21: Interferon-mediated potentiation of SMAC mimetic compound cytotoxicity by oncolytic virotherapy

Abstract

Smac mimetic compounds (SMCs) are a novel class of small molecule antagonists that target the inhibitor of apoptosis (IAP) proteins to induce cancer cell death via cytokine activation of caspase-8 death pathways. Oncolytic viruses (OVs) selectively target cancer cells for death via multiple mechanisms, including oncolysis and the induction of anti-tumor immunity. We reasoned that oncolytic viruses such as the rhabdovirus VSVΔ51 will provide a proinflammatory environment that would augment SMC-induced cancer cell death. We observed that SMC and VSVΔ51 synergy was specific to cancer cells and this combination increased the potency of cancer cell death up to 10,000-fold compared to stand-alone VSVΔ51 therapy. The combination resulted in delayed tumor growth and lead to durable cures in mouse models of cancer. Furthermore, several non-viral immunostimulatory agents, such as the viral RNA mimic poly (I:C) or the bacterial DNA mimic CpG, elicit similar responses when combined with SMC treatment. The combination leads to bystander cancer cell death via the production of type 1 interferon-dependent production of proinflammatory cytokines, such as TNF α and TRAIL, which sensitizes cancer cells to SMC-mediated caspase-8-dependent apoptosis. We thus demonstrate the novel combination of targeted immunotherapies for the treatment of cancer, which on their own are limited by various efficacy hurdles, yet when combined, the combined treatment results in strong synergy to cause cancer cell death.