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Combination of two fiber-mutant adenovirus vectors, one encoding the chemokine FKN and another encoding cytokine interleukin 12, elicits notably enhanced anti-tumor responses

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Abstract

For achieving optimal cancer immunotherapy, it is anticipated that both the activation and infiltration of immune cells into tumor are indispensable. In the present study, fiber-mutant adenovirus vectors (Ad) encoding chemokine FKN, (AdRGD-FKN), and cytokine interleukin 12, (AdRGD-IL-12), were constructed. The in vivo gene expression of AdRGD was confirmed and the combination of both FKN and IL-12 encoding Ad elicited synergistic anti-tumor activity in ovarian carcinoma, which induced tumor regression in all tumor-bearing mice, while using FKN alone did not show notable tumor-suppressive effect. The treatment with both IL-12 and FKN induced long-term specific immunity against OV-HM tumors in tumor-rejected mice. The results of immunohistochemical staining for CD3+ and perforin-positive cells suggested that the failure of using FKN alone was because of the inactivation of infiltrated immune cells. In contrast, cotransduction with IL-12 and FKN could induce more activated tumor-infiltrating immune cells than that transducted with FKN or IL-12 alone. The results indicated that using both chemokine and cytokine might be a powerful tool and a promising way for effective cancer immunotherapy.

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Abbreviations

Ad:

Adenovirus vector

AdRGD:

RGD fiber-mutant Ad

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

FBS:

Fetal bovine serum

NK:

Natural killer

PBS:

Phosphate-buffered saline

PFU:

Plaque forming unit

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Acknowledgments

We would like to thank Dr. Osamu Yoshie and Dr. Takashi Nakayama (Kinki University, Japan) for their helpful discussion and supplying the plasmid encoded chemokine. This study was supported by grants from the Ministry of Health, Labor, and Welfare of Japan, by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the National Natural Science Foundation of China (NSFC 30572270), and SRF for ROCS (2006-331).

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Authors and Affiliations

  1. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, 310058, Hangzhou, Zhejiang, People’s Republic of China

    Jian-Qing Gao, Dong-Hang Xu & Min Han

  2. Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka, 565–0871, Japan

    Naoko Kanagawa, Toshiki Sugita, Naoki Okada & Shinsaku Nakagawa

  3. Department of Biomedical Science, Dako Japan Co., Ltd, Nishinotouin-higashiiru, Shijo-dori, Shimogyo-ku, Kyoto, Japan

    Yutaka Hatanaka & Yoichi Tani

  4. National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

    Hiroyuki Mizuguchi & Yasuo Tsutsumi

  5. Kobe Gakuin University, Igawadani, Nishi-ku, Kobe, Japan

    Tadanori Mayumi

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  1. Jian-Qing Gao
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  2. Naoko Kanagawa
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Correspondence to Jian-Qing Gao or Shinsaku Nakagawa.

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Gao, JQ., Kanagawa, N., Xu, DH. et al. Combination of two fiber-mutant adenovirus vectors, one encoding the chemokine FKN and another encoding cytokine interleukin 12, elicits notably enhanced anti-tumor responses. Cancer Immunol Immunother 57, 1657–1664 (2008). https://doi.org/10.1007/s00262-008-0499-0

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  • DOI: https://doi.org/10.1007/s00262-008-0499-0

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