Dergi makalesi Açık Erişim

Photodynamic augmentation of oncolytic virus therapy for central nervous system malignancies

2023    Shimizu, Kazuhide; Kahramanian, Andranik; Jabbar, Muzammil Arif Din Abdul; Demir, Fatma Turna; Gokyer, Dilan; Uthamacumaran, Abicumaran; Rajan, Anant; Saad, Mohammad Ahsan; Gorham, Joshua; Wakimoto, Hiroko; Martuza, Robert L.; Rabkin, Samuel D.; Hasan, Tayyaba; Wakimoto, Hiroaki

Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for 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, allowing for the combination of two potentially synergistic therapies with broader targets. Here, we created G47A-KR, clinical oncolytic herpes simplex virus G47A that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47A-KR infection followed by amber LED illumination (peak wavelength: 585-595 nm) were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47A-KR infection of tumor cells mediated KR expression that was activated by LED and produced reactive oxygen species, leading to cell death that was more robust than G47A-KR without light. In vivo, we tested photodynamic-oncolytic virus (PDOV) therapy employing intratumoral injection of G47A-KR followed by laser light tumor irradiation (wavelength: 585 nm) in GBM and MM xenografts. PD-OV therapy was feasible in these models and resulted in potent anti-tumor effects that were superior to G47A-KR alone (without laser light) or laser light 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 G47A-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.