Smac mimetics and innate immune stimuli synergize to promote tumor death

• Published in: Nature biotechnology Vol. 32; no. 2; pp. 182 - 190
• Main Authors: Beug, Shawn T, Tang, Vera A, LaCasse, Eric C, Cheung, Herman H, Beauregard, Caroline E, Brun, Jan, Nuyens, Jeffrey P, Earl, Nathalie, St-Jean, Martine, Holbrook, Janelle, Dastidar, Himika, Mahoney, Douglas J, Ilkow, Carolina, Le Boeuf, Fabrice, Bell, John C, Korneluk, Robert G
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.02.2014
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis Regulatory Proteins - pharmacology; Apoptosis Regulatory Proteins - therapeutic use; Cell Death - drug effects; Chemotherapy; Clinical trials; Cytokines; Cytokines - metabolism; Drug Synergism; Female; HEK293 Cells; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - drug therapy; Oligodeoxyribonucleotides - pharmacology; Oligodeoxyribonucleotides - therapeutic use; Oncolytic Virotherapy; Pharmacology; Poly I-C - pharmacology; Poly I-C - therapeutic use; Tumors
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.2806

Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe "cytokine storm." Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-β), tumor necrosis factor alpha (TNF-α) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.