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Nat Med. 2016 Dec;22(12):1411-1420. doi: 10.1038/nm.4229. Epub 2016 Nov 14.

IAP antagonists induce anti-tumor immunity in multiple myeloma.

Author information

1
Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
2
Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA.
3
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
4
Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA.

Abstract

The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.

PMID:
27841872
PMCID:
PMC5515246
DOI:
10.1038/nm.4229
[Indexed for MEDLINE]
Free PMC Article

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