The IAP antagonist LCL161 has activity against multiple myeloma cells independent of apoptosis.
Major finding: The IAP antagonist LCL161 has activity against multiple myeloma cells independent of apoptosis.
Clinical relevance: LCL161 plus cyclophosphamide led to a PFS of 10 months in patients with refractory multiple myeloma.
Impact: Treatment regimens including LCL161 may promote antitumor immunity in patients with multiple myeloma.
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.
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