Immunomodulatory Therapy of Multiple Myeloma with SMAC Mimetics

项目摘要-摘要 多发性骨髓瘤(MM)是一种遗传异质性疾病，具有不同程度的基因组不稳定和 肿瘤内克隆异质性。这两种水平的异质性都对定向抗肿瘤靶向提出了挑战 治疗，这可以通过利用免疫系统的力量来克服。LCL161是一种SMAC模拟物 靶向细胞凋亡抑制蛋白cIAP1和-2(cIAP1/2)。我们之前报道过双性恋- 多发性骨髓瘤中cIAP1/2等位基因缺失导致非规范NFkB途径激活，并一致 LCL161对原代MM细胞、MM细胞系或异种移植模型几乎没有直接的抗肿瘤活性。 它会诱导更高水平的NFkB。然而，LCL161在体内对MM具有戏剧性的活性 在免疫活性和临床预测的VK*MYC小鼠模型中自发发展，但在 体外对这些相同的肿瘤细胞，提示宿主在介导抗肿瘤中起重要作用 效果。VK*MYC小鼠的移植和细胞耗竭实验表明巨噬细胞是 LCL161抗MM活性不依赖于获得性免疫。MΦ是MM的关键组件 并通过提供生存信号和促进免疫抑制来支持MM的生长。然而， 巨噬细胞可通过抑制CSF1R、抗CD47或 Toll样受体(TLR)激动剂+IFNG、TLRa+CD40激动剂或化疗的组合。我们发现 Smac模拟化合物(SMC)LCL161也促进巨噬细胞M1极化和有效 体内抗MM活性。具体地说，LCL161处理诱导骨髓细胞M1极化和杀瘤活性 多发性骨髓瘤患者外周血巨噬细胞共培养实验及M1细胞因子的诱导 参加了临床试验。 这项建议的目标是确定LCL161在VK*MYC小鼠中抗MM活性所涉及的机制 在梅奥诊所参加LCL161 II期临床试验的多发性骨髓瘤患者的样本中也有。

PROJECT SUMMARY—ABSTRACT Multiple myeloma (MM) is a genetically heterogeneous disease, with varying levels of genomic instability and intra-tumor clonal heterogeneity. Both levels of heterogeneity pose challenges for directed anti-tumor targeted therapy, which may be overcome by harnessing the power of the immune system. LCL161 is a SMAC mimetic targeting the cellular inhibitor of apoptosis proteins cIAP1 and -2 (cIAP1/2). We previously reported that bi- allelic deletions of cIAP1/2 in MM result in activation of the non canonical NFkB pathway, and consistently LCL161 has little direct anti-tumor activity, against primary MM cells, MM cell lines, or xenograft models where it induces even higher levels of NFkB. However, LCL161 has dramatic activity in vivo against MM that develops spontaneously in the immuno-competent and clinically predictive Vk*MYC mouse model, but not in vitro against these same tumor cells, suggesting an important role for the host in mediating the anti-tumor effect. Transplantation and cell depletion experiments in Vk*MYC mice implicated macrophages as mediator of LCL161 anti-MM activity that does not depend on adaptive immunity. MΦ are a crucial component of the MM niche and support MM growth by providing survival signals and promoting immunosuppression. However macrophages can be re-educated to acquire tumoricidal activity by CSF1R inhibition, anti-CD47 treatment or combinations of Toll-like-receptor (TLR) agonists + IFNg, TLRa + CD40 agonist or chemotherapy. We found that the SMAC mimetic compound (SMC) LCL161 also promotes macrophages M1 polarization and potent anti-MM activity in vivo. Specifically, LCL161 treatment induced M1 polarization and tumoricidal activity in BM derived macrophages co-cultures experiments, and induction of M1 cytokines in plasma from MM patients enrolled in the clinical trial. The goal of this proposal is to define the mechanisms implicated in LCL161 anti-MM activity in Vk*MYC mice and in samples obtained from MM patients enrolled in a phase II clinical trial of LCL161 at the Mayo Clinic.