Host-tumor cell interaction in myeloma: therapeutic applications

描述(由申请人提供)：多发性骨髓瘤(MM)在2007年影响了美国19,900名新患者，其中10,800人相关死亡，尽管采用常规和大剂量治疗，但仍无法治愈。目前这项名为“骨髓瘤中宿主-肿瘤细胞相互作用：治疗应用”的提案的主要目标是表征和下调宿主肿瘤促进机制，增强抗多发性骨髓瘤宿主免疫反应，以开发新的靶向疗法，实现骨髓瘤的长期无病生存和潜在治愈。该计划建立在前一资助期进展的基础上，现在有三个主要目标。我们利用我们的体外和体内模型来证明骨髓基质细胞(BMSCs)在MM细胞中促进生长和赋予耐药性的中心作用。然后，我们展示了Bortezomib和来那度胺在骨髓环境中调节MM细胞的细胞毒性，并迅速将这些发现从试验台上转移到床边和FDA批准。我们现在的研究重点是免疫辅助细胞--浆细胞样树突状细胞(PDC)在多发性骨髓瘤发病机制中的作用。我们项目1的主题是确定PDC诱导MM细胞生长的机制，以便开发针对BM环境中这种相互作用的新疗法。在之前的授予期间，我们已经根据在自体和同种异体环境中诱导免疫反应的基础上鉴定了MM抗原。相反，我们已经开始描述MM免疫功能障碍的机制(NKG2D和Th17途径)。我们项目2的主题是识别和靶向调节自身抗MM反应的细胞和可溶性因子，以开发针对这些途径的有效策略，以改善免疫反应和抑制骨髓瘤细胞生长。最后，我们在体外和体内进行了临床前研究，证明MM-DC融合可以诱导抗MM免疫反应。我们进一步证明，MM-DC融合疫苗具有良好的耐受性，并能诱导MM患者的免疫反应和病情稳定。我们项目3的主题是将疫苗接种与过继治疗结合起来，以克服宿主免疫抑制机制，从而进一步增强抗MM免疫。行政(A)和生物统计/生物信息学(B)核心将协助设计、实施、分析和报告实验室和临床研究。免疫评估和细胞制造核心(C)将提供免疫学监测并生产用于过继转移的细胞。因此，该计划代表了一个由三个项目和三个核心组成的综合和相互关联的系列，这些项目和核心在科学和临床层面上相互作用，以确定抗MM免疫的特征并从治疗上开发抗MM免疫。在项目内部和项目之间，基于实验室的机械性研究将转化为临床研究；相反，临床方案的观察将建议进行新的基础研究。最终，我们的目标是验证MM-宿主细胞相互作用作为新疗法的靶点，以改善MM患者的预后。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) affected 19,900 new individuals in the United States in 2007, with 10,800 related deaths, and remains incurable despite conventional and high dose therapies. The major goal of the current proposal, "Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications," is to characterize and down regulate host tumor promoting mechanisms and enhance anti-MM host immune responses in order to develop novel targeted therapeutics which achieve long-term disease free survival and potential cure of MM. This Program builds upon and extends progress during the prior funding period and now has three major goals. We utilized our in vitro and in vivo models to demonstrate a central role of bone marrow stromal cells (BMSCs) promoting growth and conferring drug resistance in MM cells. We then showed that bortezomib and lenalidomide mediate MM cell cytotoxicity in the BM milieu, and rapidly translated these findings from the bench to the bedside and FDA approval. We are now focusing our studies on characterizing the role of an immune accessory cell, the plasmacytoid dendritic cell (pDC), in MM pathogenesis. Our theme for Project 1 is to identify the mechanisms of pDC-induced MM cell growth in order to develop novel therapeutics targeting this interaction within the BM milieu. During the prior granting period, we have identified MM antigens based upon the induction of immune responses in both the autologous and allogeneic setting. Conversely, we have begun to characterize mechanisms underlying immune dysfunction (NKG2D and Th17 pathways) in MM. Our theme for Project 2 is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies targeting these pathways to improve immune responses and inhibit myeloma cell growth. Finally, we have carried out in vitro and in vivo preclinical studies demonstrating that MM-DC fusions can induce anti-MM immune responses. We went on to show that MM-DC fusion vaccination was well tolerated, and can induce immune responses and stabilization of disease in MM patients. Our theme for Project 3 is to couple vaccination with adoptive therapy to overcome host immunosuppressive mechanisms and thereby further enhance anti-MM immunity. Administrative (A) and Biostatistics/Bioinfomatics (B) Cores will assist in design, conduct, analysis, and reporting of laboratory and clinical studies. Immune Assessment and Cell Manufacturing Core (C) will provide immunological monitoring and produce cells for adoptive transfer. This Program therefore represents an integrated and interrelated series of three Projects and three Cores that interact on both a scientific and clinical level to characterize and therapeutically exploit anti-MM immunity. Both within and between projects, laboratory based mechanistic studies will translate to clinical studies; and conversely, observations from clinical protocols will suggest new basic investigations. Ultimately, our goal is to validate MM-host cell interactions as a target for novel therapeutics to improve patient outcome in MM.