To Understand/Augment OX40-mediated Tumor Immunotherapy

描述(由申请人提供)：有充分的文献证明，增强对癌症的免疫功能可以对疾病有治疗作用。免疫治疗的一个主要限制是增加了一个维度，即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，已经有许多方法试图通过肿瘤抗原(S)为免疫系统“增压”，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。一种成功地增强了荷瘤宿主免疫功能的方法是向肿瘤坏死因子受体家族成员添加激活的抗体或配体。这项拨款申请将集中在肿瘤坏死因子受体家族成员OX40(CD134)的免疫促进活性，它表达在激活的T细胞上。当OX40通过外源抗体或OX40配体参与时，就会激发出强大的抗肿瘤特性。我们将尝试了解OX40参与如何增强免疫功能，并利用这一知识来提高抗肿瘤免疫。基本免疫模型中的基因阵列分析为OX40参与如何增强免疫力提供了线索。这个应用程序将使用从基本免疫学模型中获得的知识，通过与显示共同伽马链的细胞因子(IL-2、IL-7和IL-15)的联合治疗来增强OX40介导的肿瘤治疗。在我们的初步DNA微阵列分析中，发现在OX40参与后，这些细胞因子受体在Ag刺激的T细胞上增加。我们还将尝试并了解体内OX40参与后肿瘤微环境中T细胞基因表达的变化。最后，由于OX40技术将在来年进入临床试验，我们将在临床试验中使用一种既定的增强免疫功能的方法(即GM-CSF转基因肿瘤)，以评估其对抗OX40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。该应用的具体目的是：1)表征从肿瘤微环境中分离的T细胞内OX40结合后发生的分子事件；2)确定常见的伽马链细胞因子在OX40增强的抗肿瘤免疫反应中的作用；3)探索抗OX40与GM-CSF分泌的肿瘤疫苗在临床前环境中的组合。该应用的最终目标将是通过更好地了解OX40受体如何增加T细胞功能的促炎特性来加强OX40介导的肿瘤治疗。

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.