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

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-?). SMCs synergize with the attenuated oncolytic vesicular stomatitis virus (VSV?51) by eliciting an innate immune response, which is dependent on the endogenous production of TNF-? and type I interferon. To improve on this SMC-mediated synergistic response, we generated TNF-?-armed VSV?51 to produce elevated levels of this death ligand. Due to ectopic expression of TNF-? from infected cells, a lower viral dose of TNF-?-armed VSV?51 combined with treatment of the SMC LCL161 was sufficient to improve the survival rate compared to LCL161 and unarmed VSV?51 co-therapy. This improved response is attributed to a bystander effect whereby the spread of TNF-? 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 VSV?51 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.


PROVIDER: S-EPMC6076221 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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