Smac mimetics synergize with immunotherapies to promote anti-cancer immunity
Shawn Beug1, Eric LaCasse1, Tarun Sanda1,2, Cristin Healy1,2, Matthew Michalicka1,2, Neena Lala-Tabbert1,2, Matthew Hunt1,2, Natalie Wright3, Glenwood Goss2,3 and Robert G. Korneluk1,2
1Children's Hospital of Eastern Ontario Research Institute, Canada; 2University of Ottawa, Canada; 3Ottawa Hospital Research Institute, Canada
Members of the Inhibitor of Apoptosis (IAP) gene family are key oncogenes found in many solid and blood cancers. Aside from their potent anti-apoptotic properties, the IAPs are central to NF-κB signaling, immunity, and in tumor evasion of immune attack. We uncovered an effective therapeutic strategy to target cancer: combining immunotherapies with a class of IAP antagonists called Smac mimetics. These small molecule compounds are chemical mimetics of the cellular pro-apoptotic protein Smac and function by inducing the degradation of the anti-apoptotic IAP proteins, cIAP1, cIAP2 and XIAP. The removal of these IAPs thereby renders cancer cells susceptible to cell death by an immune attack and by the presence of proinflammatory ligands. The combination of Smac mimetics with various innate immune stimuli, including oncolytic viruses, TLR agonists and vaccines, results in widespread bystander death of tumor cells in orthotopic mouse models of glioblastoma, multiple myeloma, lung cancer and breast cancer. We attribute this synergistic cancer cell death to the type I IFN dependent production of the proinflammatory cytokines TNFα and TRAIL. In addition, Smac mimetics cooperate with anti-PD1 or anti-CTLA4 checkpoint inhibitors to induce durable cures in tumor models for which either agent has little activity on their own. The synergistic effect from the combinatorial approach induces a long-term immunity that is dependent on cytotoxic T-cell activity. We thus demonstrate that the novel combination of various immunotherapies with Smac mimetics, which on their own are limited due to various efficacy hurdles, results in strong synergy to cause the death of a broad range of cancers. Smac mimetics are now being tested in combination with immunotherapies in Phase I/II studies in cancer patients in Canada and internationally.
Funded by the CIHR, CCSRI and Ottawa Regional Cancer Foundation.