Optimized arenaviruses with tumor-tropic mutations promote safe anti-tumor efficacy via sustainable immune modulatory properties

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Viral oncology

Background:

• Lymphocytic choriomeningitis virus (LCMV), a non-cytopathic arenavirus, is known to elicit potent anti-tumor immune responses.
• Optimizing LCMV for cancer therapy requires enhancing its tumor-targeting capabilities while ensuring safety.

Purpose of the Study:

• To engineer an improved arenavirus strain for enhanced tumor therapy.
• To evaluate the efficacy and safety of the optimized arenavirus in preclinical cancer models.

Main Methods:

• Passaging LCMV in human and murine tumor cells to induce mutations that enhance tumor tropism.
• Combining identified mutations into attenuated reassortant LCMV strains.
• Testing the lead candidate strain (WE-CL13-GP181M-185W-492I) in various human tumor cells, organoids, murine cancer models, and non-human primates.

Main Results:

• The engineered LCMV strain WE-CL13-GP181M-185W-492I showed accelerated propagation in tumor cells but limited replication in healthy human cells.
• Single intravenous administration in murine cancer models demonstrated significant anti-tumoral efficacy with minimal off-target replication and no severe symptoms.
• Treatment in non-human primates induced a robust increase in virus-mediated serum cytokines, chemokines, and T cells, indicating a favorable safety profile.

Conclusions:

• The study successfully developed an optimized arenavirus-based therapy using mutation and selection principles.
• The engineered LCMV strain exhibits potent anti-tumoral activity and a favorable safety profile in preclinical and GLP safety studies.
• This approach holds promise for developing novel oncolytic virotherapies.