Tabelecleucel: a new therapeutic option in refractory EBV-PTLD
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is classified as an immune-associated lymphoproliferative disease occurring after hematopoietic stem cells transplantation (HCT) or solid organ transplantation (SOT). Rituximab and reduction of immunosuppression are the first line therapy of EBV-DNA-emia and EBV-PTLD and are seen as the ‘gold standard’ in therapy of post-transplant EBV-related complications. In cases of failed first line therapy with rituximab, regardless of applied reduction of immunosuppression, refractory EBV-PTLD is diagnosed. Refractory EBV-PTLD has a poor outcome, with 2-year overall survival rates of 9.4% and 31.4% following HCT and SOT, respectively, in patients who have failed rituximab and/or chemotherapy. The main treatment options for patients with EBV-PTLD post-HCT who failed first line therapy include the use of EBV-specific cytotoxic T-lymphocytes (EBV-CTLs), which can be donor-derived, third-party donor, or of ‘off-the-shelf’ origin.
Tabelecleucel is a T-cell product including EBV-specific T-cells originating from a third-party EBV-seropositive donor. These EBV-CTLs were stimulated with B-cells from the same donor, able to recognize B-cells infected with EBV, with no genetic modification used, and expanded in laboratory conditions. Tabelecleucel has been investigated as an ATMP (advanced therapy medicinal product), an on-demand, allogeneic T-cell immunotherapy for the potential treatment of EBV-positive malignancies and diseases. The aim of this narrative review was to assess the third-party donor ‘off-the-shelf’ cellular product of EBV-CTLs, tabelecleucel, as a therapeutic option of treatment for refractory or relapsing EBV-PTLD.
Keywords: hematopoietic cell transplantationEpstein-Barr viruspost-transplant lymphoproliferative disorderrefractory PTLDresistant PTLD
References
- Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022; 36(7): 1720–1748.
- Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022; 140(11): 1229–1253.
- Marjanska A, Styczynski J. Who is the patient at risk for EBV reactivation and disease: expert opinion focused on post-transplant lymphoproliferative disorders following hematopoietic stem cell transplantation. Expert Opin Biol Ther. 2023; 23(6): 539–552.
- 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. 2008; 43(10): 757–770.
- Styczynski J, Velden Wv, Fox CP, et al. 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. Haematologica. 2016; 101(7): 803–811.
- Nijland M, Kersten M, Pals S, et al. Epstein-Barr virus-positive posttransplant lymphoproliferative disease after solid organ transplantation. Transplantat Direct. 2016; 2(1): e48.
- Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000; 343(7): 481–492.
- Long HM, Meckiff BJ, Taylor GS. The T-cell response to Epstein-Barr virus — new tricks from an old dog. Front Immunol. 2019; 10: 2193.
- Aftab B, Sasu B, Krishnamurthy J, et al. Toward “off‐the‐shelf” allogeneic CAR T cells. Adv Cell Gene Ther. 2020; 3(3): e86.
- Fałkowska A, Zaucha-Prażmo A, Drabko K, et al. Viral infections after hematopoetic stem cell transplantation in children with acute lymphoblastic leukemia: the Polish experience. Acta Haematol Pol. 2023; 54(4): 221–226.
- Lech-Marańda E, Budziszewska B, Mikołajczyk T, et al. Incidence and prevalence of lymphatic neoplasms in Poland 2009–2015 determined on analysis of National Health Fund data used in the ‘Maps of healthcare needs — database of systemic and implementation analyses’ project. Acta Haematol Pol. 2022; 53(2): 112–132.
- Passweg JR, Baldomero H, Chabannon C, et al. European Society for Blood and Marrow Transplantation (EBMT). Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies in Europe 2020: a report from the EBMT activity survey. Bone Marrow Transplant. 2022; 57(5): 742–752.
- Dierickx D, Pociupany M, Natkunam Y. Epstein-Barr virus-associated posttransplant lymphoproliferative disorders: new insights in pathogenesis, classification and treatment. Curr Opin Oncol. 2022; 34(5): 413–421.
- Burns DM, Clesham K, Hodgson YA, et al. Real-world outcomes with rituximab-based therapy for posttransplant lymphoproliferative disease arising after solid organ transplant. Transplantation. 2020; 104(12): 2582–2590.
- Newsletter Transplant. EDQM 2022. https://www.edqm.eu/en/newsletter-transplant (July 15, 2024).
- Dharnidharka V, Thirumalai D, Jaeger U, et al. Clinical outcomes of solid organ transplant patients with Epstein-Barr virus-driven (EBV +) post-transplant lymphoproliferative disorder (PTLD) Who Fail Rituximab Plus Chemotherapy: A Multinational, Retrospective Chart Review Study. Blood. 2021; 138(Supplement 1): 2528–2528.
- Jagadeesh D, Tsai D, Wei W, et al. Post-transplant lymphoproliferative disorder (PTLD) after solid organ transplant (SOT): A multicenter real world analysis (RWA) of 877 patients (pts) treated in the modern era. J Clin Oncol. 2020; 38(15_suppl): e20026–e20026.
- Sanz J, Storek J, Socié G, et al. Clinical outcomes of patients with Epstein-Barr virus-driven post-transplant lymphoproliferative disease following hematopoietic stem cell transplantation who fail rituximab: a multinational, retrospective chart review study. Blood. 2021; 138(Supplement 1): 1454.
- Al 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 Transplant. 2020; 55(1): 25–39.
- Shahid S, Prockop SE. Epstein-Barr virus-associated post-transplant lymphoproliferative disorders: beyond chemotherapy treatment. Cancer Drug Resist. 2021; 4(3): 646–664.
- Bogacz A, Bukowska A, Bukowska M, et al. Treatment of resistant viral infections after allogeneic hematopoietic stem cell transplantation using virus-specific T cells. Acta Haematol Pol. 2024; 55(2): 90–96.
- Papadopoulos EB, Ladanyi M, Emanuel D, et al. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med. 1994; 330(17): 1185–1191.
- Majeranowski A, Lebiedziński F, Okrój M, et al. Zanubrutinib: a novel therapeutic option for the treatment of B-cell neoplasms. Acta Haematol Pol. 2023; 54(2): 53–64.
- Styczynski J, Sadlok J, Styczynski T, et al. Management of resistant post-transplant lymphoproliferative disorder: CAR-T is a new option. Anticancer Res. 2022; 42(11): 5181–5186.
- Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest. 2020; 130(2): 733–747.
- Liu JY, Zhang JM, Zhan HS, et al. EBV-specific cytotoxic T lymphocytes for refractory EBV-associated post-transplant lymphoproliferative disorder in solid organ transplant recipients: a systematic review. Transpl Int. 2021; 34(12): 2483–2493.
- Haque T, Wilkie G, Jones M, et al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007; 110(4): 1123–1131.
- Toner K, Bollard CM. EBV+ lymphoproliferative diseases: opportunities for leveraging EBV as a therapeutic target. Blood. 2022; 139(7): 983–994.
- Mahadeo KM, Baiocchi R, Beitinjaneh A, et al. Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial. Lancet Oncol. 2024; 25(3): 376–387.
- Nikiforow S, Whangbo J, Reshef R, et al. Tabelecleucel for EBV+ PTLD after allogeneic HCT or SOT in a multicenter expanded access protocol. Blood Advances. 2024; 8(12): 3001–3012.
- Barlev A, Zimmermann H, Guzman-Becerra N, et al. Comparative analysis of tabelecleucel and current treatment in patients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease following hematopoietic cell transplant or solid organ transplant. J Med Econ. 2024; 27(1): 789–795.
- Baiocchi R, Choquet S, Ghosh M, et al. Clinical experience of tabelecleucel in Epstein–Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD) involving the central nervous system. Transpl Cell Ther. 2024; 30(2): S354.
- Grześk E, Kołtan S, Dąbrowska A, et al. Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection. Front Immunol. 2022; 13: 915986.
- Martinez OM, Krams SM. The immune response to Epstein-Barr virus and implications for posttransplant lymphoproliferative disorder. Transplantation. 2017; 101(9): 2009–2016.
- Socié G, Barba P, Barlev A, et al. Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy. Bone Marrow Transplant. 2024; 59(1): 52–58.