IAP Antagonists Promote Phagocytosis of Multiple Myeloma In Vivo Free

The cellular inhibitors of apoptosis (cIAP) 1 and 2 promote cell survival through E3-mediated ubiquitination of target proteins, resulting in NF-κB pathway activation. cIAP1/2 are potential therapeutic targets in cancer, and IAP antagonists can induce TNF-mediated apoptosis. However, cIAP1/2 are commonly deleted in multiple myeloma, resulting in constitutive noncanonical activation of the NF-κB pathway, prompting Chesi and colleagues to hypothesize that cIAP1/2 inhibition might promote multiple myeloma growth. To determine the role of IAP antagonists in multiple myeloma in vivo, the small molecule IAP antagonist LCL161 was tested in a mouse model of multiple myeloma. Unexpectedly, LCL161 reduced tumor burden with an efficacy similar to multiple myeloma standard-of-care agents including cyclophosphamide. Moreover, tissue from LCL161-treated multiple myeloma indicated phagocytosis of nonapoptotic multiple myeloma cells, suggesting that the effects of LCL161 are independent of TNF-mediated apoptosis. Twenty-six patients with relapsed–refractory multiple myeloma were treated with LCL161 in a phase II clinical trial, and cyclophosphamide was added in 23 of the patients. There were no responses to single-agent LCL161, but five patients achieved a response with LCL161 plus cyclophosphamide, including one complete response. The median progression-free survival (PFS) was 10 months. Further investigation of the molecular mechanism of action revealed that LCL161 induced a type I interferon inflammatory response in tumor cells that induced macrophages and dendritic cells to phagocytize multiple myeloma cells. Adaptive immunity was not required for the short-term activity of LCL161, but was required for long-term disease control, which occurred in a fraction of mice. Further, adding anti–PD-1 to LCL161 treatment was curative in mice with multiple myeloma. The finding that LCL161 is active against multiple myeloma in vivo by an apoptosis-independent mechanism suggests that IAP antagonists may have broader clinical activity than previously appreciated and warrant further investigation in the treatment of multiple myeloma.

Chesi M, Mirza NN, Garbitt VM, Sharik ME, Dueck AC, Asmann YW, et al. IAP antagonists induce anti-tumor immunity in multiple myeloma. Nat Med 2016;22:1411–20.

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