EXTH-40. PHOTODYNAMIC ONCOLYTIC VIRUS THERAPY FOR CENTRAL NERVOUS SYSTEM MALIGNANCIES

Abstract

Abstract Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective to treat cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies. This allows for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by amber LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested G47Δ-KR-based PD-OV therapy employing intratumoral injection of G47Δ-KR followed by amber laser (wavelength: 585 nm) tumor irradiation in GBM and MM xenografts. PD-OV therapy was feasible in GBM and MM xenografts and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser) or laser alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.