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

项目总结/摘要 多形性胶质母细胞瘤（GBM）是一种可怕的癌症，由于缺乏免疫抑制剂，中位生存期为14个月。 有效的治疗。检查点阻断免疫疗法已经显示出对几种疾病有希望的临床结果。 因此，现在有许多针对GBM的早期临床试验。试验是为两个新的 诊断和复发的GBM，在这两种情况下，检查点封锁是在以下背景下进行的： GBM的标准治疗（SOC），包括手术减积，然后分次 放疗（XRT）与伴随的和辅助的替莫唑胺（TMZ）烷化剂化疗。另外大部分 患者使用类固醇（地塞米松-Dex））以缓解术后神经系统症状 救灾我们对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 了解XRT/TMZ/Dex如何影响检查点免疫疗法的疗效，并描绘一个 临床策略，将最大限度地提高治疗效果。此外，我们还证明， 并且GBM免疫浸润的活化状态受GBM细胞的驱动基因型的影响。我们 该提案将填补关于免疫渗透物的类型和激活状态的知识空白， 肿瘤驱动基因型。 我们的建议的中心假设是：1）GBM的免疫景观与驾驶员的类型有关 肿瘤的突变（基因型）和2）GBM的SOC将影响其免疫组分和功能， 这两者都将直接影响PD-1和CTLA-4检查点阻断免疫疗法的功效。 我们需要描述这些影响并理解它们，以便修改GBM管理方案， 充分利用免疫疗法的力量。我们建议使用EGFR和PDGFR β驱动的 基因工程小鼠模型，准确地概括了人类GBM，以确定 肿瘤基因型对免疫动物群的影响，揭示SOC对免疫功能的影响， 将这些发现应用于临床实践。我们的项目将提供一个有效的翻译使用基因切割 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 机械地解释其结果。

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.