ID: 261: Smac mimetics combined with innate immune stimuli: new tools to kill tumor cells

Abstract

The Inhibitor of Apoptosis (IAP) family members are important oncogenes overexpressed in many solid and blood cancers. We have recently found that innate immune stimulants such as oncolytic viruses, TLR agonists and vaccines can potently synergize with a class of IAP-antagonist drugs known as Smac mimetic compounds, or SMCs, in various models of cancer [Beug et al., Nature Biotechnology 32: 182–90, 2014]. SMCs target and cause the degradation of the cellular inhibitors of apoptosis, cIAP1 and cIAP2, to specifically sensitize tumor cells to death signals from the immune system such as TNF α or TRAIL. Both cIAP1 and cIAP2 are ubiquitin ligases, with overlapping functions, which mediate signaling by all members of the TNF superfamily. The proteasomal-mediated degradation of cIAP1 and cIAP2 by SMCs alter immune-mediated signaling of various pathways controlled by these IAPs. SMCs are currently in early phase cancer clinical trial development and are well tolerated but show limited efficacy as monotherapy. However, in combination with immune stimulants, SMCs potently induce the bystander killing of tumor cells, which is attributable to a type I IFN dependent production of the proinflammatory cytokines TNF α and TRAIL. The approach is extremely effective in eradicating orthotopic models of mouse solid and blood cancers, including breast, glioblastoma and multiple myeloma. We propose that Smac mimetics will greatly improve the efficacy of oncolytic virus, and other immunotherapies, in the clinic.