Innate Immune Adjuvants Potentiate SMAC Mimetic-Induced Cell Death

Compounds that mimic the activity of second mitochondria-derived activator of caspase (SMAC), an antagonist of inhibitor of apoptosis (IAP) proteins that are frequently overexpressed in human cancers, sensitize tumor cells to apoptosis and have been well-tolerated in phase I trials. However, SMAC mimetic compounds (SMC) may be effective only when tumors produce sufficient amounts of death-inducing proteins such as inflammatory cytokines. Beug and colleagues hypothesized that stimulation of the innate immune system with oncolytic viruses or with synthetic TLR agonists that mimic pathogens and are used as vaccine adjuvants could induce a controlled cytokine response large enough to induce apoptosis in tumors left vulnerable to death signals by SMC treatment. Indeed, apoptosis was induced in SMC-pretreated, uninfected cancer cells after exposure to conditioned media from oncolytic virus-infected cells. Viral infection induced type I IFNs, which promoted secretion of TNF-α and TRAIL by both infected and uninfected tumor cells and induced bystander apoptosis in the presence of SMCs. Combined SMC and oncolytic virus treatment synergized to induce tumor regression and prolong survival in tumor-bearing immunocompetent mice in a TNF-α–dependent manner, and led to durable cures in 40% of mice. Synthetic TLR agonists such as CpG oligodeoxynucleotide or polyinosine–polycytidylic acid could also induce a bystander cell death effect in combination with SMCs, and synergized with SMCs to produce durable cures in 60% and 88% of mice, respectively. Of note, these combination therapies were well tolerated by mice, with body weights returning to pretreatment levels after the end of therapy. Although pathogen mimetics and SMCs currently in clinical development as cancer therapies have shown limited efficacy as monotherapies, these findings suggest that the combination of SMCs and innate immune adjuvants may safely synergize to induce tumor cell death and may have greater clinical activity than either agent alone.

Beug ST, Tang VA, LaClasse EC, Cheung HH, Beauregard CE, Brun J, et al. Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat Biotechnol 2014;32:182–90.

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