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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Medizinische Klinik und Poliklinik, Abteilung
II, Tübingen, Germany; Division of Immunology and Allergology,
University of Geneva, Switzerland; National Center for Competence and
Research Molecular Oncology, Swiss Institut for Experimental Cancer
Research, Epalinges, Switzerland; Abteilung Medizinische Virologie und
Epidemiologie der Viruskrankheiten, Tübingen, Germany; and
Institut für Zellbiologie Universität Tübingen,
Germany.
We adoptively transferred donor-derived cytomegalovirus
(CMV)-specific T-cell lines into 8 stem cell transplant recipients lacking CMV-specific T-cell proliferation. All patients, of whom one
was infected by a CMV strain that was genotypically ganciclovir resistant, had received unsuccessful antiviral chemotherapy for more
than 4 weeks. CMV-specific lines had been prepared by repetitive stimulation with CMV antigen, which increased the percentage of CMV-specific T cells and ablated alloreactivity completely even against
patients mismatched for 1 to 3 HLA antigens. After transfer of
107 T cells/m2 at a median of 120 days (range,
79-479 days) after transplantation, no side effects were noticed.
Despite cessation of antiviral chemotherapy, the CMV load dropped
significantly in all 7 evaluable patients, with a maximal reduction
after a median of 20 days (range, 5-31 days). In 2 patients with high
virus load, the antiviral effect was only transient. One of these
patients received a second T-cell infusion, which cleared the virus
completely. At a median of 11 days after transfer, CMV-specific T-cell
proliferation was demonstrated in 6 patients, and an increase in
CMV-specific CD4+ T cells was demonstrated in 5 patients.
In 6 patients, 1.12 to 41 CMV-specific CD8+ T cells/µL
blood were detected at a median of 13 days after transfer, with an
increase in all patients lacking CMV-specific CD8+ T cells
prior to transfer. Hence, anti-CMV cellular therapy was successful in 5 of 7 patients, whereas in 2 of 7 patients, who received an intensified
immune suppression at the time of or after T-cell therapy, only
transient reductions in virus load were obtained.
(Blood. 2002;99:3916-3922) Cytomegalovirus (CMV) infection after allogeneic
stem cell transplantation (SCT) is frequently associated with
life-threatening invasive visceral disease.1 During the
last few years, the introduction of prophylactic or preemptive
administration of ganciclovir has resulted in a significant reduction
in the incidence of early-onset CMV disease. Unfortunately, this has
been at the expense of an increase in late-onset CMV
disease.2-4 Because persistent CMV infection with
prolonged antiviral treatment results in a delayed CMV-specific immune
reconstitution, the onset of CMV disease after day 100 has become the
major CMV-related posttransplant complication.2-5
Cell-mediated immunity represents an essential host factor in the
control of persistent infection and the recovery from CMV disease.6-10 An increased understanding of the mechanisms
by which T cells recognize virus and tumor-specific antigens has
stimulated much interest in the use of specific T cells as adoptive
immunotherapy for viral and malignant diseases.11-16
Peripheral blood lymphocytes of the donor usually contain CMV-specific
T cells and can therefore be used to control CMV infection. However,
this kind of therapy is limited by potentially fatal complications
caused by the alloreactive T cells that are also present in the donor
lymphocyte infusion.11-14 A further problem of using
unselected populations of donor lymphocytes is the rather low frequency
of CMV-specific T cells in the donor lymphocyte
preparation.7 Enrichment of virus-specific T cells by in
vitro culture before transfer13-18 appears to reduce the risk of graft-versus-host disease (GVHD)13-16 and can
effectively restore virus-specific T-cell responses.15,16
It has been shown that prophylactic treatment of patients in the early
period following allogeneic SCT with CD8+ CMV-specific
cytotoxic T lymphocytes (CTLs) isolated from their HLA-matched sibling
donor16 results in a CD8+ T-cell response in
peripheral blood equivalent to responses in healthy seropositive
donors who resist CMV infection. Here, we investigated for the
first time the therapeutic application of CMV-specific T-cell lines in
patients lacking CMV-specific T-cell responses who suffered from
persisting or recurring CMV infection in spite of prolonged antiviral
chemotherapy. We show that this therapy has antiviral activity also in
a patient who was infected by a CMV strain that was genotypically and
phenotypically documented to be ganciclovir resistant.
Transplant protocols
All grafts from a family donor were CD34+-selected using
either the Miltenyi (Miltenyi Biotech GmbH, Bergisch-Gladbach, Germany) (n = 3) or the Cell Pro device (n = 1). If less than
1 × 105 CD3+ lymphocytes/kg in the matched
or 1 antigen-mismatch situation or less than 0.5 × 105
CD3+ lymphocytes/kg in the 3-antigen mismatch situation
were transferred, no GvHD prophylaxis was administered.
Patients undergoing bone marrow transplantation from an unrelated donor
received 3.5 mg/kg/d antithymocyte globulin (ATG; Pasteur-Merieux, MDS GmbH, Leiden, Germany) (day Antimicrobial prophylaxis
CMV disease CMV disease was diagnosed according to standard criteria.20Virus screening and antiviral therapy All CMV-seropositive patients as well as those receiving a transplant from a seropositive donor were followed up weekly by qualitative polymerase chain reaction (PCR) from whole blood beginning on day 0 and continued until day 100 after SCT, as described before.19,21-23 After day 100, patients continued to be screened by PCR when considered at high risk for late-onset CMV disease.4 PCR-based preemptive therapy was performed as reported before.19 Patients not responding to preemptive treatment with ganciclovir for 4 weeks received foscarnet (2 × 60 mg/kg/d) or cidofovir (5 mg/kg/wk) until they tested PCR negative.Protocol design SCT recipients receiving a transplant from a CMV-seropositive donor and failing antiviral chemotherapy as defined by the persistence or recurrence of CMV DNA in the peripheral blood after 4 weeks of antiviral chemotherapy and/or lacking CMV-specific T-cell proliferation were eligible for study entry. T-cell transfer was performed if a sufficient number (107/m2) of CMV-specific T cells could be generated.Patients were closely monitored for acute side effects during the first 2 to 4 hours following T-cell transfer and later on for acute and chronic GvHD. The efficacy of T-cell therapy was documented by a reduction in the virus load, increase in the absolute numbers of CMV-specific CD4+ and CD8+ T cells, and the documentation of CMV-specific T-cell proliferation. This study was performed under a protocol approved by the local human research ethics committee of the Eberhard-Karls University, Medical Faculty, Tübingen, Germany. Informed consent was obtained from all patients included in the study. Preparation of CMV-specific T-cell lines T-cell lines were prepared from fresh samples of peripheral blood (200 mL) collected from the stem cell donor. Donor-derived peripheral blood mononuclear cells (PBMNCs) were isolated by Ficoll-Hypaque gradient and incubated for 10 days in 10 mL RPMI (supplemented with 10% human AB serum from CMV-seronegative donors) with CMV lysate (1:200 diluted) in an upright 70-mL culture flask. Live cells (5 × 105) isolated from the culture flask were transferred into wells of a 24-well plate and restimulated with 106 autologous irradiated (3000 rad) feeder cells and CMV antigen (1:1000) in RPMI/10% human AB serum (PAN, Biotech GmbH, Aidenbach, Germany) supplemented with 25 U interleukin-2 (IL-2, Proleukin; Chiron, Ratingen, Germany) and gentamicin. Live cells isolated 7 days later were cultured at 5 × 105 per well and restimulated with irradiated autologous PBMNCs, CMV antigen, and IL-2.CMV specificity of the T-cell lines was confirmed by CMV-specific proliferation (see below). In addition, no T-cell proliferation above background had to be documented when the T-cell lines were stimulated with allogeneic and autologous targets. Before infusion, bacterial, fungal, or Mycoplasma contamination was excluded (sterility testing). In addition, viral growth (CMV, herpes simplex virus) and amplification of CMV RNA had to be negative prior to administration. In addition, PCR for human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus was performed and was negative in all preparations analyzed. The T-cell lines were extensively washed in phosphate-buffered saline (PBS) before infusion. Monitoring of acute and chronic toxicity of the T-cell infusions All patients received T-cell infusions in the outpatient department, where their vital signs were monitored before; immediately after; and 1, 2, and 4 hours after each infusion. Complete blood counts and liver function were evaluated weekly until 1 month following T-cell transfer. GvHD was graded by standard criteria weekly during this time period and later on every 2 weeks until 3 months after T-cell infusion.Monitoring of CMV-DNA load In addition to routine monitoring of our patients by qualitative PCR,19,22,23 we determined CMV-DNA load by quantitative PCR using the standardized and commercially available COBAS Amplicor CMV Monitor Test (Roche Diagnostics, Mannheim, Germany).Lymphoproliferation assay The proliferation assay was performed as described before.2 CMV antigen, phytohemagglutinin M form (Murex, Life Technology, Karlsruhe, Germany), and IL-2 were added at final concentrations of 1:400, 10 ng/mL, and 50 U/mL, respectively. A stimulation index of 3 was considered a positive lymphoproliferative response.Synthesis of peptides and tetramers CMV pp65 peptides for intracellular cytokine staining and generation of major histocompatibility complex (MHC)-peptide tetrameric complexes were synthesized as described15 using standard Fmoc chemistry on an automated peptide synthesizer (432A; Applied Biosystems, Weiterstadt, Germany) and purified by reverse-phase high-performance liquid chromatography (HPLC, Varian star; Zinsser, München, Germany) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (G2025A; Hewlett-Packard, Palo Alto, CA). Fast-protein liquid chromatography (FPLC)-purified, biotinylated MHC-peptide tetrameric complexes were prepared as described previously.24,25 The 3 CMV pp65 epitopes used in this study (amino acid [AA] 363-373: YSEHPTFTSQY restricted by A*0101, AA 495-503: NLVPMVATV restricted by A*0201, and AA16-24: GPISHGHVLK restricted by A*1101) represent dominant epitopes in the anti-CMV response, so that in individuals expressing the respective HLA antigens, the bulk of the responding CTLs can be detected by staining with only a single tetramer or by detection of interferon- (IFN-) production following stimulation with the
immunodominant peptide antigen.
Staining with MHC-peptide tetrameric complexes Generation of and staining with MHC-peptide tetrameric complexes (HLA A2/CMV pp65 peptide NLVPMVATV) were performed as described before.24,25 The biotinylated MHC complexes were recovered by FPLC purification, and tetramers were generated as previously described.25 A total of 2 to 5 × 105 PBMNCs were stained in a 96-well plate with 20 µg/mL phycoerythrin-labeled HLA A2 tetramer. After tetramer staining, cells were incubated with anti-CD8 and -CD3 antibodies and analyzed with a FACS Calibur (Becton Dickinson, Heidelberg, Germany) as previously described.25Quantification of circulating CMV-specific CD4+ and CD8+ T cells The absolute numbers of CMV-specific T cells were determined by measuring IFN- production and/or MHC-peptide tetrameric complex binding in 2 to 5 × 105 PBMNCs stained with anti-CD8 and
anti-CD3 antibodies. For the detection of IFN- production,
106 PBMNCs had been stimulated overnight with either
peptides (10 µg/mL) or CMV antigen (10 µg/mL) in 200 µL RPMI 1640 supplemented with Glutamax (Gibco), 10% fetal calf serum (CC-pro;
Neustadt, Germany), and 10 µg/mL Brefeldin A (Sigma, Deisenhofen,
Germany). Before analysis, the cells were stained with monoclonal
antibodies directed against CD4 or CD8 and fixed in Dulbecco PBS (dPBS;
Gibco BRL) containing 2% formaldehyde (Sigma) for 15 minutes at room temperature, washed, and resuspended in dPBS containing 0.5% saponin (Roth, Karlsruhe, Germany), 1% bovine serum albumin (Roth), and 0.2 µg/well anti-IFN- antibody (Becton Dickinson, Heidelberg, Germany). All samples were analyzed on a FACS Calibur flow
cytometer using the CellQuest software package. Absolute numbers of
peptide- and protein-specific T cells were calculated on the basis of
the absolute numbers of CD3+CD4+ and
CD3+CD8+ lymphocytes per milliliter blood and
the relative numbers of these lymphocyte fractions staining positive
for IFN- after specific stimulation.
Preparation of CMV-specific T-cell lines To obtain CMV-specific T-cell lines, we stimulated the mononuclear cells isolated from 200 mL peripheral blood of the stem cell donor 4 times with CMV antigen. In 14 of 21 cultures, this procedure efficiently increased the percentage of CMV-specific T cells. Figure 1 shows that already after 2 stimulations, the percentage of CMV-specific cells could be as high as 7.4%. After 4 stimulations, the T-cell lines (n = 14) were 77% ± 10% CD4+ and 6% ± 3% CD8+. CMV-specific cells were predominantly found in the CD4+ population (Figure 1). Furthermore, after the 4 stimulations, the T-cell lines had lost their initial alloreactivity toward the patient. Even in the donor-recipient combination that was mismatched for 3 HLA antigens, the mixed lymphocyte culture had become entirely negative (Figure 2).
Characteristics of patients and their response to cellular therapy On the basis of our study design, 21 patients were eligible for cellular anti-CMV therapy. The criteria to be enrolled in the study were as follows: (1) a CMV-seropositive donor, (2) the presence of CMV DNA in the peripheral blood after a minimum of 4 weeks of antiviral chemotherapy, and (3) absence of CMV-specific in vitro proliferative responses. For 6 patients, we did not succeed in preparing the CMV-specific T-cell lines, either because we were not able to expand the cells to the numbers required by our study design (107/m2) or because, after 4 rounds of stimulation in vitro, little or no anti-CMV specificity could be detected. One patient died before the start of the cellular therapy, one patient was excluded because he developed an Epstein-Barr virus lymphoma that was treated by infusion of unmodified donor lymphocytes, and 5 patients were excluded because they responded to the continuing antiviral therapy. The characteristics of the remaining 8 patients are shown in Table 1. Two patients (nos. 6 and 7) underwent transplantation with stem cells from their HLA-identical sibling donor, 3 patients (nos. 1, 5, and 8) underwent transplantation with stem cells from HLA-matched unrelated donors, and the other 3 patients (nos. 2-4) received grafts that were mismatched for 1 to 3 antigens. With the exception of the patients undergoing transplantation with the marrow from an HLA-identical sibling donor, all patients received ATG as GvHD prophylaxis. Preemptive anti-CMV chemotherapy was started on the day of the second positive PCR result (median, 30 days; range, 16-65 days). After a median of 8 weeks (range, 4-10 weeks) of unsuccessful antiviral chemotherapy, patients received a single dose of 107 CMV-specific T cells/m2 at the time indicated in Table 2, which was at a median of 120 days (range, 79-479 days) after SCT. At that moment, with 7 of 8 patients still receiving some form of immunosuppression, antiviral chemotherapy was stopped. After infusion of the T-cell lines, no pulmonary toxicity or other acute side effects occurred. In addition, in none of the patients was induction or aggravation of acute or chronic GvHD observed. Within 5 to 31 days, viral DNA could no longer be detected in 5 of 7 evaluable patients (Table 2 and Figure 3). Patient no. 7 was antigenemia-positive at the time of T-cell transfer, but was not evaluated for CMV-DNA load. Following T-cell therapy, this patient became and remained negative by antigenemia assay. Patient no. 5 cleared a residual viral load (1000 virus copies/mL blood) only after a second infusion of CMV-specific T-cell lines given 40 days after the first infusion. Only in patient no. 1 did CMV DNA remain detectable throughout the entire period, which, after she had refused further treatment, resulted in a CMV encephalitis at 6 weeks after cellular therapy. Patient no. 8 again became PCR-positive after high-dose corticosteroid treatment for relapse of her original disease. However, all other patients remained CMV-negative during the entire period of the study.
Reconstitution of CMV-specific T cells after adoptive transfer of polyclonal CMV-specific T-cell lines To assess the recovery of CMV-specific T-cell reactivity, we scheduled blood samples to be drawn every 14 days after adoptive immunotherapy. The following assays were performed: (1) lymphoproliferative responses after stimulation with CMV protein, (2) staining for intracellular IFN- after stimulation with CMV peptides
in vitro (n = 7), (3) analysis of ex vivo binding HLA/peptide
tetrameric complexes (n = 3), and (4) staining for intracellular
IFN- after stimulation with CMV protein in vitro (n = 6). These
data were correlated with the clinical course and the virus load in
each patient. Table 3 shows that
following T-cell therapy, 6 of 8 patients who all lacked anti-CMV
reactivity before adoptive transfer responded in vitro to the CMV
protein (stimulation index [SI] >3). Only a borderline response was
observed in patient no. 7 (SI = 2.7), while patient no. 1 remained
negative. Both patients had received CSA/MMF/prednisolone or
FK506/prednisolone as intensified immunosuppression at the time of
T-cell therapy. Interestingly, the viral load already decreased
considerably before the CMV-specific T cells appeared in the blood. In
patient no. 1, no CMV-specific proliferative T-cell response was
detected in the blood at 20 days after cellular therapy, although the
virus load had diminished to less than 10% of the level before
infusion. This is also seen in Figure 4,
which shows the anti-CMV proliferative response, the intracellular
IFN- staining, as well as the tetramer analysis in patient
no. 4 over time. At day 15 after infusion, the viral load had
decreased from an initial 11 800 virus copies/mL blood to 800. However, at that time, very few CMV-specific T cells were detected in
the blood. At day 32, when the virus had been cleared entirely, some
IFN--producing CD8+ as well as some tetramer-binding
CD8+ T cells became apparent. However, even higher numbers
of CMV-specific cells were present 6 days later. At day 38, more than
1% of the peripheral blood T cells were CMV specific, which was
reflected by the significant increase of the in vitro proliferative
response to the CMV protein. In this patient (no. 4), a T-cell clone
generated from the peripheral blood after adoptive immunotherapy
revealed specific killing of T2 cells pulsed with the CMV peptide
NLVPMVATV in a 51Cr-release assay.
The relation between the increase of CMV-specific IFN-
T-cell immunity is crucial for protection against CMV disease. After the initial response, the virus becomes latent and may therefore reactivate upon immunodeficiency. Consequently, infection of either the patient or the donor with CMV represents a serious risk factor after SCT. It has been shown that more than half of the patients lacking detectable anti-CMV T-cell responses develop CMV disease.8 Prophylaxis with ganciclovir, foscarnet, cidofovir, or a combination thereof may decrease the risk only temporarily. If during treatment, no CMV-specific T-cell immunity develops, the risk of CMV disease remains considerable.2,3,8 Pioneering work by Riddell et al and Walter et al has shown that adoptive transfer of CMV-specific CD8+ T-cell clones into patients at risk of CMV disease protected the patients from CMV-related complications.15,16 They demonstrated that when 1 to 2 × 109 CMV-specific CD8+ T cells were infused, these cells remained in the circulation for at least 8 weeks. Although the cells declined progressively in patients who did not develop a concomitant CMV-specific CD4+ T-helper response, prophylaxis against CMV infection was effective, as none of the patients developed a CMV viremia. Our approach differed in several aspects. We decided, instead of giving prophylactic anti-CMV cellular therapy, to treat patients with antiviral chemotherapy-resistant CMV viremia. To simplify our analysis, only patients who lacked a CMV-specific CD4+ T-helper response were enrolled in the study. In these patients, we have attempted to reconstitute the lacking immunity by the adoptive transfer of CMV-specific T-cell lines that had been established from the donor blood after stimulation with CMV protein. Although it is too early to draw a final conclusion based on the results in 8 patients, some of the findings on virus load, immunosuppression, and presence of CMV-specific T cells in the blood are noticeable. First, although we transferred only 1 to 5 × 106 CMV-specific CD4+ T cells, a rapid antiviral effect was seen in all patients. We believe that in most patients, this was the result of the immunotherapy rather than of a late effect of the antiviral chemotherapy that had been stopped prior to T-cell infusion. It is true that 5 of 21 patients who had been initially eligible for the study on the basis of their refractoriness to ganciclovir treatment did not enter the study because they responded just before the scheduled start of the immunotherapy. In addition, patient no. 7, whose virus load was already low during the period before immunotherapy, may essentially have responded to the ganciclovir treatment. However, in most patients, the CMV load did not decrease before 1 to 2 weeks after the CMV-specific cells had been infused; that is, with a considerable lag time after antiviral chemotherapy, or even later only after a second load of CMV-specific cells had been transferred. Within 5 to 31 days after transfer, 5 of 7 patients evaluable by PCR assay had cleared the virus from their blood. Thereafter, the CMV-specific cells persisted at numbers comparable to those in healthy individuals, showing that a normal immune response with expansion of antigen-specific cells had taken place. This significant increase of CMV-specific T cells stands in contrast to the decline that is observed after the infusion of CD8+ cells only.15,16 Therefore, we feel that although transfer of large amounts of CD8+ CMV-specific clones may protect the patient from CMV disease, adoptive-transfer protocols will be more effective when CD4+ antigen-specific T cells are given. It is interesting to note that although during the in vitro culture with CMV antigen, no detectable numbers of tetramer-binding CMV-specific CD8+ T cells had been generated, in half of the patients, the number of CMV pp65 peptide-specific CD8+ cells had increased significantly within 2 months after therapy. Furthermore, we were able to clone CMV-specific CD8+ T cells that specifically lysed NLVPMVATV peptide-pulsed T2 cells in vitro from the peripheral blood of patient no. 4. This strongly suggests that the transfer of CMV-specific CD4+ T cells may induce expansion of CMV-specific CD8+ CTLs from precursors that without T-cell help would not have been activated. Currently, we are investigating whether infusion of CD8+ CMV-specific T-cell lines together with the CD4+ cells will be able to increase the efficacy in patients with high virus loads or shorten the time of virus clearance in others. We noticed that during the viremia, very few CMV-specific T cells were found in the blood. Given the low number of cells infused, this finding is not unanticipated. In kidney transplant recipients, the CMV-specific cells that arise at the onset of viremia disappear shortly thereafter, 1 month before the virus is cleared.26 Probably, this peak of CMV-specific cells represents the freshly activated T cells that home to the infected tissues. After adoptive transfer of in vitro stimulated cells, homing to the tissues or possibly to the lymph nodes where the antigen is presented is most likely to be instantaneous. Thereafter, most CD4+ CMV-specific T cells will migrate to the blood only when the viral replication has been stopped, a phenomenon previously observed during HIV infection.27 The efficacy of the therapy in the 2 patients with the highest virus load (>105 CMV-DNA copies/mL) was less. One patient needed a second infusion to clear the virus completely. In the other patient, who was infected with a ganciclovir-resistant CMV strain, the virus load decreased initially from more than 105 CMV-DNA copies/mL blood to less than 10 CMV-DNA copies/mL blood.4 Thereafter, the patient, who refused further treatment, proceeded to a fatal CMV encephalitis. We think that also in this patient, a second infusion of CMV-specific T cells would have been capable of clearing the virus because there is no reason to believe that CTLs would be less efficient against a ganciclovir-resistant strain than against the unmutated virus. In fact, we believe that an infection with a drug-resistant strain would be one of the first indications for antiviral cellular therapy. However, it is conceivable that the limited efficacy of the therapy in this particular patient is due to the combination of the high virus load and the intensified immunosuppression that the patient received. It is obvious that any form of immunosuppression would have a negative effect on the further expansion of the CMV-specific T cells transferred. This was also evident in the patient who received high-dose corticosteroid treatment for relapse of her original disease. This patient cleared the virus rapidly but remained PCR-negative only until the immunosuppression was started. In conclusion, our results demonstrate that anti-CMV cellular therapy represents a therapeutic option in viremic patients after SCT. We show that this can be performed by infusion of low numbers of CD4+ CMV-specific T-cell lines obtained after an in vitro culture of 3 to 4 weeks. These lines can be infused without side effects, even in patients undergoing transplantation with stem cells of a donor mismatched for 1 to 3 HLA antigens. The substantial gain in time as compared with the generation of CD8+ CMV-specific clones15,16 may allow a more flexible clinical response to CMV viremia in selected patients at high risk for CMV disease.
Submitted October 12, 2001; accepted January 28, 2002.
Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 510, projekt B3); from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Tübingen (IZKF), project C2; from the Swiss National Science foundation (no. 31-53774.98); and from the foundation of Dr Henri Dubois-Ferrière-Dinu Lipatti.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hermann Einsele, Medizinische Klinik, Abteilung II, Otfried-Müller Str 10, D-72076 Tübingen, Germany; e-mail: hneinsel{at}med.uni-tuebingen.de.
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© 2002 by The American Society of Hematology.
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  A. Schub, I. G. Schuster, W. Hammerschmidt, and A. Moosmann CMV-Specific TCR-Transgenic T Cells for Immunotherapy J. Immunol., November 15, 2009; 183(10): 6819 - 6830. [Abstract] [Full Text] [PDF]
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A. N. Hasan, W. J. Kollen, D. Trivedi, A. Selvakumar, B. Dupont, M. Sadelain, and R. J. O'Reilly A Panel of Artificial APCs Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Dominant and Subdominant Viral Epitopes for Adoptive Therapy J. Immunol., August 15, 2009; 183(4): 2837 - 2850. [Abstract] [Full Text] [PDF]
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M. Boeckh and P. Ljungman How we treat cytomegalovirus in hematopoietic cell transplant recipients Blood, June 4, 2009; 113(23): 5711 - 5719. [Abstract] [Full Text] [PDF]
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K. A. McAulay, T. Haque, G. Urquhart, C. Bellamy, D. Guiretti, and D. H. Crawford Epitope Specificity and Clonality of EBV-Specific CTLs Used to Treat Posttransplant Lymphoproliferative Disease J. Immunol., March 15, 2009; 182(6): 3892 - 3901. [Abstract] [Full Text] [PDF]
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 M. M. van Loenen, R. S. Hagedoorn, M. G.D. Kester, M. Hoogeboom, R. Willemze, J.H. F. Falkenburg, and M. H.M. Heemskerk Kinetic Preservation of Dual Specificity of Coprogrammed Minor Histocompatibility Antigen-Reactive Virus-Specific T Cells Cancer Res., March 1, 2009; 69(5): 2034 - 2041. [Abstract] [Full Text] [PDF]
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 T. Crough and R. Khanna Immunobiology of Human Cytomegalovirus: from Bench to Bedside Clin. Microbiol. Rev., January 1, 2009; 22(1): 76 - 98. [Abstract] [Full Text] [PDF]
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 A. Joshi, J. Tang, M. Kuzma, J. Wagner, B. Mookerjee, J. Filicko, M. Carabasi, N. Flomenberg, and P. Flomenberg Adenovirus DNA polymerase is recognized by human CD8+ T cells J. Gen. Virol., January 1, 2009; 90(1): 84 - 94. [Abstract] [Full Text] [PDF]
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 J. Schroer and T. Shenk Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus PNAS, December 9, 2008; 105(49): 19468 - 19473. [Abstract] [Full Text] [PDF]
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K. P. Micklethwaite, L. Clancy, U. Sandher, A. M. Hansen, E. Blyth, V. Antonenas, M. M. Sartor, K. F. Bradstock, and D. J. Gottlieb Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation Blood, November 15, 2008; 112(10): 3974 - 3981. [Abstract] [Full Text] [PDF]
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M. Baron and J.-L. Davignon Inhibition of IFN-{gamma}-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2 J. Immunol., October 15, 2008; 181(8): 5530 - 5536. [Abstract] [Full Text] [PDF]
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M. S. Hossain, J. D. Roback, F. Wang, and E. K. Waller Host and Donor Immune Responses Contribute to Antiviral Effects of Amotosalen-Treated Donor Lymphocytes following Early Posttransplant Cytomegalovirus Infection J. Immunol., May 15, 2008; 180(10): 6892 - 6902. [Abstract] [Full Text] [PDF]
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A. Jorritsma, A. D. Bins, T. N.M. Schumacher, and J. B.A.G. Haanen Skewing the T-Cell Repertoire by Combined DNA Vaccination, Host Conditioning, and Adoptive Transfer Cancer Res., April 1, 2008; 68(7): 2455 - 2462. [Abstract] [Full Text] [PDF]
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K. Klenovsek, F. Weisel, A. Schneider, U. Appelt, S. Jonjic, M. Messerle, B. Bradel-Tretheway, T. H. Winkler, and M. Mach Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells Blood, November 1, 2007; 110(9): 3472 - 3479. [Abstract] [Full Text] [PDF]
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S. Delmas, P. Brousset, D. Clement, E. Le Roy, and J.-L. Davignon Anti-IE1 CD4+ T-cell clones kill peptide-pulsed, but not human cytomegalovirus-infected, target cells J. Gen. Virol., September 1, 2007; 88(9): 2441 - 2449. [Abstract] [Full Text] [PDF]
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I. R. Humphreys, A. Loewendorf, C. de Trez, K. Schneider, C. A. Benedict, M. W. Munks, C. F. Ware, and M. Croft OX40 Costimulation Promotes Persistence of Cytomegalovirus-Specific CD8 T Cells: A CD4-Dependent Mechanism J. Immunol., August 15, 2007; 179(4): 2195 - 2202. [Abstract] [Full Text] [PDF]
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 E. Biagi, V. Marin, G. M. P. Giordano Attianese, E. Dander, G. D'Amico, and A. Biondi Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies Haematologica, March 1, 2007; 92(3): 381 - 388. [Abstract] [Full Text] [PDF]
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T. C. Wehler, M. Nonn, B. Brandt, C. M. Britten, M. Grone, M. Todorova, I. Link, S. A. Khan, R. G. Meyer, C. Huber, et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines Blood, January 1, 2007; 109(1): 365 - 373. [Abstract] [Full Text] [PDF]
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R. G. Meyer, C. M. Britten, D. Wehler, K. Bender, G. Hess, A. Konur, U. F. Hartwig, T. C. Wehler, A. J. Ullmann, C. Gentilini, et al. Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell-depleted reduced-intensity transplantation Blood, January 1, 2007; 109(1): 374 - 382. [Abstract] [Full Text] [PDF]
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 J. P. Casazza, M. R. Betts, D. A. Price, M. L. Precopio, L. E. Ruff, J. M. Brenchley, B. J. Hill, M. Roederer, D. C. Douek, and R. A. Koup Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation J. Exp. Med., December 25, 2006; 203(13): 2865 - 2877. [Abstract] [Full Text] [PDF]
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B. Heemskerk, T. van Vreeswijk, L. A. Veltrop-Duits, C. C. Sombroek, K. Franken, R. M. Verhoosel, P. S. Hiemstra, D. van Leeuwen, M. E. Ressing, R. E. M. Toes, et al. Adenovirus-Specific CD4+ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction J. Immunol., December 15, 2006; 177(12): 8851 - 8859. [Abstract] [Full Text] [PDF]
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S. Kausche, T. Wehler, E. Schnurer, V. Lennerz, W. Brenner, S. Melchior, M. Grone, M. Nonn, S. Strand, R. Meyer, et al. Superior Antitumor In vitro Responses of Allogeneic Matched Sibling Compared with Autologous Patient CD8+ T Cells Cancer Res., December 1, 2006; 66(23): 11447 - 11454. [Abstract] [Full Text] [PDF]
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 L. M. Haveman, M. Bierings, E. Legger, M. R. Klein, W. de Jager, H. G. Otten, S. Albani, W. Kuis, A. Sette, and B. J. Prakken Novel pan-DR-binding T cell epitopes of adenovirus induce pro-inflammatory cytokines and chemokines in healthy donors Int. Immunol., November 1, 2006; 18(11): 1521 - 1529. [Abstract] [Full Text] [PDF]
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O. Beck, M. S. Topp, U. Koehl, E. Roilides, M. Simitsopoulou, M. Hanisch, J. Sarfati, J. P. Latge, T. Klingebiel, H. Einsele, et al. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus Blood, March 15, 2006; 107(6): 2562 - 2569. [Abstract] [Full Text] [PDF]
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 Y. M. Wang, G. Y. Zhang, Y. Wang, M. Hu, H. Wu, D. Watson, S. Hori, I. E. Alexander, D. C.H. Harris, and S. I. Alexander Foxp3-Transduced Polyclonal Regulatory T Cells Protect against Chronic Renal Injury from Adriamycin J. Am. Soc. Nephrol., March 1, 2006; 17(3): 697 - 706. [Abstract] [Full Text] [PDF]
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O. A. Shlobin, E. E. West, N. Lechtzin, S. M. Miller, M. Borja, J. B. Orens, L. K. Dropulic, and J. F. McDyer Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients J. Immunol., February 15, 2006; 176(4): 2625 - 2634. [Abstract] [Full Text] [PDF]
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 J. D. Roback Vaccine-Enhanced Donor Lymphocyte Infusion (veDLI) Hematology, January 1, 2006; 2006(1): 486 - 491. [Abstract] [Full Text] [PDF]
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Y. Chalandon, S. Degermann, J. Villard, L. Arlettaz, L. Kaiser, S. Vischer, S. Walter, M. H. M. Heemskerk, R. A. W. van Lier, C. Helg, et al. Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications Blood, January 1, 2006; 107(1): 389 - 396. [Abstract] [Full Text] [PDF]
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H. Einsele T-cell therapy for viral and fungal infections Blood, December 15, 2005; 106(13): 4023 - 4023. [Full Text] [PDF]
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K. Perruccio, A. Tosti, E. Burchielli, F. Topini, L. Ruggeri, A. Carotti, M. Capanni, E. Urbani, A. Mancusi, F. Aversa, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation Blood, December 15, 2005; 106(13): 4397 - 4406. [Abstract] [Full Text] [PDF]
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S. Delmas, L. Martin, M. Baron, J. A. Nelson, D. N. Streblow, and J.-L. Davignon Optimization of CD4+ T Lymphocyte Response to Human Cytomegalovirus Nuclear IE1 Protein through Modifications of Both Size and Cellular Localization J. Immunol., November 15, 2005; 175(10): 6812 - 6819. [Abstract] [Full Text] [PDF]
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K. S. Lang, M. Recher, A. A. Navarini, S. Freigang, N. L. Harris, M. van den Broek, B. Odermatt, H. Hengartner, and R. M. Zinkernagel Requirement for Neutralizing Antibodies to Control Bone Marrow Transplantation-Associated Persistent Viral Infection and to Reduce Immunopathology J. Immunol., October 15, 2005; 175(8): 5524 - 5531. [Abstract] [Full Text] [PDF]
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A. W. Sylwester, B. L. Mitchell, J. B. Edgar, C. Taormina, C. Pelte, F. Ruchti, P. R. Sleath, K. H. Grabstein, N. A. Hosken, F. Kern, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects J. Exp. Med., September 6, 2005; 202(5): 673 - 685. [Abstract] [Full Text] [PDF]
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M. Cobbold, N. Khan, B. Pourgheysari, S. Tauro, D. McDonald, H. Osman, M. Assenmacher, L. Billingham, C. Steward, C. Crawley, et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers J. Exp. Med., August 1, 2005; 202(3): 379 - 386. [Abstract] [Full Text] [PDF]
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 T. Chen, Q. Wang, J. Cui, W. Yang, Q. Shi, Z. Hua, J. Ji, and P. Shen Induction of Apoptosis in Mouse Liver by Microcystin-LR: A Combined Transcriptomic, Proteomic, And Simulation Strategy Mol. Cell. Proteomics, July 1, 2005; 4(7): 958 - 974. [Abstract] [Full Text] [PDF]
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A. Roth, G. M. Baerlocher, M. Schertzer, E. Chavez, U. Duhrsen, and P. M. Lansdorp Telomere loss, senescence, and genetic instability in CD4+ T lymphocytes overexpressing hTERT Blood, July 1, 2005; 106(1): 43 - 50. [Abstract] [Full Text] [PDF]
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D. Trivedi, R. Y. Williams, R. J. O'Reilly, and G. Koehne Generation of CMV-specific T lymphocytes using protein-spanning pools of pp65-derived overlapping pentadecapeptides for adoptive immunotherapy Blood, April 1, 2005; 105(7): 2793 - 2801. [Abstract] [Full Text] [PDF]
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T. J. Manley, L. Luy, T. Jones, M. Boeckh, H. Mutimer, and S. R. Riddell Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection Blood, August 15, 2004; 104(4): 1075 - 1082. [Abstract] [Full Text] [PDF]
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Z. Wang, C. La Rosa, S. Mekhoubad, S. F. Lacey, M. C. Villacres, S. Markel, J. Longmate, J. D. I. Ellenhorn, R. F. Siliciano, C. Buck, et al. Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells Blood, August 1, 2004; 104(3): 847 - 856. [Abstract] [Full Text] [PDF]
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G. Li Pira, L. Bottone, F. Ivaldi, R. Pelizzoli, F. Del Galdo, L. Lozzi, L. Bracci, A. Loregian, G. Palu, R. De Palma, et al. Identification of new Th peptides from the cytomegalovirus protein pp65 to design a peptide library for generation of CD4 T cell lines for cellular immunoreconstitution Int. Immunol., May 1, 2004; 16(5): 635 - 642. [Abstract] [Full Text] [PDF]
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G. Rauser, H. Einsele, C. Sinzger, D. Wernet, G. Kuntz, M. Assenmacher, J. D. M. Campbell, and M. S. Topp Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants Blood, May 1, 2004; 103(9): 3565 - 3572. [Abstract] [Full Text] [PDF]
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N. C. V. Verra, A. Jorritsma, K. Weijer, J. J. Ruizendaal, A. Voordouw, P. Weder, E. Hooijberg, T. N. M. Schumacher, J. B. A. G. Haanen, H. Spits, et al. Human Telomerase Reverse Transcriptase-Transduced Human Cytotoxic T Cells Suppress the Growth of Human Melanoma in Immunodeficient Mice Cancer Res., March 15, 2004; 64(6): 2153 - 2161. [Abstract] [Full Text] [PDF]
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M. Boeckh and W. G. Nichols The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy Blood, March 15, 2004; 103(6): 2003 - 2008. [Abstract] [Full Text] [PDF]
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E. Kondo, Y. Akatsuka, K. Kuzushima, K. Tsujimura, S. Asakura, K. Tajima, Y. Kagami, Y. Kodera, M. Tanimoto, Y. Morishima, et al. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles Blood, January 15, 2004; 103(2): 630 - 638. [Abstract] [Full Text] [PDF]
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J. D. Roback, M. S. Hossain, L. Lezhava, J. W. Gorechlad, S. A. Alexander, D. L. Jaye, S. Mittelstaedt, S. Talib, J. E. Hearst, C. D. Hillyer, et al. Allogeneic T Cells Treated with Amotosalen Prevent Lethal Cytomegalovirus Disease without Producing Graft-versus-Host Disease Following Bone Marrow Transplantation J. Immunol., December 1, 2003; 171(11): 6023 - 6031. [Abstract] [Full Text] [PDF]
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E. Meijer, G. J. Boland, and L. F. Verdonck Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants Clin. Microbiol. Rev., October 1, 2003; 16(4): 647 - 657. [Abstract] [Full Text] [PDF]
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G. A. Papanicolaou, J.-B. Latouche, C. Tan, J. Dupont, J. Stiles, E. G. Pamer, and M. Sadelain Rapid expansion of cytomegalovirus-specific cytotoxic T lymphocytes by artificial antigen-presenting cells expressing a single HLA allele Blood, October 1, 2003; 102(7): 2498 - 2505. [Abstract] [Full Text] [PDF]
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 B. Heemskerk, L. A. Veltrop-Duits, T. van Vreeswijk, M. M. ten Dam, S. Heidt, R. E. M. Toes, M. J. D. van Tol, and M. W. Schilham Extensive Cross-Reactivity of CD4+ Adenovirus-Specific T Cells: Implications for Immunotherapy and Gene Therapy J. Virol., June 1, 2003; 77(11): 6562 - 6566. [Abstract] [Full Text] [PDF]
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A. Kaur, N. Kassis, C. L. Hale, M. Simon, M. Elliott, A. Gomez-Yafal, J. D. Lifson, R. C. Desrosiers, F. Wang, P. Barry, et al. Direct Relationship between Suppression of Virus-Specific Immunity and Emergence of Cytomegalovirus Disease in Simian AIDS J. Virol., May 15, 2003; 77(10): 5749 - 5758. [Abstract] [Full Text] [PDF]
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C. La Rosa, Z. Wang, J. C. Brewer, S. F. Lacey, M. C. Villacres, R. Sharan, R. Krishnan, M. Crooks, S. Markel, R. Maas, et al. Preclinical development of an adjuvant-free peptide vaccine with activity against CMV pp65 in HLA transgenic mice Blood, November 15, 2002; 100(10): 3681 - 3689. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
4 to day 
1 · d
