Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

Area of Science:

• Oncology
• Virology
• Immunotherapy

Background:

• Therapeutic effectiveness of oncolytic viruses (OVs) administered intravenously is often hindered by neutralizing antibody responses.
• Repeated systemic administration of OVs is challenging due to these immune reactions.

Purpose of the Study:

• To develop a novel platform for systemic viral immunotherapy that circumvents neutralizing antibodies.
• To enable repeated intravenous delivery of oncolytic viral agents.

Main Methods:

• Development of Synthetic RNA viruses (SRVs) using viral RNA genomes (vRNA) encapsulated in lipid nanoparticles.
• Evaluation of SRVs based on Seneca Valley virus (SVV) and Coxsackievirus A21 for tumor cell lysis and anti-tumor efficacy.
• Assessment of SRV tolerability and immunomodulatory effects in preclinical models (mice and non-human primates).

Main Results:

• SRVs demonstrated successful vRNA delivery, replication, virus assembly, and spread within tumors.
• Potent anti-tumor efficacy was achieved with SRVs, even in the presence of oncolytic virus neutralizing antibodies.
• Synthetic-SVV promoted immune cell infiltration, remodeled the tumor microenvironment, and enhanced anti-PD-1 therapy efficacy.
• Synthetic-SVV was well-tolerated in mouse and non-human primate models at effective doses.

Conclusions:

• The Synthetic RNA virus platform enables repeat intravenous administration of viral immunotherapies.
• SRVs represent a promising strategy to overcome antibody-mediated limitations of traditional oncolytic viruses.
• This approach holds potential for enhancing cancer treatment outcomes through repeated systemic viral delivery.