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

The non-cytopathic arenavirus lymphocytic choriomeningitis virus (LCMV) induces strong anti-tumor responses. To generate an optimized arenavirus for tumor therapy, we passage LCMV in human or murine tumor cells. Occurring mutations shift the virus tropism toward tumor cells. By combining these mutations in attenuated reassortant LCMVs, among others, the virus strain WE-CL13-GP181M-185W-492I demonstrates accelerated propagation in various human tumor cells and organoids but limited replication in human healthy cells. In murine cancer models, single intravenous administration of WE-CL13-GP181M-185W-492I exhibits strong anti-tumoral efficacy with minimal replication in healthy tissues and no severe disease symptoms in virus-susceptible mice. In non-human primates, treatment with this recombinant virus strain substantially increases virus-mediated serum cytokines, chemokines, and T cells while maintaining a safe application. In conclusion, by applying the biological principle of mutation and selection, we develop arenavirus-based immune therapies that show anti-tumoral efficacy and safety in preclinical models and Good Laboratory Practice (GLP) safety studies.