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）：慢性淋巴细胞白血病（CLL）是西方世界最流行的白血病，被认为是无法治愈的。 CLL 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（可能在体内）的存活和对化疗的抵抗力。我们表征了一种称为护士样细胞（NLC）的辅助细胞，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，它们共同可以解释这种活性。我们还观察到，来自不同患者的 CLL 细胞在体外（可能在体内）生存对此类辅助细胞的相对依赖性也可能有所不同。来那度胺对 CLL 细胞不具有直接细胞毒性，但对 CLL 具有明显的临床活性。用这种药物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 CLL 细胞体外存活的保护作用。我们假设该药物至少部分通过调节 CLL 细胞对从白血病细胞微环境中的 NLC 接收到的生存信号作出反应的能力来发挥作用。此外，我们假设，与具有低 NLC 依赖性的 CLL 细胞患者相比，具有高度依赖 NLC 生存的白血病细胞的患者可能对来那度胺有更大的临床反应。此外，我们还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。我们有绝佳的机会在我们组织的一项全国性临床试验中检验这些假设，该试验评估了来那度胺、然后来那度胺和利妥昔单抗在既往未经治疗、需要按照现行治疗指南进行治疗的 CLL 患者中的活性。为此，我们有以下具体目标：具体目标： 1. 确定高度 NLC 依赖性是否与来那度胺的反应相关。 2. 评估来那度胺治疗是否会损害 CLL 细胞在体外接收来自 NLC 的存活信号的能力。 3. 评估治疗前骨髓活检标本中相对 NLC 含量对于来那度胺或标准化疗反应的临床意义。通过对该提案进行的工作，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相关，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工作，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，同时开展一项国家临床研究，调查该药物用于 CLL 一线治疗。将评估两种代表 CLL 微环境的潜在新型生物标志物，一种是前瞻性的，另一种是回顾性的，用于预测对该药物的临床反应。将通过在治疗期间对受试者的白血病细胞进行离体评估来研究来那度胺在 CLL 中的临床活性机制。