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* Department of Internal Medicine, Division of Gastroenterology and Hepatology,
Institute of Clinical Medicine and Research,
Department of Oncology, Institute of DNA Medicine, and
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan; and
¶ Saitama Cancer Center Research Institute for Clinical Oncology, Saitama, Japan
Dendritic/tumor fusion cell (FC) vaccine is an effective approach for various types of cancer but has not yet been standardized. Antitumor activity can be modulated by different mechanisms such as dendritic cell (DC) maturation state. This study addressed optimal strategies for FC preparations to enhance Ag-specific CTL activity. We have created three types of FC preparations by alternating fusion cell partners: 1) immature DCs fused with autologous colorectal carcinoma cells (Imm-FCs); 2) Imm-FCs followed by stimulation with penicillin-inactivated Streptococcus pyogenes (OK-432) (Imm-FCs/OK); and 3) OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cells (OK-FCs). Both OK-FCs and Imm-FCs/OK coexpressed the CEA, MUC1, and significantly higher levels of CD86, CD83, and IL-12 than those obtained with Imm-FCs. Short-term culture of fusion cell preparations promoted the fusion efficiency. Interestingly, OK-FCs were more efficient in stimulating CD4+ and CD8+ T cells capable of high levels of IFN-
production and cytolysis of autologous tumor or semiallogeneic targets. Moreover, OK-FCs are more effective inducer of CTL activation compared with Imm-FCs/OK on a per fusion cell basis. The pentameric assay confirmed that CEA- and MUC1-specific CTL was induced simultaneously by OK-FCs at high frequency. Furthermore, the cryopreserved OK-FCs retained stimulatory capacity for inducing antitumor immunity. These results suggest that OK-432 promotes fusion efficiency and induction of Ag-specific CTL by fusion cells. We conclude that DCs fused after stimulation by OK-432 may have the potential applicability to the field of antitumor immunotherapy and may provide a platform for adoptive immunotherapy in the clinical setting.
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 has been supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Cultures, Sports, Science, and Technology of Japan, the Bio-Venture Research Fund Project Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Grant-in-Aid of the Japan Medical Association, Takeda Science Foundation, and the Jikei University Research Fund.
2 Address correspondence and reprint requests to Dr. Shigeo Koido, Jikei University School of Medicine Tokyo, Japan 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8564 Japan. E-mail address: shigeo_koido{at}jikei.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; FC, fusion cell; Imm-DC, immature DC; Imm-FC, immature FC; MFI, mean fluorescence intensity; OK-FC, OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cell; PEG, polyethylene glycol; TAA, tumor-associated Ag.
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  S. Koido, E. Hara, S. Homma, M. Mitsunaga, A. Takahara, E. Nagasaki, H. Kawahara, M. Watanabe, Y. Toyama, S. Yanagisawa, et al. Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells J. Immunol., October 1, 2007; 179(7): 4874 - 4883. [Abstract] [Full Text] [PDF]
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