IAP antagonists induce anti-tumor immunity in multiple myeloma

M Chesi, NN Mirza, VM Garbitt, ME Sharik, AC Dueck… - Nature medicine, 2016 - nature.com
M Chesi, NN Mirza, VM Garbitt, ME Sharik, AC Dueck, YW Asmann, I Akhmetzyanova…
Nature medicine, 2016nature.com
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 …
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.
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