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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：
9331584
负责人：
Marta Chesi
金额：
$ 28.14万
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/9331584
关键词：
Agonist Alleles Anemia Apoptosis Apoptosis Inhibitor Bone Marrow Bortezomib CCL2 gene CD47 gene CSF1R gene Cell Line 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 Immunocompetent Immunomodulators Immunosuppression Immunosuppressive Agents Impairment 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 Recruitment Activity Reporting Role Sampling Serum Signal Transduction Solid Neoplasm Syndrome TNFRSF5 gene Therapeutic Toll-like receptors Transplantation Tumorigenicity Xenograft Model Xenograft procedure adaptive immunity angiogenesis antitumor effect bone cIAP1 protein cellular targeting chemotherapy clinical predictors clinically relevant cytokine experimental study immune activation immunoregulation in vivo inhibitor-of-apoptosis protein macrophage mimetics monocyte mouse model neoplastic cell novel phase I trial 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途径的激活，并且一致 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。