To Understand/Augment OX40-mediated Tumor Immunotherapy

了解/增强 OX40 介导的肿瘤免疫疗法

• 批准号: 7227428
• 负责人: Andrew D Weinberg
• 金额: $ 30.02万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227428
• 关键词: Understand; Augment; OX40; mediated; Tumor

DESCRIPTION (provided by applicant): It is well documented that enhancing immune function to cancer can have a therapeutic effect on the disease. A major limitation of immunotherapy is the added dimension that the tumor microenvironment can be immune-suppressive to the host that harbors cancer. Recently, there have been a number of approaches to try and "supercharge" the immune system to tumor Ag(s), so that when the immune system recognizes a tumor it can overcome immune-suppression and destroy the tumor. One approach that has successfully enhanced immune function in tumor-bearing hosts has been the addition of activating antibodies or ligands to TNF-receptor family members. This grant application will focus on the immune boosting activity of the TNF-R family member OX40 (CD134), which is expressed on activated T cells. When OX40 is engaged via an exogenous source of Ab or the OX40 ligand, potent anti-tumor properties are elicited. We will try and understand how OX40 engagement enhances immune function and use this knowledge to increase anti-tumor immunity. Gene array analysis in basic immune models has provided clues to how engagement of OX40 boosts immunity. This application will use the knowledge derived from the basic immunology models to enhance OX40-mediated tumor therapy through combination therapy with the cytokines that show a common gamma-chain (IL-2, IL-7, and IL-15). These cytokine receptors were found to be increased on Ag-stimulated T cells following OX40 engagement in our preliminary DNA microarray analyses. We will also try and understand the changes in T cell gene expression that occur in a tumor microenvironment upon OX40 engagement in vivo. Finally, because the OX40 technology will be taken to clinical trials within the coming year, we will work with an established method for enhancing immune function in clinical trials (i.e. GM-CSF transfected tumors) to assess its augmentation with anti-OX40. This will provide important preclinical information for the design of future clinical trials. The specific aims of the application are; 1) To characterize the molecular events that occur following OX40 engagement within T cells isolated from a tumor microenvironment, 2) To define the roles of common gamma-chain cytokines in OX40-enhanced anti-tumor immune responses, and 3) Explore the combination of anti-OX40 and a GM-CSF secreting tumor vaccine in a preclinical setting. The ultimate goal of the application will be to enhance OX40-mediated tumor therapy by gaining a better understanding of how this receptor can increase the proinflammatory properties of T cell function.

描述（由申请人提供）：有充分证据表明，增强对癌症的免疫功能可以对疾病产生治疗作用。免疫疗法的一个主要限制是肿瘤微环境可能对携带癌症的宿主具有免疫抑制作用。最近，已经有许多方法尝试和“增压”免疫系统肿瘤Ag（s），以便当免疫系统识别肿瘤时，它可以克服免疫抑制并摧毁肿瘤。一种已经成功增强荷瘤宿主免疫功能的方法是向TNF受体家族成员添加活化抗体或配体。这项拨款申请将集中在TNF-R家族成员OX 40（CD 134）的免疫增强活性上，该家族成员在活化的T细胞上表达。当通过Ab或0X 40配体的外源性来源接合0X 40时，引发有效的抗肿瘤性质。我们将尝试了解OX 40参与如何增强免疫功能，并利用这些知识来提高抗肿瘤免疫力。基础免疫模型中的基因阵列分析为OX 40的参与如何增强免疫力提供了线索。本申请将使用来自基本免疫学模型的知识，通过与显示共同γ链的细胞因子（IL-2、IL-7和IL-15）的联合治疗来增强OX 40介导的肿瘤治疗。在我们的初步DNA微阵列分析中，发现这些细胞因子受体在Ag刺激的T细胞上在OX 40参与后增加。我们还将尝试和理解在体内OX 40参与后肿瘤微环境中发生的T细胞基因表达的变化。最后，由于OX 40技术将在未来一年内进入临床试验，我们将在临床试验中使用已建立的增强免疫功能的方法（即GM-CSF转染的肿瘤）来评估其与抗OX 40的增强作用。这将为未来临床试验的设计提供重要的临床前信息。该申请的具体目的是：1）表征在从肿瘤微环境分离的T细胞内OX 40接合后发生的分子事件，2）确定常见γ链细胞因子在OX 40增强的抗肿瘤免疫应答中的作用，以及3）探索抗OX 40和分泌GM-CSF的肿瘤疫苗在临床前环境中的组合。该应用的最终目标是通过更好地了解这种受体如何增加T细胞功能的促炎特性来增强OX 40介导的肿瘤治疗。