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Smac mimetics and innate immune stimuli synergize to promote tumor death

Abstract

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.

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Figure 1: SMC synergizes with oncolytic rhabdoviruses to induce bystander death of cancer cells.
Figure 2: SMC treatment does not alter the antiviral response of cancer cells.
Figure 3: Roles for type 1 IFN- and NF-κB-dependent proinflammatory cytokines.
Figure 4: Combinatorial SMC and oncolytic virus treatment is efficacious in vivo and depends on cytokine signaling.
Figure 5: Adjuvants synergize with SMC therapy in murine cancer models.

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Acknowledgements

We thank D. Porter, B. Firestone, L. Zawel and J.S. Cameron of Novartis for providing LCL161. We thank S. Wang (University of Michigan) for providing SM-122 and SM-164. We thank R. Al-awar and her medicinal chemistry team at the Ontario Institute for Cancer Research (OICR) for providing OICR720. We thank S. Pichette for her assistance with the creation of VSVΔ51-TNF-α. This work is supported by grants awarded to R.G.K. by the Canadian Institutes of Health Research (CIHR, MOP #86627), the Ottawa Regional Cancer Foundation (ORCF), the Ottawa Kiwanis Medical Foundation, the Children's Hospital of Eastern Ontario (CHEO) Foundation, and The Lotte & John Hecht Memorial Foundation Innovation Grant of the Canadian Cancer Society. J.C.B. is supported by OICR and The Terry Fox Foundation. F.L.B. was supported by an industrial fellowship from CIHR. D.J.M. is the recipient of a New Investigator Award from the Alliance for Cancer Gene Therapy (USA). R.G.K. is a Fellow of the Royal Society of Canada and a distinguished professor of the University of Ottawa. We thank D. Stojdl (Children's Hospital of Eastern Ontario Research Institute) for SNB75.

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S.T.B., E.C.L., V.A.T., F.L.B., D.J.M. and R.G.K. designed the experiments. S.T.B., H.H.C., J.P.N., N.E., M.S.-J., J.H., C.E.B., V.A.T., F.L., C.I., H.D. and J.B. conducted experiments. S.T.B., E.C.L., V.A.T., J.C.B., D.J.M. and R.G.K. wrote the manuscript.

Corresponding author

Correspondence to Robert G Korneluk.

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Competing interests

R.G.K. is a scientific founder and shareholder of Aegera Therapeutics (Pharmascience Inc., Montreal, Canada) which has an SMC under clinical development. J.C.B. is the Chief Scientific Officer and a shareholder of Jennerex (Ottawa, Canada and San Francisco, USA), which has a Vaccinia-based oncolytic virus under clinical development.

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Beug, S., Tang, V., LaCasse, E. et al. Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat Biotechnol 32, 182–190 (2014). https://doi.org/10.1038/nbt.2806

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