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Combination of IAP Antagonists and TNF-α-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression.
Beug, Shawn T; Pichette, Stephanie J; St-Jean, Martine; Holbrook, Janelle; Walker, Danielle E; LaCasse, Eric C; Korneluk, Robert G.
Afiliación
  • Beug ST; Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
  • Pichette SJ; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada.
  • St-Jean M; Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
  • Holbrook J; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada.
  • Walker DE; Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
  • LaCasse EC; Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
  • Korneluk RG; Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Mol Ther Oncolytics ; 10: 28-39, 2018 Sep 28.
Article en En | MEDLINE | ID: mdl-30101187
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Oncolytics Año: 2018 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Oncolytics Año: 2018 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos