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Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

Cancer Gene Therapy volume 19, pages 118–125 (2012)Cite this article

Abstract

Carrier cells delivering a conditionally replicating adenovirus (CRAd), which selectively replicates in tumor cells and induces tumor cell lysis, have promising potential for treatment of cancer because CRAd-loaded carrier cells evade inhibition by neutralizing anti-adenovirus (Ad) antibodies and because the carrier cells are locally retained at the injection point after local injection. A previous study by Hamada et al. demonstrated that carrier cells (CRAd-containing cell fragments derived from the carrier cells) are engulfed into the target cells, probably through a pathway independent of the primary receptor for Ad, the coxsackievirus and Ad receptor (CAR) (Mol Ther, 15: 1121–1128; 2007); however, it remains to be elucidated whether carrier cells infected with a conventional CRAd, which is composed of subgroup-C Ad serotype-5 (Ad5), mediate antitumor effects on CAR-negative cells. In order to examine whether carrier cells delivering a conventional CRAd (Carrier-F5) induce lysis of CAR-negative tumor cells, CAR-positive and CAR-negative tumor cells were incubated with Carrier-F5. Carrier-F5 mediated efficient killing of CAR-positive tumor cells; however, CAR-negative tumor cells were almost refractory to Carrier-F5. On the other hand, carrier cells loaded with a fiber-substituted CRAd containing fiber proteins of Ad serotype-35 (Ad35) (CRAd-F35), which binds to human CD46 for infection, showed efficient killing of both CAR-positive and CAR-negative tumor cells. Intra-tumoral injection of carrier cells loaded with CRAd-F35 (Carrier-F35) also resulted in efficient regression of both CAR-positive and CAR-negative tumors. These results demonstrated that the expression levels of receptors for Ad are an important factor for CRAd-loaded carrier cell-mediated cancer therapy, and that Carrier-F35 would have potential as a cancer treatment for not only CAR-positive tumors but also CAR-negative tumors.

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Acknowledgements

We thank Koyori Yano, Emi Suzuki-Kouyama (National Institute of Biomedical Innovation, Osaka, Japan) and Sayuri Okamoto (Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan) for help. This work was supported by grants from the Ministry of Health, Labour, and Welfare of Japan, and a Grant-in-Aid for Scientific Research (B) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

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Authors and Affiliations

  1. Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan

    K Iguchi, F Sakurai, K Katayama, T Yamaguchi, K Kawabata & H Mizuguchi

  2. Department of Microbiology and Infectious Diseases, Division of Infectious Disease Control, Kobe University Graduate School of Medicine, Hyogo, Japan

    K Iguchi, M Kawabata & T Shirakawa

  3. Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    F Sakurai, K Tomita, K Katayama & H Mizuguchi

  4. Department of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    K Kawabata

  5. Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan

    M Tagawa

  6. The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan

    H Mizuguchi

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Iguchi, K., Sakurai, F., Tomita, K. et al. Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells. Cancer Gene Ther 19, 118–125 (2012). https://doi.org/10.1038/cgt.2011.74

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