Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus

Hiroaki Uchida, Marco Marzulli, Kenji Nakano, William F. Goins, Janet Chan, Chang Sook Hong, Lucia Mazzacurati, Ji Young Yoo, Amy Haseley, Hiroshi Nakashima, Hyunjung Baek, Heechung Kwon, Izumi Kumagai, Masahide Kuroki, Balveen Kaur, E. Antonio Chiocca, Paola Grandi, Justus B. Cohen, Joseph C. Glorioso

    Research output: Contribution to journalArticlepeer-review

    70 Citations (Scopus)

    Abstract

    Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.

    Original languageEnglish
    Pages (from-to)561-569
    Number of pages9
    JournalMolecular Therapy
    Volume21
    Issue number3
    DOIs
    Publication statusPublished - Mar 2013

    All Science Journal Classification (ASJC) codes

    • Molecular Medicine
    • Molecular Biology
    • Genetics
    • Pharmacology
    • Drug Discovery

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