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EBV-Directed T Cell Therapeutics for EBV-Associated Lymphomas

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Epstein Barr Virus

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1532))

Abstract

Epstein Barr virus (EBV) is a human gamma herpes virus that establishes latency in B cells after primary infection. EBV generally only causes a mild, self-limiting viral illness but is also associated with several malignancies including posttransplantation lymphoproliferative disorder in the immunosuppressed host as well as Hodgkin and non-Hodgkin lymphoma in the immune competent host. The expression of EBV antigens by lymphoma has important applications as targets for adoptive T cell therapy. However, as many lymphomas only express subdominant EBV antigens that are less immunogenic, novel strategies are needed to manufacture EBV-specific T cell products specific for Latent Membrane Protein 1 (LMP1) and LMP2, which are expressed in lymphomas with type II and III latency. While several techniques for manufacturing EBV-CTLs are described in the literature, this chapter focuses on one method for generating Good Manufacturing Practice (GMP)-compliant EBV-specific T cell products that are enriched with LMP1 and LMP2.

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References

  1. Kuppers R, Engert A, Hansmann ML (2012) Hodgkin lymphoma. J Clin Invest 122:3439–3447

    Article  PubMed  PubMed Central  Google Scholar 

  2. Grogg KL, Miller RF, Dogan A (2007) HIV infection and lymphoma. J Clin Pathol 60:1365–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fox CP, Haigh TA, Taylor GS et al (2010) A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy. Blood 116:3695–3704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sing AP, Ambinder RF, Hong DJ et al (1997) Isolation of Epstein-Barr Virus (EBV)-Specific cytotoxic T Lymphocytes that lyse reed-sternberg cells: implications for immune-medicated therapy of EBV hodgkin’s disease. Blood 89:1978–1986

    CAS  PubMed  Google Scholar 

  5. Chia WK, Teo M, Wang WW et al (2014) Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 22(1):132–139

    Article  CAS  PubMed  Google Scholar 

  6. Levitskaya J, Coram M, Levitsky V et al (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375(6533):685–688

    Article  CAS  PubMed  Google Scholar 

  7. Rooney CM, Smith CA, Ng C et al (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation. Lancet 345:9–13

    Article  CAS  PubMed  Google Scholar 

  8. Papadopoulos EB, Ladanyi M, Emanuel D et al (1994) Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330:1185–1191

    Article  CAS  PubMed  Google Scholar 

  9. O’Reilly RJ, Lacerda JF, Lucas KG et al (1996) Adoptive cell therapy with donor lymphocytes for EBV-associated lymphomas developing after allogeneic marrow transplants. In: DeVita VT, Hellman S, Rosenberg SA (eds) Important advances in oncology 1996. Lippincott-Raven, Philadelphia, pp 149–166

    Google Scholar 

  10. Doubrovina E, Oflaz-Sozmen B, Prockop SE et al (2012) Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation. Blood 119(11):2644–2656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Heslop HE, Ng CYC, Li C et al (1996) Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med 2:551–555

    Article  CAS  PubMed  Google Scholar 

  12. Heslop HE, Slobod KS, Pule MA et al (2010) Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115(5):925–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Haque T, Wilkie GM, Jones MM et al (2007) Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 110(4):1123–1131

    Article  CAS  PubMed  Google Scholar 

  14. Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4(10):757–768

    Article  CAS  PubMed  Google Scholar 

  15. Tierney J, Steven N, Young LS et al (1994) Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol 68(11):7374–7385

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Roskrow MA, Suzuki N, Gan Y-J et al (1998) EBV-specific cytotoxic T lymphocytes for the treatment of patients with EBV positive relapsed Hodgkin’s disease. Blood 91:2925–2934

    CAS  PubMed  Google Scholar 

  17. Bollard CM, Straathof KC, Huls MH et al (2004) The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease. J Immunother 27(4):317–327

    Article  PubMed  Google Scholar 

  18. Chia WK, Wang WW, Teo M et al (2012) A phase II study evaluating the safety and efficacy of an adenovirus DLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann Oncol 23(4):997–1005

    Article  CAS  PubMed  Google Scholar 

  19. Bollard CM, Gottschalk S, Leen AM et al (2007) Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 110(8):2838–2845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bollard CM, Gottschalk S, Torrano V et al (2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32(8):798–808

    Article  CAS  PubMed  Google Scholar 

  21. Cruz CR, Hanley PJ, Liu H et al (2010) Adverse events following infusion of T cells for adoptive immunotherapy: a 10 year experience. Cytotherapy 12(6):743–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bollard CM, Rooney CM, Heslop HE (2012) T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol 9(9):510–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hislop AD, Taylor GS, Sauce D et al (2007) Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25:587–617

    Article  CAS  PubMed  Google Scholar 

  24. Bollard CM, Gottschalk S, Huls MH et al (2011) Manufacture of GMP-grade cytotoxic T lymphocytes specific for LMP1 and LMP2 for patients with EBV-associated lymphoma. Cytotherapy 13(5):518–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ngo MC, Ando J, Leen AM et al (2014) Complementation of antigen presenting cells to generate T lymphocytes with broad target specificity. J Immunother 37(4):193–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Perna SK, Gottschalk S, Torrano V et al (2015) Administration of LMP-specific cytotoxic T-lymphocytes to patients with relapsed EBV-positive lymphoma post allogeneic stem cell transplant. BBMT 21(2):S148

    Google Scholar 

  27. Miller R, Perna SJ, Gottschalk S et al (2015) Administration of LMP-specific cytotoxic T-lymphocytes to patients with relapsed EBV-positive lymphoma post allogeneic stem cell transplant. Cytotherapy 17(6):S18

    Article  Google Scholar 

  28. Miller G, Lipman M (1973) Release of infectious Epstein-Barr virus by transformed marmoset leukocytes. Proc Natl Acad Sci U S A 70:190–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smith CA, Ng CYC, Heslop HE et al (1995) Production of genetically modified EBV-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J Hematother 4:73–79

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grants PO1 CA94237 (CMB, SG, and CMR), P50CA126752 (CMB, SG, CMR), the Leukemia Lymphoma Society (CMB, CMR, SG), and a Production Assistance for Cellular Therapies grant (N01-HB-37163) (CMR). CMB was also supported by an award from the St Baldrick’s Foundation. The LMP1-I-2 vector was provided by a grant from the National Gene Vector Laboratories (NIH-NCRR U42 RR16578). Conflict-of-interest disclosure: CMB and CMR have a licensing agreement with Cell Medica. CMR is a founder of Viracyte and The Center for Cell and Gene Therapy has a collaborative research agreement with Celgene for genetically modified T cells.

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Authors and Affiliations

  1. Department of Hematology/Oncology, Children’s National Medical Center, 111 Michigan Ave., Washington, DC, 20010, USA

    Lauren P. McLaughlin

  2. The George Washington University, Washington, DC, USA

    Lauren P. McLaughlin & Catherine M. Bollard

  3. Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Stephen Gottschalk

  4. Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital,, Baylor College of Medicine, Houston, TX, USA

    Cliona M. Rooney

  5. Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC, USA

    Catherine M. Bollard

Authors
  1. Lauren P. McLaughlin
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  2. Stephen Gottschalk
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  3. Cliona M. Rooney
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  4. Catherine M. Bollard
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Corresponding author

Correspondence to Lauren P. McLaughlin .

Editor information

Editors and Affiliations

  1. University of Szeged, Szeged, Hungary

    Janos Minarovits

  2. University of Regensburg, Regensburg, Germany

    Hans Helmut Niller

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McLaughlin, L.P., Gottschalk, S., Rooney, C.M., Bollard, C.M. (2017). EBV-Directed T Cell Therapeutics for EBV-Associated Lymphomas. In: Minarovits, J., Niller, H. (eds) Epstein Barr Virus. Methods in Molecular Biology, vol 1532. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6655-4_19

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  • DOI: https://doi.org/10.1007/978-1-4939-6655-4_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6653-0

  • Online ISBN: 978-1-4939-6655-4

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