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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1549-1555
Infusion of Cytotoxic T Cells for the Prevention and Treatment of
Epstein-Barr Virus-Induced Lymphoma in Allogeneic Transplant
Recipients
By
Cliona M. Rooney,
Colton A. Smith,
Catherine Y.C. Ng,
Susan K. Loftin,
John W. Sixbey,
Yanjun Gan,
Deo-Kumar Srivastava,
Laura C. Bowman,
Robert A. Krance,
Malcolm K. Brenner, and
Helen E. Heslop
From the Departments of Virology and Molecular Biology,
Biostatistics, and the Division of Bone Marrow Transplantation, St Jude
Children's Research Hospital, Memphis, TN; and the Departments of
Pathology and Pediatrics, University of Tennessee, Memphis, TN.
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ABSTRACT |
Epstein-Barr virus (EBV) causes potentially lethal immunoblastic
lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we
assessed the safety and efficacy of donor-derived polyclonal (CD4+ and CD8+) T-cell lines as
immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine
patients considered to be at high risk for EBV-induced lymphoma each
received 2 to 4 intravenous infusions of donor-derived EBV-specific T
lymphocytes, after they had received T-cell-depleted bone marrow from
HLA-matched unrelated donors (n = 33) or mismatched family members (n
= 6). The immunologic effects of this therapy were monitored during
and after the infusions. Infused cells were identified by detection of
the neo marker gene. EBV-specific T cells bearing the
neo marker were identified in all but 1 of the patients. Serial
analysis of DNA detected the marker gene for as long as 18 weeks in
unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six
patients (15.5%) had greatly increased amounts of EBV-DNA on study
entry (>2,000 genome copies/106 mononuclear cells),
indicating uncontrolled EBV replication, a complication that has had a
high correlation with subsequent development of overt lymphoma. All of
these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the
antiviral activity of the donor-derived cells. There were no toxic
effects that could be attributed to prophylactic T-cell therapy. Two
additional patients who did not receive prophylaxis and developed overt
immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal
donor-derived T-cell lines specific for EBV proteins can thus be used
safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of
established disease.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
AN INCREASED understanding of the
mechanisms by which T lymphocytes recognize virus- and tumor-specific
antigens1,2 has stimulated much interest in the use of
cytotoxic T cells as adoptive immunotherapy for viral and malignant
diseases.3-8 An early candidate for such treatment was
Epstein-Barr virus (EBV) infection. In immunocompetent hosts, EBV
causes a mild, self-limiting illness followed by a life-long period of
latency in which the activity of the virus in B cells is controlled by
the host's EBV-specific cytotoxic T cells.9 In otherwise
healthy persons, EBV may be related to the development of malignancies
such as Hodgkin's disease and nasopharyngeal
carcinomas.10-12 By contrast, in hosts with impaired T-cell
immunity, EBV can cause unchecked lymphoproliferation evolving to
immunoblastic lymphoma. This complication has developed in 1% to 25%
of transplant recipients, with the highest frequencies in patients
receiving bone marrow from mismatched family members or unrelated
donors, particularly if the marrow was depleted of T cells to prevent
graft-versus-host disease.13-17 In our own center, such
patients developed lymphoma with an incidence in the first year after
transplantation of 11.5% (7/61).18
Unselected populations of lymphocytes from the peripheral blood of the
donor usually contain EBV-specific T cells and therefore can be used to
control EBV lymphoproliferative disease.19,20 However, the
utility of such therapy is limited by potentially fatal complications
that arise from alloreactive T cells also present in the lymphocyte
infusion.19,20 To overcome this obstacle, we generated
EBV-specific T-cell lines from donor lymphocytes and used them as
prophylaxis against EBV-induced lymphoma in transplant recipients
considered at high risk for this disease. The infused T cells were
genetically marked so that their persistence and localization within
the body could be reliably monitored. The feasibility of this approach
was established in preliminary studies in which the gene-modified T
cells were shown to persist for extended periods in vivo and to retain
anti-EBV activity.21,22 We report here the results of a
trial of adoptive T-cell prophylactic therapy in 39 patients undergoing
bone marrow transplantation at St Jude Children's Research Hospital
(Memphis, TN).
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PATIENTS AND METHODS |
Patients.
Patients receiving T-cell-depleted bone marrow transplants from a
mismatched family member or closely matched unrelated donor between
June 1, 1993 and October 20, 1996 were eligible for this study.
Follow-up of enrolled patients ranged from 15 to 54 months posttransplantation. EBV-specific lines of cytotoxic T lymphocytes (CTLs) were successfully prepared for 69 of the 70 patients who received transplants during this time period. One donor was
seronegative and a CTL line could not be established. The recipient of
this marrow did not develop EBV-related problems.
Thirty-nine of these children subsequently became eligible for
immunoprophylaxis with the CTL lines and were enrolled in the study
(Table 1). Thirty-three had closely matched
unrelated marrow donors and 6 had mismatched family member donors. The
remaining patients were excluded because of active graft-versus-host
disease (GVHD; n = 1), pneumonitis (n = 6), diseases recurrence (n = 6), death before day 45 (n = 7), graft failure (n = 2), veno-occlusive disease (n = 1), intercurrent infection (n = 4), or refusal to participate (n = 3). Donor marrow was depleted of T cells using anti-T-cell monoclonal antibodies CD6 and CD8 as previously
described,23 and all patients received cyclosporin A to
maintain targeted plasma concentrations.23 Sixty-one other
recipients who were treated either before the availability of EBV-CTL
or who did not receive prophylaxis because they were ineligible or
declined consent, were controls. The clinical characteristics of these
patients closely matched those of the study group. Blood from patients was monitored at regular intervals for EBV-DNA levels, marker gene
levels, and immunologic assessment (see below). The clinical protocol24 was approved by the St Jude Institutional Review Board, the Recombinant DNA Advisory Committee of the National Institutes of Health, and the Food and Drug Administration.
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Table 1.
Clinical Characteristics of 100 Patients Who Received
Allogeneic Transplants With or Without Subsequent Infusions of
Prophylactic Cytotoxic T Cells
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Preparation and administration of gene-marked T-cell lines.
The preparation of EBV-specific CTLs has been described in detail
previously.21,25 In summary, EBV-specific T-cell lines were
prepared from fresh or frozen samples of peripheral blood (20 mL each)
collected from donors on the day of marrow harvest. Donor-derived
peripheral blood mononuclear cells were plated in growth medium at 2 × 106 cells per well and stimulated with 5 × 104 irradiated autologous lymphoblastoid cells. Live cells
isolated 10 days later were subcultured at 5 × 105
per well and restimulated with irradiated lymphoblastoid cells at 1.25 × 105 per well. Four days later, the cultures were
treated with interleukin-2 (Proleukin; Chiron, Emoryville, CA) at 20 U/mL. They continued to be expanded with interleukin-2 (3 times a week,
each time at 20 U/mL) and restimulated weekly with irradiated
autologous lymphoblastoid cells at a T lymphocyte:B lymphoblastoid cell
ratio of 4:1. When sufficient numbers of cytotoxic T lymphocytes were
attained, the cells were transduced with the neo-containing
G1Na retroviral vector (Genetic Therapy, Inc, Gaithersberg, MD), which
confers resistance to neomycin and its G418 analogue. The efficiency of transduction ranged from 1% to 10%, as determined by semiquantitative polymerase chain reaction (PCR) analysis.25
Before cryopreservation, T cells were examined for EBV specificity,
immunophenotype, HLA compatibility, sterility, and the presence of
competent retrovirus, as previously described.25 Samples
with satisfactory test results were thawed rapidly at 37°C and
administered intravenously to patients at a median of 88 days
posttransplantation. By protocol design, 6 patients received 4 doses of
1 × 107 cytotoxic T cells/m2 and 6 others
received 2 doses of 1 × 107 cytotoxic T
cells/m2 and 2 doses of 5 × 107
cells/m2. Because both these dose levels appeared safe and
efficacious, all remaining patients received 2 doses of 2 × 107 cells/m2. The phenotype of the infused
lines is shown in Table 2.
Detection of EBV DNA.
Peripheral blood mononuclear cells (PBMCs) were isolated on lymphocyte
separation medium (Nycomed, Oslo, Norway) from blood samples (10 to 40 mL each) that were collected weekly postinfusion for 6 weeks, monthly
for 1 year, and then every 3 months for 2 years. DNA was then isolated
on an anion exchange column (Qiagen) from 1 × 106 to
107 mononuclear cells, and samples of 0.01 to
103 ng were amplified with primer sequences that detect a
single copy of an EBV-DNA BamHI-H segment, as previously
described.21 Positivity was defined as a detectable
EBV-specific signal on Southern blotting compared with 0.01 ng of DNA
from BL2/B95-8 or IB4 cells (which both contain 2 integrated EBV
genomes per cell) diluted in 1 µg of DNA from an EBV-genome-negative
cell line, BL41 (2 copies).
Monitoring of infused T-cell lines.
To detect neo-positive cells in vivo, we analyzed DNA by the
same PCR technique used to estimate the proportion of infused cells
bearing the neo marker gene.26 Control DNA was
prepared by diluting G1Na-transduced K-562 cells (1 integrant per cell) with nontransduced cells to give mixtures containing 0.01% to 10%
neo-positive cells.
Spontaneous outgrowth of EBV+ B lymphocytes.
Where sufficient PBMCs were available, we used the spontaneous
outgrowth of EBV-positive B cells ex vivo as an additional functional
measure of the onset of uncontrolled EBV-driven lymphoproliferation. As
previously reported, such outgrowth occurs within 3 weeks of culture
initiation, when the development of overt immunoblastic lymphoma is
imminent.25
In brief, PBMCs were cultured at doubling dilution from 6 × 105/mL well to 7.5 × 104/mL in complete
medium in the absence of additional stimuli or cyclosporin. The
cultures were examined at weekly intervals, and outgrowing cells were
stained with CD19, LMP1, and EBNA 2-specific antibodies.
Limiting dilution analysis of EBV-specific precursor frequency.
PBMCs were seeded at between 5 × 105 and 500 cells/well in 96-well plates with a dilution factor of 2. Each well was
stimulated with 104 irradiated donor lymphoblastoid cell
line (LCL) (40 Gy); when PBMC dilutions reached 105 cells
or lower, 5 × 104 irradiated (30 Gy) autologous PBMCs
were added as feeder cells. After 3 to 6 weeks in culture, responder
cells were present in sufficient numbers to allow the cultures to be
assayed for cytotoxic activity against autologous LCL and HLA class I
mismatched targets. Target cells were labeled with 51Cr,
and lysis of 10% of the cells or greater was taken to indicate a
positive well, because this value exceeded the spontaneous release of
51Cr by 3 standard deviations. The frequency of CTL
precursors was estimated from the slope of a regression plot of the log
percentage of negative wells versus the number of responder
lymphocytes.
Cytotoxic activity of donor-derived EBV-specific CTL lines.
The cytotoxicity of each CTL line was analyzed in a standard 4-hour
chromium-5l release assay. Target cells included autologous and
HLA-class I-mismatched LCL and the T-cell line HSB-2, which is
sensitive to killing by lymphokine-activated killer cells. After
labeling with chromium-51, the target cells were washed 5 times and
plated at 5 × 103 cells per well with
effector cells to give effector:target ratios of 40:1, 20:1, 10:1, and
5:1. After 4 hours, supernatants were harvested and chromium release
was measured to determine specific cytotoxicity. To determine whether
cytolysis was restricted by HLA class I, target cells were preincubated
for 30 minutes with 16.5 ng/mL of W6/32 (Dako, Carpinteria, CA), a
monoclonal antibody that recognizes a monomorphic HLA class I
determinant. In some cases, the presence of HLA class II-restricted
CTLs was measured using CR3/43 (Dako), which recognizes HLA-DR, DP, DQ,
and DX as the blocking antibody. Where no antibody inhibition was
obtained, the experiments were repeated after depletion of
CD56+ and CD16+ cells to remove nonspecific
natural killer/antibody-dependent cellular cytotoxicity (NK/ADCC)
effectors.
In situ PCR analysis of tumor-infiltrating neo-positive
cells.
To document the presence of infused EBV-specific T cells in tumor
tissue, we examined biopsied tumor specimens in paraffin for
neo-bearing cells using PCR in situ, as described in detail elsewhere.27 After 30 cycles of amplification on a Hybaid
Omnislide thermocycler (National Labnet Co, Woodbridge, NJ), the
preserved material was hybridized to an oligonucleotide probe internal
to primer sequences26 that had been 3 end-labeled
with digoxigenin (Boehringer Mannheim, Indianapolis, IN) according to
the manufacturer's instructions. Bound probe was detected by
antidigoxigenin antibody conjugated to alkaline phosphatase (Boehringer
Mannheim). Paraffin-embedded BL2 and G1Na-transduced K562 served as
negative and positive controls, respectively.
Toxicity monitoring.
All patients received their infusions of gene-marked T cells in the BMT
unit or outpatient clinic of St Jude Children's Research Hospital,
where their vital signs were monitored before and immediately after
each infusion. Complete blood counts were obtained, and liver function
was evaluated 1 day after each infusion and then twice weekly until day
30. GVHD was graded by standard criteria.28
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RESULTS |
A total of 39 patients could be assessed for their responses to
infusions of EBV-specific cytotoxic T-cell lines administered as
immunoprophylaxis against EBV-related lymphoma (Table 1). We also
report the responses of 2 patients who did not receive prophylactic CTL
therapy (1 ineligible and 1 declined consent) and subsequently
developed EBV lymphoma. CTL lines were successfully generated from 69 of 70 donors. A CTL line could not be generated from the single
EBV-seronegative donor. Antibody inhibition studies showed that the CTL
lines were class I HLA-restricted in 77% of cases. In cell lines with
apparently unrestricted killing, removal of CD56+ and
CD16+ invariably showed HLA class I-restricted killing.
Some of the lines contained both HLA class I- and class II-restricted
killing, but none of the lines was exclusively HLA class II-restricted.
Reconstitution of T-cell-mediated immunity to EBV.
We have reported that gene-marked, EBV-specific CTLs can be readily
detected for prolonged periods after their infusion into patients.22 We sought to determine if such immune
reconstitution is a consistent outcome of CTL therapy. In fact,
gene-marked T cells were found in the peripheral blood of patients for
a median of 11 weeks (range, 7 to 18 weeks) and in regenerated
EBV-specific T-cell lines for up to 38 months. Measurement of the CTL
precursor frequency in 12 patients (Table
3) showed a median 32-fold increase (range, 2- to >500-fold) 1 month
after completion of infusion, reaching levels equivalent those found in
the normal range.29 The majority of patients had CTLp
levels considerably below the normal range before CTL infusion. In the
3 patients with higher levels (including unique patient no. [UPN] 345 with both high CTLp and an elevated EBV DNA), the activity was likely
to be nonspecific, because precursor frequency against HLA-mismatched
targets was as high or higher than that against autologous targets.
After treatment, the CTLp frequency for autologous LCL increased to a
much greater extent than did the frequency of CTLp for allogeneic CTLs.
Direct evidence of antiviral and antitumor activity.
Six of the patients (15.5%) had high EBV-DNA levels before study
entry. High levels of EBV-DNA result from poorly controlled EBV
reactivation and are highly predictive of the onset of overt immunoblastic lymphoma.30-32 In the control group, who did
not receive EBV-CTLs, 11.5% (7/61) of the recipients of
T-cell-depleted unrelated/mismatched donor marrow developed high
levels of EBV-DNA (>2,000 genomes per 1 × 106
mononuclear cells) after transplantation, and all rapidly progressed to
overt lymphoma.30 Table 4 shows
details of the 6 patients in the CTL group who developed increased
levels of EBV-DNA (>2,000 genomes per 1 × 106
mononuclear cells) early in the posttransplantation course, before administration of CTLs. Sequential molecular analysis of EBV-DNA in
these patients' peripheral blood showed direct evidence for the
antiviral action of the infused donor-derived T-cell lines, because
EBV-DNA levels decreased by 3 to 5 logs within 2 to 3 weeks of the
first T-cell infusion. In addition, spontaneously growing lines of
EBV-transformed B cells could no longer be derived from peripheral
blood (Table 4). None of the treated patients developed EBV lymphoma,
in contrast to the uniform occurrence of this complication in the
patients who had high EBV-DNA levels and/or spontaneous
transformation and did not receive CTL.30
The most compelling illustration of the efficacy of our cytotoxic
T-cell lines was provided by 2 patients who received their infusions
after the onset of overt lymphoma. There was a complete and sustained
response in both. The first patient has been previously reported.21 In the second patient we were able to quantify
the marker gene in tumor biopsies to demonstrate unequivocally that the
infused T-cell line was present at sites of tumor destruction. This
11-year-old boy declined the prophylaxis study and subsequently developed bulky cervical and nasopharyngeal lymphomatous disease at 210 days posttransplantation that was characterized by the presence of
EBV-specific antigens and CD20+ B lymphoblasts
(Fig 1). Treatment with infusions of
stored, EBV-specific cytotoxic T lymphocytes was begun immediately with
informed parental consent. A follow-up biopsy examination, performed 10 days after the patient had received 2 × 107 cytotoxic
T cells/m2, showed an infiltrate of smaller lymphocytes,
primarily CD3+ T cells (Fig 1). One percent of these cells
carried the neo marker gene, a proportion identical to that
found in the EBV-specific cell line that had been administered to the
patient (Figs 2 and 3). By contrast, fewer than 0.01% of the
circulating peripheral blood mononuclear cells contained the
neo marker (Fig 3). Thus, EBV-specific T lymphocytes from the
infused cell line had infiltrated this lymphoma, either accumulating or
selectively expanding at the tumor site. The inflammatory response
associated with this immune infiltrate produced airways obstruction and
mucosal sloughing, necessitating mechanical ventilation. However, the
child made a full recovery and remains in remission at 24 months after
the last T-cell infusion.
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| Fig 1.
Comparison of tumor biopsy samples before and after
adoptive T-cell therapy for EBV lymphoma in an 11-year-old boy who had
undergone allogeneic bone marrow transplantation from a matched
unrelated donor. The initial specimen had the histologic appearance of
immunoblastic lymphoma (a; hematoxylin and eosin). Most of the cells
reacted to staining for the CD20 B-cell marker (b), whereas a few were
positive for the T-cell marker (c). After adoptive immunotherapy, the
follow-up biopsy showed an infiltrate of smaller lymphocytes, the
majority of which reacted with the T-cell marker (d through f).
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| Fig 2.
In situ PCR analysis of tumor-infiltrating lymphocytes
illustrated in Fig 1d through f. The neo gene was detected in
1% of the infiltrating lymphocytes, a rate that corresponds to the
gene-marking efficiency for the EBV-specific T-cell line administered
to this patient.
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| Fig 3.
Semiquantitative PCR analysis of lymphocytes infiltrating
the tumor and in peripheral blood. One percent of the lymphocytes
infiltrating the second nasopharyngeal biopsy was positive for the
marker gene, compared with a level of 0.01% to 0.001% in a peripheral
blood sample taken on the same day. The results of PCR analysis for the
actin gene are provided for comparison of equal amounts of
DNA.
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Safety of T-cell infusions.
None of the patients had appreciable changes in liver function, renal
function, or chest x-ray appearances during the administration of
cytotoxic T cells. Acute GVHD did not appear de novo in any patient
after an infusion of T cells, although in 1 child there was
exacerbation of pre-existing chronic GVHD. Twenty-seven of the patients
in the prophylaxis study remain alive 15 to 54 months after
transplantation (mean follow-up, 30 months). Twelve patients have died:
9 from relapse, 2 from infection, and 1 from pneumonitis.
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DISCUSSION |
These results support the belief that infusions of EBV-specific
CD4+ CD8+ T cells are effective as prophylaxis
or treatment for EBV-associated immunoblastic lymphoma. Six patients
received infusions of EBV-CTLs in the presence of extremely high levels
of circulating EBV-DNA (>2,000 genome copies/106
mononuclear cells). None subsequently developed lymphoma, in contrast
to the uniform association between this complication and similarly
elevated EBV-DNA levels in previous studies.18,30 Indeed,
in the group receiving cytotoxic T cells, the elevated levels of viral
DNA returned to normal within 3 weeks after the first infusion.
Overall, 0 of 39 patients receiving CTL prophylaxis developed EBV
lymphoma, compared with an incidence of 11.5% (7/61) in the control
group in our own center. It is noteworthy that infusion of CTLs was
effective at reducing EBV-DNA levels even in a patient with apparently
high levels of CTLp. However these CTLp were likely to be nonspecific.
Such activity would not be expected to be as effective as specific CTLs
in preventing EBV-driven lymphoproliferation and could therefore
coexist with a high viral load. This patient, UPN 345, had a high EBV
viral load, malaise, and fevers and all symptoms resolved after CTL
administration. Although we cannot rule out the possibility that the
decrease in viral load was a result of recovery of endogenous
EBV-specific immunity, our own results and data from other
groups15 have shown that endogenous recovery does not
usually occur in the first 3 months after transplantation.
The most direct evidence that T cells restore antiviral and antitumor
immunity comes from the eradication of frank EBV lymphoma in 2 children
who did not receive prophylactic CTLs. In the second child, we were
able to demonstrate the infiltration, accumulation, and expansion of
gene-marked T cells within the tumor site, as well as the association
between such infiltration and the destruction of EBV-positive B
lymphoblasts. However, marked local inflammatory and necrotic reactions
associated with the rapid expansion of infused T cells in the
nasopharynx necessitated prolonged mechanical ventilation, suggesting
that the use of CTLs to prevent lymphoma in transplant recipients is
preferable and more cost effective than treatment of established
disease.
We postulate that the high degree of in vivo expansion and long-term
persistence of the infused T lymphocytes were a consequence of both the
continued presence of viral antigen and the use of polyclonal lines
containing both CD4+ and CD8+ cells, rather
than CD8+ T-cell clones alone.22 It has been
argued on theoretical grounds that single clones are preferable to
multiple clones because of their lower probability of containing cells
that cross-react with normal host antigens.33 However, in a
number of different human and murine systems, CD4+ cells
have been shown to play a crucial role in establishing or maintaining
CD8+ T-lymphocyte-mediated antiviral or antitumor
immunity.34,35 Hence, the lack of CD4+
virus-specific helper T cells may limit the capacity of the
CD8+ T-cell clones to survive for extended periods or to be
recalled should viral reactivation occur late in the clinical course.
We cannot rule out the possibility that our polyclonal lines contain T
cells that cross-react with host alloantigens; however, none of the
T-cell infusions was associated with GVHD induction.
What are the practicalities of preparing cytotoxic T lymphocytes for
the prevention or treatment of EBV-related immunoblastic lymphoma in
allogeneic transplant recipients? Because EBV is ubiquitous and
persistent, a majority of donors carry a high frequency of EBV-specific
cytotoxic T-cell precursors that can be readily reactivated and
expanded in vitro for infusion into patients requiring bone marrow
transplantation. Unique target antigens against which the T cells can
be directed are provided by the 9 virus-encoded latency-associated proteins expressed by EBV-infected tumor cells.9 Hence,
specific T-cell lines that meet the necessary criteria for infusion
could be routinely generated; in our study, viable T-cell lines were generated from more than 98% of the donors. Moreover, because the
infused cells can be expected to expand markedly in vivo and persist in
the circulation for extended periods, the preparation and infusion of
even limited numbers of T-lymphocyte precursors (2 × 107/m2) is adequate to bring the frequency of
EBV-specific T cells into the normal range, thus preventing or aborting
EBV reactivation.
One of the drawbacks of our approach is the time required to generate
CTL lines. It may be possible to simplify and accelerate the production
of cytotoxic T cells by substituting dendritic cells that express EBV
antigens for EBV-positive lymphoblastoid cell lines, such as those used
in the present study. Dendritic cells can be prepared in 7 to 10 days,36,37 rather than the 4 weeks normally required for
lymphoblastoid cells, and could then be used to stimulate T-lymphocyte
responses not only to the set of latency antigens expressed by LCL, but
also to the more restricted set of EBV antigens expressed by cells
common to Hodgkin's disease and nasopharyngeal
carcinoma.38 Dendritic cells can also induce primary immune
responses that may allow generation of EBV-specific CTL lines from
seronegative donors.37 However, because the virus in
EBV-driven lymphoproliferations of allogeneic bone marrow transplant
recipients usually derives from the donor marrow, recipients of
seronegative marrow may be low risk for EBV.
We estimate a total cost of less than $4,000 to prepare and validate
each separate T-cell line. This expense compares favorably with that of
chemoprophylaxis for other viral diseases that commonly arise after
bone marrow transplantation and is substantially less than the cost of
treating established immunoblastic lymphoma. Thus, the strategy of
antiviral prophylaxis we have outlined would be feasible for routine
clinical application in patients at high risk for development of
EBV-related cancers, and perhaps in other malignancies in which viral
antigens are readily found. The overall effectiveness of this approach
may now be assessed in a prospective randomized trial.
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FOOTNOTES |
Submitted January 12, 1998;
accepted May 1, 1998.
Supported by Grants No. P 30CA 21765 and CA 61384 from the National
Cancer Institute, by the Assisi Foundation of Memphis, and by the
American Lebanese Syrian Associated Charities (ALSAC).
Address reprint requests to Cliona M. Rooney, PhD, Center for Cell and
Gene Therapy, Baylor College of Medicine, 1102 Bates St, Suite 1100, Houston, TX 77030.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
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ACKNOWLEDGMENT |
The authors thank John Gilbert for scientific editing and the staff of
the BMT inpatient and outpatient units for clinical care of these
patients.
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Abstract
Introduction
Abstract