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Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease

By Catherine M. Bollard, Laura Aguilar, Karin C. Straathof, Benedikt Gahn, M. Helen Huls, Alexandra Rousseau, John Sixbey, M. Victoria Gresik, George Carrum, Melissa Hudson, Dagmar Dilloo, Adrian Gee, Malcolm K. Brenner, Cliona M. Rooney and Helen E. Heslop


Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen–specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen–specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma

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    1. (1999). Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease.
    2. (2002). Adapting a transforming growth factor betarelated tumor protection strategy to enhance antitumor immunity.
    3. (2001). Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to the LMP2A-antigen: a potential treatment strategy for Epstein-Barr virus-positive Hodgkin’s lymphoma.
    4. (1998). Adoptive immunotherapy for Epstein-Barr virus-associated lymphoproliferative disorders complicating marrow allografts. Springer Semin.
    5. (2000). Assessment of the stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin’s disease: Eastern Cooperative Oncology Group pilot study E1492.
    6. (2003). B cells under influence: transformation of B cells by Epstein-Barr virus.
    7. (2001). CD4 T-cell effectors inhibit Epstein-Barr virus-induced B-cell proliferation.
    8. Detection of Epstein-Barr viral genomes in ReedSternberg cells of Hodgkin’s disease.
    9. (1998). EBV-specific cytotoxic T lymphocytes for the treatment of patients with EBV positive relapsed Hodgkin’s disease.
    10. (2000). Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBVspecific cytotoxic T cells.
    11. (1999). Epstein-Barr virus and lymphoma. Cancer Treat.
    12. (1992). Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes.
    13. (1991). Epstein-Barr virus latent membrane protein expression in Hodgkin and ReedSternberg cells.
    14. (2004). Evidence for the presentation of major histocompatibility complex class I–restricted Epstein-Barr virus nuclear antigen 1 peptides to CD8 T lymphocytes.
    15. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin’s disease.
    16. (2004). Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications.
    17. (1993). Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients.
    18. (2003). Generating CTL against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive Immunotherapy of EBVassociated malignancies.
    19. (1999). High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin’s lymphoma.
    20. Immune escape mechanisms in Hodgkin’s disease.
    21. (2004). Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma.
    22. 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.
    23. (1998). Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.
    24. (1997). Inhibition of ubiquitin/proteasomedependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1.
    25. (1997). Isolation of Epstein-Barr virus (EBV)-specific cytotoxic T Lymphocytes that lyse Reed-Sternberg cells: implications for immunemedicated therapy of EBV Hodgkin’s disease.
    26. (1996). Longterm restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes.
    27. (1995). Production of genetically modified EBV-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease.
    28. (2002). Progressive differentiation and selection of the fittest in the immune response.
    29. (2004). Prompt versus preemptive intervention for EBV lymphoproliferative disease.
    30. (2002). Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin’s lymphoma: final results of the German Hodgkin’s Lymphoma Study Group Trial HD5.
    31. (2003). Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.
    32. (1995). Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease.
    33. (1993). The association of Epstein-Barr virus (EBV) with T cell lymphoproliferations and Hodgkin’s disease: two new developments in the EBV field.
    34. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell.
    35. (2004). The generation and characterization of LMP2-specific CTL for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease.
    36. (2002). Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells.
    37. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
    38. (1995). Use of genemodified virus-specific T lymphocytes to control EpsteinBarr virus-related lymphoproliferation.

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