Lenalidomide Treatment and the Chronic Lymphocytic Leukemia Microenvironment

来那度胺治疗和慢性淋巴细胞白血病微环境

基本信息

批准号：
7657255
负责人：
Thomas J Kipps
金额：
$ 33.99万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7657255
关键词：
Abbreviations Accounting Affect Antigen Targeting Antigen-Presenting Cells Antigens Apoptosis B-Lymphocytes Binding Biological Markers Biology Biopsy Biopsy Specimen CD14 gene Cell Death Cell Survival Cells Chronic Lymphocytic Leukemia Clinical Clinical Research Clinical Trials Coculture Techniques Complement Factor B Data Dependency Evaluation Follicular Lymphoma Formalin Guidelines Hand Immunohistochemistry In Vitro Individual Investigation Ligands Lymphoid Tissue Lymphoma Marrow Measures Modeling Myeloid Cells NF-kappa B Neoplasm Metastasis Patients Pharmaceutical Preparations Phenotype Population Production Proteins Relative (related person)Research Resistance Sampling Signal Transduction Supporting Cell TALL-1 protein TNF gene Testing Therapeutic Studies Time Tissues Translational Research Treatment Protocols Tumor Necrosis Factor-alpha Tumor Necrosis Factors Western World Work ZAP-70 Gene base cell type chemokine chemotherapeutic agent chemotherapy clinically significant cytotoxic density design experience functional status impaired capacity in vivo insight lenalidomide leukemia lymph nodes macrophage monocyte neoplastic cell novel protective effect public health relevance receptor response rituximab tissue fixing trait tumor

项目摘要

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.

描述（由申请人提供）：慢性淋巴细胞性白血病（CLL）是西方世界中最普遍的白血病，被认为是无法治愈的。 CLL生物学的工作表明，白血病微环境中的辅助细胞可以促进白血病 - 细胞的存活和体外化学疗法的抗性，并且大概是体内。我们已经表征了一种称为护士样细胞（NLC）的辅助细胞，该细胞可以保护白血病细胞免受凋亡的影响，并定义了几种可以同时解释这种活性的配体 - 受体相互作用。我们还观察到，来自不同患者的CLL细胞的相对依赖性对这种辅助细胞的相对依赖性有所不同，以便在体外生存，并且大概是在体内。 Lenalidomide不是直接对CLL细胞的细胞毒性，而是CLL的明显临床活性。使用该药物治疗的患者肿瘤细胞减少的机制尚不清楚。我们发现，Lenalidomide可以减轻NLC在体外对CLL细胞存活的保护作用。我们假设该药物至少部分通过调节CLL细胞的能力来应对白血病细胞微环境中NLC收到的生存信号的能力。此外，我们假设患有对NLC生存的白血病细胞的患者比具有低NLC依赖性的CLL细胞患者对Lenalidomide的生存可能更大。此外，我们已经确定了用于测量NLC在CLL患者骨髓中相对丰度的免疫组织学手段。我们推测，与NLC含量低的患者相比，骨髓中NLC含量较高的患者对化学治疗剂和/或对列那度胺的反应可能不同。在我们组织的一项国家临床试验的背景下，我们有很棒的机会来测试这些假设，评估Lenalidomide的活性，然后在以前未经治疗的CLL患者中，这些患者需要通过当前治疗指南进行治疗。为此，我们具有以下特定目的：具体目的：1。确定高NLC依赖性是否与对Lenalidomide的反应有关。 2。评估Lenalidomide治疗是否会损害CLL细胞在体外接收NLC的生存信号的能力。 3。评估对骨髓活检的相对NLC含量在对Lenalidomide或对标准化疗的反应方面的临床意义。通过该提案所做的工作，我们将确定Lenalidomide的临床活性是否与影响白血病微环境的能力有关，并洞悉具有对治疗反应和整体生存的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工作，旨在了解Lenalidomide对慢性淋巴细胞性白血病（CLL）微环境的影响，伴随着一项国家临床研究，研究了该药物对CLL前线治疗的代理。将评估代表CLL微环境的两个潜在的新型生物标志物，一种前瞻性和回顾性的一种，用于预测对该药物的临床反应。研究负责在治疗期间对受试者的白血病细胞进行的，对Lenalidomide在CLL中的临床活性的机制进行研究。