Abstract
Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.
Highlights
Gliomas are the most common primary malignant brain tumors
Oncolytic herpes simplex virus (HSV) represent a promising therapeutic strategy against tumors: immunovirotherapy is based on the ability of viruses to stimulate the immune response of the host against infected tumor cells, and tumors treated with oncolytic HSVs (oHSVs) become a sort of “agnostic vaccine” against neo-antigens expressed by targeted cells [7,13,14,21]
We showed that R-115, an oHSV fully retargeted to human HER2 and armed with murine interleukin 12 (mIL12), is able to infect HER2 positive glioblastoma cells and to induce a potent and long-lasting immune response against tumor cells [39]
Summary
Gliomas are the most common primary malignant brain tumors. Glioblastoma represents the most aggressive form, with poor prognosis, and leads to patient death with a median survival time of about 15 months from diagnosis [1]. The virus itself acts as an immunological adjuvant triggering immune response [7,8], potentially favoring an agnostic vaccination against tumor associated antigens (TAA) released following the lysis of tumor cells [9,10]. This immunotherapeutic effect is of paramount importance especially in immunosuppressive tumors as glioblastomas, where cancer cells progressively become stealth to the immune system and a pro-tumorigenic immune infiltrate prevails [11,12]. This feature is crucial to counteract glioblastoma, a tumor with a markedly migratory phenotype
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