Photodynamic augmentation of oncolytic virus therapy for central nervous system malignancies
Kazuhide Shimizu1, Andranik Kahramanian2, Muzammil Arif Din Abdul Jabbar3
1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA; Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
Abstract:
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 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 (peak wavelength: 585-595 nm) 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 LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested photodynamic-oncolytic virus (PD-OV) therapy employing intratumoral injection of G47Δ-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 G47Δ-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 G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.
Insights
Oncolytic virus G47Δ-KR combined with photodynamic therapy shows potent anti-tumor effects for brain cancers. This photodynamic-oncolytic virus therapy approach warrants further research for clinical translation.
Area of Science:
- Oncolytic virotherapy
- Photodynamic therapy
- Cancer research
Background:
- Oncolytic viruses (OVs) offer potential for treating refractory cancers, including CNS malignancies.
- Combining OVs with other therapies can enhance efficacy by improving tumor cell killing and modifying the tumor microenvironment (TME).
- Photodynamic therapy (PDT) induces cancer cell death and primes the TME for synergistic effects with secondary treatments.
Purpose of the Study:
- To develop and evaluate a novel photodynamic-oncolytic virus (PD-OV) therapy.
- To assess the efficacy of G47Δ-KR, an oncolytic herpes simplex virus expressing KillerRed, in combination with light activation.
- To investigate the therapeutic potential of PD-OV therapy for neuro-oncological malignancies.
Main Methods:
- Engineered G47Δ-KR oncolytic virus expressing KillerRed (KR) photosensitizer.
- In vitro assessment of KR expression, reactive oxygen species (ROS) production, and cytotoxicity in glioblastoma (GBM) and malignant meningioma (MM) cells upon LED illumination.
- In vivo evaluation of PD-OV therapy efficacy in GBM and MM xenograft models using intratumoral G47Δ-KR injection and laser irradiation.
- RNA sequencing analysis of tumor tissues to assess immune cell infiltration post-treatment.
Main Results:
- G47Δ-KR expression and subsequent ROS generation upon LED activation led to enhanced cancer cell death in vitro.
- PD-OV therapy demonstrated significant anti-tumor effects in vivo, outperforming G47Δ-KR or light treatment alone.
- RNA sequencing revealed increased infiltration of immune cells within the TME following PD-OV therapy.
Conclusions:
- G47Δ-KR enables effective photodynamic-oncolytic virus (PD-OV) therapy for neuro-oncological malignancies.
- The combination therapy shows promise for enhancing anti-tumor responses and modulating the tumor immune microenvironment.
- Further research is warranted to advance this PD-OV strategy towards clinical application.
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