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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-02-0391.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 649-654
NEOPLASIA
Immunotherapy with a posttranscriptionally modified DNA vaccine
induces complete protection against metastatic neuroblastoma
Ursula Pertl,
Harald Wodrich,
J. Michael Ruehlmann,
Stephen D. Gillies,
Holger N. Lode, and
Ralph A. Reisfeld
From the Department of Immunology, The Scripps Research
Institute, La Jolla, CA; Department of Pediatrics, Charité
Children's Hospital, Berlin, Germany; and EMD-Lexigen
Research Center, Bedford, MA.
The successful induction of a T-cell-mediated tumor-protective
immunity against poorly immunogenic malignancies remains a major
challenge for cancer immunotherapy. We achieved this by immunization
with a tyrosine hydroxylase (mTH)-based DNA vaccine, enhanced with the
posttranscriptional regulatory acting RNA element (WPRE), derived from
woodchuck hepatitis virus in combination with an antibody-cytokine
fusion protein (ch14.18-IL-2) that targets interleukin-2 (IL-2) to the
tumor microenvironment. This DNA vaccine mTH-WPRE was carried by
attenuated Salmonella typhimurium and applied by oral
gavage in a mouse model of neuroblastoma. Mice immunized with the
mTH-WPRE vaccine, and which additionally received a boost with
suboptimal doses of ch14.18-IL-2, were completely protected against
hepatic neuroblastoma metastases. In contrast, all controls presented
with disseminated metastases. Both T-cell and natural killer (NK)
cell-dependent mechanisms were involved in the induction of a systemic
tumor-protective immunity. Thus, up-regulation of interferon-
(IFN-) expression in CD8+ T cells occurred only in those
animals that received the mTH-WPRE vaccine plus the ch14.18-IL-2
boost. Up-regulation of this proinflammatory cytokine was not observed
in mice immunized with mTH-WPRE vaccine alone. A role for NK cells was
indicated by the complete abrogation of systemic tumor-protective
immunity in all animals that were depleted of NK cells in vivo. Taken
together, these data demonstrate that immunization with a
posttranscriptionally enhanced DNA vaccine encoding the WPRE sequence,
combined with a boost of the ch14.18-IL-2 fusion protein, completely
protects against hepatic metastases in a murine model of neuroblastoma
and therefore may lead to a new strategy for immunotherapy and
prevention of metastatic neuroblastoma.
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