PQD2 Rational Combination of Standard Agents and Immunotherapy to Treat Myeloma

PQD2 标准药物与免疫疗法的合理组合治疗骨髓瘤

基本信息

批准号：
9335305
负责人：
Marta Chesi
金额：
$ 34.45万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-17 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335305
关键词：
Affect Alkylating Agents Anemia Back Blood Bone Marrow Cell Death Cells Cessation of life Clinic Clinical Clinical Trials Complex Cyclophosphamide DNA Data Dendritic Cells Drug usage Enrollment Event Future Genetic Genetically Engineered Mouse Genomics Glucocorticoids Growth Heterogeneity Human IL6 gene Immune Immune checkpoint inhibitor Immune response Immune system Immunocompetent Immunologic Deficiency Syndromes Immunologics Immunomodulators Immunotherapy In Vitro Inflammatory Innate Immune System Interferon Type I Interferon-alpha Interferons Maintenance Malignant Bone Neoplasm Malignant Neoplasms Measurable Mediating Mediator of activation protein Melphalan Modeling Molecular Monoclonal Antibodies Multiple Myeloma Mus Neoplasm Transplantation Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacotherapy Phase II Clinical Trials Plasma Cells Predictive Value Production Property Proteasome Inhibitor Relapse Sampling Sampling Studies Thalidomide Treatment outcome Work adaptive immune response analog antitumor effect base bone congenic cytokine cytotoxic high risk immunoregulation in vivo innovation lenalidomide macrophage mimetics monocyte mouse model novel novel therapeutics public health relevance response standard measure standard of care targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a cancer of bone marrow plasma cells that results in over ten thousand deaths a year in the USA. For a while it responds well to treatment with DNA alkylators, glucocorticoids, proteasome inhibitors and the IMiD class of immunomodulators (thalidomide, lenalidomide and pomalidomide). All of these drugs can have profound effects on the immune system, and may interact either positively or negatively with different immunotherapies. Using the immunocompetent Vk*MYC genetically engineered mouse model of multiple myeloma we have noted marked in vivo but little in vitro anti-MM activity of SMAC-mimetic compounds (SMC), which we found activate the innate immune system causing a type I interferon dependent anti-tumor response. We have previously shown that response in this mouse model has a 68% positive predictive value for response in patients with MM. Based on these data we have intiated a phase II clinical trial in MM, and the first patients are responding to treatment. We propose to explore the combination of standard of care agents with SMC using the Vk*MYC mouse model to determine what properties of the former are synergistic or antagonistic for the combination. In parallel we will study the samples obtained from patients enrolled in the clinical trial. Preliminary studies suggest that these drugs are suppressing monocyte/macrophage secretion of inflammatory cytokines, and activating plasmacyoid dendritic cells to secrete interferon, resulting in MM cell death in vivo. The current proposal will use congenic tumor transplant models with selective immuno depletion, genetic depletion, and selecive add-back to precisely identify the host cells mediating the anti-MM effect in vivo and the effects of the combintaion with a standard of care agent. Finally we will analyze blood and bone marrow samples from MM patients treated on a phase II clinical trial of an IAP-antagonist to determine the immunologic sequelae of in vivo drug treatment. These studies will pave the way for the rational combination of standard of care agents with a new class of immunomodularity drugs for the treatment of multiple myeloma.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种骨髓浆细胞癌症，在美国每年导致超过一万人死亡。在一段时间内，它对 DNA 烷化剂、糖皮质激素、蛋白酶体抑制剂和 IMiD 类免疫调节剂（沙利度胺、来那度胺和泊马度胺）的治疗反应良好。所有这些药物都可以对免疫系统产生深远的影响，并且可能与不同的免疫疗法产生积极或消极的相互作用。使用具有免疫活性的 Vk*MYC 多发性骨髓瘤基因工程小鼠模型，我们注意到 SMAC 模拟化合物 (SMC) 在体内具有显着的抗 MM 活性，但在体外却很少，我们发现它可以激活先天免疫系统，从而导致 I 型干扰素依赖性抗肿瘤反应。我们之前已经表明，该小鼠模型的反应对于 MM 患者的反应具有 68% 的阳性预测值。基于这些数据，我们启动了 MM 的 II 期临床试验，第一批患者正在对治疗产生反应。我们建议使用 Vk*MYC 小鼠模型探索标准护理剂与 SMC 的组合，以确定前者的哪些特性对于组合具有协同或拮抗作用。与此同时，我们将研究从参加临床试验的患者获得的样本。初步研究表明这些药物抑制单核细胞/巨噬细胞分泌炎症细胞因子，并激活浆细胞树突状细胞分泌干扰素，导致体内MM细胞死亡。目前的提案将使用具有选择性免疫耗竭、遗传耗竭和选择性回加的同源肿瘤移植模型来精确识别介导体内抗MM效应的宿主细胞以及与标准护理剂组合的效果。最后，我们将分析接受 IAP 拮抗剂 II 期临床试验治疗的 MM 患者的血液和骨髓样本，以确定体内药物治疗的免疫学后遗症。这些研究将为标准治疗药物与新型免疫调节药物的合理组合治疗多发性骨髓瘤铺平道路。