Epstein-Barr virus-associated post-transplant lymphoproliferative disorders: beyond chemotherapy treatment

Abstract

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of both allogeneic solid organ (SOT) and hematopoietic cell transplantation (HCT). The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma. Most commonly, PTLDs are Epstein-Barr virus (EBV) positive and result from loss of immune surveillance over EBV. Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different, resistance to treatment is unique, and there are specific concerns for organ toxicity. While recipients of HCT have a limited time during which they are at risk for this complication, recipients of SOT have a lifelong requirement for immunosuppression, so approaches that limit compromising or help restore immune surveillance are of high interest. Furthermore, while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy, the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms. Therefore, reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib, reduced dosing of standard chemotherapeutic agents, and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored. Here, we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.

Keywords

Post-transplant lymphoproliferative disease / PTLD / Epstein-Barr virus / EBV / rituximab / CD20 monoclonal antibody / immunotherapy / chemoimmunotherapy / EBV-specific cytotoxic T lymphocytes / EBV CTLs

References

[1] Samant H,Kothadia JP.Post Transplant Lymphoproliferative Disorders. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.

[2] Weissmann DJ,Harris NL,Delmonico F.Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin.Am J Clin Pathol1995;103:748-55

[3] Jacobson CA.Lymphoma: risk and response after solid organ transplant.Oncology (Williston Park)2010;24:936-44

[4] Murray RJ,Brooks JM.Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies.J Exp Med1992;176:157-68 PMCID:PMC2119296

[5] Hislop AD,Sauce D.Cellular responses to viral infection in humans: lessons from Epstein-Barr virus.Annu Rev Immunol2007;25:587-617

[6] Prockop SE.Epstein-Barr virus lymphoproliferative disease after solid organ transplantation.Cytotherapy2017;19:1270-83

[7] Taylor AL,Callaghan CJ.Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation.Transplantation2006;82:375-81

[8] Trappe RU,Zimmermann H.Response to Rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into Rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial.J Clin Oncol2017;35:536-43

[9] Styczynski J,Gil L.Impact of donor Epstein-Barr virus serostatus on the incidence of graft-versus-host disease in patients with acute leukemia after hematopoietic stem-cell transplantation: a study from the acute leukemia and infectious diseases working parties of the european society for blood and marrow transplantation.J Clin Oncol2016;34:2212-20

[10] Ibrahim HA.Posttransplant lymphoproliferative disorders.Adv Hematol2012;2012:230173 PMCID:PMC3337580

[11] Opelz G,Naujokat C.Epidemiology of pretransplant EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma.Transplantation2009;88:962-7

[12] Boubenider S,Goupy C,Marchand S.Incidence and consequences of post-transplantation lymphoproliferative disorders.J Nephrol1997;10:136-45

[13] Gupta D,Chakraborty S.Post transplant lymphoproliferative disorder.Indian J Hematol Blood Transfus2020;36:229-37 PMCID:PMC7229077

[14] Petrara MR,Serraino D,De Rossi A.Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment.Cancer Lett2015;369:37-44

[15] Engels EA,Fraumeni JF Jr.Spectrum of cancer risk among US solid organ transplant recipients.JAMA2011;306:1891-901 PMCID:PMC3310893

[16] Dierickx D.Post-transplantation lymphoproliferative disorders in adults.N Engl J Med2018;378:549-62

[17] Stojanova J,Rousseau A.Post-transplant lymphoproliferative disease (PTLD): pharmacological, virological and other determinants.Pharmacol Res2011;63:1-7

[18] Taylor AL,Bradley JA.Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation.Crit Rev Oncol Hematol2005;56:155-67

[19] Trappe R,Leblond V.German PTLD Study GroupEuropean PTLD NetworkSequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.Lancet Oncol2012;13:196-206

[20] Cheson BD,Barrington SF.AllianceAustralasian Leukaemia and Lymphoma GroupEastern Cooperative Oncology GroupEuropean Mantle Cell Lymphoma ConsortiumItalian Lymphoma FoundationEuropean Organisation for ResearchTreatment of Cancer/Dutch Hemato-Oncology GroupGrupo Español de Médula ÓseaGerman High-Grade Lymphoma Study GroupGerman Hodgkin's Study GroupJapanese Lymphorra Study GroupLymphoma Study AssociationNCIC Clinical Trials GroupNordic Lymphoma Study GroupSouthwest Oncology GroupUnited Kingdom National Cancer Research InstituteRecommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.J Clin Oncol2014;32:3059-68 PMCID:PMC4979083

[21] Al-Mansour Z,Evens AM.Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies.Curr Hematol Malig Rep2013;8:173-83 PMCID:PMC4831913

[22] Caillard S,Provot F.Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score.J Clin Oncol2013;31:1302-9

[23] Trappe RU,Dierickx D.German PTLD Study Group and the European PTLD NetworkInternational 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 Transplant2015;15:1091-100

[24] Dierickx D,Morscio J,Verhoef G.Validation of prognostic scores in post-transplantation lymphoproliferative disorders.J Clin Oncol2013;31:3443-4

[25] Podoltsev N,Yao X,Deng Y.Chemoimmunotherapy and withdrawal of immunosuppression for monomorphic posttransplant lymphoproliferative disorders.Clin Lymphoma Myeloma Leuk2013;13:716-20 PMCID:PMC3846604

[26] Styczynski J,Tridello G.Infectious Diseases Working Party of the European Group for Blood and Marrow TransplantationResponse to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.Clin Infect Dis2013;57:794-802

[27] Prockop S,Suser S.Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation.J Clin Invest2020;130:733-47 PMCID:PMC6994129

[28] Reshef R,Luskin MR.Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder.Am J Transplant2011;11:336-47 PMCID:PMC3079420

[29] Gu Z,Yuan L.Successful treatment of polymorphic post-transplant lymphoproliferative disorder after allo-HSCT with reduction of immunosuppression.Int J Clin Exp Med2014;7:1904-9 PMCID:PMC4132163

[30] Starzl TE,Porter KA.Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy.Lancet1984;1:583-7 PMCID:PMC2987704

[31] Fox CP,Parker AN.EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.Bone Marrow Transplant2014;49:280-6

[32] Ocheni S,Zabelina T.EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT.Bone Marrow Transplant2008;42:181-6

[33] Styczynski J,Gil L.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 Dis2009;11:383-92

[34] Tsai DE,Tomaszewski JE.Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients.Transplantation2001;71:1076-88

[35] Swinnen LJ,Grogan TM.Prospective study of sequential reduction in immunosuppression, interferon alpha-2B, and chemotherapy for posttransplantation lymphoproliferative disorder.Transplantation2008;86:215-22 PMCID:PMC4029101

[36] Elstrom RL,Aqui NA.Treatment of PTLD with rituximab or chemotherapy.Am J Transplant2006;6:569-76

[37] Ghobrial IM,Maurer MJ.Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders.J Clin Oncol2005;23:7574-82

[38] Swinnen LJ,Carr TJ,Fisher RI.Aggressive treatment for postcardiac transplant lymphoproliferation.Blood1995;86:3333-40

[39] Knight JS,Cibrik DM,Kaminski MS.Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center.J Clin Oncol2009;27:3354-62

[40] Jagadeesh D,Draper J.Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations.Curr Treat Options Oncol2012;13:122-36

[41] Oton AB,Leleu X.Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant.Leuk Lymphoma2008;49:1738-44

[42] Caillard S,Agodoa L,Abbott K.Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression.Transplantation2005;80:1233-43

[43] Schober T,Kreipe H.Characteristics of early and late PTLD development in pediatric solid organ transplant recipients.Transplantation2013;95:240-6

[44] Orjuela MA,Liu X.CD20 expression predicts survival in paediatric post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation.Br J Haematol2011;152:733-42

[45] Maecker B,Zimmermann M.CNS or bone marrow involvement as risk factors for poor survival in post-transplantation lymphoproliferative disorders in children after solid organ transplantation.J Clin Oncol2007;25:4902-8

[46] Nepomuceno RR,Natkunam Y,Krams SM.Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas.Cancer Res2003;63:4472-80

[47] Cullis B,McCullagh P.Sirolimus-induced remission of posttransplantation lymphoproliferative disorder.Am J Kidney Dis2006;47:e67-72

[48] Boratyńska M,Smolska D,Klinger M.Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies.Transplant Proc2007;39:2736-9

[49] Salles G,Foà R.Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience.Adv Ther2017;34:2232-73 PMCID:PMC5656728

[50] Tomblyn M,Einsele H.Center for International Blood and Marrow ResearchNational Marrow Donor programEuropean Blood and MarrowTransplant GroupAmerican Society of Blood and Marrow TransplantationCanadian Blood and Marrow Transplant GroupInfectious Diseases Society of AmericaSociety for Healthcare Epidemiology of AmericaAssociation of Medical Microbiology and Infectious Disease CanadaCenters for Disease Control and PreventionGuidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.Biol Blood Marrow Transplant2009;15:1143-238 PMCID:PMC3103296

[51] Styczynski J,Fox CP.Sixth European Conference on Infections in Leukemiaa joint venture of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (EBMT-IDWP)the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (EORTC-IDG)the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN)Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines.Haematologica2016;101:803-11 PMCID:PMC5004459

[52] Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment.Nephrol Dial Transplant2002;17 Suppl 4:31-3, 5

[53] Yang J,Flinn IW.Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response.Blood2000;96:4055-63

[54] Choquet S,Herbrecht R.Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study.Blood2006;107:3053-7

[55] Choquet S,LeBlond V.Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution.Ann Hematol2007;86:599-607

[56] González-Barca E,Capote FJ.GEL/TAMO (Grupo Español de Linfomas); GELCAB (Grupo para el Estudio de los Linfomas Catalano-Balear); GOTEL (Grupo Oncológico para el Tratamiento y Estudio de los Linfomas)Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease.Haematologica2007;92:1489-94

[57] Teeling JL,Wiegman LJ.The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20.J Immunol2006;177:362-71

[58] Herter S,Mundigl O.Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.Mol Cancer Ther2013;12:2031-42

[59] Coiffier B,Pedersen LM.Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study.Blood2008;111:1094-100

[60] Ghione P,De Paola N.Alternative anti-CD20 antibody versus desensitization for lymphoma patients with drug hypersensitivity reactions requiring discontinuation of rituximab, obinutuzumab, or ofatumumab.J Clin Oncol2020;38:8062

[61] Hamed R, Bazarbachi AH, Mohty M. Epstein-Barr virus-related post-transplant lymphoproliferative disease (EBV-PTLD) in the setting of allogeneic stem cell transplantation: a comprehensive review from pathogenesis to forthcoming treatment modalities.Bone Marrow Transplant2020;55:25-39

[62] Gross TG,Perkins SL.Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report.Am J Transplant2012;12:3069-75 PMCID:PMC3484187

[63] Rummel MJ,Kim SZ.Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma.J Clin Oncol2005;23:3383-9

[64] Duval A,Brennetot C.The mutator pathway is a feature of immunodeficiency-related lymphomas.Proc Natl Acad Sci U S A2004;101:5002-7 PMCID:PMC387363

[65] Le DT,Wang H.PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[66] Kinch A,Baecklund E,Molin D.Expression of PD-1, PD-L1, and PD-L2 in posttransplant lymphoproliferative disorder after solid organ transplantation.Leuk Lymphoma2019;60:376-84

[67] Ferreiro JF,Dierickx D.EBV-positive and EBV-negative posttransplant diffuse large B cell lymphomas have distinct genomic and transcriptomic features.Am J Transplant2016;16:414-25

[68] Veloza L,Castrejon N.Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome.Histopathology2019;75:799-812

[69] Kassa C,Sinkó J,Kertész G.Successful nivolumab therapy in an allogeneic stem cell transplant child with post-transplant lymphoproliferative disorder.Pediatr Transplant2018;22:e13302

[70] Volk V,Danisch S.PD-1 blockade aggravates Epstein-Barr Virus(+) post-transplant lymphoproliferative disorder in humanized mice resulting in central nervous system involvement and CD4(+) T cell dysregulations.Front Oncol2020;10:614876 PMCID:PMC7837057

[71] Shannon-Lowe C.The global landscape of EBV-associated tumors.Front Oncol2019;9:713 PMCID:PMC6691157

[72] Tse E.Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target.Exp Mol Med2015;47:e136 PMCID:PMC4314579

[73] Thompson MP.Epstein-Barr virus and cancer.Clin Cancer Res2004;10:803-21

[74] Ghosh SK,Williams RM.Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents.Blood2012;119:1008-17 PMCID:PMC3271713

[75] Anisimová E,Roubal J.Effects of n-butyrate and phorbol ester (TPA) on induction of Epstein-Barr virus antigens and cell differentiation.Arch Virol1984;81:223-37

[76] Saemundsen AK,Klein G.Effect of n-butyrate on cellular and viral DNA synthesis in cells latently infected with Epstein-Barr virus.Virology1980;107:557-61

[77] Mentzer SJ,Reilly JJ,Faller DV.Arginine butyrate-induced susceptibility to ganciclovir in an Epstein-Barr-virus-associated lymphoma.Blood Cells Mol Dis1998;24:114-23

[78] Perrine SP,Small T.A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies.Blood2007;109:2571-8 PMCID:PMC1852196

[79] Sutrave G.Adoptive cell therapies for posttransplant infections.Curr Opin Oncol2019;31:574-90

[80] Papadopoulos EB,Emanuel D.Infusions of donor leukocytes to treat Epstein-Barr Virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.N Engl J Med1994;330:1185-91

[81] Gottschalk S,Heslop HE.Post-transplant lymphoproliferative disorders.Annu Rev Med2005;56:29-44

[82] Slobod KS,Woodruff L.T cell immunotherapeutic populations control viral infections in bone marrow transplant recipients.Immunol Res2001;24:289-301

[83] Gustafsson A,Zou JZ.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.Blood2000;95:807-14

[84] Comoli P,Zecca M.Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation.Am J Transplant2007;7:1648-55

[85] O'Reilly RJ,Trivedi D,Kollen W.Adoptive transfer of antigen-specific T-cells of donor type for immunotherapy of viral infections following allogeneic hematopoietic cell transplants.Immunol Res2007;38:237-50

[86] Comoli P,Basso S.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.Blood2002;99:2592-8

[87] Khanna R,Sherritt M.Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease.Proc Natl Acad Sci U S A1999;96:10391-6 PMCID:PMC17898

[88] Savoldo B,Hammer MM.Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs).Blood2006;108:2942-9 PMCID:PMC1895521

[89] Pakakasama S,Morriss MC.Treatment of Epstein-Barr virus lymphoproliferative disease after hematopoietic stem-cell transplantation with hydroxyurea and cytotoxic T-cell lymphocytes.Transplantation2004;78:755-7

[90] Haque T,Taylor C.Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells.Lancet2002;360:436-42

[91] Haque T,Jones MM.Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.Blood2007;110:1123-31

[92] Gandhi MK,Dua U.Immunity, homing and efficacy of allogeneic adoptive immunotherapy for posttransplant lymphoproliferative disorders.Am J Transplant2007;7:1293-9

[93] Sun Q,Reddy V.Safety of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for patients with refractory EBV-related lymphoma.Br J Haematol2002;118:799-808

[94] Chiou FK,Wilkie GM,Morland B.Cytotoxic T-lymphocyte therapy for post-transplant lymphoproliferative disorder after solid organ transplantation in children.Pediatr Transplant2018;22

[95] Tzannou I,Naik S,Martinez CA.Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation.J Clin Oncol2017;35:3547-57 PMCID:PMC5662844

[96] Papadopoulou A,Katari UL.Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT.Sci Transl Med2014;6:242ra83 PMCID:PMC4181611

[97] Heslop HE,Li C.Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes.Nat Med1996;2:551-5

[98] Bollard CM,Torrano V.Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.J Clin Oncol2014;32:798-808 PMCID:PMC3940538

[99] Doubrovina E,Prockop SE.Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.Blood2012;119:2644-56 PMCID:PMC3311278

[100] Koehne G,Doubrovina E.Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes.Nat Biotechnol2003;21:405-13

[101] Gerdemann U,Katari UL.Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.Mol Ther2012;20:1622-32 PMCID:PMC3412490

[102] Gottschalk S,Perez M.An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs.Blood2001;97:835-43

[103] Dalton T,Pankov D.Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy.Blood2020;135:1870-81 PMCID:PMC7243148

[104] Cho SG,Sohn HJ.Long-term outcome of extranodal NK/T cell lymphoma patients treated with postremission therapy using EBV LMP1 and LMP2a-specific CTLs.Mol Ther2015;23:1401-9 PMCID:PMC4817864

[105] Gottschalk S,Sili U.Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies.Blood2003;101:1905-12

[106] Sieber M.Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?.Cell Commun Signal2009;7:25 PMCID:PMC2774854

[107] Brewin J,Straathof K.Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease.Blood2009;114:4792-803

[108] Reik A,Wagner J.Zinc finger nucleases targeting the glucocorticoid receptor allow IL-13 zetakine transgenic CTLs to kill glioblastoma cells in vivo in the presence of immunosuppressing glucocorticoids.Cancer Res2008;68:2557

[109] Mika T,Ladigan S.Refractory Epstein-Barr Virus (EBV)-related post-transplant lymphoproliferative disease: cure by combined brentuximab vedotin and allogeneic EBV-specific T-lymphocytes.Front Med (Lausanne)2019;6:295 PMCID:PMC6930172

[110] Hsu C,Ejadi S.Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 Study.J Clin Oncol2017;35:4050-6

[111] Ma BBY,Goh BC.Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: an international, multicenter study of the mayo clinic phase 2 consortium (NCI-9742).J Clin Oncol2018;36:1412-8 PMCID:PMC5941615

[112] Fang W,Ma Y.Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials.Lancet Oncol2018;19:1338-50

[113] Jiang L,Lung HL.EBNA1-targeted inhibitors: novel approaches for the treatment of Epstein-Barr virus-associated cancers.Theranostics2018;8:5307-19 PMCID:PMC6276081

[114] Maier S,Hartmann A.Cellular target genes of Epstein-Barr virus nuclear antigen 2.J Virol2006;80:9761-71 PMCID:PMC1617228

[115] Shatzer A,Chavez M.Ganetespib, an HSP90 inhibitor, kills Epstein-Barr virus (EBV)-infected B and T cells and reduces the percentage of EBV-infected cells in the blood.Leuk Lymphoma2017;58:923-31 PMCID:PMC6358278

[116] Rooney CM,Ng CY.Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation.Lancet1995;345:9-13

[117] Rooney CM,Ng CY.Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.Blood1998;92:1549-55

[118] Heslop HE,Pule MA.Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.Blood2010;115:925-35 PMCID:PMC2817637

[119] Lucas KG,Heller G,O'Reilly RJ.The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation.Blood1996;87:2594-603

[120] Imashuku S,Yamori M.Bone marrow transplatation for Epstein-Barr virus-related clonal T cell proliferation associated with hemophagocytosis.Bone Marrow Transplant1997;19:1059-60

[121] Comoli P,Labirio M,Maccario R.T cell therapy of Epstein-Barr virus and adenovirus infections after hemopoietic stem cell transplant.Blood Cells Mol Dis2008;40:68-70

[122] Moosmann A,Tischer J.Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells.Blood2010;115:2960-70

[123] Icheva V,Wolff D.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 Oncol2012;31:39-48

[124] Gerdemann U,Papadopoulou A.Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant.Mol Ther2013;21:2113-21 PMCID:PMC3831033

[125] Lucas KG,Garcia A.Adoptive immunotherapy with allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent, EBV-positive Hodgkin disease.Cancer2004;100:1892-901

[126] Leen AM,Mendizabal AM.Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.Blood2013;121:5113-23 PMCID:PMC3695359

[127] Gallot G,Saïagh S.T-cell therapy using a bank of EBV-specific cytotoxic T cells: lessons from a phase I/II feasibility and safety study.J Immunother2014;37:170-9

[128] Vickers MA,Robinson N.Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.Br J Haematol2014;167:402-10 PMCID:PMC4232001

[129] Alonso L,Benitez MI.Adoptive immunotherapy with virus specific T cell: experience of 2 Spanish cell-therapy laboratories.Bone Marrow Transplant2019;53:P089