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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-04-1096.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 3950-3959
GENE THERAPY
Tumor suppression induced by intratumor administration of
adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte
growth factor, and naive dendritic cells
Toshiaki Kikuchi,
Makoto Maemondo,
Koh Narumi,
Kunio Matsumoto,
Toshikazu Nakamura, and
Toshihiro Nukiwa
From the Department of Respiratory Oncology and
Molecular Medicine, Division of Cancer Control, Institute of
Development, Aging and Cancer, Tohoku University, Sendai, Japan; and
the Division of Molecular Regenerative Medicine, Course of Advanced
Medicine, Osaka University Graduate School of Medicine, Suita, Osaka,
Japan.
NK4, a 4-kringle antagonist of hepatocyte growth factor (HGF), is a
potent inhibitor of tumor angiogenesis and functions independently of
its HGF-antagonistic activity. We have shown previously that in vivo
genetic modification of tumors with an adenovirus vector that expresses
NK4 (AdNK4) restrains tumor angiogenesis and slows the rate of tumor
growth in vivo. In the present study, we investigated the hypothesis
that this can be made more efficient by also administering bone
marrow-generated dendritic cells (DCs) to the tumor. The data show
that the growth of mouse subcutaneous tumors is significantly suppressed by direct administration of DCs into established
tumors that had been pretreated with AdNK4 3 days previously. The
synergistic antitumor effect produced by the combination therapy of
AdNK4 with DCs correlated with the in vivo priming of tumor-specific cytotoxic T lymphocytes. Analysis of mice treated with
fluorescence-labeled DCs suggested that DCs injected into the
flank tumor could migrate to lymphoid organs in vivo for
activation of immune-relevant processes. Knockout mice experiments
demonstrated that the tumor regression produced by this combination
therapy depends on both major histocompatibility complex (MHC)
class I antigen presentation of DCs injected into the tumors and
CD8+ T cells of the treated host. Finally, a mechanism for
this synergism was suggested by the histological observation that tumor
necrosis and apoptosis were induced by genetic engineering of the
tumors to express NK4. These findings should be useful in designing
novel strategies that use a combination of 2 monotherapies
directed against the vascular and immune systems for cancer therapy.
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