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Blood, 15 July 2001, Vol. 98, No. 2, pp. 287-295
GENE THERAPY
Development of herpes simplex virus-1 amplicon-based
immunotherapy for chronic lymphocytic leukemia
Khaled A. Tolba,
William J. Bowers,
Shannon P. Hilchey,
Marc W. Halterman,
Darlene F. Howard,
Rita E. Giuliano,
Howard J. Federoff, and
Joseph D. Rosenblatt
From the Departments of Medicine, Neurology,
Microbiology and Immunology, University of Rochester Cancer Center; and
the Center for Aging and Developmental Biology, University of Rochester
School of Medicine and Dentistry, Rochester, NY.
Herpes simplex virus (HSV)-based vectors have favorable biologic
features for gene therapy of leukemia and lymphoma. These include high
transduction efficiency, ability to infect postmitotic cells, and large
packaging capacity. The usefulness of HSV amplicon vectors for the
transduction of primary human B-cell chronic lymphocytic leukemia (CLL)
was explored. Vectors were constructed encoding  -galactosidase
(LacZ), CD80 (B7.1), or CD154 (CD40L) and were packaged using either a standard helper virus (HSVlac, HSVB7.1, and
HSVCD40L) or a helper virus-free method (hf-HSVlac, hf-HSVB7.1, and
hf-HSVCD40L). Both helper-containing and helper-free vector stocks were
studied for their ability to transduce CLL cells, up-regulate
costimulatory molecules, stimulate allogeneic T-cell proliferation in a
mixed lymphocyte tumor reaction, and generate autologous cytotoxic
T lymphocytes (CTLs). Although helper-containing and
helper-free amplicon stocks were equivalent in their ability to
transduce CLL cells, a vigorous T-cell proliferative response was
obtained using cells transduced with hf-HSVB7.1 but not with HSVB7.1.
CLL cells transduced with either HSVCD40L or hf-HSVCD40L were compared
for their ability to up-regulate resident B7.1 and to function as
T-cell stimulators. Significantly enhanced B7.1 expression in response
to CD40L was observed using hf-HSVCD40L but not with HSVCD40L. CLL
cells transduced with hf-HSVCD40L were also more effective at
stimulating T-cell proliferation than those transduced with HSVCD40L
stocks and were successful in stimulating autologous CTL activity. It
is concluded that HSV amplicons are efficient vectors for gene therapy
of hematologic malignancies and that helper virus-free HSV amplicon
preparations are better suited for immunotherapy.
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