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Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV

Cancer Gene Therapy volume 9, pages 356–364 (2002)Cite this article

Abstract

Here we developed an effective therapeutic approach using a replication-conditional mutant of herpes simplex virus (HSV), G207, for the treatment of metastatic tumors in the immunologically privileged central nervous system. An experimental model of brain metastasis was developed using BALB/c mice that harbored both intracranial (i.c.) and subcutaneous (s.c.) mouse CT26 colon adenocarcinoma tumors. Intratumoral injections of G207 into s.c. tumors elicited cytotoxic T-cell responses not only to HSV but also to a tumor antigen; however, only a limited antitumor effect was observed on metastatic brain tumors. To improve this antitumor effect, G207 was also injected into the brain tumor. After intratumoral injections of G207 into both i.c. and s.c. CT26 tumors, a significant antitumor effect was observed in the metastatic brain tumors. This therapeutic efficacy was absent in athymic mice, indicating that the antitumor effect could be mediated by T cells. Cytotoxic T-cell responses to HSV and the tumor antigen were induced by injections of G207 into i.c. and s.c. CT26 tumors. These results suggest that HSV-infected brain tumors may be efficiently eliminated by the induced anti-HSV T cells as well as by antitumor T cells. Therefore, this strategy of immuno-viral therapy, involving direct viral oncolytic activities and inducing antitumor and antiviral immune responses, may be useful for the treatment of tumors in the immunologically privileged central nervous system.

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Acknowledgements

We thank Robert L Martuza and Samuel D Rabkin (Harvard Medical School) for critical comments on the manuscript, and Wangjie Yu for technical assistance. This study was supported, in part, by grants from the Ministry of Education, Science, Sports, and Culture in Japan, the Human Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Keio Gijuku Academic Development Funds.

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Authors and Affiliations

  1. Division of Cellular Signaling, Institute for Advanced Medical Research, Shinju-ku, Tokyo, 160-8582, Japan

    Masahiro Toda, Yukihiko Iizuka & Yutaka Kawakami

  2. Department of Neurosurgery, Keio University School of Medicine, Shinju-ku, Tokyo, 160-8582, Japan

    Masahiro Toda & Takeshi Kawase

  3. Department of Physiology, Keio University School of Medicine, Shinju-ku, Tokyo, 160-8582, Japan

    Masahiro Toda, Yukihiko Iizuka & Keiichi Uyemura

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  1. Masahiro Toda
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  2. Yukihiko Iizuka
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  5. Yutaka Kawakami
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Correspondence to Masahiro Toda.

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Toda, M., Iizuka, Y., Kawase, T. et al. Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV. Cancer Gene Ther 9, 356–364 (2002). https://doi.org/10.1038/sj.cgt.7700446

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