Immunomodulatory Therapy of Multiple Myeloma with SMAC Mimetics

项目摘要 多发性骨髓瘤（MM）是一种遗传异质性疾病，具有不同水平的基因组不稳定性， 肿瘤内克隆异质性。两种水平的异质性都对定向抗肿瘤靶向治疗提出了挑战。 治疗，这可以通过利用免疫系统的力量来克服。LCL 161是SMAC模拟物 靶向细胞凋亡抑制蛋白cIAP 1和cIAP-2（cIAP 1/2）。我们之前报道过，双- MM中cIAP 1/2的等位基因缺失导致非经典NFkB通路的激活，并且一致地 LCL 161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，LCL 161在体内对MM具有显著的活性， 在免疫活性和临床预测性Vk*MYC小鼠模型中自发发生，但在 体外对这些相同的肿瘤细胞，这表明宿主在介导抗肿瘤作用中的重要作用。 效果Vk*MYC小鼠的移植和细胞耗竭实验表明巨噬细胞是 LCL 161抗MM活性不依赖于获得性免疫。MΦ是MM的重要组成部分 通过提供生存信号和促进免疫抑制来定位和支持MM生长。然而 巨噬细胞可以通过CSF 1 R抑制、抗CD 47治疗或 Toll样受体（TLR）激动剂+ IFNg、TLRa + CD 40激动剂或化疗的组合。我们发现 SMAC模拟化合物（SMC）LCL 161也促进巨噬细胞M1极化， 体内抗MM活性。具体而言，LCL 161处理诱导BM中的M1极化和杀肿瘤活性。 衍生的巨噬细胞共培养实验，以及MM患者血浆中M1细胞因子的诱导 参加了临床试验 本提案的目的是确定LCL 161在Vk*MYC小鼠中抗MM活性的相关机制 以及从在马约诊所参加LCL 161的II期临床试验的MM患者获得的样品中。

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.