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Pathogen-Specific T Cells Beyond CMV, EBV and Adenovirus

  • CART and Immunotherapy (M Ruella and P Hanley, Section Editors)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Infectious diseases contribute significantly to morbidity and mortality in recipients of allogeneic haematopoietic stem cell transplantation (aHSCT), particularly in the era of highly immunosuppressive transplant regimens and alternate donor transplants. Delayed cellular immune recovery is a major mechanism for the increased risk in these patients. Adoptive cell therapy with ex vivo manipulated pathogen-specific T cells (PSTs) is increasingly taking its place as a treatment strategy using donor-derived or third party–banked cells.

Recent Findings

The majority of clinical trial data in the form of early-phase studies has been in the prophylaxis or treatment of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus (AdV). Advancements in methods to select and enrich PSTs offer the opportunity to target the less common viral pathogens as well as fungi with this technology. Early clinical studies of PSTs targeting polyomaviruses (BK virus and JC virus), human herpesvirus 6 (HHV6), varicella zoster virus (VZV) and Aspergillus spp. have shown promising results in small numbers of patients. Other potential targets include herpes simplex virus (HSV), respiratory viruses and other invasive fungal species.

Summary

In this review, we describe the burden of disease of this wider spectrum of pathogens, the progress in the development of manufacturing capability, early clinical results and the opportunities and challenges for implementation in the clinic.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005;36:757. https://doi.org/10.1038/sj.bmt.1705140.

    Article  CAS  PubMed  Google Scholar 

  2. Mehta RS, Rezvani K. Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection. Virulence. 2016;7(8):901–16. https://doi.org/10.1080/21505594.2016.1208866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tanaka Y, Kurosawa S, Tajima K, Tanaka T, Ito R, Inoue Y, et al. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016;51(4):553–9. https://doi.org/10.1038/bmt.2015.330.

    Article  CAS  PubMed  Google Scholar 

  4. Young J-AH, Logan BR, Wu J, Wingard JR, Weisdorf DJ, Mudrick C, et al. Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biol Blood Marrow Transplant. 2016;22(2):359–70. https://doi.org/10.1016/j.bbmt.2015.09.013.

    Article  PubMed  Google Scholar 

  5. D’Souza A, Fretham C. Center for International Blood and Marrow Transplant Research summary slides—HCT trends and survival data. 2018. https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx. Accessed 22/4/19 2019.

  6. Yamasaki S, Aoki J, Mori J, Mizuno S, Uchida N, Ohashi K, et al. Better disease control before allogeneic stem cell transplantation is crucial to improve the outcomes of transplantation for acute myeloid leukemia patients with extramedullary disease. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0527-z.

  7. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98(10):2942–7. https://doi.org/10.1182/blood.V98.10.2942.

    Article  CAS  PubMed  Google Scholar 

  8. Kawamura K. Effect of antithymocyte globulin on HLA-mismatched unrelated transplantation. Int J Hematol. 2019. https://doi.org/10.1007/s12185-019-02597-y.

  9. Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991;325(23):1601–7. https://doi.org/10.1056/nejm199112053252303.

    Article  CAS  PubMed  Google Scholar 

  10. Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants; the City of Hope-Stanford-Syntex CMV Study Group. N Engl J Med. 1991;324(15):1005–11. https://doi.org/10.1056/nejm199104113241501.

    Article  CAS  PubMed  Google Scholar 

  11. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37. https://doi.org/10.1038/ni.1679.

    Article  CAS  PubMed  Google Scholar 

  12. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77(8):4911–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kollman C, Howe CWS, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98(7):2043–51. https://doi.org/10.1182/blood.V98.7.2043.

    Article  CAS  PubMed  Google Scholar 

  14. Heining C, Spyridonidis A, Bernhardt E, Schulte-Mönting J, Behringer D, Grüllich C, et al. Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients. Bone Marrow Transplant. 2007;39:613. https://doi.org/10.1038/sj.bmt.1705648.

    Article  CAS  PubMed  Google Scholar 

  15. Baron F, Storer B, Maris MB, Storek J, Piette F, Metcalf M, et al. Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006;12(11):1176–87. https://doi.org/10.1016/j.bbmt.2006.07.004.

    Article  PubMed  Google Scholar 

  16. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344–53. https://doi.org/10.1182/blood-2014-02-514778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143–238. https://doi.org/10.1016/j.bbmt.2009.06.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vadakekolathu J, Rutella S. T-cell manipulation strategies to prevent graft-versus-host disease in haploidentical stem cell transplantation. Biomedicines. 2017;5(2):33.

    Article  PubMed Central  Google Scholar 

  19. Fry TJ, Mackall CL. Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant. 2005;35:S53. https://doi.org/10.1038/sj.bmt.1704848.

    Article  PubMed  Google Scholar 

  20. Bolotin E, Annett G, Parkman R, Weinberg K. Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant. 1999;23:783. https://doi.org/10.1038/sj.bmt.1701655.

    Article  CAS  PubMed  Google Scholar 

  21. Williams KM, Gress RE. Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation. Best Pract Res Clin Haematol. 2008;21(3):579–96. https://doi.org/10.1016/j.beha.2008.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sutrave G, Blyth E, Gottlieb DJ. Cellular therapy for multiple pathogen infections after hematopoietic stem cell transplant. Cytotherapy. 2017;19(11):1284–301. https://doi.org/10.1016/j.jcyt.2017.07.012.

    Article  CAS  PubMed  Google Scholar 

  23. Auletta JJ, Lazarus HM. Immune restoration following hematopoietic stem cell transplantation: an evolving target. Bone Marrow Transplant. 2005;35(9):835–57.

    Article  CAS  PubMed  Google Scholar 

  24. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115(19):3861–8. https://doi.org/10.1182/blood-2009-12-234096.

    Article  CAS  PubMed  Google Scholar 

  25. Parody R, Martino R, Rovira M, Vazquez L, Vázquez MJ, de la Cámara R, et al. Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2006;12(7):734–48. https://doi.org/10.1016/j.bbmt.2006.03.007.

    Article  PubMed  Google Scholar 

  26. Sartori AM. A review of the varicella vaccine in immunocompromised individuals. Int J Infect Dis. 2004;8(5):259–70. https://doi.org/10.1016/j.ijid.2003.09.006.

    Article  PubMed  Google Scholar 

  27. Boeckh M, Kim HW, Flowers MED, Meyers JD, Bowden RA. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation—a randomized double-blind placebo-controlled study. Blood. 2006;107(5):1800–5. https://doi.org/10.1182/blood-2005-09-3624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Erard V, Guthrie KA, Varley C, Heugel J, Wald A, Flowers MED, et al. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007;110(8):3071–7. https://doi.org/10.1182/blood-2007-03-077644.

    Article  CAS  PubMed  Google Scholar 

  29. Vink P, Ramon Torrell JM, Sanchez Fructuoso A, Kim SJ, Kim SI, Zaltzman J, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in chronically immunosuppressed adults following renal transplant: a phase III, randomized clinical trial. Clin Infect Dis. 2019. https://doi.org/10.1093/cid/ciz177.

  30. Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol. 1999;73(10):8040–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Becerra A, Gibson L, Stern LJ, Calvo-Calle JM. Immune response to HHV-6 and implications for immunotherapy. Curr Opin Virol. 2014;9:154–61. https://doi.org/10.1016/j.coviro.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  32. De Bolle L, Naesens L, De Clercq E. Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Microbiol Rev. 2005;18(1):217–45. https://doi.org/10.1128/CMR.18.1.217-245.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Boutolleau D, Fernandez C, André E, Imbert-Marcille B-M, Milpied N, Agut H, et al. Human herpesvirus (HHV)-6 and HHV-7: two closely related viruses with different infection profiles in stem cell transplantation recipients. J Infect Dis. 2003;187(2):179–86. https://doi.org/10.1086/367677.

    Article  PubMed  Google Scholar 

  34. Brennan Y, Gottlieb DJ, Baewer D, Blyth E. A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation. J Clin Virol. 2015;72:82–4. https://doi.org/10.1016/j.jcv.2015.09.013.

    Article  PubMed  Google Scholar 

  35. de Pagter PJ, Schuurman R, Keukens L, Schutten M, Cornelissen JJ, van Baarle D, et al. Human herpes virus 6 reactivation: important predictor for poor outcome after myeloablative, but not non-myeloablative allo-SCT. Bone Marrow Transplant. 2013;48(11):1460–4. https://doi.org/10.1038/bmt.2013.78.

    Article  PubMed  Google Scholar 

  36. de Pagter PJ, Schuurman R, Meijer E, van Baarle D, Sanders EA, Boelens JJ. Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation. J Clin Virol. 2008;43(4):361–6. https://doi.org/10.1016/j.jcv.2008.08.008.

    Article  CAS  PubMed  Google Scholar 

  37. Lin R, Liu Q. Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation. J Hematol Oncol. 2013;6(1):94. https://doi.org/10.1186/1756-8722-6-94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future [version 1; peer review: 2 approved]. F1000Res. 2018;7(1726). https://doi.org/10.12688/f1000research.16157.1.

  39. Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med. 1981;305(2):63–7. https://doi.org/10.1056/nejm198107093050202.

    Article  CAS  PubMed  Google Scholar 

  40. Bustamante CI, Wade JC. Herpes simplex virus infection in the immunocompromised cancer patient. J Clin Oncol. 1991;9(10):1903–15. https://doi.org/10.1200/jco.1991.9.10.1903.

    Article  CAS  PubMed  Google Scholar 

  41. Mueller SN, Jones CM, Smith CM, Heath WR, Carbone FR. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J Exp Med. 2002;195(5):651–6. https://doi.org/10.1084/jem.20012023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ghiasi H, Cai S, Perng G-C, Nesburn AB, Wechsler SL. Perforin pathway is essential for protection of mice against lethal ocular HSV-1 challenge but not corneal scarring. Virus Res. 1999;65(2):97–101. https://doi.org/10.1016/S0168-1702(99)00107-0.

    Article  CAS  PubMed  Google Scholar 

  43. Chakrabarti S, Milligan DW, Collingham KE, Ratcliffe D, Pillay D, Cane PA. Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance. J Infect Dis. 2000;181(6):2055–8. https://doi.org/10.1086/315524.

    Article  CAS  PubMed  Google Scholar 

  44. Stránská R, Schuurman R, Nienhuis E, Goedegebuure IW, Polman M, Weel JF, et al. Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol. 2005;32(1):7–18. https://doi.org/10.1016/j.jcv.2004.04.002.

    Article  CAS  PubMed  Google Scholar 

  45. Frobert E, Burrel S, Ducastelle-Lepretre S, Billaud G, Ader F, Casalegno JS, et al. Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France. Antivir Res. 2014;111:36–41. https://doi.org/10.1016/j.antiviral.2014.08.013.

    Article  CAS  PubMed  Google Scholar 

  46. Kakiuchi S, Tsuji M, Nishimura H, Yoshikawa T, Wang L, Takayama-Ito M, et al. Association of the emergence of acyclovir-resistant herpes simplex virus type 1 with prognosis in hematopoietic stem cell transplantation patients. J Infect Dis. 2017;215(6):865–73. https://doi.org/10.1093/infdis/jix042.

    Article  CAS  PubMed  Google Scholar 

  47. Mateen FJ, Muralidharan R, Carone M, van de Beek D, Harrison DM, Aksamit AJ, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol. 2011;70(2):305–22. https://doi.org/10.1002/ana.22408.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ruggeri A, Roth-Guepin G, Battipaglia G, Mamez AC, Malard F, Gomez A, et al. Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients. Transpl Infect Dis. 2015;17(6):822–30. https://doi.org/10.1111/tid.12455.

    Article  CAS  PubMed  Google Scholar 

  49. Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, et al. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2018;73(1):12–21. https://doi.org/10.1093/jac/dkx324.

    Article  CAS  PubMed  Google Scholar 

  50. Giraud G, Priftakis P, Bogdanovic G, Remberger M, Dubrulle M, Hau A, et al. BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts. Bone Marrow Transplant. 2008;41(8):737–42. https://doi.org/10.1038/sj.bmt.1705962.

    Article  CAS  PubMed  Google Scholar 

  51. Gilis L, Morisset S, Billaud G, Ducastelle-Lepretre S, Labussiere-Wallet H, Nicolini FE, et al. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014;49(5):664–70. https://doi.org/10.1038/bmt.2013.235.

    Article  CAS  PubMed  Google Scholar 

  52. Knoll GA, Humar A, Fergusson D, Johnston O, House AA, Kim SJ, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA. 2014;312(20):2106–14. https://doi.org/10.1001/jama.2014.14721.

    Article  CAS  PubMed  Google Scholar 

  53. Ljungman P, Deliliers GL, Platzbecker U, Matthes-Martin S, Bacigalupo A, Einsele H, et al. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The infectious diseases working party of the European Group for Blood and Marrow Transplantation. Blood. 2001;97(2):388–92.

    Article  CAS  PubMed  Google Scholar 

  54. Sim SA, Leung VKY, Ritchie D, Slavin MA, Sullivan SG, Teh BW. Viral respiratory tract infections in allogeneic hematopoietic stem cell transplantation recipients in the era of molecular testing. Biol Blood Marrow Transplant. 2018;24(7):1490–6. https://doi.org/10.1016/j.bbmt.2018.03.004.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117(10):2755–63. https://doi.org/10.1182/blood-2010-08-263400.

    Article  CAS  PubMed  Google Scholar 

  56. Hutspardol S, Essa M, Richardson S, Schechter T, Ali M, Krueger J, et al. Significant transplantation-related mortality from respiratory virus infections within the first one hundred days in children after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(10):1802–7. https://doi.org/10.1016/j.bbmt.2015.06.015.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Tramontana AR, George B, Hurt AC, Doyle JS, Langan K, Reid AB, et al. Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia. Emerg Infect Dis. 2010;16(7):1068–75. https://doi.org/10.3201/eid1607.091691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Martino R, Porras RP, Rabella N, Williams JV, Ramila E, Margall N, et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant. 2005;11(10):781–96. https://doi.org/10.1016/j.bbmt.2005.07.007.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39(9):1300–6. https://doi.org/10.1086/425004.

    Article  PubMed  Google Scholar 

  60. Ljungman P, Avetisyan G. Influenza vaccination in hematopoietic SCT recipients. Bone Marrow Transplant. 2008;42(10):637–41. https://doi.org/10.1038/bmt.2008.264.

    Article  CAS  PubMed  Google Scholar 

  61. Ambati A, Einarsdottir S, Magalhaes I, Poiret T, Bodenstein R, LeBlanc K, et al. Immunogenicity of virosomal adjuvanted trivalent influenza vaccination in allogeneic stem cell transplant recipients. Transpl Infect Dis. 2015;17(3):371–9. https://doi.org/10.1111/tid.12382.

    Article  CAS  PubMed  Google Scholar 

  62. Girmenia C, Raiola AM, Piciocchi A, Algarotti A, Stanzani M, Cudillo L, et al. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Biol Blood Marrow Transplant. 2014;20(6):872–80. https://doi.org/10.1016/j.bbmt.2014.03.004.

    Article  PubMed  Google Scholar 

  63. Yong MK, Ananda-Rajah M, Cameron PU, Morrissey CO, Spencer A, Ritchie D, et al. Cytomegalovirus reactivation is associated with increased risk of late-onset invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a multicenter study in the current era of viral load monitoring. Biol Blood Marrow Transplant. 2017;23(11):1961–7. https://doi.org/10.1016/j.bbmt.2017.07.025.

    Article  PubMed  Google Scholar 

  64. Chapman B, Slavin M, Marriott D, Halliday C, Kidd S, Arthur I, et al. Changing epidemiology of candidaemia in Australia. J Antimicrob Chemother. 2017;72(4):1103–8. https://doi.org/10.1093/jac/dkw422.

    Article  CAS  PubMed  Google Scholar 

  65. Kennedy KJ, Daveson K, Slavin MA, van Hal SJ, Sorrell TC, Lee A, et al. Mucormycosis in Australia: contemporary epidemiology and outcomes. Clin Microbiol Infect. 2016;22(9):775–81. https://doi.org/10.1016/j.cmi.2016.01.005.

    Article  CAS  PubMed  Google Scholar 

  66. Ananda-Rajah MR, Cheng A, Morrissey CO, Spelman T, Dooley M, Neville AM, et al. Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrob Agents Chemother. 2011;55(5):1953–60. https://doi.org/10.1128/AAC.01423-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lamoth F, Chung SJ, Damonti L, Alexander BD. Changing epidemiology of invasive mold infections in patients receiving azole prophylaxis. Clin Infect Dis. 2017;64(11):1619–21. https://doi.org/10.1093/cid/cix130.

    Article  PubMed  Google Scholar 

  68. Ethier MC, Science M, Beyene J, Briel M, Lehrnbecher T, Sung L. Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials. Br J Cancer. 2012;106(10):1626–37. https://doi.org/10.1038/bjc.2012.147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Heng SC, Morrissey O, Chen SC, Thursky K, Manser RL, Nation RL, et al. Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: a systematic review and meta-analysis. Crit Rev Microbiol. 2015;41(1):124–34. https://doi.org/10.3109/1040841X.2013.804033.

    Article  CAS  PubMed  Google Scholar 

  70. Hill JA, Mayer BT, Xie H, Leisenring WM, Huang M-L, Stevens-Ayers T, et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017;129(16):2316–25. https://doi.org/10.1182/blood-2016-10-748426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yong MK, Slavin MA, Kontoyiannis DP. Invasive fungal disease and cytomegalovirus infection: is there an association? Curr Opin Infect Dis. 2018;31(6):481–9. https://doi.org/10.1097/QCO.0000000000000502.

    Article  PubMed  Google Scholar 

  72. Goncalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martinez L, Rodrigues F, et al. Evaluation of bronchoalveolar lavage fluid cytokines as biomarkers for invasive pulmonary aspergillosis in at-risk patients. Front Microbiol. 2017;8:2362. https://doi.org/10.3389/fmicb.2017.02362.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Khanna N, Stuehler C, Conrad B, Lurati S, Krappmann S, Einsele H, et al. Generation of a multipathogen-specific T-cell product for adoptive immunotherapy based on activation-dependent expression of CD154. Blood. 2011;118(4):1121–31. https://doi.org/10.1182/blood-2010-12-322610.

    Article  CAS  PubMed  Google Scholar 

  74. Withers B, Blyth E, Clancy LE, Yong A, Fraser C, Burgess J, et al. Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells. Blood Adv. 2017;1(24):2193–205. https://doi.org/10.1182/bloodadvances.2017010223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH, et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood. 2013;121(26):5113–23. https://doi.org/10.1182/blood-2013-02-486324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gerdemann U, Katari UL, Papadopoulou A, Keirnan JM, Craddock JA, Liu H, et al. Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant. Mol Ther. 2013;21(11):2113–21. https://doi.org/10.1038/mt.2013.151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Feucht J, Opherk K, Lang P, Kayser S, Hartl L, Bethge W, et al. Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood. 2015;125(12):1986–94. https://doi.org/10.1182/blood-2014-06-573725.

    Article  CAS  PubMed  Google Scholar 

  78. Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood. 2005;106(13):4397–406. https://doi.org/10.1182/blood-2005-05-1775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Balduzzi A, Lucchini G, Hirsch HH, Basso S, Cioni M, Rovelli A, et al. Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplant. 2011;46(7):987–92. https://doi.org/10.1038/bmt.2010.221.

    Article  CAS  PubMed  Google Scholar 

  80. •• Papadopoulou A, Gerdemann U, Katari UL, Tzannou I, Liu H, Martinez C, et al. Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci Transl Med. 2014;6(242):242ra83-ra83. https://doi.org/10.1126/scitranslmed.3008825 This study showed the feasibility of rapid manufacture of multipathogen specificity (CMV, EBV, adenovirus, HHV6 and BKV) from stem cell donors and the clinical effect in viral control in patients with viral infection and virus-related disease post transplantation.

    Article  CAS  Google Scholar 

  81. Ma CK, Blyth E, Clancy L, Simms R, Burgess J, Brown R, et al. 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. 2015;17(10):1406–20. https://doi.org/10.1016/j.jcyt.2015.07.005.

    Article  CAS  PubMed  Google Scholar 

  82. Olson AL, Muftuoglu M, Kaur I, Li L, Abueg G, Chemaly R, et al. Efficacy of third party BK virus (BKV) specific cytotoxic T-lymphocytes generated by ex vivo expansion for the treatment of BKV infection in stem cell transplant recipients, a phase 2 trial. Am Soc Hematol. 2016.

  83. Pello OM, Innes AJ, Bradshaw A, Finn SA, Uddin S, Bray E, et al. BKV-specific T cells in the treatment of severe refractory haemorrhagic cystitis after HLA-haploidentical haematopoietic cell transplantation. Eur J Haematol. 2017;98(6):632–4. https://doi.org/10.1111/ejh.12848.

    Article  CAS  PubMed  Google Scholar 

  84. Tzannou I, Papadopoulou A, Naik S, Leung K, Martinez CA, Ramos CA, et al. Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2017;35(31):3547–57. https://doi.org/10.1200/jco.2017.73.0655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Riddell SR, Greenberg PD. The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells. J Immunol Methods. 1990;128(2):189–201.

    Article  CAS  PubMed  Google Scholar 

  86. Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science (New York, NY). 1992;257(5067):238–41.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  88. Smith CA, Ng CY, Heslop HE, Holladay MS, Richardson S, Turner EV, et al. Production of genetically modified Epstein-Barr virus-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J Hematother. 1995;4(2):73–9. https://doi.org/10.1089/scd.1.1995.4.73.

    Article  CAS  PubMed  Google Scholar 

  89. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, et al. 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. 1995;333(16):1038–44. https://doi.org/10.1056/nejm199510193331603.

    Article  CAS  PubMed  Google Scholar 

  90. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood. 1998;92(5):1549–55.

    CAS  PubMed  Google Scholar 

  91. Blyth E, Clancy L, Simms R, Gaundar S, O’Connell P, Micklethwaite K, et al. BK virus-specific T cells for use in cellular therapy show specificity to multiple antigens and polyfunctional cytokine responses. Transplantation. 2011;92(10):1077–84. https://doi.org/10.1097/TP.0b013e31823328c0.

    Article  CAS  PubMed  Google Scholar 

  92. Blyth E, Gaundar SS, Clancy L, Simms RM, Bilmon I, Micklethwaite KP, et al. Clinical-grade varicella zoster virus-specific T cells produced for adoptive immunotherapy in hemopoietic stem cell transplant recipients. Cytotherapy. 2012;14(6):724–32. https://doi.org/10.3109/14653249.2012.663486.

    Article  CAS  PubMed  Google Scholar 

  93. Gaundar SS, Blyth E, Clancy L, Simms RM, Ma CKK, Gottlieb DJ. In vitro generation of influenza-specific polyfunctional CD4+ T cells suitable for adoptive immunotherapy. Cytotherapy. 2012;14(2):182–93. https://doi.org/10.3109/14653249.2011.613932.

    Article  CAS  PubMed  Google Scholar 

  94. Lamarche C, Orio J, Georges-Tobar V, Pincez T, Goupil M, Dahmani A, et al. Clinical-scale rapid autologous BK virus-specific T cell line generation from kidney transplant recipients with active viremia for adoptive immunotherapy. Transplantation. 2017;101(11):2713–21. https://doi.org/10.1097/tp.0000000000001698.

    Article  CAS  PubMed  Google Scholar 

  95. Ma CK, Clancy L, Deo S, Blyth E, Micklethwaite KP, Gottlieb DJ. Herpes simplex virus type 1 (HSV-1) specific T-cell generation from HLA-A1- and HLA-A2-positive donors for adoptive immunotherapy. Cytotherapy. 2017;19(1):107–18. https://doi.org/10.1016/j.jcyt.2016.09.013.

    Article  CAS  PubMed  Google Scholar 

  96. • Vasileiou S, Turney AM, Kuvalekar M, Mukhi SS, Watanabe A, Lulla P, et al. Rapid generation of multivirus-specific T lymphocytes for the prevention and treatment of respiratory viral infections. Haematologica. 2019. https://doi.org/10.3324/haematol.2018.206896 In this study, multivirus-specific PSTs were generated to 12 immunodominant respiratory viral antigens derived from respiratory syncitial virus, influenza, parainfluenza and human metapneumonvirus via a GMP-compliant manufacturing methodology. The expanded cells showed multipathogen specificity without activity against non-infected autologous or allogeneic targets ex vivo . In vivo viral clearance was demonstrated in 4 out of 5 post-aHSCT patients with respiratory viral infections who were administered the cell product. This represents a potential new treatment for such infections, given the lack of conventional therapeutic options.

  97. Tramsen L, Koehl U, Tonn T, Latge JP, Schuster FR, Borkhardt A, et al. Clinical-scale generation of human anti-Aspergillus T cells for adoptive immunotherapy. Bone Marrow Transplant. 2009;43(1):13–9. https://doi.org/10.1038/bmt.2008.271.

    Article  CAS  PubMed  Google Scholar 

  98. Gaundar SS, Clancy L, Blyth E, Meyer W, Gottlieb DJ. Robust polyfunctional T-helper 1 responses to multiple fungal antigens from a cell population generated using an environmental strain of Aspergillus fumigatus. Cytotherapy. 2012;14(9):1119–30. https://doi.org/10.3109/14653249.2012.704013.

    Article  CAS  PubMed  Google Scholar 

  99. Tramsen L, Schmidt S, Boenig H, Latge JP, Lass-Florl C, Roeger F, et al. Clinical-scale generation of multi-specific anti-fungal T cells targeting Candida, Aspergillus and mucormycetes. Cytotherapy. 2013;15(3):344–51. https://doi.org/10.1016/j.jcyt.2012.11.014.

    Article  CAS  PubMed  Google Scholar 

  100. Bacher P, Jochheim-Richter A, Mockel-Tenbrink N, Kniemeyer O, Wingenfeld E, Alex R, et al. Clinical-scale isolation of the total Aspergillus fumigatus-reactive T-helper cell repertoire for adoptive transfer. Cytotherapy. 2015;17(10):1396–405. https://doi.org/10.1016/j.jcyt.2015.05.011.

    Article  CAS  PubMed  Google Scholar 

  101. Deo SS, Virassamy B, Halliday C, Clancy L, Chen S, Meyer W, et al. Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells. Cytotherapy. 2016;18(1):65–79. https://doi.org/10.1016/j.jcyt.2015.09.013.

    Article  CAS  PubMed  Google Scholar 

  102. Papadopoulou A, Alvanou M, Koukoulias K, Athanasiou E, Lazaridou A, Savvopoulos N, et al. Clinical-scale production of Aspergillus-specific T cells for the treatment of invasive aspergillosis in the immunocompromised host. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0501-9.

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

    Article  CAS  PubMed  Google Scholar 

  104. Castellano-Gonzalez G, Clancy LE, Gottlieb D. Prospects for adoptive T-cell therapy for invasive fungal disease. Curr Opin Infect Dis. 2017;30(6):518–27. https://doi.org/10.1097/qco.0000000000000403.

    Article  CAS  PubMed  Google Scholar 

  105. Baugh KA, Tzannou I, Leen AM. Infusion of cytotoxic T lymphocytes for the treatment of viral infections in hematopoetic stem cell transplant patients. Curr Opin Infect Dis. 2018;31(4):292–300. https://doi.org/10.1097/qco.0000000000000456.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115(5):925–35. https://doi.org/10.1182/blood-2009-08-239186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance RA, et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996;2(5):551–5.

    Article  CAS  PubMed  Google Scholar 

  108. Barrett AJ, Prockop S, Bollard CM. Reprint of: virus-specific T cells: broadening applicability. Biol Blood Marrow Transplant. 2018;24(3s):S1–s6. https://doi.org/10.1016/j.bbmt.2017.12.787.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Chinen J, Buckley RH. Transplantation immunology: solid organ and bone marrow. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S324–S35. https://doi.org/10.1016/j.jaci.2009.11.014.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Prockop SE, Vatsayan A. Epstein-Barr virus lymphoproliferative disease after solid organ transplantation. Cytotherapy. 2017;19(11):1270–83. https://doi.org/10.1016/j.jcyt.2017.08.010.

    Article  CAS  PubMed  Google Scholar 

  111. • Withers B, Clancy L, Burgess J, Simms R, Brown R, Micklethwaite K, et al. Establishment and operation of a third-party virus-specific T cell bank within an allogeneic stem cell transplant program. Biol Blood Marrow Transplant. 2018;24(12):2433–42. https://doi.org/10.1016/j.bbmt.2018.08.024 Findings from this study showed that only a small number of carefully selected third-party donors are required to generate a PST bank covering the majority of common HLA restrictions. Whilst this study was limited to CMV, EBV and AdV, other studies have used third party–banked cells for BKV and HHV6 [103].

    Article  CAS  PubMed  Google Scholar 

  112. Sukdolak C, Tischer S, Dieks D, Figueiredo C, Goudeva L, Heuft HG, et al. CMV-, EBV- and ADV-specific T cell immunity: screening and monitoring of potential third-party donors to improve post-transplantation outcome. Biol Blood Marrow Transplant. 2013;19(10):1480–92. https://doi.org/10.1016/j.bbmt.2013.07.015.

    Article  CAS  PubMed  Google Scholar 

  113. Bieling M, Tischer S, Kalinke U, Blasczyk R, Buus S, Maecker-Kolhoff B, et al. Personalized adoptive immunotherapy for patients with EBV-associated tumors and complications: evaluation of novel naturally processed and presented EBV-derived T-cell epitopes. Oncotarget. 2018;9(4):4737–57. https://doi.org/10.18632/oncotarget.23531.

    Article  PubMed  Google Scholar 

  114. D’Orsogna LJ, van der Meer-Prins EMW, Zoet YM, Roelen DL, Doxiadis IIN, Claas FHJ. Detection of allo-HLA cross-reactivity by virus-specific memory T-cell clones using single HLA-transfected K562 cells. In: Christiansen FT, Tait BD, editors. Immunogenetics: methods and applications in clinical practice. Totowa: Humana; 2012. p. 339–49.

    Chapter  Google Scholar 

  115. Paul S, Lindestam Arlehamn CS, Scriba TJ, Dillon MB, Oseroff C, Hinz D, et al. Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes. J Immunol Methods. 2015;422:28–34. https://doi.org/10.1016/j.jim.2015.03.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

WJ is supported by a PhD scholarship from the Haematology Society of Australia and New Zealand (HSANZ) and Leukaemia Foundation Australia. MY is a National Health and Medical Research Council of Australia (NHMRC) Early Career Fellow (GNT1161521). EB is a New South Wales Cancer Institute Early Career Fellow and former NHMRC Post-Doctoral Fellow (GNT1089398).

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Authors and Affiliations

  1. Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia

    Wei Jiang, Barbara Withers, Gaurav Sutrave & Emily Blyth

  2. Westmead Institute of Medical Research, University of Sydney, Sydney, Australia

    Wei Jiang, Barbara Withers, Gaurav Sutrave, Leighton E. Clancy & Emily Blyth

  3. St Vincent’s Hospital, Darlinghurst, Australia

    Barbara Withers & Emily Blyth

  4. BMT and Cell Therapies Program, Westmead Hospital, Sydney, Australia

    Gaurav Sutrave & Emily Blyth

  5. Sydney Cellular Therapies Laboratory, Westmead, Australia

    Leighton E. Clancy

  6. National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia

    Michelle I. Yong

  7. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

    Michelle I. Yong

  8. The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia

    Michelle I. Yong

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Wei Jiang, Barbara Withers, Gaurav Sutrave, Leighton E. Clancy and Michelle I. Yong declare that they have no conflict of interest.

Emily Blyth has two patents: patent AU2015902675 issued and patent AU2018/050630 pending.

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Jiang, W., Withers, B., Sutrave, G. et al. Pathogen-Specific T Cells Beyond CMV, EBV and Adenovirus. Curr Hematol Malig Rep 14, 247–260 (2019). https://doi.org/10.1007/s11899-019-00521-z

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