EBV-associated lymphoproliferative disease post-CAR-T cell therapy

Abstract

Epstein–Barr virus (EBV)-associated lymphoproliferative diseases (EBV-LPDs) are common complications that occur after solid organ transplantation or allogeneic hematopoietic stem-cell transplantation (HSCT). However, their occurrence and treatment post-chimeric antigen receptor-modified T (CAR-T) cell therapy has not been reported. Two patients had been diagnosed with EBV-positive aggressive B-cell lymphoma and experienced relapses after multiple lines of treatment. After receiving CAR-T cell therapy in tandem with autologous HSCT, the patients achieved complete remission. However, with a median time of 38.5 months after CAR-T cell therapy, B-cell-derived EBV-LPDs were diagnosed, and they were relieved through the administration of immune checkpoint inhibitor or B-cell-depleting agents. Collectively, our report suggests that EBV-LPDs may represent a long-term adverse event after CAR-T cell therapy, especially in patients who previously had EBV-positive disorders, and they can be resolved by immune normalization strategy or B-cell depleting therapy.

Keywords

EBV-associated lymphoproliferative disease / chimeric antigen receptor T-cell / autologous stem cell transplantation / immune checkpoint inhibitor

References

[1] Dharnidharka VR, Webster AC, Martinez OM, Preiksaitis JK, Leblond V, Choquet S. Post-transplant lymphoproliferative disorders. Nat Rev Dis Primers 2016; 2(1): 15088

[2] Jindra P, Koza V, Boudová L, Vozobulová V, Cerná K, Karas M, Lysák D, Svojgrová M. Epstein-Barr virus-associated B-cell lymphoproliferative disorder in CLL patients after treatment with fludarabine and cyclophosphamide followed by high-dose chemotherapy with autologous stem cell transplantation. Bone Marrow Transplant 2003; 31(10): 951–952

[3] Nash RA, Dansey R, Storek J, Georges GE, Bowen JD, Holmberg LA, Kraft GH, Mayes MD, McDonagh KT, Chen CS, Dipersio J, Lemaistre CF, Pavletic S, Sullivan KM, Sunderhaus J, Furst DE, McSweeney PA. Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases. Biol Blood Marrow Transplant 2003; 9(9): 583–591

[4] Cao Y, Xiao Y, Wang N, Wang G, Huang L, Hong Z, Meng L, Zhou X, Wang J, Yang Y, Xu H, Zhang S, Xiao M, Chen L, Zheng M, Li C, Mao X, Gu C, Zhang T, Zhang Y, Zhou J. CD19/CD22 chimeric antigen receptor T cell cocktail therapy following autologous transplantation in patients with relapsed/refractory aggressive B cell lymphomas. Transplant Cell Ther 2021; 27(11): 910.e1–910.e11

[5] Luo H, Liu D, Liu W, Jin J, Bi X, Zhang P, Gu J, Zheng M, Xiao M, Liu X, Zhou J, Wang QF. Clinical and genetic characterization of Epstein-Barr virus-associated T/NK-cell lymphoproliferative diseases. J Allergy Clin Immunol 2023; 151(4): 1096–1109

[6] Turvey SE, Durandy A, Fischer A, Fung SY, Geha RS, Gewies A, Giese T, Greil J, Keller B, McKinnon ML, Neven B, Rozmus J, Ruland J, Snow AL, Stepensky P, Warnatz K. The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency. J Allergy Clin Immunol 2014; 134(2): 276–284

[7] Katano H, Ali MA, Patera AC, Catalfamo M, Jaffe ES, Kimura H, Dale JK, Straus SE, Cohen JI. Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 2004; 103(4): 1244–1252

[8] Tangye SG, Palendira U, Edwards ES. Human immunity against EBV-lessons from the clinic. J Exp Med 2017; 214(2): 269–283

[9] Lünemann A, Rowe M, Nadal D. Innate immune recognition of EBV. Curr Top Microbiol Immunol 2015; 391: 265–287

[10] Liu P, Pan X, Chen C, Niu T, Shuai X, Wang J, Chen X, Liu J, Guo Y, Xie L, Wu Y, Liu Y, Liu T. Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults. Blood 2020; 135(11): 826–833

[11] Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell 2018; 175(2): 313–326

[12] Au WY, Pang A, Choy C, Chim CS, Kwong YL. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood 2004; 104(1): 243–249

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Higher Education Press