PQD2 Rational Combination of Standard Agents and Immunotherapy to Treat 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，在美国每年导致超过1万人死亡。在一段时间内，它对DNA烷基化剂、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，并可能与不同的免疫疗法产生积极或消极的相互作用。利用免疫活性的Vk*MYC基因工程小鼠多发性骨髓瘤模型，我们注意到smac模拟化合物（SMC）在体内有明显的抗mm活性，但在体外几乎没有，我们发现SMC激活先天免疫系统，引起I型干扰素依赖的抗肿瘤反应。我们之前的研究表明，在这种小鼠模型中，对MM患者的反应有68%的阳性预测值。基于这些数据，我们已经启动了MM的II期临床试验，第一批患者对治疗有反应。我们建议使用Vk*MYC小鼠模型探索标准护理剂与SMC的联合使用，以确定前者的哪些特性对联合使用具有协同作用或拮抗作用。同时，我们将研究从参加临床试验的患者身上获得的样本。初步研究表明，这些药物

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.