Immunomodulatory Therapy of Multiple Myeloma with SMAC Mimetics

使用 SMAC 模拟物对多发性骨髓瘤进行免疫调节治疗

基本信息

批准号：
9152284
负责人：
Marta Chesi
金额：
$ 26.33万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9152284
关键词：
Agonist Anemia Apoptosis Apoptosis Inhibitor Bone Marrow Bone Marrow Cells Bortezomib CCL2 gene CD47 gene CSF1R gene Cell Line Cell Transplantation Cells Chemotactic Factors Clinic Clinical Clinical Trials Coculture Techniques Cyclophosphamide Dexamethasone Dichloromethylene Diphosphonate Disease Dose-Limiting Enrollment Evaluation Genetic Heterogeneity Genetically Engineered Mouse Genomic Instability Goals Growth Heterogeneity Human IL8 gene Immune Immune response Immune system Immunomodulators Immunosuppression Immunosuppressive Agents In Vitro Interleukin-12 Liposomes Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Molecular Profiling Molecular Target Multiple Myeloma Mus Oxides Pathway interactions Patients Phase II Clinical Trials Plasma Plasma Cells Pre-Clinical Model Reporting Role Sampling Serum Signal Transduction Solid Neoplasm Syndrome TNFRSF5 gene Therapeutic Toll-like receptors Transplantation Xenograft Model Xenograft procedure adaptive immunity angiogenesis antitumor effect bone cIAP1 protein cellular targeting chemotherapy clinically relevant cytokine in vivo inhibitor-of-apoptosis protein macrophage mimetics monocyte mouse model neoplastic cell novel phase I trial research study synergism targeted treatment tumor tumorigenic

项目摘要

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.

项目摘要 - 提取多发性骨髓瘤（MM）是一种遗传异质性疾病，基因组不稳定性水平不同肿瘤内克隆异质性。两个级别的异质性构成针对的抗肿瘤的挑战治疗，可以通过利用免疫系统的力量来克服。 LCL161是SMAC模拟物靶向细胞凋亡蛋白CIAP1和-2（CIAP1/2）的细胞抑制剂。我们以前曾报道过 MM中CIAP1/2的等位基因缺失导致非规范NFKB途径的激活，并始终如一地激活 LCL161几乎没有直接抗肿瘤活性，针对原代MM细胞，MM细胞系或异种移植模型，其中它影响了更高水平的NFKB。但是，LCL161在对MM的体内具有戏剧性的活性在免疫能力和临床预测的VK*MYC鼠标模型中开发赞助商友好体外针对这些相同的肿瘤细胞，这表明宿主在介导抗肿瘤中的重要作用影响。 VK*MYC小鼠中的移植和细胞耗竭实验以巨噬细胞为中介 LCL161不取决于适应性免疫史的抗MM活性。 Mφ是MM的关键组成部分利基市场和支持MM生长通过提供生存信号并促进免疫抑制。然而可以通过CSF1R抑制，抗CD47治疗或 Toll样受体（TLR）激动剂 + IFNG，TLRA + CD40激动剂或化学疗法的组合。我们发现 SMAC模拟化合物（SMC）LCL161还促进了巨噬细胞M1极化和有效体内抗MM活性。具体而言，LCL161处理诱导BM中的M1极化和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。该提案的目的是定义在VK*MYC小鼠中LCL161抗MM活性中实现的机制在从梅奥诊所LCL161的II期临床试验中获得的MM患者获得的样品中。