Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy

Glioblastoma (GBM) is an aggressive, immunotherapy-resistant brain tumor. Here, we engineered an oncolytic virus platform based on herpes simplex virus 1 for GBM viroimmunotherapy. We mutated the highly cytopathic MacIntyre strain to increase spread and oncolytic activity, limit genetic drift, prevent neuron infection and enable PET tracing. We incorporated microRNA target cassettes to attenuate replication in healthy brain cells. Moreover, we engineered the gD envelope protein to specifically target GBM using EGFR-specific or integrin-specific binders. Lastly, we incorporated five immunomodulators to remodel the tumor microenvironment (TME) by locally expressing IL-12, anti-PD1, a bispecific T cell engager, 15-hydroxyprostaglandin dehydrogenase and anti-TREM2 to target T cells and myeloid cells in the GBM TME. A single intratumoral injection increased survival in GBM preclinical models, while promoting tumor-specific T cell, natural killer cell and myeloid cell responses in the TME. In summary, we engineered a retargeted, safe and traceable oncolytic virus with strong cytotoxic and immunostimulatory activities for GBM immunotherapy.