Combination of IAP Antagonists and TNF-α-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression

Shawn T Beug; Stephanie J Pichette; Martine St-Jean; Janelle Holbrook; Danielle E Walker; Eric C LaCasse; Robert G Korneluk

doi:10.1016/j.omto.2018.06.002

Combination of IAP Antagonists and TNF-α-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression

Mol Ther Oncolytics. 2018 Jun 21:10:28-39. doi: 10.1016/j.omto.2018.06.002. eCollection 2018 Sep 28.

Authors

Shawn T Beug^{1

2}, Stephanie J Pichette^{1

2}, Martine St-Jean¹, Janelle Holbrook¹, Danielle E Walker¹, Eric C LaCasse¹, Robert G Korneluk^{1

2}

Affiliations

¹ Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
² Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada.

Abstract

Smac mimetic compounds (SMCs) are anti-cancer drugs that antagonize Inhibitor of Apoptosis proteins, which consequently sensitize cancer cells to death in the presence of proinflammatory ligands such as tumor necrosis factor alpha (TNF-α). SMCs synergize with the attenuated oncolytic vesicular stomatitis virus (VSVΔ51) by eliciting an innate immune response, which is dependent on the endogenous production of TNF-α and type I interferon. To improve on this SMC-mediated synergistic response, we generated TNF-α-armed VSVΔ51 to produce elevated levels of this death ligand. Due to ectopic expression of TNF-α from infected cells, a lower viral dose of TNF-α-armed VSVΔ51 combined with treatment of the SMC LCL161 was sufficient to improve the survival rate compared to LCL161 and unarmed VSVΔ51 co-therapy. This improved response is attributed to a bystander effect whereby the spread of TNF-α from infected cells leads to the death of uninfected cells in the presence of LCL161. In addition, the treatments induced vascular collapse in solid tumors with a concomitant increase of tumor cell death, revealing another mechanism by which cytokine-armed VSVΔ51 in combination with LCL161 can kill tumor cells. Our studies demonstrate the potential for cytokine-engineered oncolytic virus and SMCs as a new combination immunotherapy for cancer treatment.

Keywords: SMC; Smac mimetic compound; Smac mimetics; TNF-α; VSV; cIAP1/cIAP2; cancer; cellular inhibitor of apoptosis 1/2; immunotherapy; oncolytic virus; tumor necrosis factor alpha; vascular collapse; vesicular stomatitis virus.