Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma

项目摘要/摘要 多形性胶质母细胞瘤(GBM)是一种可怕的癌症，由于缺乏 有效的治疗。检查点阻断免疫疗法已经显示出几种有希望的临床结果 因此，现在有许多针对GBM的早期临床试验。试验是为这两个新的 在两种情况下，检查点封锁都是在以下背景下实施的 GBM的标准护理(SOC)治疗，包括手术去髓核，然后分次 放射治疗(XRT)配合替莫唑胺(TMZ)烷化化疗。此外，大多数 患者使用类固醇(地塞米松-地塞米松)来缓解术后神经症状 如释重负。我们对XRT/TMZ和类固醇暴露如何影响 肿瘤微环境(TME)，特别是免疫细胞成分。因此，迫切需要 为了了解XRT/TMZ/Dex对检查点免疫疗法的疗效的影响，并描绘出 将使治疗效果最大化的临床策略。此外，我们还证明了构图 GBM细胞的驱动基因对GBM免疫浸润物的激活状态有影响。我们的 该提案将填补关于免疫渗入的类型和激活状态的知识空白 肿瘤驱动基因分型。 我们建议的中心假设是：1)基底膜的免疫格局与司机的类型有关 肿瘤的突变(基因)和2)GBM的SOC将影响其免疫成分和功能， 两者都将直接影响PD-1和CTLA-4检查点阻断免疫疗法的疗效。 我们需要描述这些影响并了解它们，以便修改GBM管理协议以 充分利用免疫疗法的力量。我们建议使用EGFR和PDGFR驱动 基因工程小鼠模型，它准确地概括了人的GBM，以确定 肿瘤基因对免疫动物的影响，揭示SOC对免疫功能的影响及其相互关系 这些发现将用于临床实践。我们的项目将提供对基因切割的有效翻译使用 GBM的边缘模型，准确地概括人类疾病，为临床试验的进行提供信息，并 机械地解释他们的结果。

Project Summary/Abstract Glioblastoma multiforme (GBM) is a dreadful cancer with a median survival of 14 months due to a lack of effective therapy. Checkpoint blockade immunotherapies have shown promising clinical outcomes for several cancers, and as such there are now many early stage clinical trials for GBM. Trials are designed for both newly diagnosed and recurrent GBMs and in both cases, checkpoint blockade is administered on the background of standard of care (SOC) therapy for GBM, which consists of surgical debulking, followed by fractionated radiation (XRT) with concomitant and adjuvant temozolomide (TMZ) alkylating chemotherapy. In addition, most patients are subjected to steroid use (dexamethasone-Dex)) to alleviate post surgery neurological symptomatic relief. There is a critical deficiency in our understanding on how XRT/TMZ and steroid exposure affect the tumor microenvironment (TME), specifically the immune cells component. Therefore there is a pressing need to understand how the efficacy of checkpoint immunotherapies is affected by XRT/TMZ/Dex and delineate a clinical strategy that will maximize treatment effectiveness. In addition, we demonstrate that the composition and activation status of GBM immune infiltrates is influenced by the driver genotype of the GBM cells. Our proposal will fill a knowledge gap regarding the type and activation status of the immune infiltrate vis-à-vis tumor driver genotypes. The central hypotheses of our proposal are: 1) the immune landscape of GBM is related to the type of driver mutations (genotype) of the tumor and 2) the SOC for GBM will affect its immune component and function, both of which will directly influence the efficacy of PD-1 and CTLA-4 checkpoint blockade immunotherapies. We need to delineate those effects and understand them in order to modify GBM management protocols to take full advantage of the power of immunotherapy. We propose to use EGFR- and PDGFR-driven genetically engineered mouse models, which accurately recapitulate human GBM, to determine the effects of tumor genotype on the immunofauna, to unveil the consequences of SOC on immune function and to relate those findings to clinical practice. Our project will deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate human disease to inform the conduct of clinical trials and to mechanistically interpret their outcomes.