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Enhancing the Antitumor Efficacy of Oncolytic Adenovirus Through Sonodynamic Therapy-Augmented Virus Replication
Junqiang Ding1, Runping Su2, Rong Yang2
1School of Pharmacy, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Abstract:
The therapeutic efficacy of oncolytic adenoviruses (OAs) relies on efficient viral transduction and replication. However, the limited expression of coxsackie-adenovirus receptors in many tumors, along with the intracellular antiviral signaling, poses significant obstacles to OA infection and oncolysis. Here, we present sonosensitizer-armed OAs (saOAs) that potentiate the antitumor efficacy of oncolytic virotherapy through sonodynamic therapy-augmented virus replication. The saOAs could not only efficiently infect tumor cells via transferrin receptor-mediated endocytosis but also exhibit enhanced viral replication and tumor oncolysis under ultrasound irradiation. We revealed that the sonosensitizer loaded on the viruses induced the generation of ROS within tumor cells, which triggered JNK-mediated autophagy, ultimately leading to the enhanced viral replication. In mouse models of malignant melanoma, the combination of saOAs and sonodynamic therapy elicited a robust antitumor immune response, resulting in significant inhibition of melanoma growth and improved host survival. This work highlights the potential of sonodynamic therapy in enhancing the effectiveness of OAs and provides a promising platform for fully exploiting the antitumor efficacy of oncolytic virotherapy.
Insights
Sonosensitizer-armed oncolytic adenoviruses (saOAs) enhance cancer treatment by using ultrasound to boost viral replication and oncolysis. This combination therapy triggers an immune response, inhibiting melanoma growth and improving survival in mouse models.
Area of Science:
- Oncolytic virotherapy
- Sonodynamic therapy
- Cancer immunotherapy
Background:
- Oncolytic adenoviruses (OAs) show therapeutic promise but face challenges like limited tumor receptor expression and antiviral signaling.
- Efficient viral transduction and replication are crucial for the efficacy of OAs in cancer treatment.
Purpose of the Study:
- To develop sonosensitizer-armed OAs (saOAs) to enhance oncolytic virotherapy efficacy.
- To investigate the mechanism of saOAs-mediated tumor cell infection, viral replication, and oncolysis under ultrasound irradiation.
- To evaluate the antitumor efficacy and immune response of saOAs combined with sonodynamic therapy in preclinical models.
Main Methods:
- Construction and characterization of sonosensitizer-armed oncolytic adenoviruses (saOAs).
- Assessment of saOA infection via transferrin receptor-mediated endocytosis.
- Evaluation of viral replication and oncolysis under ultrasound irradiation.
- Investigation of reactive oxygen species (ROS) generation, JNK-mediated autophagy, and viral replication pathways.
- Preclinical testing in mouse models of malignant melanoma, including assessment of tumor growth inhibition and host survival.
Main Results:
- saOAs demonstrated efficient tumor cell infection independent of coxsackie-adenovirus receptors.
- Ultrasound irradiation significantly enhanced viral replication and tumor oncolysis mediated by saOAs.
- Sonosensitizer-induced ROS triggered JNK-mediated autophagy, leading to increased viral replication.
- Combination therapy of saOAs and sonodynamic therapy elicited a robust antitumor immune response in melanoma mouse models.
- Significant inhibition of melanoma growth and improved host survival were observed with the combined therapy.
Conclusions:
- Sonodynamic therapy can potentiate the antitumor efficacy of oncolytic adenoviruses.
- saOAs offer a promising platform for enhancing oncolytic virotherapy by augmenting viral replication and inducing antitumor immunity.
- This approach provides a novel strategy for exploiting the full potential of oncolytic virotherapy against cancer.
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