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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-01-0039.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4059-4066
IMMUNOBIOLOGY
Autologous Epstein-Barr virus (EBV)-specific cytotoxic T
cells for the treatment of persistent active EBV infection
Barbara Savoldo,
M. Helen Huls,
Zhensheng Liu,
Takayuki Okamura,
Hans-Dieter Volk,
Petra Reinke,
Robert Sabat,
Nina Babel,
James F. Jones,
Jennifer Webster-Cyriaque,
Adrian P. Gee,
Malcolm K. Brenner,
Helen E. Heslop, and
Cliona M. Rooney
From the Center for Cell and Gene Therapy, the
Departments of Pediatrics and of Medicine, Baylor College of Medicine,
Houston, TX; the Departments of Medical Immunology and Nephrology,
Charité Hospital, Humboldt-University of Berlin,
Germany; the Department of Pediatrics, National Jewish
Medical and Research Center, Denver, CO; and the Lineberger
Comprehensive Cancer Center, University of North Carolina at Chapel
Hill.
Chronic active Epstein-Barr virus (CAEBV) infection
syndrome is a heterogeneous EBV-related disorder characterized by
chronic fatigue, fever, lymphadenopathy, and/or hepatosplenomegaly,
associated with abnormal patterns of antibody to EBV. CAEBV can range
from disabling mild/moderate forms to rapidly lethal disorders. Even patients with mild/moderate disease frequently suffer adverse effects
from long-term anti-inflammatory agents and have a quality of life that
progressively deteriorates. It is still unknown why these individuals
are unable to produce an effective immune response to control EBV, and
no effective treatment is currently available. Since ex vivo-expanded
EBV-specific cytotoxic T lymphocytes (EBV-CTLs) can safely restore
EBV-specific cellular immune responses in immunodeficient patients,
we assessed the possibility that adoptive immunotherapy might also
effectively treat CAEBV infection. Following stimulation with
irradiated EBV-transformed lymphoblastoid cell lines (LCLs), EBV-CTLs were successfully generated from 8 of 8 patients with the
mild/moderate form of CAEBV infection. These CTLs were predominantly CD3+ CD8+ cells and produced specific killing
of the autologous LCLs. There were 5 patients with 1- to 12-year
histories of disease who were treated with 1 to 4 injections of
EBV-CTLs. Following infusion, there was resolution of fatigue and
malaise, disappearance of fever, and regression of lymphadenopathy and
splenomegaly. The pattern and titers of anti-EBV antibodies also
normalized. No toxicity was observed. There were 4 patients who did not
show any relapse of disease within 6 to 36 months follow-up; one
patient had recurrence of fatigue and myalgia one year after CTL
infusion. We suggest that adoptive immunotherapy with
autologous EBV-CTLs may represent a safe and feasible alternative
treatment for patients affected with mild/moderate CAEBV infection and
that this approach should be evaluated in the more severe forms of the disease.
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