Development of live-attenuated lymphocytic choriomeningitis virus vectors for potent alarmin-driven CD8+ T cell induction in tumor immunotherapy

Effective cancer immunotherapy requires potent tumor antigen-specific effector CD8+ T cell (CTLeff) responses, culminating in an inflammatory activation of the tumor microenvironment. We describe the artificial reengineering of the lymphocytic choriomeningitis virus (LCMV) genome to serve as replication-competent but stably attenuated immunotherapy platform (artLCMV). artLCMV targeted dendritic cells, thereby delivering tumor-associated antigens for efficient CTL induction. Additionally, owing to in vivo spread, artLCMV infected lymphoid tissue stroma expressing interleukin-33, an alarmin released from necrotic cells. Interleukin-33 signals accounted for artLCMV-induced effector CTL responses of higher magnitude and functionality than those induced by replication-deficient LCMV-, adenovirus 5- or vaccinia virus-based vectors. Accordingly, superior immunotherapeutic efficacy of artLCMV in transplantable tumor models depended on interleukin-33 signaling, and massive CTLeff influx was associated with an inflammatory conversion of the tumor. These properties, together with low seroprevalence but excellent immunogenicity of LCMV in humans, suggest artLCMV holds promise as a cancer immunotherapy platform. We implanted EG7-OVA tumor cells subcutaneously into the flank of C57BL/6 mice. On day 7, when tumors became palpable, we treated them with artLCMV-OVA or left them untreated. Tumor tissue was analyzed on d9 after treatment. Gene expression profiles of inflammation-associated genes from tumor tissue of untreated or artLCMV-OVA treated animals was determined by Nanostring technology. 2 groups (untreated vs artLCMV-OVA), n=4 mice per group.