Skip to main content
SpringerLink
Log in
Book cover

Cell and Gene Therapies pp 137–157Cite as

Cytotoxic T Cells for Infections: From Donor Specific to “Off the Shelf”

  • Chapter
  • First Online:

  • 1061 Accesses

Abstract

Allogeneic haematopoietic cell transplantation (HCT) results in a period of profound immunosuppression, with both quantitative and functional deficiencies in virus-specific T cells, rendering recipients susceptible to opportunistic and latent viruses. These infections can cause significant morbidity and contribute to mortality post-transplant. The main viral pathogens causing life-threatening disease in the post-transplant period include Cytomegalovirus (CMV) and Epstein-Barr viruses (EBV), both of which are often asymptomatic in immunocompetent hosts. Although there are pharmacological antiviral therapies available, these have significant side-effects, may not be effective for each virus, do not reconstitute viral immunity and may provoke drug resistance. Therefore, research has focused on developing adoptive cellular therapies, consisting of virus-specific cytotoxic T lymphocytes (CTLs), to correct the deficiencies in viral immunity post-transplant. In this review, we begin by detailing the advances made in producing single-virus-specific T cells, in particular for CMV and EBV, and then proceed to describe the progress in developing multi-virus-specific T cells and in broadening the repertoire of available donor sources with the generation of virus-specific T cells from virus-naïve individuals and the use of third-party donors.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Barker JN, Doubrovina E, Sauter C, Jaroscak JJ, Perales MA, Doubrovin M et al (2010) Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes. Blood 116(23):5045–5049

    Article  CAS  Google Scholar 

  • Bate SL, Dollard SC, Cannon MJ (2010) Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. Clin Infect Dis 50(11):1439–1447

    Article  Google Scholar 

  • Blyth E, Clancy L, Simms R, Ma CK, Burgess J, Deo S et al (2013) Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. Blood 121(18):3745–3758

    Article  CAS  Google Scholar 

  • Boeckh M, Ljungman P (2009) How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood 113(23):5711–5719

    Article  CAS  Google Scholar 

  • Brewin J, Mancao C, Straathof K, Karlsson H, Samarasinghe S, Amrolia PJ et al (2009) Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease. Blood 114(23):4792–4803

    Article  CAS  Google Scholar 

  • Carpenter B, Haque T, Dimopoulou M, Atkinson C, Roughton M, Grace S et al (2010) Incidence and dynamics of Epstein-Barr virus reactivation after alemtuzumab-based conditioning for allogeneic hematopoietic stem-cell transplantation. Transplantation 90(5):564–570

    Article  CAS  Google Scholar 

  • Chen F, Peniket A, Tholouli E, Bloor A, Chakraverty R, Marks D et al (2014) CMV-specific T-cell therapy improves immune reconstitution following unrelated donor HCT: results of a randomized controlled trial. Biol Blood Marrow Transplant 20(2):S49

    Article  Google Scholar 

  • Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H et al (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 202(3):379–386

    Article  CAS  Google Scholar 

  • Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S, Teruya-Feldstein J 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  Google Scholar 

  • Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Loffler J et al (2002) Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99(11):3916–3922

    Article  CAS  Google Scholar 

  • Erard V, Guthrie KA, Seo S, Smith J, Huang M, Chien J et al (2015) Reduced mortality of cytomegalovirus pneumonia after hematopoietic cell transplantation due to antiviral therapy and changes in transplantation practices. Clin Infect Dis 61(1):31–39

    Article  CAS  Google Scholar 

  • Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM et al (2010) Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116(20):4360–4367

    Article  CAS  Google Scholar 

  • Gerdemann U, Keirnan JM, Katari UL, Yanagisawa R, Christin AS, Huye LE et al (2012) Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections. Mol Ther 20(8):1622–1632

    Article  CAS  Google Scholar 

  • Gottschalk S, Rooney CM, Heslop HE (2005) Post-transplant lymphoproliferative disorders. Annu Rev Med 56:29–44

    Article  CAS  Google Scholar 

  • Hanley PJ, Bollard CM (2014) Controlling cytomegalovirus: helping the immune system take the lead. Viruses 6(6):2242–2258

    Article  CAS  Google Scholar 

  • Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M, Khalil M et al (2009) Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood 114(9):1958–1967

    Article  CAS  Google Scholar 

  • Hanley PJ, Leen A, Gee AP, Leung K, Martinez C, Krance RA et al (2013) Multi-virus-specific T-cell therapy for patients after hematopoietic stem cell and cord blood transplantation. Blood 122(21):140

    Google Scholar 

  • Hanley PJ, Melenhorst JJ, Nikiforow S, Scheinberg P, Blaney JW, Demmler-Harrison G et al (2015) CMV-specific T cells generated from naive T cells recognize atypical epitopes and may be protective in vivo. Sci Transl Med 7(285):285ra63

    Article  Google Scholar 

  • Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A et al (2002) Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360(9331):436–442

    Article  Google Scholar 

  • Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P 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  Google Scholar 

  • Heslop HE, Brenner MK, Rooney CM (1994) Donor T cells to treat EBV-associated lymphoma. N Engl J Med 331(10):679–680

    Article  CAS  Google Scholar 

  • Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance RA 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(5):551–555

    Article  CAS  Google Scholar 

  • Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA 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  Google Scholar 

  • Jedema I, van de Meent M, Pots J, Kester MG, van der Beek MT, Falkenburg JH (2011) Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells. Haematologica 96(8):1204–1212

    Article  CAS  Google Scholar 

  • Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM, Sobocinski KA et al (2009) Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 113(20):4992–5001

    Article  CAS  Google Scholar 

  • Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS et al (2006) Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 12(10):1160–1166

    Article  CAS  Google Scholar 

  • Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ et al (2009) Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114(19):4283–4292

    Article  CAS  Google Scholar 

  • Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH et al (2013) Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121(26):5113–5123

    Article  CAS  Google Scholar 

  • Ma CK, Blyth E, Clancy L, Simms R, Burgess J, Brown R et al (2015) Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immunotherapy in patients undergoing allogeneic hematopoietic stem cell transplantation. Cytotherapy 17(10):1406–1420

    Article  CAS  Google Scholar 

  • Mackinnon S, Thomson K, Verfuerth S, Peggs K, Lowdell M (2008) Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol Dis 40(1):63–67

    Article  CAS  Google Scholar 

  • Menger L, Gouble A, Marzolini MA, Pachnio A, Bergerhoff K, Henry JY et al (2015) TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells. Blood 126(26):2781–2789

    Article  CAS  Google Scholar 

  • Micklethwaite K, Hansen A, Foster A, Snape E, Antonenas V, Sartor M et al (2007) Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13(6):707–714

    Article  CAS  Google Scholar 

  • Nichols WG, Corey L, Gooley T, Davis C, Boeckh M (2002) High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis 185(3):273–282

    Article  Google Scholar 

  • Nikiforow S, Alyea EP (2014) Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions. Hematology 2014(1):570–575

    Article  Google Scholar 

  • Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH 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(17):1185–1191

    Article  CAS  Google Scholar 

  • Papadopoulou A, Gerdemann U, Katari UL, Tzannou I, Liu H, Martinez C et al (2014) Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HCT. Sci Transl Med 6(242):242ra83

    Article  Google Scholar 

  • Park KD, Marti L, Kurtzberg J, Szabolcs P (2006) In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes. Blood 108(5):1770–1773

    Article  CAS  Google Scholar 

  • Passweg JR, Baldomero H, Gratwohl A, Bregni M, Cesaro S, Dreger P et al (2012) The EBMT activity survey: 1990–2010. Bone Marrow Transplant 47(7):906–923

    Article  CAS  Google Scholar 

  • Patel S, Lam S, Cruz CR, Wright K, Cochran C, Ambinder RF et al (2016) Functionally active HIV-specific T cells that target gag and Nef can be expanded from virus-naive donors and target a range of viral epitopes: implications for a cure strategy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 22(3):536–541

    Article  CAS  Google Scholar 

  • Peggs KS (2009) Adoptive T cell immunotherapy for cytomegalovirus. Expert Opin Biol Ther 9(6):725–736

    Article  CAS  Google Scholar 

  • Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA et al (2003) Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362(9393):1375–1377

    Article  Google Scholar 

  • Peggs KS, Verfuerth S, Pizzey A, Chow SL, Thomson K, Mackinnon S (2009) Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogeneic stem cell transplantation. Clin Infect Dis 49(12):1851–1860

    Article  CAS  Google Scholar 

  • Peggs KS, Thomson K, Samuel E, Dyer G, Armoogum J, Chakraverty R et al (2011) Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis 52(1):49–57

    Article  CAS  Google Scholar 

  • Peggs KS, Tholouli E, Chakraverty R, Nikolousis E, Bloor A, Devereux S et al (2014) CMV~IMPACT: results of a randomized controlled trial of Immuno-prophylactic adoptive cellular therapy following sibling donor allogeneic HCT. Blood 124(21):1109

    Google Scholar 

  • Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A et al (2005) Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 106(13):4397–4406

    Article  CAS  Google Scholar 

  • Ramirez N, Olavarria E (2013) Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies. Bone Marrow Transplant 48(10):1265–1270

    Article  CAS  Google Scholar 

  • Rasche L, Kapp M, Einsele H, Mielke S (2014) EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transplant 49(2):163–167

    Article  CAS  Google Scholar 

  • Reusser P, Riddell SR, Meyers JD, Greenberg PD (1991) Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78(5):1373–1380

    CAS  PubMed  Google Scholar 

  • Ricciardelli I, Brewin J, Lugthart G, Albon SJ, Pule M, Amrolia PJ (2013) Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy. Am J Transplant 13(12):3244–3252

    Article  CAS  Google Scholar 

  • Rickinson AB, Long HM, Palendira U, Munz C, Hislop AD (2014) Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol 35(4):159–169

    Article  CAS  Google Scholar 

  • Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257(5067):238–241

    Article  CAS  Google Scholar 

  • Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA et al (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345(8941):9–13

    Article  CAS  Google Scholar 

  • Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y 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(5):1549–1555

    CAS  PubMed  Google Scholar 

  • Rouce RH, Louis CU, Heslop HE (2014) Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant. Curr Opin Hematol 21(6):476–481

    Article  CAS  Google Scholar 

  • Savoldo B, Cubbage ML, Durett AG, Goss J, Huls MH, Liu Z et al (2002) Generation of EBV-specific CD4+ cytotoxic T cells from virus naive individuals. J Immunol 168(2):909–918

    Article  CAS  Google Scholar 

  • Schmitt A, Tonn T, Busch DH, Grigoleit GU, Einsele H, Odendahl M et al (2011) Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 51(3):591–599

    Article  CAS  Google Scholar 

  • Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 43(9):1143–1151

    Article  Google Scholar 

  • Styczynski J, Einsele H, Gil L, Ljungman P (2009) Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transpl Infect Dis 11(5):383–392

    Article  CAS  Google Scholar 

  • Tomblyn M, Lazarus HM (2008) Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant 42(9):569–579

    Article  CAS  Google Scholar 

  • Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED et al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333(16):1038–1044

    Article  CAS  Google Scholar 

  • Zandvliet ML, van Liempt E, Jedema I, Veltrop-Duits LA, Willemze R, Guchelaar HJ et al (2010) Co-ordinated isolation of CD8(+) and CD4(+) T cells recognizing a broad repertoire of cytomegalovirus pp65 and IE1 epitopes for highly specific adoptive immunotherapy. Cytotherapy 12(7):933–944

    Article  CAS  Google Scholar 

  • Zhang LJ, Hanff P, Rutherford C, Churchill WH, Crumpacker CS (1995) Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood. J Infect Dis 171(4):1002–1006

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UCL Cancer Institute, University College London, London, UK

    Maria A. V. Marzolini & Karl S. Peggs

Authors
  1. Maria A. V. Marzolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl S. Peggs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl S. Peggs .

Editor information

Editors and Affiliations

  1. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Miguel-Angel Perales

  2. Cancer Treatment Centers of America, Deerfield, IL, USA

    Syed A. Abutalib

  3. Center for Cancer and Immunology Research Children’s National and The George Washington University, Division Allergy and Immunology, Washington, DC, USA

    Catherine Bollard

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Marzolini, M.A.V., Peggs, K.S. (2019). Cytotoxic T Cells for Infections: From Donor Specific to “Off the Shelf”. In: Perales, MA., Abutalib, S., Bollard, C. (eds) Cell and Gene Therapies. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-54368-0_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-54368-0_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-54367-3

  • Online ISBN: 978-3-319-54368-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation