Advertisement

Cellular therapy for multiple pathogen infections after hematopoietic stem cell transplant

  • Gaurav Sutrave
    Affiliations
    Department of Haematology, Westmead Hospital, Sydney, Australia

    The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
    Search for articles by this author
  • Emily Blyth
    Affiliations
    Department of Haematology, Westmead Hospital, Sydney, Australia

    The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
    Search for articles by this author
  • David J. Gottlieb
    Correspondence
    Correspondence: David J. Gottlieb, MBBS, FRACP, FRCPA, MD, Department of Medicine, Westmead Hospital, Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia.
    Affiliations
    Department of Haematology, Westmead Hospital, Sydney, Australia

    The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
    Search for articles by this author
Published:September 16, 2017DOI:https://doi.org/10.1016/j.jcyt.2017.07.012

      Highlights

      • HSCT results in profound T-cell immunodeficiency that varies in duration.
      • Multiple infections are common post-HSCT and may result in significant morbidity and death.
      • ACT with multi-pathogen-specific T cells can rapidly reconstitute T-cell immunity.
      • Use of third-party T-cell infusions can broaden applicability of ACT.

      Abstract

      Hematopoietic stem cell transplantation (HSCT) represents the only crative treatment option for many hematological conditions but results in a profound T-cell deficiency in the post-HSCT period. Infections account for a significant proportion of non-relapse morbidity and mortality, and infections with multiple organisms either simultaneously or at different times after transplant are common. Adoptive cellular therapy (ACT) with prophylactic or therapeutic infusion of donor derived or third-party, pathogen-specific T-cells represents a novel methodology to rapidly reconstitute T-cell mediated immunity in this context. For cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, clear evidence of efficacy with limited toxicity has been observed, with response rates up to 90%. Infusion of third-party, partially human leukocyte antigen–matched pathogen-specific T-cells have also demonstrated remarkable efficacy with responses seen in up to 70% of patients with resistant CMV, EBV and adenoviral infection. This review addresses the nature of post-HSCT immune deficiency, the common infections that occur in the post-HSCT period and how advances in ACT manufacturing methodologies is allowing for wider implementation of T-cell therapies targeting multiple pathogens in HSCT recipients.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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: 553-559
        • Hill J.A.
        • Mayer B.T.
        • Xie H.
        • Leisenring W.M.
        • 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: 2316-2335
        • Boeckh M.
        • Nichols W.G.
        • Papanicolaou G.
        • Rubin R.
        • Wingard J.R.
        • Zaia J.
        Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies.
        Biol Blood Marrow Transplant. 2003; 9: 543-558
        • Hakki M.
        • Riddell S.R.
        • Storek J.
        • Carter R.A.
        • Stevens-Ayers T.
        • Sudour P.
        • et al.
        Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.
        Blood. 2003; 102: 3060-3067
        • Doubrovina E.
        • Oflaz-Sozmen B.
        • Prockop S.E.
        • Kernan N.A.
        • Abramson S.
        • Teruya-Feldstein J.
        • et al.
        Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
        Blood. 2012; 119: 2644-2656
        • Chang Y.-J.
        • Zhao X.-Y.
        • Huang X.J.
        Immune reconstitution after haploidentical hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2014; 20: 440-449
        • Mehta R.S.
        • Rezvani K.
        Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection.
        Virulence. 2016; 7: 901-916
        • Williams K.M.
        • Gress R.E.
        Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation.
        Best Pract Res Clin Haematol. 2008; 21: 579-596
        • Cerutti A.
        The regulation of IgA class switching.
        Nat Rev Immunol. 2008; 8: 421-434
        • 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: 783-788
        • Seggewiss R.
        • Einsele H.
        Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update.
        Blood. 2010; 115: 3861-3868
        • Auletta J.J.
        • Lazarus H.M.
        Immune restoration following hematopoietic stem cell transplantation: an evolving target.
        Bone Marrow Transplant. 2005; 35: 835-857
        • Inazawa N.
        • Hori T.
        • Yamamoto M.
        • Igarashi K.
        • Tsutsumi H.
        • Nojima M.
        • et al.
        Multiplex PCR for virus infections after allogeneic hematopoietic stem cell transplantation.
        Blood. 2014; 124: 5845
        • Staras S.A.S.
        • Dollard S.C.
        • Radford K.W.
        • Flanders W.D.
        • Pass R.F.
        • Cannon M.J.
        Seroprevalence of cytomegalovirus infection in the United States, 1988–1994.
        Clin Infect Dis. 2006; 43: 1143-1151
        • Gandhi M.K.
        • Khanna R.
        Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments.
        Lancet Infect Dis. 2004; 4: 725-738
        • Ljungman P.
        Prevention and treatment of viral infections in stem cell transplant recipients.
        Br J Haematol. 2002; 118: 44-57
        • Boeckh M.
        • Leisenring W.
        • Riddell S.R.
        • Bowden R.A.
        • Huang M.-L.
        • Myerson D.
        • et al.
        Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity.
        Blood. 2003; 101: 407-414
        • Ljungman P.
        • Hakki M.
        • Boeckh M.
        Cytomegalovirus in hematopoietic stem cell transplant recipients.
        Hematol Oncol Clin North Am. 2011; 25: 151-169
        • Green M.L.
        • Leisenring W.
        • Xie H.
        • Mast T.C.
        • Cui Y.
        • Sandmaier B.M.
        • et al.
        Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study.
        Lancet Haematol. 2016; 3: e119-27
        • Yanada M.
        • Yamamoto K.
        • Emi N.
        • Naoe T.
        • Suzuki R.
        • Taji H.
        • et al.
        Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation.
        Bone Marrow Transplant. 2003; 32: 801-807
        • Teira P.
        • Battiwalla M.
        • Ramanathan M.
        • Barrett A.J.
        • Ahn K.W.
        • Chen M.
        • et al.
        Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.
        Blood. 2016; 127: 2427-2438
        • Marty F.M.
        • Ljungman P.
        • Papanicolaou G.A.
        • Winston D.J.
        • Chemaly R.F.
        • Strasfeld L.
        • et al.
        Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial.
        Lancet Infect Dis. 2011; 11: 284-292
        • Marty F.M.
        • Winston D.J.
        • Rowley S.D.
        • Vance E.
        • Papanicolaou G.A.
        • Mullane K.M.
        • et al.
        CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation.
        NEJM. 2013; 369: 1227-1236
        • Chemaly R.F.
        • Ullmann A.J.
        • Stoelben S.
        • Richard M.P.
        • Bornhäuser M.
        • Groth C.
        • et al.
        Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.
        NEJM. 2014; 370: 1781-1789
        • Jain N.
        • Lu K.
        • Ito S.
        • Muranski P.
        • Hourigan C.S.
        • Haggerty J.
        • et al.
        The clinical and financial burden of preemptive management of CMV disease after allogeneic stem cell transplantation—implications for preventative treatment approaches.
        Cytotherapy. 2014; 16: 927-933
        • Broers A.E.
        • van Der Holt R.
        • van Esser J.W.
        • Gratama J.W.
        • Henzen-Logmans S.
        • Kuenen-Boumeester V.
        • et al.
        Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation.
        Blood. 2000; 95: 2240-2245
        • Landais E.
        • Saulquin X.
        • Houssaint E.
        The human T cell immune response to Epstein-Barr virus.
        Int J Dev Biol. 2005; 49: 285-292
        • van Esser J.W.J.
        • van der Holt B.
        • Meijer E.
        • Niesters H.G.M.
        • Trenschel R.
        • Thijsen S.F.T.
        • et al.
        Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell–depleted SCT.
        Blood. 2001; 98: 972-978
        • Styczynski J.
        • Reusser P.
        • Einsele H.
        • de la Camara R.
        • Cordonnier C.
        • Ward K.N.
        • et al.
        Second European Conference on Infections in, Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia.
        Bone Marrow Transplant. 2009; 43: 757-770
        • Lin R.
        • Liu Q.
        Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation.
        J Hematol Oncol. 2013; 6: 94
        • Lenaerts L.
        • De Clercq E.
        • Naesens L.
        Clinical features and treatment of adenovirus infections.
        Rev Med Virol. 2008; 18: 357-374
        • Heemskerk B.
        • Lankester A.C.
        • Vreeswijk T.V.
        • Beersma M.F.C.
        • Claas E.C.J.
        • Veltrop-Duits L.A.
        • et al.
        Immune reconstitution and clearance of human adenovirus viremia in pediatric stem-cell recipients.
        J Infect Dis. 2005; 191: 520-530
        • Myers G.D.
        • Bollard C.M.
        • Wu M.F.
        • Weiss H.
        • Rooney C.M.
        • Heslop H.E.
        • et al.
        Reconstitution of adenovirus-specific cell-mediated immunity in pediatric patients after hematopoietic stem cell transplantation.
        Bone Marrow Transplant. 2007; 39: 677-686
        • Gustafson I.
        • Lindblom A.
        • Yun Z.
        • Omar H.
        • Engstrom L.
        • Lewensohn-Fuchs I.
        • et al.
        Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients.
        J Clin Virol. 2008; 43: 79-85
        • Ip W.W.
        • Qasim W.
        Management of adenovirus in children after allogeneic hematopoietic stem cell transplantation.
        Adv Hematol. 2013; 2013: 1-12
        • Leen A.M.
        • Rooney C.M.
        Adenovirus as an emerging pathogen in immunocompromised patients.
        Br J Haematol. 2005; 128: 135-144
        • Ljungman P.
        • Ribaud P.
        • Eyrich M.
        • Matthes-Martin S.
        • Einsele H.
        • Bleakley M.
        • et al.
        Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
        Bone Marrow Transplant. 2003; 31: 481-486
        • Grimley M.S.
        • Chemaly R.F.
        • Englund J.A.
        • Kurtzberg J.
        • Chittick G.
        • Brundage T.M.
        • et al.
        Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult allogeneic hematopoietic cell transplant recipients: a randomized placebo-controlled phase II trial.
        Biol Blood Marrow Transplant. 2017; 23: 512-521
        • Oxman M.N.
        Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence.
        J Am Osteopath Assoc. 2009; 109: S13-17
        • Sartori A.M.
        A review of the varicella vaccine in immunocompromised individuals.
        Int J Infect Dis. 2004; 8: 259-270
        • Su S.H.
        • Martel-Laferrière V.
        • Labbé A.-C.
        • Snydman D.R.
        • Kent D.
        • Laverdière M.
        • et al.
        High incidence of herpes zoster in nonmyeloablative hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2011; 17: 1012-1017
        • Boeckh M.
        • Kim H.W.
        • Flowers M.E.D.
        • Meyers J.D.
        • Bowden R.A.
        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: 1800-1805
        • Antonsson A.
        • Pawlita M.
        • Feltkamp M.C.W.
        • Bouwes Bavinck J.N.
        • Euvrard S.
        • Harwood C.A.
        • et al.
        Longitudinal study of seroprevalence and serostability of the human polyomaviruses JCV and BKV in organ transplant recipients.
        J Med Virol. 2015; 85: 327-335
        • 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: 1077-1084
        • Mani J.
        • Jin N.
        • Schmitt M.
        Cellular immunotherapy for patients with reactivation of JC and BK polyomaviruses after transplantation.
        Cytotherapy. 2014; 16: 1325-1335
        • Philippe M.
        • Ranchon F.
        • Gilis L.
        • Schwiertz V.
        • Vantard N.
        • Ader F.
        • et al.
        Cidofovir in the treatment of BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2016; 22: 723-730
        • Bernhoff E.
        • Tylden G.D.
        • Kjerpeseth L.J.
        • Gutteberg T.J.
        • Hirsch H.H.
        • Rinaldo C.H.
        Leflunomide inhibition of BK virus replication in renal tubular epithelial cells.
        J Virol. 2010; 84: 2150-2156
        • Sharma B.N.
        • Li R.
        • Bernhoff E.
        • Gutteberg T.J.
        • Rinaldo C.H.
        Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells.
        Antiviral Res. 2011; 92: 115-123
        • Miller A.N.
        • Glode A.
        • Hogan K.R.
        • Schaub C.
        • Kramer C.
        • Stuart R.K.
        • et al.
        Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus–associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients.
        Biol Blood Marrow Transplant. 2011; 17: 1176-1181
        • Chen X.C.
        • Liu T.
        • Li J.J.
        • He C.
        • Meng W.T.
        • Huang R.
        Efficacy and safety of leflunomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients.
        Acta Haematol. 2013; 130: 52-56
        • De Bolle L.
        • Naesens L.
        • De Clercq E.
        Update on human herpesvirus 6 biology, clinical features, and therapy.
        Clin Microbiol Rev. 2005; 18: 217-245
        • Becerra A.
        • Gibson L.
        • Stern L.J.
        • Calvo-Calle J.M.
        Immune response to HHV-6 and implications for immunotherapy.
        Curr Opin Virol. 2014; 9: 154-161
        • Brennan Y.
        • Gottlieb D.J.
        • Baewer D.
        • Blyth E.
        A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation.
        J Clin Virol. 2015; 72: 82-84
        • 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: 179-186
        • Ljungman P.
        • Singh N.
        Human herpesvirus-6 infection in solid organ and stem cell transplant recipients.
        J Clin Virol. 2006; 37: S87-91
        • Zerr D.M.
        Human herpesvirus 6 (HHV-6) disease in the setting of transplantation.
        Curr Opin Infect Dis. 2012; 25: 438-444
        • Kontoyiannis D.P.
        • Marr K.S.
        • Park B.J.
        • Alexander B.D.
        • Anaissie E.J.
        • Walsh T.J.
        • et al.
        Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.
        Clin Infect Dis. 2010; 50: 1091-1100
        • Simms-Waldrip T.
        • Rosen G.
        • Nielsen-Saines K.
        • Ikeda A.
        • Brown B.
        • Moore T.
        Invasive fungal infections in pediatric hematopoietic stem cell transplant patients.
        Infect Dis. 2015; 47: 218-224
        • Person A.K.
        • Kontoyiannis D.P.
        • Alexander B.D.
        Fungal infections in transplant and oncology patients.
        Infect Dis Clin North Am. 2010; 24: 439-459
        • Liu Y.-C.
        • Chien S.-H.
        • Fan N.-W.
        • Hu M.-H.
        • Gau J.-P.
        • Liu C.-J.
        • et al.
        Incidence and risk factors of probable and proven invasive fungal infection in adult patients receiving allogeneic hematopoietic stem cell transplantation.
        J Microbiol Immunol Infect. 2016; 49: 567-574
        • Bacher P.
        • Kniemeyer O.
        • Teutschbein J.
        • Thon M.
        • Vodisch M.
        • Wartenberg D.
        • et al.
        Identification of immunogenic antigens from Aspergillus fumigatus by direct multiparameter characterization of specific conventional and regulatory CD4+ T cells.
        J Immunol. 2014; 193: 3332-3343
        • Hebart H.
        • Bollinger C.
        • Fisch P.
        • Sarfati J.
        • Meisner C.
        • Baur M.
        • et al.
        Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies.
        Blood. 2002; 100: 4521-4528
        • Stevens D.A.
        Th1/Th2 in aspergillosis.
        Med Mycol. 2006; 44: S229-35
        • Potenza L.
        • Vallerini D.
        • Barozzi P.
        • Riva G.
        • Forghieri F.
        • Beauvais A.
        • et al.
        Characterization of specific immune responses to different Aspergillus antigens during the course of invasive aspergillosis in hematologic patients.
        PLoS ONE. 2013; 8 (e74326)
        • Fukuda T.
        • Boeckh M.
        • Carter R.A.
        • Sandmaier B.M.
        • Maris M.B.
        • Maloney D.G.
        • et al.
        Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning.
        Blood. 2003; 102: 827-833
        • Xu S.X.
        • Shen J.L.
        • Tang X.F.
        • Feng B.
        • Xu H.Q.
        Newer antifungal agents micafungin and voriconazole for fungal infection prevention during hematopoietic cell transplantation: a meta-analysis.
        Eur Rev Med Pharmacol Sci. 2016; 20: 381-390
        • Abidi M.Z.
        • Sohail M.R.
        • Cummins N.
        • Wilhelm M.
        • Wengenack N.
        • Brumble L.
        • et al.
        Stability in the cumulative incidence, severity, and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995–2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.
        Mycoses. 2014; 57: 687-698
        • Singh N.
        • Paterson D.L.
        Aspergillus infections in transplant recipients.
        Clin Microbiol Rev. 2005; 18: 44-69
        • Rustia E.
        • Violago L.
        • Jin Z.
        • Foca M.D.
        • Kahn J.M.
        • Arnold S.
        • et al.
        Risk factors and utility of a risk-based algorithm for monitoring cytomegalovirus, epstein-barr virus, and adenovirus infections in pediatric recipients after allogeneic hematopoietic cell transplantation.
        Biol Blood Marrow Transplant. 2016; 22: 1646-1653
        • Inazawa N.
        • Hori T.
        • Hatakeyama N.
        • Yamamoto M.
        • Yoto Y.
        • Nojima M.
        • et al.
        Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation.
        J Med Virol. 2015; 87: 1427-1435
        • Olkinuora H.A.
        • Taskinen M.H.
        • Saarinen-Pihkala U.M.
        • Vettenranta K.K.
        Multiple viral infections post-hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts.
        Pediatr Transplant. 2010; 14: 242-248
        • Watcharananan S.P.
        • Kiertiburanakul S.
        • Piyatuctsanawong W.
        • Anurathapan U.
        • Sungkanuparph S.
        • Pakakasama S.
        • et al.
        Cytomegalovirus, adenovirus, and polyomavirus co-infection among pediatric recipients of allogeneic stem cell transplantation: characteristics and outcome.
        Pediatr Transplant. 2010; 14: 675
        • Koskenvuo M.
        • Rahiala J.
        • Sadeghi M.
        • Waris M.
        • Vuorinen T.
        • Lappalainen M.
        • et al.
        Viremic co-infections in children with allogeneic haematopoietic stem cell transplantation are predominated by human polyomaviruses.
        Infect Dis. 2017; 49: 35-41
        • Schabert V.F.
        • Mozaffari E.
        • Lee Y.-C.
        • Casciano R.
        Double-Stranded DNA (dsDNA) viral infections among allogeneic Hematopoietic Cell Transplant (HCT) recipients in the first year after transplant.
        Blood. 2015; 126: 3296
        • Papadopoulos E.B.
        • Ladanyi M.
        • Emanuel D.
        • Mackinnon S.
        • Boulad F.
        • Carabasi M.H.
        • et al.
        Infusions of donor leukocytes to treat Epstein-Barr virus–associated lymphoproliferative disorders after allogeneic bone marrow transplantation.
        NEJM. 1994; 330: 1185-1191
        • Taylor G.S.
        • Long H.M.
        • Brooks J.M.
        • Rickinson A.B.
        • Hislop A.D.
        The immunology of Epstein-Barr virus–induced disease.
        Annu Rev Immunol. 2015; 33: 787-821
        • Crough T.
        • Khanna R.
        Immunobiology of human cytomegalovirus: from bench to bedside.
        Clin Microbiol Rev. 2009; 22: 76-98
        • Feuchtinger T.
        • Matthes-Martin S.
        • Richard C.
        • Lion T.
        • Fuhrer M.
        • Hamprecht K.
        • et al.
        Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation.
        Br J Haematol. 2006; 134: 64-76
        • Walter E.A.
        • Greenberg P.D.
        • Gilbert M.J.
        • Finch R.J.
        • Watanabe K.S.
        • Thomas E.D.
        • 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: 1038-1044
        • Roskrow M.A.
        • Suzuki N.
        • Gan Y.-J.
        • Sixbey J.W.
        • Ng C.Y.C.
        • Kimbrough S.
        • et al.
        Epstein-Barr Virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease.
        Blood. 1998; 91: 2925-2934
        • Feuchtinger T.
        • Opherk K.
        • Bethge W.A.
        • Topp M.S.
        • Schuster F.R.
        • Weissinger E.M.
        • et al.
        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. 2010; 116: 4360-4367
        • Moosmann A.
        • Bigalke I.
        • Tischer J.
        • Schirrmann L.
        • Kasten J.
        • Tippmer S.
        • et al.
        Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells.
        Blood. 2010; 115: 2960-2970
        • Micklethwaite K.
        • Hansen A.
        • Foster A.
        • Snape E.
        • Antonenas V.
        • Sartor M.
        • et al.
        Ex Vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2007; 13: 707-714
        • Trivedi D.
        • Williams R.Y.
        • O'Reilly R.J.
        • Koehne G.
        Generation of CMV-specific T lymphocytes using protein-spanning pools of pp65-derived overlapping pentadecapeptides for adoptive immunotherapy.
        Blood. 2005; 105: 2793-2801
        • Micklethwaite K.P.
        • Clancy L.
        • Sandher U.
        • Hansen A.M.
        • Blyth E.
        • Antonenas V.
        • et al.
        Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation.
        Blood. 2008; 112: 3974-3981
        • Leen A.M.
        • Molldrem J.J.
        • Carrum G.
        • Huls M.H.
        • Leung K.S.
        • Gee A.P.
        • et al.
        Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals.
        Nat Med. 2006; 12: 1160-1166
        • Gerdemann U.
        • Christin A.S.
        • Vera J.F.
        • Ramos C.A.
        • Fujita Y.
        • Liu H.
        • et al.
        Nucleofection of DCs to generate multivirus-specific T cells for prevention or treatment of viral infections in the immunocompromised host.
        Mol Ther. 2009; 17: 1616-1625
        • Horn B.
        • Bao L.
        • Dunham K.
        • Stamer M.
        • Adler S.
        • Cowan M.
        • et al.
        Infusion of cytomegalovirus specific cytotoxic T lymphocytes from a sero-negative donor can facilitate resolution of infection and immune reconstitution.
        Pediatr Infect Dis J. 2009; 28: 65-67
        • Jedema I.
        • van de Meent M.
        • Pots J.
        • Kester M.G.
        • van der Beek M.T.
        • Falkenburg J.H.
        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. 2011; 96: 1204-1212
        • Hanley P.J.
        • Melenhorst J.J.
        • Nikiforow S.
        • Scheinberg P.
        • Blaney J.W.
        • Demmler-Harrison G.
        • et al.
        CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo.
        Sci Transl Med. 2015; 7: 285ra63
        • Vera J.F.
        • Brenner L.J.
        • Gerdemann U.
        • Ngo M.C.
        • Sili U.
        • Liu H.
        • et al.
        Accelerated production of antigen-specific T-cells for pre-clinical and clinical applications using Gas-permeable Rapid Expansion cultureware (G-Rex).
        J Immunother. 2010; 33: 305-315
        • Cobbold M.
        • Khan N.
        • Pourgheysari B.
        • Tauro S.
        • McDonald D.
        • Osman H.
        • et al.
        Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers.
        J Exp Med. 2005; 202: 379-386
        • Schmitt A.
        • Tonn T.
        • Busch D.H.
        • Grigoleit G.U.
        • Einsele H.
        • Odendahl M.
        • et al.
        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. 2011; 51: 591-599
        • Peggs K.S.
        • Thomson K.
        • Samuel E.
        • Dyer G.
        • Armoogum J.
        • Chakraverty R.
        • et al.
        Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation.
        Clin Infect Dis. 2011; 52: 49-57
        • Uhlin M.
        • Gertow J.
        • Uzunel M.
        • Okas M.
        • Berglund S.
        • Watz E.
        • et al.
        Rapid salvage treatment with virus-specific T cells for therapy-resistant disease.
        Clin Infect Dis. 2012; 55: 1064-1073
        • Meij P.
        • Jedema I.
        • Zandvliet M.L.
        • van der Heiden P.L.J.
        • van de Meent M.
        • van Egmond H.M.E.
        • et al.
        Effective treatment of refractory CMV reactivation after allogeneic stem cell transplantation with in vitro-generated CMV pp65-specific CD8+ T-cell lines.
        J Immunother. 2012; 35: 621
        • Icheva V.
        • Kayser S.
        • Wolff D.
        • Tuve S.
        • Kyzirakos C.
        • Bethge W.
        • et al.
        Adoptive transfer of Epstein-Barr Virus (EBV) nuclear antigen 1–specific T cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation.
        J Clin Oncol. 2013; 31: 39-48
        • 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: 1986-1994
        • Neuenhahn M.
        • Albrecht J.
        • Odendahl M.
        • Schlott F.
        • Dossinger G.
        • Schiemann M.
        • et al.
        Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT.
        Leukemia. 2017; https://doi.org/10.1038/leu.2017.6
        • Imashuku S.
        • Goto T.
        • Matsumura T.
        • Naya M.
        • Yamori M.
        • Hojo M.
        • et al.
        Unsuccessful CTL transfusion in a case of post-BMT Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD).
        Bone Marrow Transplant. 1997; 20: 337-340
        • Lucas K.G.
        • Burton R.L.
        • Zimmerman S.E.
        • Wang J.
        • Cornetta K.G.
        • Robertson K.A.
        • et al.
        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. 1998; 91: 3654
        • Gustafsson A.
        • Levitsky V.
        • Zou J.Z.
        • Frisan T.
        • Dalianis T.
        • Ljungman P.
        • et al.
        Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells.
        Blood. 2000; 95: 807
        • Einsele H.
        • Roosnek E.
        • Rufer N.
        • Sinzger C.
        • Riegler S.
        • Loffler J.
        • et al.
        Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy.
        Blood. 2002; 99: 3916-3922
        • Peggs K.S.
        • Verfuerth S.
        • Pizzey A.
        • Khan N.
        • Guiver M.
        • Moss P.A.
        • et al.
        Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.
        Lancet. 2003; 362: 1375-1377
        • 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: 4397-4406
        • Comoli P.
        • Basso S.
        • Zecca M.
        • Pagliara D.
        • Baldanti F.
        • Bernardo M.E.
        • et al.
        Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation.
        Am J Transplant. 2007; 7: 1648-1655
        • Heslop H.E.
        • Slobod K.S.
        • Pule M.A.
        • Hale G.A.
        • Rousseau A.
        • Smith C.A.
        • 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: 925-935
        • Balduzzi A.
        • Lucchini G.
        • Hirsch H.H.
        • 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: 987-992
        • Bao L.
        • Cowan M.J.
        • Dunham K.
        • Horn B.
        • McGuirk J.
        • Gilman A.
        • et al.
        Adoptive immunotherapy with CMV-specific cytotoxic T lymphocytes for stem cell transplant patients with refractory CMV infections.
        J Immunother. 2012; 35: 293
        • Koehne G.
        • Hasan A.
        • Doubrovina E.
        • Prockop S.
        • Tyler E.
        • Wasilewski G.
        • et al.
        Immunotherapy with donor T cells sensitized with overlapping pentadecapeptides for treatment of persistent cytomegalovirus infection or viremia.
        Biol Blood Marrow Transplant. 2015; 21: 1663-1678
        • Bleakley M.
        • Heimfeld S.
        • Loeb K.R.
        • Jones L.A.
        • Chaney C.
        • Seropian S.
        • et al.
        Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts.
        J Clin Invest. 2015; 125: 2677-2689
        • Amrolia P.J.
        • Muccioli-Casadei G.
        • Huls H.
        • Adams S.
        • Durett A.
        • Gee A.
        • et al.
        Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation.
        Blood. 2006; 108: 1797-1808
        • Mielke S.
        • McIver Z.A.
        • Shenoy A.
        • Fellowes V.
        • Khuu H.
        • Stroncek D.F.
        • et al.
        Selectively T cell-depleted allografts from HLA-matched sibling donors followed by low-dose posttransplantation immunosuppression to improve transplantation outcome in patients with hematologic malignancies.
        Biol Blood Marrow Transplant. 2011; 17: 1855-1861
        • Perruccio K.
        • Topini F.
        • Tosti A.
        • Carotti A.
        • Aloisi T.
        • Aversa F.
        • et al.
        Photodynamic purging of alloreactive T cells for adoptive immunotherapy after haploidentical stem cell transplantation.
        Blood Cells Mol Dis. 2008; 40: 76-83
        • Roy D.-C.
        • Lachance S.
        • Roy J.
        • Walker I.
        • Maertens J.
        • Delisle J.-S.
        • et al.
        Donor lymphocytes depleted of Alloreactive T-Cells (ATIR101) Improve Event-Free Survival (GRFS) and Overall survival in a T-cell depleted haploidentical HSCT: phase 2 trial in patients with AML and ALL.
        Blood. 2016; 128: 1226
        • Mielke S.
        • Nunes R.
        • Rezvani K.
        • Fellowes V.S.
        • Venne A.
        • Solomon S.R.
        • et al.
        A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique.
        Blood. 2008; 111: 4392-4402
        • McIver Z.A.
        • Melenhorst J.J.
        • Grim A.
        • Naguib N.
        • Weber G.
        • Fellowes V.
        • et al.
        Immune reconstitution in recipients of photodepleted HLA-identical sibling donor stem cell transplantations: T cell subset frequencies predict outcome.
        Biol Blood Marrow Transplant. 2011; 17: 1846-1854
        • Blyth E.
        • Clancy L.
        • Simms R.
        • Ma C.K.K.
        • 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: 3745
        • Gottschalk S.
        • Ng C.Y.
        • Perez M.
        • Smith C.A.
        • Sample C.
        • Brenner M.K.
        • et al.
        An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs.
        Blood. 2001; 97: 835-843
        • McLaughlin L.P.
        • Lang H.
        • Williams E.
        • Wright K.E.
        • Powell A.
        • Cruz C.R.
        • et al.
        Human parainfluenza virus-3 can be targeted by rapidly ex vivo expanded T lymphocytes.
        Cytotherapy. 2016; 18: 1515-1524
        • Gaundar S.S.
        • Blyth E.
        • Clancy L.
        • Simms R.M.
        • Ma C.K.K.
        • Gottlieb D.J.
        In vitro generation of influenza-specific polyfunctional CD4+ T cells suitable for adoptive immunotherapy.
        Cytotherapy. 2012; 14: 182-193
        • Dong L.
        • Gao Z.Y.
        • Chang L.J.
        • Liang Y.
        • Tan X.-Y.
        • Liu J.-H.
        • et al.
        Adoptive transfer of cytomegalovirus/Epstein-Barr virus-specific immune effector cells for therapeutic and preventive/preemptive treatment of pediatric allogeneic cell transplant recipients.
        J Pediatr Hematol Oncol. 2010; 32: e31-7
        • Leen A.M.
        • Christin A.
        • Myers G.D.
        • Liu H.
        • Cruz C.R.
        • Hanley P.J.
        • et al.
        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. 2009; 114: 4283-4292
        • Gerdemann U.
        • Katari U.L.
        • Papadopoulou A.
        • Keirnan J.M.
        • Craddock J.A.
        • 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: 2113-2121
        • Papadopoulou A.
        • Gerdemann U.
        • Katari U.L.
        • 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: 242ra83
        • Ma C.K.K.
        • 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: 1406-1420
        • Gerdemann U.
        • Keirnan J.M.
        • Katari U.L.
        • Yanagisawa R.
        • Christin A.S.
        • Huye L.E.
        • et al.
        Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.
        Mol Ther. 2012; 20: 1622-1632
        • Peggs K.S.
        • Thomson K.
        • Hart D.P.
        • Geary J.
        • Morris E.C.
        • Yong K.
        • et al.
        Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.
        Blood. 2004; 103: 1548-1556
        • Leen A.M.
        • Bollard C.M.
        • Mendizabal A.M.
        • Shpall E.J.
        • Szabolcs P.
        • Antin J.H.
        • 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: 5113-5123
        • Haque T.
        • Wilkie G.M.
        • Jones M.M.
        • Higgins C.D.
        • Urquhart G.
        • Wingate P.
        • et al.
        Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.
        Blood. 2007; 110: 1123-1131
        • Haque T.
        • Wilkie G.M.
        • Taylor C.
        • Amlot P.L.
        • Murad P.
        • Iley A.
        • et al.
        Treatment of Epstein-Barr-virus–positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells.
        Lancet. 2002; 360: 436-442
        • Haque T.
        • McAulay K.A.
        • Kelly D.
        • Crawford D.K.
        Allogeneic T-cell therapy for Epstein-Barr virus-positive posttransplant lymphoproliferative disease: long-term follow-up.
        Transplantation. 2010; 90: 93-94
        • Qasim W.
        • Derniame S.
        • Gilmour K.
        • Chiesa R.
        • Weber M.
        • Adams S.
        • et al.
        Third-party virus-specific T cells eradicate adenoviraemia but trigger bystander graft-versus-host disease.
        Br J Haematol. 2011; 154: 150-153
        • Barker J.N.
        • Doubrovina E.
        • Sauter C.
        • Jaroscak J.J.
        • Perales M.A.
        • Doubrovin M.
        • et al.
        Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes.
        Blood. 2010; 116: 5045-5049
        • Vickers M.A.
        • Wilkie G.M.
        • Robinson N.
        • Rivera N.
        • Haque T.
        • Crawford D.H.
        • et al.
        Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.
        Br J Haematol. 2014; 167: 402-410
        • Withers B.
        • Blyth E.
        • Clancy L.
        • Burgess J.
        • Simms R.
        • Micklethwaite K.
        • et al.
        Third-party donor virus-specific t cells are efficacious in the treatment of refractory viral infection following allogeneic HSCT, but may not persist post-infusion.
        Blood. 2015; 126: 623