Lenalidomide Treatment and the Chronic Lymphocytic Leukemia Microenvironment

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病，被认为是无法治愈的。CLL的生物学研究表明，白血病微环境中的辅助细胞可以促进白血病细胞在体外和体内的存活和对化疗的耐药性。我们描述了一类辅助细胞，称为nursel样细胞（NLC），它可以保护白血病细胞免于凋亡，并定义了几种配体-受体相互作用，这些相互作用可以共同解释这种活性。我们还观察到，来自不同患者的CLL细胞在体外和体内对这些辅助细胞的相对依赖性可能不同。来那度胺对CLL细胞没有直接的细胞毒性，但对CLL有明显的临床活性。使用该药治疗的患者肿瘤细胞减少的机制尚不清楚。我们发现来那度胺可以减轻NLC对体外CLL细胞存活的保护作用。我们假设这种药物至少部分通过调节CLL细胞在白血病细胞微环境中对来自NLC的生存信号作出反应的能力起作用。此外，我们假设高度依赖NLC生存的白血病细胞患者可能比低NLC依赖的CLL细胞患者对来那度胺的临床反应更大。此外，我们已经确定了免疫组织学方法来测量CLL患者骨髓中NLC的相对丰度。我们推测骨髓中NLC含量高的患者对化疗药物和/或来那度胺的反应可能与NLC含量低的患者不同。我们有很好的机会在我们组织的全国临床试验的背景下测试这些假设，评估来那度胺的活性，然后来那度胺和利妥昔单抗，在以前未经治疗的CLL患者中，他们需要目前的治疗指南。为此，我们有以下具体目标：确定高NLC依赖性是否与来那度胺反应相关。2. 评估来那度胺治疗是否会损害CLL细胞在体外接受NLC存活信号的能力。3. 评估预处理骨髓活检标本中相对NLC含量对来那度胺或标准化疗反应的临床意义。通过这项研究，我们将确定来那度胺的临床活性是否与其影响白血病微环境的能力有关，并深入了解对治疗反应和总体生存有潜在影响的患者特征。公共卫生相关性：该提案是一项双向转化研究，旨在了解来那度胺对慢性淋巴细胞白血病（CLL）微环境的影响，并伴有一项关于来那度胺用于CLL一线治疗的国家临床研究。两种潜在的新型生物标志物代表CLL微环境将被评估，一个是前瞻性的，一个是回顾性的，用于预测该药物的临床反应。来那度胺治疗慢性淋巴细胞临床活性的机制研究将通过在治疗期间对受试者白血病细胞进行离体评估来进行。

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world and is considered incurable. Work on the biology of CLL has revealed that accessory cells in the leukemia microenvironment can promote leukemia-cell survival and resistance to chemotherapy in vitro, and presumably in vivo. We have characterized a type of accessory cell, called nurselike cells (NLC), which can protect leukemia cells from apoptosis, and defined several ligand-receptor interactions that together can account for such activity. We also have observed that CLL cells from different patients can vary in their relative dependency on such accessory cells for survival in vitro, and presumably in vivo. Lenalidomide is not directly cytotoxic to CLL cells, but has apparent clinical activity in CLL. The mechanism(s) for tumor-cell reduction in patients treated with this drug is unknown. We found that lenalidomide can mitigate the protective influence of NLC on CLL cell survival in vitro. We hypothesize that this drug functions at least in part by modulating the capacity of CLL cells to respond to the survival signals received from NLC in the leukemia-cell microenvironment. Furthermore, we hypothesize that patients with leukemia cells with high dependency on NLC for survival might enjoy greater clinical responses to lenalidomide than patients with CLL cells that have low NLC-dependency. In addition, we have identified immunohistologic means with which to measure the relative abundance of NLC in the marrow of patients with CLL. We speculate that patients with high NLC content in the marrow might have different responses to chemotherapeutic agents and/or to lenalidomide than patients with low NLC content. We have the outstanding opportunity to test these hypotheses in the context of a national clinical trial that we organized, evaluating the activity of lenalidomide, and then lenalidomide and rituximab, in previously untreated CLL patients who require therapy by current treatment guidelines. For this we have the following specific aims: Specific aims: 1. Determine whether high NLC dependency is associated with response to lenalidomide. 2. Assess whether treatment with lenalidomide impairs the capacity of CLL cells to receive survival signals from NLC in vitro. 3. Assess the clinical significance of the relative NLC content in pretreatment marrow biopsy specimens with regard to the response to lenalidomide or to standard chemotherapy. Through work performed on this proposal we will determine whether clinical activity of lenalidomide is related to its capacity to affect the leukemia microenvironment and gain insight into patient-features that have a potential bearing on the response to therapy and overall survival. Public Health Relevance: The proposal is a bidirectional translational research effort designed to understand the impact of lenalidomide on the chronic lymphocytic leukemia (CLL) microenvironment that accompanies a national clinical study investigating this agent for the frontline treatment of CLL. Two potential novel biomarkers representing the CLL microenvironment will be evaluated, one prospectively and one retrospectively for utility in predicting clinical response to this agent. Investigation of the mechanisms responsible for the clinical activity of lenalidomide in CLL will be performed by ex-vivo evaluation of the subject's leukemia cells during therapy.