Therapeutic vaccination for glioblastoma elicited by retargeted oncolytic herpes virus.

BACKGROUND: Glioblastoma is an aggressive tumor with poor prognosis and limited treatment options due to its resistance to chemotherapy and radiotherapy, high heterogeneity, and ability to evade the immune system. Nevertheless, immunotherapy and oncolytic virotherapy are emerging as promising strategies. This study aimed to evaluate the therapeutic efficacy of an engineered oncolytic Herpes Simplex Virus for glioblastoma treatment. METHODS: We investigated the efficacy of R-115, a retargeted oncolytic Herpes Simplex Virus directed against the human epidermal growth factor receptor 2 (HER2) and engineered to express murine interleukin-12, in an immunocompetent glioblastoma model that recapitulates HER2 tumor heterogeneity. We tested the translatability and reliability of R-115 by assessing overall survival in HER2(+) or HER2(+)/HER2(-) mixed tumors treated with different schedules. We assessed the potential of the treatment to elicit an antitumor vaccination effect by rechallenging previously treated mice with HER2-negative cells in the absence of any further therapy. Additionally, we characterized both the immune and tumor components by analyzing immune cells' proliferation, activation and the resulting tumor cells reduction. RESULTS: R-115 exhibited potent cytotoxic and immune-stimulatory effects, significantly prolonging survival and eradicating tumors in approximately 25% of treated mice independently from tumor composition and treatment schedule. Furthermore, it induced long-term immune memory, enabling the eradication of secondary transplanted tumors, effectively acting as a tumor-agnostic vaccination. Notably, in addition to the direct oncolysis mediated by the virus, R-115 treatment induced an immune response even against HER2-negative glioblastoma cells, potentially via cross-presentation or epitope spreading. CONCLUSIONS: Our findings candidate R-115 as a promising alternative to standard glioblastoma treatments and support further investigation to advance its clinical application.