| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Departments of
* Gene Therapy and
Urology, Chiba University Graduate School of Medicine, Chiba, Japan;
Department of Pediatric Surgery and
Operating Unit of Clinical Trials of Gene Therapy, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and
¶ DNAVEC Corporation, Tsukuba, Ibaraki, Japan
We recently demonstrated efficient antitumor immunity against murine tumors using dendritic cells (DCs) activated by recombinant Sendai viruses (rSeVs), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacy of this method in preventing metastatic diseases. In this study, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV (rSeV/dF) using a murine model of lung metastasis. Bolus and i.v. administration of DCs harboring rSeV/dF-expressing GFP without pulsation of tumor Ag (DC-rSeV/dF-GFP) 2 days before tumor inoculation showed efficient prevention against lung metastasis of c1300 neuroblastoma, but not of RM-9 prostatic cancer. We found that the timing of DC therapy was critical for the inhibition of pulmonary metastasis of RM-9, and that the optimal effect of DCs was seen 28 days before tumor inoculation. Interestingly, the antimetastatic effect was sustained for over 3 mo, even when administered DCs were already cleared from the lung and organs related to the immune system. Although NK cell activity had already declined to baseline at the time of tumor inoculation, Ab-mediated depletion studies revealed that CD4+ cells as well as the presence of, but not the activation of, NK cells were crucial to the prevention of lung metastasis. These results are the first demonstration of efficient inhibition of lung metastasis via bolus administration of virally activated DCs that was sustained and NK/CD4+ cell-dependent, and may suggest a potentially new mechanism of DC-based immunotherapy for advanced malignancies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Research Grants from the 21st Century Center of Excellence Program, Chiba University Graduate School of Medicine; by Grants-in-Aid (to T.I. and Y.Y.) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology; and by Uehara Memorial Foundation (to Y.Y.).
2 Current address: Operating Unit for Clinical Trials of Gene Therapy, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan. E-mail address: yonemitu{at}med.kyushu-u.ac.jp
3 Address correspondence and reprint requests to Dr. Yoshikazu Yonemitsu, Department of Gene Therapy, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. E-mail address: yonemitu{at}faculty.chiba-u.jp
4 Abbreviations used in this paper: DC, dendritic cell; rSeV, recombinant Sendai virus; rSeV/dF, F gene-deleted nontransmissible rSeV; iDC, immature DC.
5 The online version of this article contains supplemental material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
