IAP antagonists induce anti-tumor immunity in multiple myeloma.
IAP antagonists induce anti-tumor immunity in multiple myeloma.
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DOI：
10.1038/nm.4229
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发表时间：
2016-12
期刊：
影响因子：
82.9
通讯作者：
Bergsagel PL
中科院分区：
文献类型：
--
作者：
Chesi M;Mirza NN;Garbitt VM;Sharik ME;Dueck AC;Asmann YW;Akhmetzyanova I;Kosiorek HE;Calcinotto A;Riggs DL;Keane N;Ahmann GJ;Morrison KM;Fonseca R;Lacy MQ;Dingli D;Kumar SK;Ailawadhi S;Dispenzieri A;Buadi F;Gertz MA;Reeder CB;Lin Y;Chanan-Khan AA;Stewart AK;Fooksman D;Bergsagel PL
细胞凋亡抑制因子cIAP 1和cIAP −2在约3%的癌症中扩增，由于其在逃避细胞凋亡中的作用，在多种恶性肿瘤中被鉴定为潜在的治疗靶点。因此，小分子IAP拮抗剂，如LCL 161，由于其诱导TNF介导的癌细胞凋亡的能力而进入临床试验。然而，cIAP1和cIAP2在多发性骨髓瘤中反复同源缺失，导致非经典NFkB通路的组成性激活。因此，在转基因骨髓瘤小鼠模型和复发难治性骨髓瘤患者中观察到LCL 161的稳健体内抗骨髓瘤活性是违反直觉的，其中添加环磷酰胺导致中位无进展生存期为10个月。这种作用不是由于直接诱导肿瘤细胞死亡，而是由于肿瘤细胞自主I型干扰素信号传导的上调和强烈的炎症反应，巨噬细胞和树突细胞的活化导致肿瘤细胞的吞噬作用。用LCL 161治疗在一部分转基因Vk*MYC小鼠中建立了长期抗肿瘤保护和治愈。值得注意的是，LCL 161与免疫检查点抑制剂抗PD 1的组合在所有治疗的小鼠中都是治愈性的。
The cellular inhibitor of apoptosis cIAP1 and −2 are amplified in about 3% of cancers, and were identified in multiple malignancies as potential therapeutic targets due to their role in evasion of apoptosis. Consequently, small molecule IAP antagonists, like LCL161, have entered clinical trials for their ability to induce TNF-mediated apoptosis of cancer cells. However, cIAP1 and −2 are recurrently homozygously deleted in multiple myeloma resulting in constitutive activation of the non-canonical NFkB pathway. It was therefore counterintuitive to observe a robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and patients with relapsed-refractory myeloma, where addition of cyclophosphamide resulted in a median progression free survival of 10 months. This effect is not due to direct induction of tumor cell death, but rather to upregulation of a tumor cell autonomous type I interferon signaling and a strong inflammatory response with activation of macrophages and dendritic cells resulting in phagocytosis of tumor cells. Treatment with LCL161 established long-term anti-tumor protection and cure in a fraction of transgenic Vk*MYC mice. Remarkably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all treated mice.
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