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Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment

      Abstract

      Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.

      Key Words

      Introduction

      Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for many patients with malignant and non-malignant blood disorders. [
      • Majhail NS
      • Farnia SH
      • Carpenter PA
      • et al.
      Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.
      ] However, the morbidity and mortality related to disease relapse, regimen-related toxicity, graft-versus-host disease (GVHD) and opportunistic infections limit the success of HSCT in these applications.[
      • Aschan J.
      Risk assessment in haematopoietic stem cell transplantation: conditioning.
      ,
      • Fraser CJ
      • Scott Baker K
      The management and outcome of chronic graft-versus-host disease.
      ,
      • Leather HL
      • Wingard JR.
      Infections following hematopoietic stem cell transplantation.
      ] Central to the paradigm of HSCT is the immunosuppression required to allow engraftment of donor cells within the host, and to prevent GVHD due to the alloreactive donor cells attacking the host tissues. This immune suppression predisposes HSCT recipients to opportunistic infections. Additionally, patients who have received anti-B-cell–targeted immunotherapy with either chimeric antigen receptor–modified T cells, antibodies or bispecific antibodies have impaired humoral immunity even before HSCT that can further delay immune recovery [
      • Hill JA
      • Li D
      • Hay KA
      • et al.
      Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunPeriodicalapy.
      ]. HSCT recipients with more rapid recovery of innate, and especially adaptive immune function, not only have a decreased incidence of infections but also disease relapse [
      • Ogonek J
      • Kralj Juric M
      • Ghimire S
      • et al.
      Immune reconstitution after allogeneic hematopoietic stem cell transplantation.
      ]. Therefore, timely immune reconstitution is essential for the long-term survival of patients after HSCT.
      Among HSCT recipients, the risk of bacterial and fungal infections decreases with reconstitution of innate immune function, typically by the end of the first month after graft infusion. Those who develop GVHD and require systemic steroids have a significantly increased risk of developing life-threatening and fatal infections due to delayed immune recovery. Indeed, patients who develop acute graft-versus-host disease (aGVHD) experience approximately 60% more infections than patients who do not develop aGVHD [
      • Miller HK
      • Braun TM
      • Stillwell T
      • et al.
      Infectious risk after allogeneic hematopoietic cell transplantation complicated by acute graft-versus-host disease.
      ]. In contrast to the typically rapid reconstitution of innate immunity, the pace of reconstitution of T-cell immunity is variable and can take several months to years. The risk of morbidity and mortality related to acquired and latent viral infections continues until effective T-cell reconstitution.
      The pace of immune recovery is slower in older HSCT recipients as well as in recipients of human leukocyte antigen (HLA)-disparate or T-cell–depleted grafts, as well as those who develop GVHD [
      • Tomblyn M
      • Chiller T
      • Einsele H
      • et al.
      Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.
      ]. In addition, exposure to lympholytic components of conditioning regimens, especially serotherapy, has been demonstrated to correlate with immune reconstitution [
      • Booth C
      • Veys P.
      T cell depletion in paediatric stem cell transplantation.
      ]. While HSCT recipient age and donor/recipient HLA disparities cannot be modified, several other factors can be modified, and current prospective trials are evaluating the potential to improve early T-cell reconstitution with better targeting of immune ablative therapies used in conditioning regimens.
      Community-acquired viral infections are potentially preventable by limited exposure with protective isolation. However, patients remain at risk for reactivation of latent viruses that have previously infected and remain dormant in either recipient cells or transferred donor cells [
      • Tomblyn M
      • Chiller T
      • Einsele H
      • et al.
      Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.
      ,
      • Young JH
      • Logan BR
      • Wu J
      • et al.
      Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors.
      ]. In this review, we will review standard approaches to prophylaxis and treatment of viral infections with currently available antiviral agents as well as the limitations of these therapies. We then discuss the expanding use of adoptive cell therapy with viral-specific T cells.
      Summary: The morbidity and mortality from viral infections in HSCT recipients is primarily due to impaired T-cell reconstitution. There is increasing evidence that the pace of T-cell reconstitution is modifiable and, as such, improving the reliability with which HSCT recipients achieve early T-cell reconstitution is a priority for the field.

      Viral infections in HSCT recipients

      Identification of patients at risk for specific viral infections allows for risk-adapted approaches to prophylaxis and pre-emptive therapy. Risk of specific viral infections depends on recipient age, serostatus of both the recipient and donor, degree of HLA match, stem cell source and graft manipulation (specifically T-cell depletion). Recently milestones of CD4+ reconstitution associated with the incidence of viral reactivation as well as infection-related mortality have been identified in retrospective and prospective studies [
      • Admiraal R
      • de Koning CCH
      • Lindemans CA
      • et al.
      Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation.
      ,
      • Admiraal R
      • Lindemans CA
      • van Kesteren C
      • et al.
      Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation.
      ]. Paired with improvements in early diagnosis of viral infections, stratified approaches can limit the morbidity and mortality associated with infectious complications of HSCT as well as the toxicity of treatment [
      • Tomblyn M
      • Chiller T
      • Einsele H
      • et al.
      Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.
      ].
      Reactivation of latent herpes viruses is among the most important infectious complications of HSCT. It is important to recognize that the reservoir for these viruses is the HSCT donor as well as the recipient, as latently infected cells can be transferred with the graft. These viruses have developed the unique ability to establish latency following primary infection in specific cell populations, i.e., varicella virus (VZV) in the dorsal root and autonomic ganglia along the entire neuroaxis, herpes simplex virus (HSV) in the dorsal root ganglia of sensory neurons and Epstein–Barr virus (EBV) in memory B cells [
      • Chiu YF
      • Sugden B.
      Epstein-Barr virus: the path from latent to productive infection.
      ], whereas the reservoir of latent cytomegalovirus (CMV) is incompletely understood [
      • Jarvis MA
      • Nelson JA.
      Human cytomegalovirus persistence and latency in endothelial cells and macrophages.
      ]. Latent infection is defined as the state in which viral genome is retained, but viral gene expression is highly restricted, and no infectious virions are produced. Replication and latency are maintained through a delicate balance between productive (lytic) and non-productive (latent) phases of viral life cycle. T-cell–mediated immune control, as well as changes in the differentiation/activation state of cells harboring integrated viral genome, controls transition between these states [
      • Jarvis MA
      • Nelson JA.
      Human cytomegalovirus persistence and latency in endothelial cells and macrophages.
      ,
      • Murata T
      • Tsurumi T.
      Switching of EBV cycles between latent and lytic states.
      ]. While isolated reactivation events occur intermittently in the immunocompetent host without causing clinical symptoms [
      • Vogl BA
      • Fagin U
      • Nerbas L
      • Schlenke P
      • Lamprecht P
      • Jabs WJ.
      Longitudinal analysis of frequency and reactivity of Epstein-Barr virus-specific T lymphocytes and their association with intermittent viral reactivation.
      ], immunosuppression may result in reactivation and lead to viremia and/or virus-associated systemic or end-organ disease [
      • Ljungman P
      • Boeckh M
      • Hirsch HH
      • et al.
      Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.
      ]. The risk factors associated with reactivation, the clinical manifestations of reactivation and the standard approaches to prophylaxis, monitoring and treatment are different for different viruses and discussed separately. While reduction of immunosuppressants to improve immune control of viruses is a rational approach, it may not be feasible in many cases due to the risk of GVHD.
      HSV reactivation is uncommon, given near-universal prophylaxis with acyclovir, but can manifest as stomatitis, encephalitis, hepatitis, esophagitis, pneumonitis and bone marrow suppression [
      • Wingard JR
      • Hsu J
      • Hiemenz JW.
      Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology.
      ,
      • Gluckman E
      • Lotsberg J
      • Devergie A
      • et al.
      [Use of acyclovir in the prevention of herpes infections after allogenic bone marrow grafts].
      ]. Some studies have shown valaciclovir to be safe and effective alternative to acyclovir, whereas foscarnet, due to its toxicity, is used only to treat acyclovir-resistant HSV [
      • Warkentin DI
      • Epstein JB
      • Campbell LM
      • et al.
      Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients.
      ,
      • Ljungman P.
      Prevention and treatment of viral infections in stem cell transplant recipients.
      ]. Reactivation of the VZV can result in limited or extensive cutaneous eruptions, encephalitis, pneumonitis or hepatitis. Long-term prophylaxis with acyclovir or valacyclovir is safe and effective in preventing VZV recurrence and reducing progression of VZV infection [
      • Boeckh M
      • Kim HW
      • Flowers ME
      • Meyers JD
      • Bowden RA.
      Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationࣧa randomized double-blind placebo-controlled study.
      ,
      • Shepp DH
      • Dandliker PS
      • Meyers JD.
      Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine.
      ,
      • Oshima K
      • Takahashi T
      • Mori T
      • et al.
      One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group.
      ]. Again, foscarnet and cidofovir are used only for acyclovir resistant VZV infection [
      • Boeckh M
      • Kim HW
      • Flowers ME
      • Meyers JD
      • Bowden RA.
      Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationࣧa randomized double-blind placebo-controlled study.
      ,
      • Shepp DH
      • Dandliker PS
      • Meyers JD.
      Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine.
      ,
      • Oshima K
      • Takahashi T
      • Mori T
      • et al.
      One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group.
      ]. VZV-passive immunization with varicella-zoster immune globulin is recommended for all immunocompromised HSCT recipients following VZV exposure [
      • Marin M
      • Guris D
      • Chaves SS
      • et al.
      Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ]. Also, inactivated VZV vaccine given to HSCT recipients before and at least 90 days after the transplant is of benefit in reducing the risk of zoster [
      • Hata A
      • Asanuma H
      • Rinki M
      • et al.
      Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants.
      ,
      • Baumrin E
      • Izaguirre NE
      • Bausk B
      • et al.
      Safety and reactogenicity of the recombinant zoster vaccine after allogeneic hematopoietic cell transplantation.
      ].
      Human herpesvirus 6 (HHV-6) reactivation after HSCT is especially common in recipients of umbilical cord transplant, and although it is associated with encephalitis, bone marrow suppression, pneumonitis, CMV reactivation and an increased risk of GVHD and mortality, it also can resolve without intervention [
      • Wainwright MS
      • Martin PL
      • Morse RP
      • et al.
      Human herpesvirus 6 limbic encephalitis after stem cell transplantation.
      ,
      • Zerr DM
      • Boeckh M
      • Delaney C
      • et al.
      HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation.
      ,
      • Zerr DM
      • Corey L
      • Kim HW
      • Huang ML
      • Nguy L
      • Boeckh M.
      Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation.
      ,
      • Drobyski WR
      • Dunne WM
      • Burd EM
      • et al.
      Human herpesvirus-6 (HHV-6) infection in allogeneic bone marrow transplant recipients: evidence of a marrow-suppressive role for HHV-6 in vivo.
      ,
      • Ogata M.
      [Human herpesvirus-6 encephalitis in allogeneic hematopoietic stem cell transplantation].
      ]. Routine prophylactic or pre-emptive therapy of HHV-6 viremia is not recommended, and, as such, routine monitoring for reactivation is not uniformly practiced. Patients with HHV-6 encephalitis are treated with foscarnet or ganciclovir as first-line therapies and cidofovir as second-line therapy [
      • Zerr DM
      • Gupta D
      • Huang ML
      • Carter R
      • Corey L.
      Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients.
      ].
      CMV is the most common clinically significant infection after HSCT [
      • Teira P
      • Battiwalla M
      • Ramanathan M
      • et al.
      Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.
      ]. CMV viremia alone can cause marrow suppression, and CMV disease manifestations include encephalitis, retinitis, pneumonitis, enteritis and hepatitis. In the absence of prophylaxis, CMV reactivation occurs in 60–70% of at-risk HSCT recipients and is associated with decreased survival [
      • Einsele H
      • Ljungman P
      • Boeckh M.
      How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.
      ]. The management of CMV has evolved over recent years. Until approximately 2017, most centers applied risk-stratified prophylaxis in the greatest-risk patients combined with pre-emptive therapy for CMV reactivation in both adult and pediatric recipients of HSCT. It is important to note that to be effective, pre-emptive therapy depends on close monitoring with highly sensitive assays [
      • Goodrich JM
      • Bowden RA
      • Fisher L
      • Keller C
      • Schoch G
      • Meyers JD.
      Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant.
      ,
      • Prentice HG
      • Gluckman E
      • Powles RL
      • et al.
      Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group.
      ,
      • Ljungman P
      • de La Camara R
      • Milpied N
      • et al.
      Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants.
      ]. In 2017, letermovir was approved for CMV prophylaxis in adults. Current approaches combining sensitive assays for the rapid detection of viral reactivation with prompt initiation of antiviral therapy have reduced the incidence of CMV disease; however, those individuals who develop persistent viremia or CMV disease still experience high mortality. Patients who have evidence of CMV replication with or without prophylaxis typically receive first-line pre-emptive treatment with ganciclovir/valganciclovir [
      • Ljungman P
      • de la Camara R
      • Cordonnier C
      • et al.
      Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT.
      ,
      • Einsele H
      • Reusser P
      • Bornhauser M
      • et al.
      Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation.
      ,
      • van der Heiden PL
      • Kalpoe JS
      • Barge RM
      • Willemze R
      • Kroes AC
      • Schippers EF.
      Oral valganciclovir as pre-emptive therapy has similar efficacy on cytomegalovirus DNA load reduction as intravenous ganciclovir in allogeneic stem cell transplantation recipients.
      ]. Foscarnet, alone or in combination with ganciclovir, is generally used as second-line treatment due to toxicity [
      • Bacigalupo A
      • Boyd A
      • Slipper J
      • Curtis J
      • Clissold S.
      Foscarnet in the management of cytomegalovirus infections in hematopoietic stem cell transplant patients.
      ,
      • Ljungman P
      • Deliliers GL
      • Platzbecker U
      • 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.
      ], and cidofovir is less commonly used. Mutations in the CMV genome are associated with resistance to each of these antiviral agents.
      Prophylaxis against reactivation of EBV is not standard, as EBV reactivation occurs in only 10–15% of EBV-seropositive recipients, with only 1–4% developing EBV-related post-transplant lymphoproliferative disease (PTLD). The incidence is greater for recipients of cord blood transplants (when administered with ATG) and ex vivo T-cell–depleted grafts; hence, some regimens even include prophylaxis with a single peri-transplant dose of rituximab [
      • Majhail NS
      • Farnia SH
      • Carpenter PA
      • et al.
      Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.
      ]. EBV reactivation can manifest as viremia alone, hepatitis, hemophagocytic lymphohistiocytosis or PTLD [
      • Reddy N
      • Rezvani K
      • Barrett AJ
      • Savani BN.
      Strategies to prevent EBV reactivation and posttransplant lymphoproliferative disorders (PTLD) after allogeneic stem cell transplantation in high-risk patients.
      ,
      • Xuan L
      • Jiang X
      • Sun J
      • et al.
      Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.
      ]. Standard first-line treatment of PTLD with rituximab is effective in more than 50% of cases [
      • Darenkov IA
      • Marcarelli MA
      • Basadonna GP
      • et al.
      Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.
      ] but pre-emptive treatment for EBV viral reactivation without evidence of PTLD is becoming increasingly standard [
      • Kuehnle I
      • Huls MH
      • Liu Z
      • et al.
      CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation.
      ,
      • van Esser JW
      • Niesters HG
      • van der Holt B
      • et al.
      Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation.
      ,
      • Worth A
      • Conyers R
      • Cohen J
      • et al.
      Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation.
      ]. Of note, rituximab is ineffective in the treatment of CD20-negative PTLD.
      Adenovirus is another potentially lethal infection in the post-HSCT period that is more common in pediatric recipients [
      • Flomenberg P
      • Babbitt J
      • Drobyski WR
      • et al.
      Increasing incidence of adenovirus disease in bone marrow transplant recipients.
      ]. Pre-emptive treatment with cidofovir has been associated with clinical improvement but unfortunately does not translate into improved survival [
      • Bordigoni P
      • Carret AS
      • Venard V
      • Witz F
      • Le Faou A
      Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation.
      ,
      • Yusuf U
      • Hale GA
      • Carr J
      • et al.
      Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients.
      ]. Brincidofovir, an orally bioavailable lipid conjugate of cidofovir, was shown to be well-tolerated and efficacious in patients who were unresponsive to cidofovir [
      • Hiwarkar P
      • Amrolia P
      • Sivaprakasam P
      • et al.
      Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.
      ] but is not currently available, efficacy is variable and some patients cannot tolerate the medication due to gastrointestinal toxicity. Ribavirin also has been used historically but was associated with poor efficacy.
      Finally, there are also some viruses that cause significant morbidity and mortality post-HSCT, such as BK virus, hemorrhagic cystitis and JC virus progressive multifocal encephalopathy, respectively, for which there are not widely accepted effective antiviral agents.
      Critical to the development of rational treatment algorithms is the identification of factors predictive of virus reactivation, refractory viremia and viral disease following HSCT. These factors can then be used to identify patients at high risk for viral infection–related morbidity and mortality for monitoring, prophylaxis and treatment. This approach has identified recipient (age and serostatus), donor (serostatus and HLA disparity), transplant (cell source and conditioning), virus (genetic resistance and organ trophism) and post-transplant (pace of immune reconstitution and GVHD)–specific factors that need to be considered in assessing each recipients’ risk for viral reactivation and disease. It has been shown that serological donor (D)/recipient (R) mismatch increases the risk of CMV and EBV infection post-transplant, with CMV D–/R+ associated with the greatest risk for CMV infection after allo-HSCT [
      • George B
      • Pati N
      • Gilroy N
      • et al.
      Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
      ,
      • Walker RC
      • Marshall WF
      • Strickler JG
      • et al.
      Pretransplantation assessment of the risk of lymphoproliferative disorder.
      ] and EBVD+/R– increasing the incidence of EBV-related PTLD after HSCT 10- to 75-fold over that in EBV-seropositive recipients [
      • Styczynski J
      • van der Velden W
      • Fox CP
      • et al.
      Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation.
      ]. A D/R HLA mismatch is significantly associated with increased risk of CMV viremia and EBV-PTLD following HSCT [
      • Sundin M
      • Le Blanc K
      • Ringdén O
      • et al.
      The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation.
      ,
      • Landgren O
      • Gilbert ES
      • Rizzo JD
      • et al.
      Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.
      ].
      Use of T-cell depletion agents, such as anti-thymocyte globulin, anti-CD3 monoclonal antibodies or alemtuzumab, causing immune suppression, is a significant risk factor in viral reactivation [
      • George B
      • Kerridge IH
      • Gilroy N
      • et al.
      A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group.
      ,
      • Chiereghin A
      • Prete A
      • Belotti T
      • et al.
      Prospective Epstein-Barr virus-related post-transplant lymphoproliferative disorder prevention program in pediatric allogeneic hematopoietic stem cell transplant: virological monitoring and first-line treatment.
      ]. High or rising viral loads after HSCT despite first-line therapy are correlated with the development of CMV disease and in increase in mortality. Studies have shown significantly increased risk of death in patients with CMV viral loads of >500 IU/mL, with the greatest risk observed in the first 60 days post-HSCT in patients whose viral loads were 500–1000 and >1000 IU/mL [
      • Green ML
      • Leisenring W
      • Stachel D
      • et al.
      Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation.
      ,
      • Green ML
      • Leisenring W
      • Xie H
      • et al.
      Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study.
      ] and more recently in those with a time-averaged area under the curve of CMV viral load by day 100 [
      • Stern A
      • Su Y
      • Dumke H
      • et al.
      Cytomegalovirus viral load kinetics predict cytomegalovirus end-organ disease and mortality after hematopoietic cell transplant.
      ].
      In the post-HSCT period, reactivation risk is also increased by aGVHD due to impairment in innate and adaptive virus-directed immune responses [
      • Uhlin M
      • Wikell H
      • Sundin M
      • et al.
      Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.
      ,
      • Laberko A
      • Bogoyavlenskaya A
      • Shelikhova L
      • et al.
      Risk factors for and the clinical impact of cytomegalovirus and Epstein-Barr virus infections in pediatric recipients of TCR-α/β- and CD19-depleted grafts.
      ]. Recovery of T-cell immunity has been associated with control of viral reactivation for almost 2 decades, with a study by Hakki et al. [
      • Hakki M
      • Riddell SR
      • Storek J
      • et al.
      Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.
      ] demonstrating low CD4+ (<100 × 109/L) and CD8+ (<50 × 109/L) T-cell counts associated with poor CMV-specific immunity at 3 months after HSCT. More recently a milestone of CD4+ immune recovery (50 × 109/L) at day 100 has been demonstrated to protect from the excess mortality associated with reactivation of adenovirus.
      As discussed previously, reactivation of viral infections can be prevented and treated with a variety of antiviral medications. However, viruses can acquire clinical and genetic resistance to these drugs, which additionally are expensive, highly toxic and may require daily intravenous infusion. Acquired viral infections that are potentially lethal in the post-HSCT setting are primarily respiratory in nature and include parainfluenza, influenza virus, respiratory syncytial virus and most recently Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2_. Although there are antiviral agents potentially active for some of these, their efficacy is lower in immune-compromised hosts. These therapeutic hurdles have increased the interest in an immunotherapeutic approach to treat both acquired and latent viral disorders in the post-HSCT setting.
      Summary: Identification of those HSCT recipients who are at the greatest risk of morbidity and mortality related to viral infections should be based on established factors, including pre-transplant infections, transplant type and milestones of immune reconstitution such as CD4 T cell counts. This will allow for risk-stratified approaches to the prevention and management of these infections, including identifying HSCT recipients for whom alternative therapies including adoptive T-cell therapy may be needed.

      Adoptive therapy with viral-specific T cells for refractory infections

      The initial adoptive T-cell therapy based on non-specific donor-derived lymphocyte infusions showed promising results in restoring anti-viral immunity. [
      • Papadopoulos EB
      • Ladanyi M
      • Emanuel D
      • et al.
      Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.
      ] However, relative high frequencies of alloreactive T cells in donor-derived lymphocyte infusions resulted in a significant incidence of GVHD [
      • Kolb HJ
      • Mittermüller J
      • Clemm C
      • et al.
      Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.
      ]. Adoptive transfer of virus-specific cytotoxic T cells (VSTs) is a safe and potentially effective method for providing viral-specific immunity in patients following HSCT (Table 1). More than 20 years ago, it was demonstrated that adoptively transferred CMV specific T-cell clones could restore CMV-specific immunity in HSCT recipients [
      • 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.
      ]. At around the same time, it was demonstrated that gene-marked EBV-specific cytotoxic T cells generated from HSCT donors could persist long term and prevent, as well as eradicate, EBV PTLD [
      • Rooney CM
      • Smith CA
      • Ng CY
      • et al.
      Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.
      ]. Since that time, clinical studies have demonstrated clearance of infection in recipients of HSCT donor-derived viral-specific T cells [
      • 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.
      ,
      • Rooney CM
      • Smith CA
      • Ng CY
      • et al.
      Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.
      ,
      • Einsele H
      • Roosnek E
      • Rufer N
      • et al.
      Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy.
      ,
      • Feuchtinger T
      • Opherk K
      • Bethge WA
      • 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.
      ,
      • Neuenhahn M
      • Albrecht J
      • Odendahl 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.
      ,
      • Peggs KS
      • Verfuerth S
      • Pizzey A
      • et al.
      Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.
      ,
      • Walter EA
      • Greenberg PD
      • Gilbert MJ
      • et al.
      Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor.
      ,
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      ,
      • Haque T
      • Wilkie GM
      • Jones MM
      • et al.
      Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.
      ,
      • Heslop HE
      • Slobod KS
      • Pule MA
      • et al.
      Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.
      ,
      • Icheva V
      • Kayser S
      • Wolff D
      • 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.
      ,
      • Merlo A
      • Turrini R
      • Dolcetti R
      • Zanovello P
      • Amadori A
      • Rosato A.
      Adoptive cell therapy against EBV-related malignancies: a survey of clinical results.
      ,
      • Rooney CM
      • Smith CA
      • Ng CYC
      • et al.
      Use of gene-modified virus-specific t-lymphocytes to control Epstein-Barr-virus-related lymphoproliferation.
      ]. Limitations of the early studies included concerns around lengthy production methods, the use of viral vectors for transduction, difficulty in generating T-cell lines from seronegative donors and an inability to control the viral epitope/HLA allele combination recognized by each T-cell line. These limitations were initially addressed by more rapid and GMP-compliant methodologies such as the use of HLA class I/peptide multimer cell sorting [
      • Cobbold M
      • Khan N
      • Pourgheysari B
      • et al.
      Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers.
      ,
      • Schmitt A
      • Tonn T
      • Busch DH
      • 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.
      ] and interferon-γ capture assays [
      • Feucht J
      • Opherk K
      • Lang P
      • et al.
      Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.
      ,
      • Moosmann A
      • Bigalke I
      • Tischer J
      • et al.
      Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells.
      ,
      • Peggs KS
      • Thomson K
      • Samuel E
      • et al.
      Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation.
      ]. Although the former approach allows selection of CD8+ antigen-specific T cells only, the latter strategies offer the advantage of enriching for both CD8+ and CD4+ T cells needed for long-lasting immune surveillance. This is a crucial point when fighting some pathogens, such as adenoviruses, that are mainly controlled by CD4+ cytotoxic T cells.
      Table 1Virus-specific T cells derived from HSCT donors.
      StudyTargetResults
      Riddell et al.
      • 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.
      CMVProphylactic treatment of viremia and pneumonia in 3 of 3 patients
      Einsele et al.
      • Einsele H
      • Roosnek E
      • Rufer N
      • et al.
      Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy.
      CMV5 of 7 patients cleared CMV infection
      Feuchtinger et al.
      • Feuchtinger T
      • Opherk K
      • Bethge WA
      • 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.
      CMV15 of 18 patients cleared CMV infection or CMV burden significantly reduced
      Neuenhahn et al.
      • Neuenhahn M
      • Albrecht J
      • Odendahl 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.
      CMVCMV epitope-specific T cells detectable in all treated patients. 62.5% complete and 25% partial virological response rates.
      Peggs et al.
      • Peggs KS
      • Verfuerth S
      • Pizzey A
      • et al.
      Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.
      CMV14 of 16 patients did not develop viral reactivation post-infusion, CMV immunity restored
      Walter et al.
      • Walter EA
      • Greenberg PD
      • Gilbert MJ
      • et al.
      Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor.
      CMVPrevention of CMV infection in 11 of 11 patients, CMV immunity restored
      Cobbold et al.
      • Cobbold M
      • Khan N
      • Pourgheysari B
      • et al.
      Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers.
      CMV8 of 9 patients cleared infection
      Schmitt et al.
      • Schmitt A
      • Tonn T
      • Busch DH
      • 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.
      CMV2 of 2 patients cleared CMV
      Peggs et al.
      • Peggs KS
      • Thomson K
      • Samuel E
      • et al.
      Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation.
      CMV2 of 11 patients treated pre-emptively required no antiviral drug treatment. None of 7 patients treated prophylactically required antiviral drug therapy within the next 6 months.
      Fabrizio et al.

      Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5(2):496-503.

      CMVResponders (CR, PR) 17/25 HSCT, 40/76 third-party, 3/3 both
      Rooney et al.
      • Rooney CM
      • Smith CA
      • Ng CY
      • et al.
      Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.
      EBVNone of 39 patients who received prophylactic T cells developed PTLD
      Dubrovina et al.
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      EBV13 of 19 patients achieved CR
      Haque et al.
      • Haque T
      • Wilkie GM
      • Jones MM
      • et al.
      Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.
      EBV14 of 33 patients treated with EBV-CTL achieved CR, 3 of 33 achieved PR
      Heslop et al.
      • Heslop HE
      • Slobod KS
      • Pule MA
      • et al.
      Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.
      EBV11 of 13 patients treated for EBV-PTLD achieved CR. None of the patients treated prophylactically developed PTLD
      Icheva et al.
      • Icheva V
      • Kayser S
      • Wolff D
      • 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.
      EBV7 of 10 patients had clinical and virological response
      Rooney et al.
      • Rooney CM
      • Smith CA
      • Ng CYC
      • et al.
      Use of gene-modified virus-specific t-lymphocytes to control Epstein-Barr-virus-related lymphoproliferation.
      EBV3 of 3 patients cleared CMV. Prevention of CMV infection in 7 of 7 patients
      Moosmann et al.
      • Moosmann A
      • Bigalke I
      • Tischer J
      • et al.
      Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells.
      EBV3 of 6 patients with PTLD achieved CR
      Feucht et al.
      • Leen AM
      • Christin A
      • Myers GD
      • 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.
      AdV5 of 6 patients had durable clearance/decrease of viral copies
      Feuchinger et al.
      • Feuchtinger T
      • Matthes-Martin S
      • Richard C
      • et al.
      Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation.
      AdV18 of 30 patients had CR, 4 of 30 patients had PR.
      Gerdemann et al.
      • Gerdemann U
      • Katari UL
      • Papadopoulou A
      • 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.
      CMV, EBV, AdV8 of 10 patients with CR, including patients with dual infections
      Leen et al.
      • Leen AM
      • Christin A
      • Myers GD
      • 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.
      CMV, EBV, AdV11 of 13 patients with CR
      Leen et al.
      • Leen AM
      • Christin A
      • Myers GD
      • 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.
      EBV, AdVNone of 13 patients developed PTLD. 2 of 2 patients had resolution of AdV infection
      Ma et al.
      • Ma CK
      • Blyth E
      • Clancy L
      • et al.
      Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immotherunapy in patients undergoing allogeneic hematopoietic stem cell transplantation.
      CMV, EBV, AdV, VZV6 of 10 patients with CMV reactivation, no EBV, AdV or VZV disease
      AdV, adenovirus; CMV, cytomegalovirus; CR, complete response; EBV, Epstein–Barr virus; HSCT, hematopoietic stem cell transplant; PR, partial response; PTLD, post-transplant lymphoproliferative disorder; VZV, varicella-zoster virus.
      In one first study using adoptive transfer of adenovirus (AdV)-specific T cells, 9 children with systemic AdV infection after HSCT were successfully treated with IFN-γ–secreting cells [
      • Feuchtinger T
      • Matthes-Martin S
      • Richard C
      • et al.
      Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation.
      ]. This study also showed that even low numbers of adoptively transferred T cells induced AdV-specific T responses and resulted in decreased viral load [
      • Feuchtinger T
      • Matthes-Martin S
      • Richard C
      • et al.
      Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation.
      ]. In a further clinical trial, 30 patients with AdV disease or viremia were treated with hexon-specific T cells, and 86% of patients had complete clearance of viremia without relevant side effects [
      • Feucht J
      • Opherk K
      • Lang P
      • et al.
      Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.
      ]. In addition, in multiple studies, HLA mismatch between the transplant donor-derived viral-specific T cells and the recipient did not increase the incidence of GVHD [
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      ,
      • Heslop HE
      • Slobod KS
      • Pule MA
      • et al.
      Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.
      ,
      • Perruccio K
      • Tosti A
      • Burchielli E
      • et al.
      Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.
      ,
      • Gerdemann U
      • Katari UL
      • Papadopoulou A
      • 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.
      ,
      • Leen AM
      • Myers GD
      • Sili U
      • et al.
      Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals.
      ,
      • Leen AM
      • Christin A
      • Myers GD
      • 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.
      ,
      • Vickers MA
      • Wilkie GM
      • Robinson N
      • 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.
      ]. However, the limitation that T cells generated from an HLA nonidentical donor could recognize virally infected cells through an HLA allele not shared by the recipient and thus be ineffective in the recognizing recipient infected targets was demonstrated. [
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      ]
      Subsequently, to decrease the cost and time required to generate a separate T-cell line for each virus of interest, methods were established to simultaneously generate cell lines with activity against multiple viruses. The first adoptive transfer of multi-virus–specific T-cells provided long-term immunity and clearance of infection in 11 patients with CMV, EBV or AdV infection [
      • Leen AM
      • Myers GD
      • Sili U
      • et al.
      Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals.
      ]. Another study showed that EBV- and AdV-specific T cells efficiently reconstituted antiviral immunity after HSCT without causing toxicity or inducing GVHD [
      • Leen AM
      • Christin A
      • Myers GD
      • 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.
      ]. The addition of VZV specificity to CMV, EBV and AdV tri-specific T cells in patients undergoing allogeneic HSCT did not cause VZV reactivation, although longer follow-up is required to determine efficacy of VZV-specific T cells in the prophylaxis of VZV infection [
      • Ma CK
      • Blyth E
      • Clancy L
      • et al.
      Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immotherunapy in patients undergoing allogeneic hematopoietic stem cell transplantation.
      ]. There is now interest in developing an armamentarium of viral-specific T cells targeting both latent and acquired viruses including HHV-6, VZV, RSV, influenza and even severe acute respiratory syndrome coronavirus 2 [
      • Keller MD
      • Harris KM
      • Jensen-Wachspress MA
      • et al.
      SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.
      ,
      • Keller MD
      • Bollard CM.
      Virus-specific T-cell therapies for patients with primary immune deficiency.
      ]. Despite these promising results, concerns about the ability to generate T-cell lines with balanced antiviral composition due to antigenic competition (e.g., a predominance of CMV-specific T cells) remain [
      • Gerdemann U
      • Keirnan JM
      • Katari UL
      • et al.
      Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.
      ,
      • Roubalova K
      • Nemeckova S
      • Krystofova J
      • Hainz P
      • Pumannova M
      • Hamsikova E.
      Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients.
      ].
      Overall, the efficacy of adoptively transferred VSTs for viral infections in HSCT recipients has been greater than 70% [
      • Bollard CM
      • Heslop HE.
      T cells for viral infections after allogeneic hematopoietic stem cell transplant.
      ]. The toxicity associated with this therapy has been limited to an expected incidence of GVHD with no graft rejection, neurologic toxicity or cytokine release syndrome. Recipient factors may be critical to maximizing responses. As many HSCT recipients are receiving calcineurin inhibitors (CIs) for the prevention of GVHD at the time of adoptive T-cell therapy, viral-specific T cells resistant to the inhibitory effects of CIs or steroids are being evaluated [
      • Amini L
      • Wagner DL
      • Rössler U
      • et al.
      CRISPR-Cas9-edited tacrolimus-resistant antiviral T cells for advanced adoptive immunotherapy in transplant recipients.
      ]. However, in studies for treatment of EBV-PTLD responses are not impaired by concomitant CI therapy [
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      ]. In contrast, a minimal level of CD4 immune reconstitution (CD4 >50/μL) was associated with a greater response rate to adoptively transferred CMV specific VSTs [

      Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5(2):496-503.

      ].
      Summary: Emerging data support the safety and efficacy of adoptive therapy with T cells specific for either single or multiple viruses in preventing and treating infections in the post HSCT period. Logistical issues can limit the generation of HSCT donor-derived VSTs.

      Third-party off-the-shelf T-cell therapy may be effective in HSCT recipients

      The generation and adoptive transfer of stem cell donor–derived VSTs for each patient is not always feasible due to challenges with manufacturing, production complexity, time and cost. Donor-derived VSTs are also challenging to generate if the donor is not immune, as in the case of cord blood donors and virus-naïve donors. In addition, in the HLA-disparate HSCT setting, if the infected cells are of host origin, VSTs of donor origin may be restricted for recognition through an HLA allele not shared by the recipient and thus ineffective. These limitations can be circumvented with the use of off-the-shelf products. An early demonstration of this approach was a pivotal multi-center phase 2 clinical trial, 33 recipients of solid-organ transplant with progressive PTLD received EBV-specific T cells generated from partially HLA-matched unrelated donors. The response rate in these patients was striking, achieving 64% response at 5 weeks, although it decreased to 52% at 6 months [
      • Haque T
      • Wilkie GM
      • Jones MM
      • et al.
      Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial.
      ]. Subsequent phase 2 clinical trials have demonstrated safety and efficacy of banked VSTs in treatment of severe and drug-refractory infections after HSCT [
      • Withers B
      • Blyth E
      • Clancy LE
      • et al.
      Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells.
      ,
      • Leen AM
      • Bollard CM
      • Mendizabal AM
      • et al.
      Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.
      ,
      • Prockop S
      • Doubrovina E
      • Baroudy K
      • et al.
      Banked EBV-specific T-cells from HLA-partially matched normal donors to induce durable remissions of rituximab refractory EBV+ B-cell lymphomas post hematopoietic and organ allografts.
      ], including those caused by BKV and HHV-6 [
      • Tzannou I
      • Papadopoulou A
      • Naik S
      • 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.
      ]. Although most of the publications describe a relatively small number of patients, the emerging efficacy and safety data are similar to those reported with HSCT donor-derived products (Table 2). Thus, there is expanding experience to demonstrate that banked, VSTs generated from HLA-.partially matched healthy virus-immune donors can safely treat severe viral infections after HSCT [
      • Vickers MA
      • Wilkie GM
      • Robinson N
      • 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.
      ,
      • Leen AM
      • Bollard CM
      • Mendizabal AM
      • et al.
      Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.
      ,
      • Prockop S
      • Doubrovina E
      • Baroudy K
      • et al.
      Banked EBV-specific T-cells from HLA-partially matched normal donors to induce durable remissions of rituximab refractory EBV+ B-cell lymphomas post hematopoietic and organ allografts.
      ,
      • Tzannou I
      • Papadopoulou A
      • Naik S
      • 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.
      ,
      • O'Reilly RJ
      • Prockop S
      • Hasan AN
      • Koehne G
      • Doubrovina E.
      Virus-specific T-cell banks for 'off the shelf' adoptive therapy of refractory infections.
      ,
      • Prockop S
      • Doubrovina E
      • Rodriguez-Sanchez I
      • et al.
      Adoptive T-cell therapy with 3rd party CMV-pp65-specific CTLs for CMV viremia and disease arising after allogeneic hematopoietic stem cell transplant.
      • Nelson AS
      • Heyenbruch D
      • Rubinstein JD
      • et al.
      Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.
      ]. As these off-the-shelf cellular products are allogeneic to the recipient and HSCT donor, they are not expected to persist long term, albeit they have been found to induce long-lasting clinical responses [
      • Withers B
      • Blyth E
      • Clancy LE
      • et al.
      Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells.
      ,
      • Haque T
      • Amlot PL
      • Helling N
      • et al.
      Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients.
      ], possibly through a bystander stimulation of endogenous immunity [

      Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5(2):496-503.

      ,
      • Arasaratnam RJ
      • Tzannou I
      • Gray T
      • et al.
      Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.
      ,
      • Bollard CM
      • Gottschalk S
      • Torrano V
      • et al.
      Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.
      ].
      Table 2Third-party–derived virus-specific T cells.
      StudyTargetResults
      Fabrizio et al.

      Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5(2):496-503.

      CMVResponders (CR, PR) 17/25 HSCT, 40/76 third-party, 3/3 both
      Prockop et al.
      • Nelson AS
      • Heyenbruch D
      • Rubinstein JD
      • et al.
      Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.
      CMV18 of 50 patients had CR, 14 had PR
      Vickers et al.
      • Vickers MA
      • Wilkie GM
      • Robinson N
      • 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.
      EBV8 of 10 patients with PTLD achieved CR
      Prockop et al.
      • Prockop S
      • Doubrovina E
      • Rodriguez-Sanchez I
      • et al.
      Adoptive T-cell therapy with 3rd party CMV-pp65-specific CTLs for CMV viremia and disease arising after allogeneic hematopoietic stem cell transplant.
      EBV19 of 34 patients achieved CR, 3 PR
      Bollard et al.
      • Scheinberg P
      • Melenhorst JJ
      • Brenchley JM
      • et al.
      The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor.
      EBV11 of 21 patients achieved CR, 2 PR (1 CR)
      Withers et al.
      • Withers B
      • Blyth E
      • Clancy LE
      • et al.
      Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells.
      CMV, EBV, AdV23 of 30 patients achieved CR, 5 of 30 PR
      Leen et al.
      • Leen AM
      • Bollard CM
      • Mendizabal AM
      • et al.
      Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.
      CMV, EBV, AdVCMV: 9 of 17 achieved CR, 8 of 17 PR

      EBV: 3 of 9 achieved CR, 3 of 9 PR

      AdV: 7 of 17 achieved CR, 7 of 17 PR
      Gottlieb et al.
      • Gottlieb DJ
      • Clancy LE
      • Withers B
      • et al.
      Prophylactic antigen-specific T-cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant.
      CMV, EBV, AdV23/25 patients had complete viral clearance of the infection, 2 had a partial viral response.
      AdV, adenovirus; CMV, cytomegalovirus; CR, complete response; EBV, Epstein–Barr virus; HSCT, hematopoietic stem cell transplant; PR, partial response.
      Summary: Well-characterized third-party virus-specific T cells can be successfully used to treat viral infections and virus-induced malignancies after HSCT.

      Next steps in adoptive therapy with viral-specific T cells

      The currently available data are derived from heterogeneous studies conducted in different clinical contexts; therefore, optimal dosing and administration schedules for VSTs are not known. Nonetheless, even when doses as low as 4.1 × 103/kg have been administered, clinical responses have been achieved [
      • Feucht J
      • Opherk K
      • Lang P
      • et al.
      Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.
      ]. An important point that should be considered is that efficacy partly depends on in vivo expansion, and that memory cells have a greater potential for expansion than terminally differentiated T cells [
      • Scheinberg P
      • Melenhorst JJ
      • Brenchley JM
      • et al.
      The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor.
      ]; thus, selection of this subset may improve the efficiency of the product. To date, most trials exploring the use of adoptively transferred viral-specific T cells have been in second or later line of therapy after failure of antiviral drugs. Despite issues of feasibility and the potential for failure due to viral recognition through a non-shared HLA allele in the HLA-disparate setting, HSCT donor-derived viral-specific T cells have demonstrated benefit for refractory infections as well as for prophylaxis and first-line treatment. Infusion of third-party derived partially HLA-matched VSTs have demonstrated benefit in the refractory setting but could be considered as a first-line therapy or even prophylactically in high-risk patients with predicted intolerance to antiviral medications due to organ dysfunction. Preliminary feasibility, safety and efficacy of allogeneic, off-the-shelf, multi-virus–specific T-cell therapy as first-line therapy [
      • Gottlieb D
      • Jiang W
      • Avdic S
      • et al.
      Administration of third-party virus-specific t-cells (VST) at the time of initial therapy for infection after haemopoietic stem cell transplant is safe and associated with favourable clinical outcomes (the R3ACT-Quickly trial).
      ] and as prophylaxis [
      • Gottlieb DJ
      • Clancy LE
      • Withers B
      • et al.
      Prophylactic antigen-specific T-cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant.
      ] has been demonstrated and is currently being explored in trials with commercial products such as Atara's Tabelecleucel and AlloVir's Viralym-M and ALVR106.
      Summary: Pivotal late-phase studies are necessary to confirm the suitability of adoptive third-party viral specific T-cell therapy as prophylaxis and first-line treatment of severe and life-threatening viral infections.

      Determining the clinical benefit and durability of responses to adoptive virus-specific T-cell therapies

      While multiple studies demonstrate responses to adoptive VST treatment, the clinical benefit of these responses and their durability have not been uniformly assessed. For instance, although the assessment of complete response of viremia has been standard, assessment of invasive viral disease (e.g., CMV enteritis) has varied, as some trials required re-biopsy and others required determination of clinical resolution. Similarly, there have not been standard criteria applied for determination of partial responses (PRs), with viremia PR from a 50% decrease in the viral load [
      • Leen AM
      • Bollard CM
      • Mendizabal AM
      • et al.
      Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation.
      ,
      • Tzannou I
      • Papadopoulou A
      • Naik S
      • 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.
      ] to a 1-log [
      • Naik S
      • Nicholas SK
      • Martinez CA
      • et al.
      Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes.
      ] or 2-log [
      • Nelson AS
      • Heyenbruch D
      • Rubinstein JD
      • et al.
      Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.
      ] decrease. Although there are no standards, it is important to note that the approval by the Food and Drug Administration of maribavir included the definition of a PR as a 1-log decrease in CMV viremia. In this scenario, we would like to emphasize the potential clinically significant importance of PR, especially in infections refractory to other treatments, as it could reflect durable control and be a bridge to or stimulate eventual immune recovery post-HSCT. The achievement of PR may also prevent greater health care use, like hospitalization and intensive care unit admission. Studies are needed to further address established criteria for response assessment.
      Summary: Standard definitions of complete responses and PRs are needed for clinical trials of adoptive virus-specific T-cell therapies to allow meaningful assessment of clinical benefit and comparisons across studies.

      Expanding applicability and accessibility

      Current approaches to expand the efficacy of adoptive T-cell therapies for infections in immune-compromised hosts include (i) targeting a wider array of viral and non-viral (e.g., fungal) infections; (ii) generating T cells for adoptive therapy that are resistant to immunosuppressive medications that patients are frequently on and (iii) combination therapy to improve antigen presentation by and/or T-cell recognition of the target [
      • Dalton T
      • Doubrovina E
      • Pankov D
      • et al.
      Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy.
      ,
      • Li G
      • Tang L
      • Hou C
      • et al.
      Peripheral injection of Tim-3 antibody attenuates VSV encephalitis by enhancing MHC-I presentation.
      ]. Studies have shown that immunosuppressive therapy used in the prevention and treatment of GVHD inhibits T-cell activation. While in prospective clinical trials it has not been demonstrated that immunosuppressive agents significantly impair responses to adoptively transferred VSTs [
      • Doubrovina E
      • Oflaz-Sozmen B
      • Prockop SE
      • et al.
      Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.
      ,
      • Prockop S
      • Doubrovina E
      • Baroudy K
      • et al.
      Banked EBV-specific T-cells from HLA-partially matched normal donors to induce durable remissions of rituximab refractory EBV+ B-cell lymphomas post hematopoietic and organ allografts.
      ], patients requiring high doses of glucocorticoids are typically excluded from these clinical trials. To overcome these challenges, genetic modification of VSTs to render them resistant to glucocorticoid [
      • Menger L
      • Gouble A
      • Marzolini MA
      • et al.
      TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells.
      ] or calcineurin inhibitors [
      • Ricciardelli I
      • Brewin J
      • Lugthart G
      • Albon SJ
      • Pule M
      • Amrolia PJ.
      Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy.
      ,
      • De Angelis B
      • Dotti G
      • Quintarelli C
      • et al.
      Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506).
      ] or modifications which interfere with expression of PD-1 have been introduced in the VSTs [
      • Su S
      • Zou Z
      • Chen F
      • et al.
      CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer.
      ]. The introduction of safety switch technology in the field of adoptive T-cell therapy may improve the safety of cell-based therapies [
      • Straathof KC
      • Pule MA
      • Yotnda P
      • et al.
      An inducible caspase 9 safety switch for T-cell therapy.
      ]. For example, targeting epidermal growth factor receptor with monoclonal antibody (cetuximab) may regulate the survival of chimeric antigen receptor-modified T cells, thus further improving the safety of adoptive T-cell therapy [
      • Paszkiewicz PJ
      • Frassle SP
      • Srivastava S
      • et al.
      Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia.
      ].
      Summary: Current efforts are expanding applicability and accessibility of adoptive virus-specific T cell therapies to a broader number of targets in a broader number of patients.

      Conclusions

      Despite recent advances in the field of HSCT, viral infections remain a frequent cause of morbidity and mortality among HSCT recipients. Adoptive transfer of VSTs has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pre-transplant clinical criteria but milestones of immune reconstitution as well. These factors can better identify those at greatest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral-specific T cells should be considered for either prophylaxis, first-line or second-line treatment early after inadequate response to first-line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation is challenging in regions in which commercial polymerase chain reaction assays are not widely available and in-house assays may have different thresholds and be difficult to compare. In addition, for those HSCT recipients requiring therapy, there is limited access to antivirals including foscarnet, cidofovir and even rituximab [
      • Gale RP
      • Seber A
      • Bonfim C
      • Pasquini M.
      Haematopoietic cell transplants in Latin America.
      ], much less adoptive T-cell therapies.
      It is essential to systematically address both manufacturing and clinical challenges to improve T-cell therapy not only for patients following allo-HSCT but also for other at-risk immune-compromised populations. In this regard, the use of virus-specific T cells has been successfully applied in the setting of primary immune deficiencies [
      • Naik S
      • Nicholas SK
      • Martinez CA
      • et al.
      Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes.
      ,
      • Ciccocioppo R
      • Comoli P
      • Gallia A
      • Basso S
      • Baldanti F
      • Corazza GR.
      Autologous human cytomegalovirus-specific cytotoxic T cells as rescue therapy for ulcerative enteritis in primary immunodeficiency.
      ], where virus-specific T cells were obtained either from the patient or from HLA-partially matched family or third-party donors. The growing availability of GMP facilities, although mainly in Western countries, and the rapid advancements in technology and cell manipulation may favor the rapid adoption of this treatment strategy, while eventually leading to improvement of patient outcomes and quality of life.

      Conflicts of Interest

      JJB reported consulting for Avrobio, BlueRock, Race Oncology, Advanced Clinical, Omeros, Sanofi, Medexus, Equillium, Sobi. AA served on the safety monitoring committee for Sangamo Therapeutics and has no financial interest in the development of gene therapies. SP received support for the conduct of clinical trials through MSK from AlloVir, Atara and Jasper; inventor of IP related to third-party viral specific T cells program with all rights assigned to MSK. CB reported consulting for Zodiac, Amgen and Novartis. SC reported royalties, consulting and shares for ExCellThera. DP reported honoraria paid to Fiona Stanley Hospital from Novartis, Gilead, BMS-Celgene and Jazz. AS reported consulting for Spotlight Therapeutics, Medexus Inc and Vertex Pharmaceuticals; research funding from CRISPR Therapeutics Research; collaboration with Magenta Therapeutics; honoraria from Vindico Medical Education; and Clinical Trial site-PI for CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis and Magenta.

      Funding

      No funding was received.

      Author Contributions

      All authors contributed to the content and reviewed the final version of this manuscript.

      References

        • Majhail NS
        • Farnia SH
        • Carpenter PA
        • et al.
        Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation.
        Biol Blood Marrow Transplant. 2015; 21: 1863-1869
        • Aschan J.
        Risk assessment in haematopoietic stem cell transplantation: conditioning.
        Best Pract Res Clin Haematol. 2007; 20: 295-310
        • Fraser CJ
        • Scott Baker K
        The management and outcome of chronic graft-versus-host disease.
        Br J Haematol. 2007; 138: 131-145
        • Leather HL
        • Wingard JR.
        Infections following hematopoietic stem cell transplantation.
        Infect Dis Clin North Am. 2001; 15: 483-520
        • Hill JA
        • Li D
        • Hay KA
        • et al.
        Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunPeriodicalapy.
        Blood. 2018; 131: 121-130
        • Ogonek J
        • Kralj Juric M
        • Ghimire S
        • et al.
        Immune reconstitution after allogeneic hematopoietic stem cell transplantation.
        Front Immunol. 2016; 7: 507
        • Miller HK
        • Braun TM
        • Stillwell T
        • et al.
        Infectious risk after allogeneic hematopoietic cell transplantation complicated by acute graft-versus-host disease.
        Biol Blood Marrow Transplant. 2017; 23: 522-528
        • Tomblyn M
        • Chiller T
        • Einsele H
        • et al.
        Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.
        Biol Blood Marrow Transplant. 2009; 15: 1143-1238
        • Booth C
        • Veys P.
        T cell depletion in paediatric stem cell transplantation.
        Clin Exp Immunol. 2013; 172
        • Young JH
        • Logan BR
        • Wu J
        • et al.
        Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors.
        Biol Blood Marrow Transplant. 2016; 22: 359-370
        • Admiraal R
        • de Koning CCH
        • Lindemans CA
        • et al.
        Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation.
        J Allergy Clin Immunol. 2017; 140 (e9): 1643-1650
        • Admiraal R
        • Lindemans CA
        • van Kesteren C
        • et al.
        Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation.
        Blood. 2016; 128: 2734-2741
        • Chiu YF
        • Sugden B.
        Epstein-Barr virus: the path from latent to productive infection.
        Annu Rev Virol. 2016; 3: 359-372
        • Jarvis MA
        • Nelson JA.
        Human cytomegalovirus persistence and latency in endothelial cells and macrophages.
        Curr Opin Microbiol. 2002; 5: 403-407
        • Murata T
        • Tsurumi T.
        Switching of EBV cycles between latent and lytic states.
        Rev Med Virol. 2014; 24: 142-153
        • Vogl BA
        • Fagin U
        • Nerbas L
        • Schlenke P
        • Lamprecht P
        • Jabs WJ.
        Longitudinal analysis of frequency and reactivity of Epstein-Barr virus-specific T lymphocytes and their association with intermittent viral reactivation.
        J Med Virol. 2012; 84: 119-131
        • Ljungman P
        • Boeckh M
        • Hirsch HH
        • et al.
        Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.
        Clin Infect Dis. 2017; 64: 87-91
        • Wingard JR
        • Hsu J
        • Hiemenz JW.
        Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology.
        Infect Dis Clin North Am. 2010; 24: 257-272
        • Gluckman E
        • Lotsberg J
        • Devergie A
        • et al.
        [Use of acyclovir in the prevention of herpes infections after allogenic bone marrow grafts].
        Rev Fr Transfus Immunohematol. 1984; 27 (Utilisation de l'acyclovir dans la prevention des infections herpetiques apres greffe de moelle osseuse allogenique): 391-396
        • Warkentin DI
        • Epstein JB
        • Campbell LM
        • et al.
        Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients.
        Ann Pharmacother. 2002; 36: 1525-1531
        • Ljungman P.
        Prevention and treatment of viral infections in stem cell transplant recipients.
        Br J Haematol. 2002; 118: 44-57
        • Boeckh M
        • Kim HW
        • Flowers ME
        • Meyers JD
        • Bowden RA.
        Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantationࣧa randomized double-blind placebo-controlled study.
        Blood. 2006; 107: 1800-1805
        • Shepp DH
        • Dandliker PS
        • Meyers JD.
        Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine.
        N Engl J Med. 1986; 314: 208-212
        • Oshima K
        • Takahashi T
        • Mori T
        • et al.
        One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group.
        Transpl Infect Dis. 2010; 12: 421-427
        • Marin M
        • Guris D
        • Chaves SS
        • et al.
        Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2007; 56: 1-40
        • Hata A
        • Asanuma H
        • Rinki M
        • et al.
        Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants.
        N Engl J Med. 2002; 347: 26-34
        • Baumrin E
        • Izaguirre NE
        • Bausk B
        • et al.
        Safety and reactogenicity of the recombinant zoster vaccine after allogeneic hematopoietic cell transplantation.
        Blood Adv. 23 2021; 5: 1585-1593
        • Wainwright MS
        • Martin PL
        • Morse RP
        • et al.
        Human herpesvirus 6 limbic encephalitis after stem cell transplantation.
        Ann Neurol. 2001; 50: 612-619
        • Zerr DM
        • Boeckh M
        • Delaney C
        • et al.
        HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation.
        Biol Blood Marrow Transplant. 2012; 18: 1700-1708
        • Zerr DM
        • Corey L
        • Kim HW
        • Huang ML
        • Nguy L
        • Boeckh M.
        Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation.
        Clin Infect Dis. 2005; 40: 932-940
        • Drobyski WR
        • Dunne WM
        • Burd EM
        • et al.
        Human herpesvirus-6 (HHV-6) infection in allogeneic bone marrow transplant recipients: evidence of a marrow-suppressive role for HHV-6 in vivo.
        J Infect Dis. 1993; 167: 735-739
        • Ogata M.
        [Human herpesvirus-6 encephalitis in allogeneic hematopoietic stem cell transplantation].
        Brain Nerve. 2015; 67: 919-930
        • Zerr DM
        • Gupta D
        • Huang ML
        • Carter R
        • Corey L.
        Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients.
        Clin Infect Dis. 2002; 34: 309-317
        • Teira P
        • Battiwalla M
        • Ramanathan 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
        • Einsele H
        • Ljungman P
        • Boeckh M.
        How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.
        Blood. 2020; 135 (05/07/2020)
        • Goodrich JM
        • Bowden RA
        • Fisher L
        • Keller C
        • Schoch G
        • Meyers JD.
        Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant.
        Ann Intern Med. 1993; 118: 173-178
        • Prentice HG
        • Gluckman E
        • Powles RL
        • et al.
        Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group.
        Lancet. 1994; 343: 749-753
        • Ljungman P
        • de La Camara R
        • Milpied N
        • et al.
        Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants.
        Blood. 2002; 99: 3050-3056
        • Ljungman P
        • de la Camara R
        • Cordonnier C
        • et al.
        Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT.
        Bone Marrow Transplant. 2008; 42: 227-240
        • Einsele H
        • Reusser P
        • Bornhauser M
        • et al.
        Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation.
        Blood. 2006; 107: 3002-3008
        • van der Heiden PL
        • Kalpoe JS
        • Barge RM
        • Willemze R
        • Kroes AC
        • Schippers EF.
        Oral valganciclovir as pre-emptive therapy has similar efficacy on cytomegalovirus DNA load reduction as intravenous ganciclovir in allogeneic stem cell transplantation recipients.
        Bone Marrow Transplant. 2006; 37: 693-698
        • Bacigalupo A
        • Boyd A
        • Slipper J
        • Curtis J
        • Clissold S.
        Foscarnet in the management of cytomegalovirus infections in hematopoietic stem cell transplant patients.
        Expert Rev Anti Infect Ther. 2012; 10: 1249-1264
        • Ljungman P
        • Deliliers GL
        • Platzbecker U
        • 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: 388-392
        • Reddy N
        • Rezvani K
        • Barrett AJ
        • Savani BN.
        Strategies to prevent EBV reactivation and posttransplant lymphoproliferative disorders (PTLD) after allogeneic stem cell transplantation in high-risk patients.
        Biol Blood Marrow Transplant. 2011; 17: 591-597
        • Xuan L
        • Jiang X
        • Sun J
        • et al.
        Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.
        Transplantation. 2013; 96: 560-566
        • Darenkov IA
        • Marcarelli MA
        • Basadonna GP
        • et al.
        Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.
        Transplantation. 1997; 64: 848-852
        • Kuehnle I
        • Huls MH
        • Liu Z
        • et al.
        CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation.
        Blood. 2000; 95: 1502-1505
        • van Esser JW
        • Niesters HG
        • van der Holt B
        • et al.
        Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation.
        Blood. 2002; 99: 4364-4369
        • Worth A
        • Conyers R
        • Cohen J
        • et al.
        Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation.
        Br J Haematol. 2011; 155: 377-385
        • Flomenberg P
        • Babbitt J
        • Drobyski WR
        • et al.
        Increasing incidence of adenovirus disease in bone marrow transplant recipients.
        J Infect Dis. 1994; 169: 775-781
        • Bordigoni P
        • Carret AS
        • Venard V
        • Witz F
        • Le Faou A
        Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation.
        Clin Infect Dis. 2001; 32: 1290-1297
        • Yusuf U
        • Hale GA
        • Carr J
        • et al.
        Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients.
        Transplantation. 2006; 81: 1398-1404
        • Hiwarkar P
        • Amrolia P
        • Sivaprakasam P
        • et al.
        Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.
        Blood. 2017; 129: 2033-2037
        • George B
        • Pati N
        • Gilroy N
        • et al.
        Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
        Transpl Infect Dis. 2010; 12: 322-329
        • Walker RC
        • Marshall WF
        • Strickler JG
        • et al.
        Pretransplantation assessment of the risk of lymphoproliferative disorder.
        Clin Infect Dis. 1995; 20: 1346-1353
        • Styczynski J
        • van der Velden W
        • Fox CP
        • et al.
        Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation.
        Haematologica. 2016; 101: 803-811
        • Sundin M
        • Le Blanc K
        • Ringdén O
        • et al.
        The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation.
        Haematologica. 2006; 91: 1059-1067
        • Landgren O
        • Gilbert ES
        • Rizzo JD
        • et al.
        Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.
        Blood. 2009; 113: 4992-5001
        • George B
        • Kerridge IH
        • Gilroy N
        • et al.
        A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group.
        Transpl Infect Dis. 2012; 14: 141-148
        • Chiereghin A
        • Prete A
        • Belotti T
        • et al.
        Prospective Epstein-Barr virus-related post-transplant lymphoproliferative disorder prevention program in pediatric allogeneic hematopoietic stem cell transplant: virological monitoring and first-line treatment.
        Transpl Infect Dis. 2016; 18: 44-54
        • Green ML
        • Leisenring W
        • Stachel D
        • et al.
        Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation.
        Biol Blood Marrow Transplant. 2012; 18: 1687-1699
        • Green ML
        • Leisenring W
        • Xie H
        • 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-e127
        • Stern A
        • Su Y
        • Dumke H
        • et al.
        Cytomegalovirus viral load kinetics predict cytomegalovirus end-organ disease and mortality after hematopoietic cell transplant.
        J Infect Dis. 2021; 224: 620-631
        • Uhlin M
        • Wikell H
        • Sundin M
        • et al.
        Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.
        Haematologica. 2014; 99: 346-352
        • Laberko A
        • Bogoyavlenskaya A
        • Shelikhova L
        • et al.
        Risk factors for and the clinical impact of cytomegalovirus and Epstein-Barr virus infections in pediatric recipients of TCR-α/β- and CD19-depleted grafts.
        Biol Blood Marrow Transplant. 2017; 23: 483-490
        • Hakki M
        • Riddell SR
        • Storek J
        • 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
        • Papadopoulos EB
        • Ladanyi M
        • Emanuel D
        • et al.
        Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.
        N Engl J Med. 1994; 330: 1185-1191
        • Kolb HJ
        • Mittermüller J
        • Clemm C
        • et al.
        Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.
        Blood. 1990; 76: 2462-2465
        • 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. 1992; 257: 238-241
        • Rooney CM
        • Smith CA
        • Ng CY
        • 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: 1549-1555
        • Einsele H
        • Roosnek E
        • Rufer N
        • 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
        • Feuchtinger T
        • Opherk K
        • Bethge WA
        • 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
        • Neuenhahn M
        • Albrecht J
        • Odendahl 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; 31: 2161-2171
        • Peggs KS
        • Verfuerth S
        • Pizzey A
        • et al.
        Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.
        Lancet. 25 2003; 362: 1375-1377
        • Walter EA
        • Greenberg PD
        • Gilbert MJ
        • 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
        • Doubrovina E
        • Oflaz-Sozmen B
        • Prockop SE
        • 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
        • Haque T
        • Wilkie GM
        • Jones MM
        • 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
        • Heslop HE
        • Slobod KS
        • Pule MA
        • 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
        • Icheva V
        • Kayser S
        • Wolff D
        • 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
        • Merlo A
        • Turrini R
        • Dolcetti R
        • Zanovello P
        • Amadori A
        • Rosato A.
        Adoptive cell therapy against EBV-related malignancies: a survey of clinical results.
        Expert Opin Biol Ther. 2008; 8: 1265-1294
        • Rooney CM
        • Smith CA
        • Ng CYC
        • et al.
        Use of gene-modified virus-specific t-lymphocytes to control Epstein-Barr-virus-related lymphoproliferation.
        Lancet. 1995; 345: 9-13
        • Cobbold M
        • Khan N
        • Pourgheysari B
        • 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 DH
        • 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
        • Feucht J
        • Opherk K
        • Lang P
        • 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
        • Moosmann A
        • Bigalke I
        • Tischer J
        • et al.
        Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells.
        Blood. 2010; 115: 2960-2970
        • Peggs KS
        • Thomson K
        • Samuel E
        • 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
        • Feuchtinger T
        • Matthes-Martin S
        • Richard C
        • 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
        • Perruccio K
        • Tosti A
        • Burchielli E
        • et al.
        Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.
        Blood. 2005; 106: 4397-4406
        • Gerdemann U
        • Katari UL
        • Papadopoulou A
        • 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
        • Leen AM
        • Myers GD
        • Sili U
        • 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
        • Leen AM
        • Christin A
        • Myers GD
        • 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
        • Vickers MA
        • Wilkie GM
        • Robinson N
        • 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
        • Ma CK
        • Blyth E
        • Clancy L
        • et al.
        Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immotherunapy in patients undergoing allogeneic hematopoietic stem cell transplantation.
        Cytotherapy. 2015; 17: 1406-1420
        • Keller MD
        • Harris KM
        • Jensen-Wachspress MA
        • et al.
        SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.
        Blood. 2020; 12 (136(25)): 2905-2917
        • Keller MD
        • Bollard CM.
        Virus-specific T-cell therapies for patients with primary immune deficiency.
        Blood. 2020; 135: 620-628
        • Gerdemann U
        • Keirnan JM
        • Katari UL
        • et al.
        Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.
        Mol Ther. 2012; 20: 1622-1632
        • Roubalova K
        • Nemeckova S
        • Krystofova J
        • Hainz P
        • Pumannova M
        • Hamsikova E.
        Antigenic competition in the generation of multi-virus-specific cell lines for immunotherapy of human cytomegalovirus, polyomavirus BK, Epstein-Barr virus and adenovirus infection in haematopoietic stem cell transplant recipients.
        Immunol Lett. 2020; 228: 64-69
        • Bollard CM
        • Heslop HE.
        T cells for viral infections after allogeneic hematopoietic stem cell transplant.
        Blood. 2016; 127: 3331-3340
        • Amini L
        • Wagner DL
        • Rössler U
        • et al.
        CRISPR-Cas9-edited tacrolimus-resistant antiviral T cells for advanced adoptive immunotherapy in transplant recipients.
        Mol Ther. 2021; 29: 32-46
      1. Fabrizio VA, Rodriguez-Sanchez MI, Mauguen A, et al. Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses. Blood Adv. 2021;5(2):496-503.

        • Withers B
        • Blyth E
        • Clancy LE
        • 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: 2193-2205
        • Leen AM
        • Bollard CM
        • Mendizabal AM
        • 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
        • Prockop S
        • Doubrovina E
        • Baroudy K
        • et al.
        Banked EBV-specific T-cells from HLA-partially matched normal donors to induce durable remissions of rituximab refractory EBV+ B-cell lymphomas post hematopoietic and organ allografts.
        J Clin Oncol. 2015; 33: 10016
        • Tzannou I
        • Papadopoulou A
        • Naik S
        • 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: 3547-3557
        • O'Reilly RJ
        • Prockop S
        • Hasan AN
        • Koehne G
        • Doubrovina E.
        Virus-specific T-cell banks for 'off the shelf' adoptive therapy of refractory infections.
        Bone Marrow Transplant. 2016; 51: 1163-1172
        • Prockop S
        • Doubrovina E
        • Rodriguez-Sanchez I
        • et al.
        Adoptive T-cell therapy with 3rd party CMV-pp65-specific CTLs for CMV viremia and disease arising after allogeneic hematopoietic stem cell transplant.
        Blood. 2017; : 130
        • Nelson AS
        • Heyenbruch D
        • Rubinstein JD
        • et al.
        Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.
        Blood Adv. 2020; 4: 5745-5754
        • Haque T
        • Amlot PL
        • Helling N
        • et al.
        Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients.
        J Immunol. 1998; 160: 6204-6209
        • Arasaratnam RJ
        • Tzannou I
        • Gray T
        • et al.
        Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.
        Am J Transplant. 2018; 18: 2238-2249
        • Bollard CM
        • Gottschalk S
        • Torrano V
        • et al.
        Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.
        J Clin Oncol. 2014; 32: 798-808
        • Scheinberg P
        • Melenhorst JJ
        • Brenchley JM
        • et al.
        The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor.
        Blood. 2009; 114: 5071-5080
        • Gottlieb D
        • Jiang W
        • Avdic S
        • et al.
        Administration of third-party virus-specific t-cells (VST) at the time of initial therapy for infection after haemopoietic stem cell transplant is safe and associated with favourable clinical outcomes (the R3ACT-Quickly trial).
        Blood. 2019; 134: 251
        • Gottlieb DJ
        • Clancy LE
        • Withers B
        • et al.
        Prophylactic antigen-specific T-cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant.
        Clin Transl Immunol. 2021; 10: e1249
        • Naik S
        • Nicholas SK
        • Martinez CA
        • et al.
        Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes.
        J Allergy Clin Immunol. May 2016; 137 (e1): 1498-1505
        • Dalton T
        • Doubrovina E
        • Pankov D
        • et al.
        Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy.
        Blood. 2020; 135: 1870-1881
        • Li G
        • Tang L
        • Hou C
        • et al.
        Peripheral injection of Tim-3 antibody attenuates VSV encephalitis by enhancing MHC-I presentation.
        Front Immunol. 2021; 12667478
        • Menger L
        • Gouble A
        • Marzolini MA
        • et al.
        TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells.
        Blood. 2015; 126: 2781-2789
        • Ricciardelli I
        • Brewin J
        • Lugthart G
        • Albon SJ
        • Pule M
        • Amrolia PJ.
        Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy.
        Am J Transplant. 2013; 13: 3244-3252
        • De Angelis B
        • Dotti G
        • Quintarelli C
        • et al.
        Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506).
        Blood. 2009; 114: 4784-4791
        • Su S
        • Zou Z
        • Chen F
        • et al.
        CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer.
        Oncoimmunology. 2017; 6e1249558
        • Straathof KC
        • Pule MA
        • Yotnda P
        • et al.
        An inducible caspase 9 safety switch for T-cell therapy.
        Blood. 2005; 105: 4247-4254
        • Paszkiewicz PJ
        • Frassle SP
        • Srivastava S
        • et al.
        Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia.
        J Clin Invest. 2016; 126: 4262-4272
        • Gale RP
        • Seber A
        • Bonfim C
        • Pasquini M.
        Haematopoietic cell transplants in Latin America.
        Bone Marrow Transplant. 2016; 51: 898-905
        • Ciccocioppo R
        • Comoli P
        • Gallia A
        • Basso S
        • Baldanti F
        • Corazza GR.
        Autologous human cytomegalovirus-specific cytotoxic T cells as rescue therapy for ulcerative enteritis in primary immunodeficiency.
        J Clin Immunol. 2014; 34: 681-685