IAP antagonists induce anti-tumor immunity in multiple myeloma

Marta Chesi, Noweeda N. Mirza, Victoria M. Garbitt, Meaghen E. Sharik, Amylou Dueck, Yan Asmann, Ilseyar Akhmetzyanova, Heidi E. Kosiorek, Arianna Calcinotto, Daniel L. Riggs, Niamh Keane, Gregory J. Ahmann, Kevin M. Morrison, Rafael Fonseca, Martha Lacy, David M Dingli, Shaji K Kumar, Sikander Ailawadhi, Angela Dispenzieri, Francis BuadiMorie Gertz, Craig B. Reeder, Yi Lin, Asher A Chanan Khan, Alexander Keith Stewart, David Fooksman, Peter Leif Bergsagel

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53 Scopus citations

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)-ΰ B 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.

Original languageEnglish (US)
Pages (from-to)1411-1420
Number of pages10
JournalNature Medicine
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chesi, M., Mirza, N. N., Garbitt, V. M., Sharik, M. E., Dueck, A., Asmann, Y., Akhmetzyanova, I., Kosiorek, H. E., Calcinotto, A., Riggs, D. L., Keane, N., Ahmann, G. J., Morrison, K. M., Fonseca, R., Lacy, M., Dingli, D. M., Kumar, S. K., Ailawadhi, S., Dispenzieri, A., ... Bergsagel, P. L. (2016). IAP antagonists induce anti-tumor immunity in multiple myeloma. Nature Medicine, 22(12), 1411-1420. https://doi.org/10.1038/nm.4229