T Cell Therapies

  • S. Gottschalk
  • C. M. Bollard
  • K. C. Straathof
  • C. U. Louis
  • B. Savoldo
  • G. Dotti
  • M. K. Brenner
  • H. E. Heslop
  • C. M. Rooney
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/4)


T cell therapies are increasingly used for the treatment of malignancies and viral-associated diseases. Initial studies focused on the use of unmanipulated T cell populations after allogeneic stem cell transplantation. More recently, the use of antigen-specific T cells has been explored. This chapter reviews the clinical experience with polyclonal Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) for the treatment of EBV-associated malignancies. Strategies on how to improve the antitumor activity of EBV-specific CTL are being discussed. If effective, these strategies will have broad implications for T cell therapies for a range of human tumors with defined antigens.


Hematopoietic Stem Cell Transplantation Chimeric Antigen Receptor Adoptive Immunotherapy Donor Lymphocyte Infusion Hematopoietic Stem Cell Transplantation Recipient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors were supported by NIH grants PO1 CA94237 and the GCRC at Baylor College of Medicine (grant RR00188). S.G. is the recipient of a Doris Duke Clinical Scientist Development Award. H.E.H is the recipient of a Doris Duke Distinguished Clinical Scientist Award.


  1. Berger C, Flowers ME, Warren EH, Riddell SR (2006) Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107:2294–2302CrossRefPubMedGoogle Scholar
  2. Bollard CM, Rossig C, Calonge MJ et al. (2002) Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 99:3179–3187CrossRefPubMedGoogle Scholar
  3. Bollard CM, Aguilar L, Straathof KC et al. (2004a) Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. J Exp Med 200:1623–1633CrossRefPubMedGoogle Scholar
  4. Bollard CM, Straathof K, Huls MH et al. (2004b) The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease. J Immunother 27:317–327CrossRefPubMedGoogle Scholar
  5. Bollard CM, Buza E, Huls HM et al. (2005) The use of autologous LMP2-specific CTL for the treatment of relapsed EBV-positive Hodgkin disease and non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstr) 106:773Google Scholar
  6. Bonini C, Ferrari G, Verzeletti S et al. (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724CrossRefPubMedGoogle Scholar
  7. Chua D, Huang J, Zheng B et al. (2001) Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 94:73–80CrossRefPubMedGoogle Scholar
  8. Cohen JI (2000) Epstein-Barr virus infection. N Engl J Med 343:481–492CrossRefPubMedGoogle Scholar
  9. Comoli P, Pedrazzoli P, Maccario R et al. (2005) Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol 23:8942–8949CrossRefPubMedGoogle Scholar
  10. Dotti G, Savoldo B, Pule M et al. (2005) Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood 105:4677–4684CrossRefPubMedGoogle Scholar
  11. Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666–675CrossRefPubMedGoogle Scholar
  12. Dudley ME, Wunderlich JR, Robbins PF et al. (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854CrossRefPubMedGoogle Scholar
  13. Duraiswamy J, Bharadwaj M, Tellam J et al. (2004) Induction of therapeutic T-cell responses to subdominant tumor-associated viral oncogene after immunization with replication-incompetent polyepitope adenovirus vaccine. Cancer Res 64:1483–1489CrossRefPubMedGoogle Scholar
  14. Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90:720–724CrossRefPubMedGoogle Scholar
  15. Gahn B, Siller-Lopez F, Pirooz AD et al. (2001) Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to LMP2A antigen: a potential treatment strategy for Epstein-Barr virus-positive Hodgkin's lymphoma. Int J Cancer 93:706–713CrossRefPubMedGoogle Scholar
  16. Gottschalk S, Ng CY, Perez M et al. (2001) An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 97:835–843CrossRefPubMedGoogle Scholar
  17. Gottschalk S, Edwards OL, Sili U et al. (2003) Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies. Blood 101:1905–1912CrossRefPubMedGoogle Scholar
  18. Haque T, Amlot PL, Helling N et al. (1998) Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients. J Immunol 160:6204–6209PubMedGoogle Scholar
  19. Haque T, Wilkie GM, Taylor C et al. (2002) Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360:436–442CrossRefPubMedGoogle Scholar
  20. Heslop HE, Brenner MK, Rooney CM (1994) Donor T cells to treat EBV-associated lymphoma. N Engl J Med 331:679–680CrossRefPubMedGoogle Scholar
  21. Heslop HE, Ng CY, 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
  22. Hsu JL, Glaser SL (2000) Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit Rev Oncol Hematol 34:27–53CrossRefPubMedGoogle Scholar
  23. Khanna R, Bell S, Sherritt M et al. (1999) Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease. Proc Natl Acad Sci USA 96:10391–10396CrossRefPubMedGoogle Scholar
  24. Kolb HJ, Mittermuller J, Clemm C et al. (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465PubMedGoogle Scholar
  25. Kolb HJ, Simoes B, Schmid C (2004) Cellular immunotherapy after allogeneic stem cell transplantation in hematologic malignancies. Curr Opin Oncol 16:167–173CrossRefPubMedGoogle Scholar
  26. Krance RA, Kuehnle I, Rill DR et al. (2003) Hematopoietic and immunomodulatory effects of lytic CD45 monoclonal antibodies in patients with hematologic malignancy. Biol Blood Marrow Transplant 9:273–281CrossRefPubMedGoogle Scholar
  27. Louis CU, Straathof K, Torrano V et al. (2006) Treatment of Epstein-Barr virus-positive nasopharyngeal carcinoma with adoptively transferred cytotoxic T cells. 97th AACR Annual Meeting Abstr 4000Google Scholar
  28. Lucas KG, Burton RL, Zimmerman SE et al. (1998) Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation. Blood 91:3654–3661PubMedGoogle Scholar
  29. Morgan RA, Dudley ME, Wunderlich JR et al. (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129CrossRefPubMedGoogle Scholar
  30. O'Reilly RJ, Small TN, Papadopoulos E et al. (1997) Biology and adoptive cell therapy of Epstein-Barr virus-associated lymphoproliferative disorders in recipients of marrow allografts. Immunol Rev 157:195–216CrossRefPubMedGoogle Scholar
  31. Pakakasama S, Eames GM, Morriss MC et al. (2004) Treatment of Epstein-Barr virus lymphoproliferative disease after hematopoietic stem-cell transplantation with hydroxyurea and cytotoxic T-cell lymphocytes. Transplantation 78:755–757CrossRefPubMedGoogle Scholar
  32. 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
  33. Peggs KS, Verfuerth S, Pizzey A et al. (2003) Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362:1375–1377CrossRefPubMedGoogle Scholar
  34. Porter DL, Orloff GJ, Antin JH (1994) Donor mononuclear cell infusions as therapy for B-cell lymphoproliferative disorder following allogeneic bone marrow transplant. Transplant Sci 4:12–14CrossRefPubMedGoogle Scholar
  35. Pule M, Finney H, Lawson A (2003) Artificial T-cell receptors. Cytotherapy 5:211–226CrossRefPubMedGoogle Scholar
  36. Rickinson AB, Kieff E (2001) Epstein-Barr virus. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams and Williams, Philadelphia, pp 2575–2628Google Scholar
  37. Riddell SR, Watanabe KS, Goodrich JM et al. (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238–241CrossRefPubMedGoogle Scholar
  38. Rooney CM, Smith CA, Ng CY et al. (1998) Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92:1549–1555PubMedGoogle Scholar
  39. Roskrow MA, Suzuki N, Gan Y et al. (1998) Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease. Blood 91:2925–2934PubMedGoogle Scholar
  40. Rossig C, Bollard CM, Nuchtern JG, Rooney CM, Brenner MK (2002) Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood 99:2009–2016CrossRefPubMedGoogle Scholar
  41. Savoldo B, Goss JA, Hammer MM et al. (2006) Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood 108:2942–2949CrossRefPubMedGoogle Scholar
  42. Serafini M, Manganini M, Borleri G et al. (2004) Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum Gene Ther 15:63–76CrossRefPubMedGoogle Scholar
  43. Straathof KC, Bollard CM, Popat U et al. (2005a) Treatment of nasopharyngeal carcinoma with Epstein-Barr virus—specific T lymphocytes. Blood 105:1898–1904CrossRefPubMedGoogle Scholar
  44. Straathof KC, Pule MA, Yotnda P et al. (2005b) An inducible caspase 9 safety switch for T-cell therapy. Blood 105:4247–4254CrossRefPubMedGoogle Scholar
  45. Thomis DC, Marktel S, Bonini C et al. (2001) A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97:1249–1257CrossRefPubMedGoogle Scholar
  46. Wulf GG, Luo KL, Goodell MA, Brenner MK (2003) Anti-CD45-mediated cytoreduction to facilitate allogeneic stem cell transplantation. Blood 101:2434–2439CrossRefPubMedGoogle Scholar
  47. Yee C, Thompson JA, Byrd D et al. (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168–16173CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • S. Gottschalk
    • 1
  • C. M. Bollard
    • 1
  • K. C. Straathof
    • 1
  • C. U. Louis
    • 1
  • B. Savoldo
    • 1
  • G. Dotti
    • 1
  • M. K. Brenner
    • 1
  • H. E. Heslop
    • 1
  • C. M. Rooney
    • 1
  1. 1.Center for Gene and Cell TherapyBaylor College of MedicineHoustonUSA

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