Epstein Barr Virus pp 255-265

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

| Cite as

EBV-Directed T Cell Therapeutics for EBV-Associated Lymphomas

  • Lauren P. McLaughlin
  • Stephen Gottschalk
  • Cliona M. Rooney
  • Catherine M. Bollard
Protocol

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.

Key words

Epstein Barr virus Lymphoma Adoptive T cell therapy Good manufacturing practice 

References

  1. 1.
    Kuppers R, Engert A, Hansmann ML (2012) Hodgkin lymphoma. J Clin Invest 122:3439–3447CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Grogg KL, Miller RF, Dogan A (2007) HIV infection and lymphoma. J Clin Pathol 60:1365–1372CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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 116:3695–3704CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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 89:1978–1986PubMedGoogle Scholar
  5. 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):132–139CrossRefPubMedGoogle Scholar
  6. 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):685–688CrossRefPubMedGoogle Scholar
  7. 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 345:9–13CrossRefPubMedGoogle Scholar
  8. 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 330:1185–1191CrossRefPubMedGoogle Scholar
  9. 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 149–166Google Scholar
  10. 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):2644–2656CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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 2:551–555CrossRefPubMedGoogle Scholar
  12. 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):925–935CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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):1123–1131CrossRefPubMedGoogle Scholar
  14. 14.
    Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4(10):757–768CrossRefPubMedGoogle Scholar
  15. 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):7374–7385PubMedPubMedCentralGoogle Scholar
  16. 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 91:2925–2934PubMedGoogle Scholar
  17. 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):317–327CrossRefPubMedGoogle Scholar
  18. 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):997–1005CrossRefPubMedGoogle Scholar
  19. 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):2838–2845CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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):798–808CrossRefPubMedGoogle Scholar
  21. 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):743–749CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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):510–519CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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 25:587–617CrossRefPubMedGoogle Scholar
  24. 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):518–522CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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):193–203CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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):S148Google Scholar
  27. 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):S18CrossRefGoogle Scholar
  28. 28.
    Miller G, Lipman M (1973) Release of infectious Epstein-Barr virus by transformed marmoset leukocytes. Proc Natl Acad Sci U S A 70:190–194CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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 4:73–79CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Lauren P. McLaughlin
    • 1
    • 2
  • Stephen Gottschalk
    • 3
  • Cliona M. Rooney
    • 4
  • Catherine M. Bollard
    • 2
    • 5
  1. 1.Department of Hematology/OncologyChildren’s National Medical CenterWashington, DCUSA
  2. 2.The George Washington UniversityWashington, DCUSA
  3. 3.Texas Children’s Cancer Center, Texas Children’s HospitalBaylor College of MedicineHoustonUSA
  4. 4.Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital,Baylor College of MedicineHoustonUSA
  5. 5.Center for Cancer and Immunology Research, Children’s National Medical CenterWashington, DCUSA

Personalised recommendations