Etanercept Therapy in Follicular Lymphoma

描述(申请人提供)：尽管已经开发了几种新的治疗方法来治疗滤泡性淋巴瘤(FL)，但总体存活率尚未显著提高。体外研究表明FL细胞的存活受到肿瘤微环境信号的影响。FL细胞与称为滤泡树突状细胞(FDC)的基质成分相关，它为FL细胞和趋化因子提供抗凋亡信号，可能有助于FL细胞在淋巴滤泡中的定位。由于FDCs为淋巴瘤细胞提供生存和归巢信号，因此在微环境中靶向这些细胞可能是FL的一种新的治疗方法。肿瘤坏死因子(TNF)在FL细胞中高表达，上调FL细胞与FDC相互作用中至关重要的黏附分子、细胞因子和趋化因子的表达。依那西普是一种可溶的、二聚体的重组人p75 TNFR，与人IgG1的Fc片段融合，开发用于中和肿瘤坏死因子(并且是被批准的治疗类风湿关节炎的药物，具有良好的毒副作用)。我们推测，阻断肿瘤坏死因子将影响肿瘤微环境，从而改变FL细胞与FDC的相互作用，从而改变FL细胞的存活。为了研究这一假设，我们提出了三个具体目标。首先，对复发性FL患者进行依那西普的临床试验。第二，通过对替代标志物的研究，探讨依那西普对肿瘤微环境的直接和间接影响。我们将研究对FDCs、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。由于肿瘤坏死因子在T细胞功能中很重要，了解依那西普对这些患者T细胞的影响将是很重要的。这项研究是治疗FL的一种新方法，靶向肿瘤的微环境可能会抑制肿瘤细胞的生长和存活。

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.