Etanercept Therapy in Follicular Lymphoma

依那西普治疗滤泡性淋巴瘤

• 批准号: 6585639
• 负责人: Arnold S. Freedman
• 金额: $ 28.47万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-12 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6585639
• 关键词: B lymphocyte; T lymphocyte; chimeric proteins; clinical research; clinical trial phase I; computed axial tomography; dendritic cells; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; human subject; human therapy evaluation; immunofluorescence technique; immunoglobulin G; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonHodgkin's lymphoma; patient oriented research; pharmacokinetics; positron emission tomography; recombinant proteins; rheumatoid arthritis; serum; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Although several novel therapeutic approaches have been developed for treatment of follicular lymphomas (FL), the overall survival has not yet been significantly improved. In vitro studies have provided evidence that FL cell survival is influenced by signals from the neoplastic microenvironment. FL cells associate with stromal elements known as follicular dendritic cells (FDCs), which provide anti-apoptotic signals to FL cells and chemotactic factors that likely contribute to the localization of FL cells within lymphoid follicles. Since FDCs provide survival and homing signals to lymphoma cells, targeting these cells in the microenvironment may be a novel treatment approach for FL. TNF( is overexpressed by FL cells, and TNF( upregulates the expression of adhesion molecules, cytokines and chemokines which are critical to FL cell-FDC interactions. Etanercept is a soluble, dimeric, recombinant human p75 TNFR, fused to the Fc fragment of human IgG1, developed for neutralization of TNF( and is an approved therapy for rheumatoid arthritis with an favorable toxicity profile. We hypothesize that TNF( blockade will affect the tumor microenvironment and therefore alter FL celI-FDC interactions, and FL cell survival. To investigate this hypothesis we propose three specific aims. First, to undertake a clinical trial of etanercept for patients with relapsed FL. Second, to investigate effects of etanercept on the tumor microenvironment directly and indirectly through studies of surrogate markers. We will investigate effects on FDCs, surrogate peripheral blood and serum markers as well as utilize PET scanning to assess the potential biologic activity of etanercept. Third, to investigate the effects of etanercept on T cell activation. Since TNF( is important in T cell function, it will be important to understand the effects of etanercept on T cells in these patients. This study is a novel approach to treating FL, where targeting the microenvironment of the tumor may inhibit the growth and survival of the neoplastic cells.

描述（由申请人提供）：尽管已经开发出几种新的治疗方法用于治疗滤泡性淋巴瘤（FL），但总生存率尚未显着改善。体外研究提供的证据表明 FL 细胞存活受到肿瘤微环境信号的影响。 FL 细胞与称为滤泡树突细胞 (FDC) 的基质成分相关，后者向 FL 细胞提供抗凋亡信号和可能有助于 FL 细胞在淋巴滤泡内定位的趋化因子。由于 FDC 为淋巴瘤细胞提供生存和归巢信号，因此针对微环境中的这些细胞可能是治疗 FL 的一种新方法。 TNF( 在 FL 细胞中过表达，TNF( 上调对 FL 细胞与 FDC 相互作用至关重要的粘附分子、细胞因子和趋化因子的表达。依那西普是一种可溶性二聚体重组人 p75 TNFR，与人 IgG1 的 Fc 片段融合，开发用于中和 TNF(，是一种经批准的治疗类风湿性关节炎的疗法 具有良好的毒性特征。我们假设TNF(阻断剂)会影响肿瘤微环境，从而改变FL细胞-FDC相互作用以及FL细胞存活。为了研究这一假设，我们提出了三个具体目标。第一，对复发性FL患者进行依那西普的临床试验。第二，通过替代研究直接和间接研究依那西普对肿瘤微环境的影响。 标记。我们将研究对 FDC、替代外周血和血清标志物的影响，并利用 PET 扫描来评估依那西普的潜在生物活性。 第三，研究依那西普对T细胞活化的影响。由于 TNF(在 T 细胞功能中很重要，因此了解依那西普对这些患者 T 细胞的影响也很重要。这项研究是一种治疗 FL 的新方法，其目标是 肿瘤的微环境可能会抑制肿瘤细胞的生长和存活。