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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-05-1514.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1905-1912
IMMUNOBIOLOGY
Generating CTLs against the subdominant Epstein-Barr virus LMP1
antigen for the adoptive immunotherapy of EBV-associated
malignancies
Stephen Gottschalk,
Oliver L. Edwards,
Uluhan Sili,
M. Helen Huls,
Tatiana Goltsova,
Alan R. Davis,
Helen E. Heslop, and
Cliona M. Rooney
From the Center for Cell and Gene Therapy, Texas
Children's Cancer Center, Departments of Pediatrics, Medicine, and
Molecular Virology and Microbiology, Baylor College of Medicine,
Houston, TX.
The Epstein-Barr virus (EBV)-encoded LMP1 protein is expressed in
EBV-positive Hodgkin disease and is a potential target for cytotoxic
T-lymphocyte (CTL) therapy. However, the LMP1-specific CTL frequency is
low, and so far the generation of LMP1-specific CTLs has required
T-cell cloning. The toxicity of LMP1 has prevented the use of dendritic
cells (DCs) for CTL stimulation, and we reasoned that an inactive,
nontoxic LMP1 mutant ( LMP1) could be expressed in DCs and would
enable the activation and expansion of polyclonal LMP1-specific CTLs.
Recombinant adenoviral vectors expressing LMP1 or LMP1 were tested
for their ability to transduce DCs. LMP1 expression was toxic within 48 hours whereas high levels of LMP1 expression were achieved with
minimal toxicity. LMP1-expressing DCs were able to reactivate and
expand LMP1-specific CTLs from 3 healthy EBV-seropositive donors.
LMP1-specific T cells were detected by interferon- (IFN-)
enzyme-linked immunospot assay (ELISPOT) assays using the
HLA-A2-restricted LMP1 peptide, YLQQNWWTL (YLQ). YLQ-specific T cells
were undetectable (less than 0.001%) in donor peripheral blood
mononuclear cells (PBMCs); however, after stimulation the frequency
increased to 0.5% to 3.8%. Lysis of autologous target cells by CTLs
was dependent on the level of LMP1 expression. In contrast, the
frequency of YLQ-specific CTLs in EBV-specific CTLs reactivated
and expanded using lymphoblastoid cell lines was low and no
LMP1-specific cytotoxic activity was observed. Thus, LMP1 expression
in DCs is nontoxic and enables the generation of LMP1-specific CTLs for
future adoptive immunotherapy protocols for patients with LMP1-positive
malignancies such as EBV-positive Hodgkin disease. Targeting LMP1 in
these malignancies may improve the efficacy of current adoptive
immunotherapy approaches.
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