Smac mimetics synergize with immune checkpoint inhibitors to promote anti-cancer immunity
Shawn T. Beug1,2, Caroline E. Beauregard1,2, Cristin Healy1,2, Tarun Sanda1,2, Aditya Mohan1, XueQing Lun3, Donna L. Senger3, Stephen M. Robbins3, Peter Staeheli4, Peter A. Forsyth5, Tommy Alain1,2, Eric C. LaCasse1* & Robert G. Korneluk1,2*
1Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; 2University of Ottawa; 3Arnie Charbonneau Cancer Institute, University of Calgary, Canada; 4University Medical Center Freiburg, Germany; 5H. Lee Moffitt Cancer Center, Tampa, USA
Small-molecule Inhibitor-of-APoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumors to TNFalpha-induced killing while simultaneously blocking TNFalpha growth-promoting activities. SMCs mimic the activity of an endogenous polypeptide IAP inhibitor called Smac, which is released from the mitochondria upon cell death induction. SMCs target and degrade two specific IAP, cIAP1 and cIAP2, proteins that control several immunomodulatory properties within immune cells by altering NF-kappaB and TNF superfamily signaling pathways, including T-cell co-stimulation.
We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics, such as anti-PD1 monoclonal antibodies, to produce durable cures in syngeneic mouse models of multiple myeloma, breast cancer and glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I interferon and TNFalpha signaling. Furthermore, our results implicate an important role for TNFalpha-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs.
Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.