Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications

多发性骨髓瘤（MM）在2001年在美国影响了14，400个新个体，总共有50，000名患者，并且尽管常规和高剂量治疗仍然无法治愈。因此，迫切需要针对肿瘤细胞及其微环境的独特靶标的新型治疗干预措施。当前提案的主要目标，“骨髓瘤中的宿主-肿瘤细胞相互作用：治疗应用”，是开发针对宿主-肿瘤细胞相互作用的新疗法，以克服耐药性，实现MM的长期无病生存和潜在治愈。首先，我们将尝试在治疗上利用针对MM的同种异体供体免疫应答的相互作用，并定义新疗法的靶抗原（Ritz的项目）。其次，我们将尝试增加自体抗MM 免疫，并类似地鉴定新的靶抗原（Munshi的Project）。在每种情况下，新靶标的分子鉴定和验证将产生MM特异性免疫疗法。重要的是，我们在BM环境中的MM细胞的临床前体外以及体内动物模型证明了靶向MM细胞-宿主骨髓（BM）相互作用的新型药剂可以克服经典的耐药性。我们的衍生临床试验表明，这些药物可以实现反应，在某些情况下，完全反应，在大多数患者与MM难治性所有已知的目前的治疗。因此，本计划（安德森项目）的一个新的重要目标是定义和验证MM-宿主相互作用作为MM新治疗模式的目标。管理和研究护理（A）和生物统计学/生物信息学（B）核心将协助设计、执行、分析和报告实验室和临床研究。免疫评估核心（C）将在这些新疗法后提供免疫学监测。因此，该计划是一个综合的，相互关联的，相互依存的三个项目系列 三个核心在科学和临床层面上相互作用。预计，无论是在项目内部还是项目之间，基于实验室的机制研究将转化为临床研究，相反，临床方案的观察结果将提示新的基础研究。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。

Multiple myeloma (MM) affected 14,400 new individuals in the United States in 2001, with 50,000 total patients, and remains incurable despite conventional and high dose therapies. Novel therapeutic interventions are therefore urgently needed with targets unique to the tumor cell and its microenvironment. The major goal of the current proposal, "Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications", is to develop novel therapies targeting host-tumor cell interactions to overcome drug resistance and 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. First, we will attempt to therapeutically exploit the interaction of the allogeneic donor immune response against MM and define target antigens for novel therapeutics (Project by Ritz). Second, we will attempt to augment autologous anti-MM immunity using vaccination strategies, and similarly identify novel target antigens (Project by Munshi). In each case molecular identification and validation of novel targets will derive MM specific immune therapies. Importantly, our preclinical in vitro as well as in vivo animal models of MM cells in the BM milieu, demonstrate that novel agents targeting the MM cell-host bone marrow (BM) interaction can overcome classical drug resistance. Our derived clinical trials show that these agents can achieve responses, in some cases complete responses, in the majority of patients with MM refractory to all known current therapies. Therefore a new and important goal of this Program (Project by Anderson) is to define and validate MM-host interactions as targets in a new treatment paradigm for MM. Administrative and Research Nursing (A) and Biostatistics/ Bioinfomatics (B) Cores will assist in design, conduct, analysis, and reporting of laboratory and clinical studies. Immune Assessment Core (C) will provide immunological monitoring after these novel therapies. This Program therefore represents an integrated, interrelated, and interdependent series of three Projects and three Cores which interact on both a scientific and clinical level. It is anticipated, both within and between projects, that laboratory based mechanistic studies will translate to clinical studies, and that 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.