for rapid isolation of EBV-CTLs.Google Scholar
  23. 23.
    Feuchtinger T, Opherk K, Bethge WA, et al. Adoptive transfer of pp 65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood. 2010;116:4360–7.PubMedCrossRefGoogle Scholar
  24. 24.•
    Gerdemann U, Keirnan JM, Katari UL, et al. Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections. Mol Ther. 2012;20:1622–32. Use of synthetic peptides and cytokines to facilitate the rapid expansion of multi-virus-specific CTLs.PubMedCrossRefGoogle Scholar
  25. 25.
    De Angelis B, Dotti G, Quintarelli C, et al. Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506). Blood. 2009;114:4784–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Brewin J, Mancao C, Straathof K, et al. Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease. Blood. 2009;114:4792–803.PubMedCrossRefGoogle Scholar
  27. 27.
    Quintarelli C, Savoldo B, Dotti G. Gene therapy to improve function of T cells for adoptive immunotherapy. Methods Mol Biol. 2010;651:119–30.PubMedCrossRefGoogle Scholar
  28. 28.
    Marin V, Cribioli E, Philip B, et al. Comparison of different suicide gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods 2012.Google Scholar
  29. 29.
    He J, Tang XF, Chen QY, et al. Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy. Chin J Cancer. 2012;31:287–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Louis CU, Straathof K, Bollard CM, et al. Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood. 2009;113:2442–50.PubMedCrossRefGoogle Scholar
  31. 31.•
    Perna SK, De Angelis B, Pagliara D, et al. Interleukin 15 provides relief to cytotoxic T lymphocytes from regulatory T cell-mediated inhibition: implications for adoptive T-cell based therapies of lymphoma. Clin Cancer Res 2012. Role of IL-15 in promoting the survival and expansion of EBV-CTLs in the presence of regulatory T-cells.Google Scholar
  32. 32.
    Foster AE, Dotti G, Lu A, et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J Immunother. 2008;31:500–5.PubMedCrossRefGoogle Scholar
  33. 33.•
    Ouyang J, Juszczynski P, Rodig SJ, et al. Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders. Blood. 2011;117:4315–22. Role of galectin-1 in EBV-positive lymphomas and the EBV-specific CTL immune response.PubMedCrossRefGoogle Scholar
  34. 34.
    Juszczynski P, Ouyang J, Monti S, et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2007;104:13134–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Young RM, Hardy IR, Clarke RL, et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood. 2009;113:2508–16.PubMedCrossRefGoogle Scholar
  36. 36.•
    Hatton O, Phillips LK, Vaysberg M, Hurwich J, Krams SM, Martinez OM. Syk activation of phosphatidylinositol 3-kinase/Akt prevents HtrA2-dependent loss of X-linked inhibitor of apoptosis protein (XIAP) to promote survival of Epstein-Barr virus+ (EBV+) B cell lymphomas. J Biol Chem. 2011;286:37368–78. LMP-2 signaling through the Syk and the PI3K/Akt pathway in EBV-positive lymphomas.PubMedCrossRefGoogle Scholar
  37. 37.
    Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 2008;111:2230–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Gururajan M, Dasu T, Shahidain S, et al. Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth. J Immunol. 2007;178:111–21.PubMedGoogle Scholar
  39. 39.
    Suljagic M, Longo PG, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood. 2010;116:4894–905.PubMedCrossRefGoogle Scholar
  40. 40.
    Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578–85.PubMedCrossRefGoogle Scholar
  41. 41.
    Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006;319:998–1008.PubMedCrossRefGoogle Scholar
  42. 42.
    Caldwell RG, Brown RC, Longnecker R. Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice. J Virol. 2000;74:1101–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Bultema R, Longnecker R, Swanson-Mungerson M. Epstein-Barr virus LMP2A accelerates MYC-induced lymphomagenesis. Oncogene. 2009;28:1471–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Rovedo M, Longnecker R. Epstein-Barr virus latent membrane protein 2A preferentially signals through the Src family kinase Lyn. J Virol. 2008;82:8520–8.PubMedCrossRefGoogle Scholar
  45. 45.•
    Dargart JL, Fish K, Gordon LI, Longnecker R, Cen O. Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A. Antiviral Res. 2012;95:49–56. Dasatinib inhibts LMP-2-mediated activation of the Lyn pathway and leads to regression of EBV(+) lymphomas in a murine model.PubMedCrossRefGoogle Scholar
  46. 46.
    Dawson CW, Tramountanis G, Eliopoulos AG, Young LS. Epstein-Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J Biol Chem. 2003;278:3694–704.PubMedCrossRefGoogle Scholar
  47. 47.
    Lambert SL, Martinez OM. Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol. 2007;179:8225–34.PubMedGoogle Scholar
  48. 48.•
    Hatton O, Lambert SL, Krams SM, Martinez OM. Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+ B cell lymphomas. PLoS One. 2012;7:e42610. LMP-1 activates the P13K/Akt pathway through Syk activation.PubMedCrossRefGoogle Scholar
  49. 49.
    Meckes DG, Jr., Menaker NF, Raab-Traub N. EBV LMP1 Modulates Lipid Raft Microdomains and the Vimentin Cytoskeleton for Signal Transduction and Transformation. J Virol 2012.Google Scholar
  50. 50.
    Kanemitsu N, Isobe Y, Masuda A, et al. Expression of Epstein-Barr virus-encoded proteins in extranodal NK/T-cell Lymphoma, nasal type (ENKL): differences in biologic and clinical behaviors of LMP1-positive and -negative ENKL. Clin Cancer Res. 2012;18:2164–72.PubMedCrossRefGoogle Scholar
  51. 51.
    Or YY, Hui AB, To KF, Lam CN, Lo KW. PIK3CA mutations in nasopharyngeal carcinoma. Int J Cancer. 2006;118:1065–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Ma BB, Lui VW, Hui EP, et al. The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines. Invest New Drugs. 2010;28:413–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Mei YP, Zhou JM, Wang Y, et al. Silencing of LMP1 induces cell cycle arrest and enhances chemosensitivity through inhibition of AKT signaling pathway in EBV-positive nasopharyngeal carcinoma cells. Cell Cycle. 2007;6:1379–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Ma BB, Lui VW, Hui CW, et al. Preclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines. Invest New Drugs 2012.Google Scholar
  55. 55.•
    Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611–8. EBV as a mechanism of PD-L1 induction in EBV-positive lymphomas.PubMedCrossRefGoogle Scholar
  56. 56.•
    Shirley CM, Chen J, Shamay M, et al. Bortezomib induction of C/EBPbeta mediates Epstein-Barr virus lytic activation in Burkitt lymphoma. Blood. 2011;117:6297–303. Bortezomib induces the unfolded protein response and CEBP-α-mediated lytic activation of EBV in Burkitt lymphoma.PubMedCrossRefGoogle Scholar
  57. 57.
    Sides MD, Block GJ, Shan B, et al. Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells. Virology. 2011;416:86–97.PubMedCrossRefGoogle Scholar
  58. 58.
    Sivachandran N, Wang X, Frappier L. Functions of the Epstein-Barr virus EBNA1 protein in viral reactivation and lytic infection. J Virol. 2012;86:6146–58.PubMedCrossRefGoogle Scholar
  59. 59.•
    Li R, Wang L, Liao G, et al. SUMO binding by the Epstein-Barr virus protein kinase BGLF4 is crucial for BGLF4 function. J Virol. 2012;86:5412–21. Role of SUMO binding of BGLF4 in the DNA damage response and EBV replication.PubMedCrossRefGoogle Scholar
  60. 60.
    Hui KF, Chiang AK. Suberoylanilide hydroxamic acid induces viral lytic cycle in Epstein-Barr virus-positive epithelial malignancies and mediates enhanced cell death. Int J Cancer. 2010;126:2479–89.PubMedGoogle Scholar
  61. 61.•
    Ghosh SK, Perrine SP, Williams RM, Faller DV. Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Blood. 2012;119:1008–17. Lytic induction of EBV with histone deacetylase inhibitors.PubMedCrossRefGoogle Scholar
  62. 62.•
    Wildeman MA, Novalic Z, Verkuijlen SA, et al. Cytolytic virus activation therapy for epstein-barr virus-driven tumors. Clin Cancer Res. 2012;18:5061–70. Lytic induction of EBV with gemcitabine and valproic acid.PubMedCrossRefGoogle Scholar
  63. 63.
    Jones K, Nourse J, Corbett G, Gandhi MK. Sodium valproate in combination with ganciclovir induces lysis of EBV-infected lymphoma cells without impairing EBV-specific T-cell immunity. Int J Lab Hematol. 2010;32:e169–74.PubMedCrossRefGoogle Scholar
  64. 64.
    Perrine SP, Hermine O, Small T, et al. A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood. 2007;109:2571–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Jung EJ, Lee YM, Lee BL, Chang MS, Kim WH. Lytic induction and apoptosis of Epstein-Barr virus-associated gastric cancer cell line with epigenetic modifiers and ganciclovir. Cancer Lett. 2007;247:77–83.PubMedCrossRefGoogle Scholar
  66. 66.•
    Li Y, Zhang Y, Fu M, et al. Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma. Mol Med Report. 2012;6:477–82. Lytic induction of EBV with parthenolide.Google Scholar
  67. 67.
    Hagemeier SR, Barlow EA, Meng Q, Kenney SC. The cellular ataxia telangiectasia-mutated (ATM) kinase promotes Epstein-Barr virus (EBV) lytic reactivation in response to multiple different types of lytic-inducing stimuli. J Virol 2012. Role of ATM kinase in EBV lytic activation.Google Scholar
  68. 68.
    Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196:1749–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Moutschen M, Leonard P, Sokal EM, et al. Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. Vaccine. 2007;25:4697–705.PubMedCrossRefGoogle Scholar
  70. 70.
    Elliott SL, Suhrbier A, Miles JJ, et al. Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J Virol. 2008;82:1448–57.PubMedCrossRefGoogle Scholar
  71. 71.••
    Cohen JI, Fauci AS, Varmus H, Nabel GJ. Epstein-Barr virus: an important vaccine target for cancer prevention. Sci Transl Med 2011;3:107fs107. Overview of EBV vaccine development, clinical trials, and future directions.Google Scholar
  72. 72.
    Rees L, Tizard EJ, Morgan AJ, et al. A phase I trial of epstein-barr virus gp350 vaccine for children with chronic kidney disease awaiting transplantation. Transplantation. 2009;88:1025–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations