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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 807-814
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Microbiology and Tumor Biology Center, Karolinska Institet;
Department of Pediatrics, Department of Immunology, Microbiology,
Pathology, and Infectious Diseases, Department of Hematology, and
Center for Allogeneic Stem Cell Transplantation, Huddinge Hospital,
Stockholm, Sweden.
A semiquantitative polymerase chain reaction assay was used to
monitor the blood levels of Epstein-Barr virus (EBV)-DNA in 9 patients
receiving allogeneic bone marrow transplants (BMT). Four of 5 recipients of HLA-mismatched T-cell-depleted grafts showed a 4- to
5-log increase of EBV-DNA within 1 to 3 months after BMT.
Administration of 2 to 4 infusions of 107 EBV-specific
cytotoxic T-lymphocytes (CTLs)/m2 starting from the time of
maximal virus load resulted in a 2- to 3-log decrease of virus titers
in 3 patients. One patient, who received a T-cell culture lacking a
major EBV-specific component, progressed to fatal EBV-positive
lymphoma. Administration of EBV-CTLs before the onset of the EBV-DNA
peak resulted in stabilization of the virus titers within 2 to 3 logs
above the normal levels in the fifth patient. A moderate increase of
virus titers was also detected in 3 of 4 patients receiving
unmanipulated HLA-matched grafts, whereas 1 patient with
Wiskott-Aldrich syndrome reached a 5-log increase of EBV-DNA load
within 70 days after BMT. Our results suggest that a rapid increase of
circulating EBV-DNA occurs in the absence of EBV-specific T-cell
precursors or in the presence of congenital immune defects that prevent
the reestablishment of virus-specific immunity. Prophylactic
administration of EBV-CTLs early after BMT appears to provide the most
effective protection against the development of EBV-associated
lymphoproliferative disease.
(Blood. 2000;95:807-814)
After a mild, self-limiting primary infection that
usually occurs during childhood, Epstein-Barr virus (EBV) persists for life in healthy immunocompetent carriers (reviewed in 1).
Latently infected B lymphocytes, which can grow in vitro as immortal
EBV-carrying lymphoblastoid cell lines (LCLs), are found in the blood
and lymphoid organs of the vast majority of adults.2-4
These EBV-infected cells are kept in check by a strong specific
immunity that can be readily monitored by the reactivation of
EBV-specific cytotoxic T lymphocytes (EBV-CTLs) upon in vitro
stimulation of lymphocytes from healthy virus carriers with the
autologous EBV-transformed LCL.5 In carriers of congenital
immune defects and persons who have become immunosuppressed as a
consequence of medication or during human immunodeficiency virus
infection, EBV-infected B lymphocytes may give rise to lymphoma or
leukemia.6,7
Patients receiving immunosuppressive therapy after organ or bone marrow
transplantation (BMT) run a particularly high risk of developing
EBV-associated posttransplant lymphoproliferative disease
(PTLD).8,9 The disease often presents early after transplantation with fever and disseminated adenopathy and may take a
rapidly fatal course, not responding to reduced immunosuppression or
chemotherapy. Whereas PTLD in organ transplant recipients is of
recipient cell origin, donor B cells usually cause the
lymphoproliferative disorders occurring after BMT.10 The
incidence of PTLD varies depending on the type of
transplant.11 Although this complication is observed in
less than 1% of recipients of unmanipulated BMT from HLA-compatible
related donors, in settings in which mismatched, T-cell-depleted
(TCD), or unrelated stem cell grafts are used, PTLD may occur in up to
25% of patients.
The prophylactic and therapeutic aspects of PTLD have been the subject
of several recent reviews.12-15 Papadopoulos et
al16 were the first to report that infusion of
donor lymphocytes induced clinical remission of PTLD in 5 recipients of
allogeneic BMT. The therapeutic effect was attributed to the
reconstruction of EBV-specific immunity by repletion of CTL precursors
present in the lymphocyte infusion. However, the concomitant infusion
of alloreactive T cells was associated with a significantly increased risk of serious graft-versus-host disease (GVHD). To avoid this problem, Heslop et al17 and Rooney et al18
successfully applied EBV-specific cytotoxic T-cell cultures reactivated
in vitro by stimulation of donor lymphocytes. Using genetically marked
EBV-CTLs, they demonstrated that the virus-specific effectors persisted in the recipient for at least 18 months and could expand in vitro as
well as in vivo in response to renewed challenge with EBV-infected cells.15 Previous studies have shown a correlation between
the occurrence of PTLD and the amount of EBV-DNA detected in the
peripheral blood of transplant recipients.19-21 Thus,
semiquantitative polymerase chain reaction (PCR) techniques have the
potential to identify patients at risk of developing EBV-associated
lymphomas. However, it is unclear to what extent the levels of EBV-DNA
correlate with the presence of subclinical or clinically manifest PTLD,
disease outcome, or the levels of EBV-specific immunity in these patients.
The purpose of this study was to examine the correlation between the
levels of EBV-DNA in the blood of BMT recipients early after
transplantation and (1) the type of transplant received, (2) the
presence of underlying immune defects, and (3) the clinical outcome of
adoptive EBV-CTL therapy.
Patients
Transplant regimens
Chimerism assay
Semiquantitative EBV-specific PCR The details of the PCR assay were described previously.31 Briefly, peripheral blood mononuclear cells (PBMCs) isolated by centrifugation on Lymphoprep gradients (Nycomed, Oslo, Norway) were resuspended in lysis buffer (25 µL/106 cells) containing 10 mmol/L Tris-HCl, pH 9.0, 0.1 mmol/L ethylenediaminetetraacetic acid, 0.5% Nonidet P-40, 0.5% Tween-20, and 400 µg/mL proteinase-K. After incubation for 1 hour at 55°C, the proteinase-K was inactivated by heating for 15 minutes at 95°C. EBV-DNA was amplified with a set of nested primers derived from the EBNA1 coding region of the prototype B95.8 EBV genome. After denaturation at 94°C for 5 minutes, 25 PCR cycles of 1-minute denaturation at 94°C, 1-minute annealing at 55°C, and 1-minute extension at 72°C were run with the following pair of outer primers: EB3, 5'-AAGGAGGGTGGTTTGGAAAG-3'; and EB4, 5'-AGACAATGGACTCCCTTAGC-3' (nucleotides 109 331-109 350 and 109 608-109 627, respectively). One tenth of the resulting products was further amplified by 30 PCR cycles of 1-minute denaturation at 94°C, 1-minute annealing at 60°C, and 1-minute extension at 72°C using the following pair of inner primers: EB1, 5'-ATCGTGGTCAAGGAGGTTCC-3' (nucleotides 109 352-109 371); and EB2, 5'-ACTCAATGGTGTAAGACGAC-3' (nucleotides 109 541-109 560). The PCR products were resolved by electrophoresis in a 1.5% agarose gel containing 0.5 µg/mL ethidium bromide. DNA isolated from the EBV-negative T-cell line HSB2, water, and lysis buffer were included as negative controls in each assay. The DNA equivalents of 50, 10, and 2 cells from the EBV-positive BL line Namalwa, which contains 2 EBV genome copies per cell, were included in each test as positive controls. Calibration tests performed by diluting graded numbers of Namalwa in EBV-negative cells have shown that this PCR method allows detection of 1 EBV genome copy per 106 cells.Determination of EBV load A simplified method was developed for routine determination of EBV-DNA load in BMT recipients. Serial 5-fold dilutions of DNA extracted from PBMCs were prepared starting from the amount of DNA corresponding to 106 cells, and each sample was analyzed for the presence of EBV-DNA. The last positive dilution and the preceding and following dilutions were retested in 10 independent PCR reactions each. The minimal number of cells containing 1 EBV genome equivalent was calculated from the number of positive reactions in each dilution according to the Poisson distribution and is expressed as "EBV load." In routine tests, only the initial set of dilutions was analyzed, and the last positive sample was used to estimate the EBV-DNA load. The validity and reproducibility of this simplified method were confirmed on several occasions by complete 10-sample dilution assays.Generation and characterization of EBV-specific CTLs After informed consent, an additional 100 mL of blood was drawn from each bone marrow donor at the time of retyping or workup, 3 to 6 weeks before BMT. An EBV-transformed LCL was established by infection of 107 PBMCs with spent supernatant from the EBV producer B95.8 cell line,32 and the remaining PBMCs were cryopreserved for later use. EBV-specific CTLs were generated by stimulation of PBMCs with the autologous LCL, as described previously.33 After 3 consecutive restimulations, the cultures were expanded in interleukin (IL)-2-containing medium (30% MLA144 culture supernatant, 10 U/mL human recombinant IL-2). Restimulation with a mixture of allogeneic phytohemagglutinin (PHA)-activated (10 µg/mL for 1 hour at 37°C) and irradiated (3000 rad) PBMCs and the autologous LCL (9:1 ratio) was used for large-scale expansion. The EBV specificity of the cultures was tested in standard 4-hour 51Cr-release assays using a panel of targets including the autologous LCLs, allogeneic LCLs matched through 1 or several MHC class I alleles, mismatched LCLs, and donor PHA-activated blasts.CTL infusions EBV-CTLs were given to the patients when the virus load reached or exceeded an arbitrarily set level of 1 EBV genome in 103 cells, or when sufficient numbers of cells became available. In standard protocols, the patients received 4 weekly doses of approximately 107 cells/m2 by IV infusion. The CTL cultures were washed extensively in phosphate-buffered saline before infusion. Tests performed at the time of injections confirmed that the cells were free of bacteria, Mycoplasma contamination, and infectious EBV and did not contain reverse transcriptase activity.
Monitoring of EBV-DNA load The EBV-DNA load was monitored by semiquantitative PCR in 5 recipients of HLA-mismatched TCD bone marrow grafts and 4 recipients of unmanipulated HLA-compatible bone marrow. All donor-recipient pairs were EBV seropositive as determined by detection of serum IgG antibodies to viral capsid antigen before the initiation of workup procedures (data not shown). Table 1 summarizes the clinical characteristics of the patients. Monitoring was initiated within 2 to 3 weeks after transplantation and was continued at regular intervals for at least 100 days and up to 450 days. Pretransplant levels of EBV-DNA were measured in some cases, depending on the availability of material, and were found to be within the range detected by our PCR assays in PBMCs from healthy EBV carriers (i.e., < 1 EBV genome in 106 cells).31 EBV-DNA titers greater than 1 genome/105 cells were detected in all patients within 3 weeks after BMT, at which time bone marrow engraftment was also confirmed. In 4 patients receiving TCD grafts and 1 WAS patient receiving an unmanipulated graft, the EBV-DNA load showed a rapid increase, reaching 1 genome in 6.4 cells (patients 1 and 6), 1 genome in 32 cells (patients 2 and 4), and 1 genome in 160 cells (patient 3) within 31 to 130 days after grafting (Figures 1-5). In the fifth patient receiving a TCD graft, CTL therapy was initiated at day 31 after BMT when the PCR assay detected an EBV-DNA load of 1 genome in 800 cells (Figure 6). In 3 patients receiving unmanipulated grafts (patients 7, 8, and 9), the viral load did not exceed 1 genome in 4000 cells during observation periods ranging between 120 and 336 days after BMT (Figure 7). Although recipients of HLA-mismatched grafts received a stronger immunosuppressive regimen, as a rule, there was no obvious correlation between the amount of medication and the magnitude of EBV-DNA load during the posttransplant period. This is illustrated by the comparison of serum CsA levels and EBV-DNA loads in patients 1, 5, and 6. Administration of antiviral therapy either at the time of BMT (patients 2 and 6) or after detection of elevated CMV-DNA and/or EBV-DNA titers (patients 1, 2, and 4) had no apparent effect on the EBV-DNA load.
Generation of EBV-specific CTL lines EBV-specific CTL lines were initiated before BMT in 6 patients considered to be at risk of EBV-PTLD because of T-cell depletion of the grafts or congenital immunodeficiency. Donor lymphocytes were stimulated with the autologous B95.8 virus-transformed LCL according to standard protocols developed in our laboratory. After 3 consecutive restimulations, each CTL line was tested against autologous and allogeneic HLA class I-matched or -mismatched LCLs and autologous PHA blasts. Representative experiments illustrating the cytotoxic activity at the time of CTL transfer are shown in Figure 8. All CTL lines lysed the autologous LCLs in standard 4-hour 51Cr-release assays (32% to 58% specific lysis at a 10:1 effector-target ratio). In 4 cases (donors 1, 2, 3, and 6), the pattern of cytotoxic activity corresponded to that observed in EBV-specific cultures; that is, virtually no lysis of HLA-mismatched LCLs and autologous or allogeneic PHA blasts (data not shown) and variable levels of killing of LCLs matched through single HLA class I alleles. It was shown previously that the level of lysis against allogeneic HLA-matched LCLs correlates with the immunogenicity of the presented epitopes and with variations in the EBV-specific CTL repertoire of the responder.34 The CTL culture from donor 5 appeared to be EBV specific in that it lysed the autologous LCL but not a panel of HLA-mismatched LCLs, but the class I restriction could not be determined because of lack of appropriate single matched targets. The CTL culture from donor 4 lysed equally well the autologous and allogeneic class I-matched or -mismatched LCLs. This pattern of recognition corresponds to that observed in cultures containing lymphokine activated killing activity and is probably due to failure to achieve a significant enrichment of EBV-specific CTLs.
Effect of CTL therapy on EBV-DNA load Previous reports have shown that detection of EBV-DNA titers exceeding the normal levels by at least 3 to 4 logs is highly predictive of EBV-PTLD. Therefore, in patients 1, 2, 3, 4, and 6, infusions of donor-derived CTL lines were initiated at the earliest possible time after detection of EBV-DNA titers exceeding an arbitrarily set threshold of 1 genome in 103 cells. Patient 5 received CTL infusions at the earliest possible time after transplantation. The treatment was initiated already at day 31 after BMT. Patients 3 and 4 received only 2 CTL infusions because of shortage of cells or unavailability of the patient, whereas the other patients received all 4 infusions. The weekly interval between infusions was occasionally prolonged, pending availability of sufficient numbers of CTLs. In patient 5, the last infusion was postponed for 2 weeks because of fever, pancytopenia, and a limited reactivation of acute GVHD of the skin, which also coincided with tapering of ongoing prednisolone medication (Figure 6). None of the other patients had clinical symptoms of GVHD in connection with or after the CTL infusions. In patients 1, 2, 3, and 6, the infusions were followed by a 2- to 4-log decrease of EBV-DNA titers within 3 to 4 weeks of the first CTL infusion. In patient 1, the EBV-DNA load remained relatively stable during the subsequent observation period of 273 days. In patients 2, 3, and 6, the initial decrease of EBV-DNA titers was followed by a slow increase in titers, which eventually culminated in new peaks registered at 243, 366, and 248 days after BMT, respectively. A spontaneous decrease of EBV-DNA titers was documented in patients 2 and 3, whereas additional tests could not be performed in patient 6. Patient 5, who received CTL transfer early after BMT, did not reach the high EBV-DNA load observed in other recipients of TCD grafts but remained within values ranging between 1 genome in 4 × 103 to 105 cells during the entire observation period of 215 days. The adoptive T-cell transfer had no obvious effect in patient 4, who received a CTL culture lacking a clear EBV-specific component. This patient died shortly after the last CTL infusion from a disseminated EBV-positive non-Hodgkin lymphoma (NHL) (see Figure 4 for details). None of the remaining patients developed PTLD during follow-up. Patient 3 died in a relapse of his T-cell ALL 16 months after transplantation. The other patients were still disease free 471 to 568 days after transplantation.
The results of this study support the notion that infusions of EBV-specific CTLs are effective in the prophylaxis of EBV-associated immunoblastic lymphomas in patients receiving TCD HLA-mismatched bone marrow grafts from EBV-seropositive donors. Furthermore, the design of our study, with monitoring of EBV-DNA load in peripheral blood initiated within the first 2 to 3 weeks after BMT, yielded interesting new insights into the early dynamics of EBV reactivation and the correlation between the rise in virus titers and the type of graft and amount of immunosuppressive therapy administered to these patients.
We wish to thank the patients and their families and the personnel at the Departments of Pediatrics, Center of Allogeneic Stem Cell Transplantation, and Outpatient Units at Huddinge Hospital who made this work possible by collecting samples and providing competent and compassionate medical care.
Submitted April 22, 1999; accepted September 30, 1999.
Supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation, the Foundation for Strategic Research, and the Karolinska Institute, Stockholm, Sweden.
A.G. and V.L. contributed equally to this work.
Reprints: Maria G. Masucci, Microbiology and Tumor Biology Center, Karolinska Institute, Box 280, 171 77 Stockholm, Sweden; e-mail: maria.masucci{at}mtc.ki.se.
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.
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H.-J. Wagner, Y. C. Cheng, M. H. Huls, A. P. Gee, I. Kuehnle, R. A. Krance, M. K. Brenner, C. M. Rooney, and H. E. Heslop Prompt versus preemptive intervention for EBV lymphoproliferative disease Blood, May 15, 2004; 103(10): 3979 - 3981. [Abstract] [Full Text] [PDF]
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P. Meij, J. W. J. van Esser, H. G. M. Niesters, D. van Baarle, F. Miedema, N. Blake, A. B. Rickinson, I. Leiner, E. Pamer, B. Lowenberg, et al. Impaired recovery of Epstein-Barr virus (EBV)--specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease Blood, June 1, 2003; 101(11): 4290 - 4297. [Abstract] [Full Text] [PDF]
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H. E. Heslop, F. K. Stevenson, and J. J. Molldrem Immunotherapy of Hematologic Malignancy Hematology, January 1, 2003; 2003(1): 331 - 349. [Abstract] [Full Text] [PDF]
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B. Savoldo, M. H. Huls, Z. Liu, T. Okamura, H.-D. Volk, P. Reinke, R. Sabat, N. Babel, J. F. Jones, J. Webster-Cyriaque, et al. Autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection Blood, December 1, 2002; 100(12): 4059 - 4066. [Abstract] [Full Text] [PDF]
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J. W. J. van Esser, H. G. M. Niesters, B. van der Holt, E. Meijer, A. D. M. E. Osterhaus, J. W. Gratama, L. F. Verdonck, B. Lowenberg, and J. J. Cornelissen Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation Blood, May 29, 2002; 99(12): 4364 - 4369. [Abstract] [Full Text] [PDF]
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C. Rossig, C. M. Bollard, J. G. Nuchtern, C. M. Rooney, and M. K. Brenner Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy Blood, March 15, 2002; 99(6): 2009 - 2016. [Abstract] [Full Text] [PDF]
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B. C. Gartner, H. Schafer, K. Marggraff, G. Eisele, M. Schafer, K. Roemer, H.-J. Laws, M. Sester, U. Sester, H. Einsele, et al. Evaluation of Use of Epstein-Barr Viral Load in Patients after Allogeneic Stem Cell Transplantation To Diagnose and Monitor Posttransplant Lymphoproliferative Disease J. Clin. Microbiol., February 1, 2002; 40(2): 351 - 358. [Abstract] [Full Text] [PDF]
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B. Savoldo, M. L. Cubbage, A. G. Durett, J. Goss, M. H. Huls, Z. Liu, L. Teresita, A. P. Gee, P. D. Ling, M. K. Brenner, et al. Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals J. Immunol., January 15, 2002; 168(2): 909 - 918. [Abstract] [Full Text] [PDF]
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J. W. J. van Esser, B. van der Holt, E. Meijer, H. G. M. Niesters, R. Trenschel, S. F. T. Thijsen, A. M. van Loon, F. Frassoni, A. Bacigalupo, U. W. Schaefer, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT Blood, August 15, 2001; 98(4): 972 - 978. [Abstract] [Full Text] [PDF]
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S. J. C. Stevens, I. Pronk, and J. M. Middeldorp Toward Standardization of Epstein-Barr Virus DNA Load Monitoring: Unfractionated Whole Blood as Preferred Clinical Specimen J. Clin. Microbiol., April 1, 2001; 39(4): 1211 - 1216. [Abstract] [Full Text]
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E. J. Wagar, M. A. Cromwell, L. D. Shultz, B. A. Woda, J. L. Sullivan, R. M. Hesselton, and D. L. Greiner Regulation of Human Cell Engraftment and Development of EBV-Related Lymphoproliferative Disorders in Hu-PBL-scid Mice J. Immunol., July 1, 2000; 165(1): 518 - 527. [Abstract] [Full Text] [PDF]
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M. Brenner, C. Rossig, U. Sili, J. W. Young, and E. Goulmy Transfusion Medicine: New Clinical Applications of Cellular Immunotherapy Hematology, January 1, 2000; 2000(1): 356 - 375. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
1·d
