Improving Glioma Immunotherapy Efficacy by Regulating Tumor Inflammation

通过调节肿瘤炎症提高胶质瘤免疫治疗效果

基本信息

批准号：
10750788
负责人：
Behnam Badie
金额：
$ 44万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750788
关键词：
Ablation Address Age Alzheimer&apos s disease patient Attenuated Cells Chronic Clinical Trials Combined Modality Therapy Data Development Diagnosis Dose Down-Regulation Effector Cell Endothelial Cells Functional disorder Future Genetic Glioblastoma Glioma Goals Growth Heterogeneity Human Immune Immune response Immunoglobulins Immunologics Immunotherapy Infiltration Inflammation Inflammatory Invaded Knockout Mice Ligands Macrophage Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Membrane Mesenchymal Modeling Molecular Mus Oncogenic Pathway interactions Patients Pattern recognition receptor Pharmaceutical Preparations Process Proteins Radiation therapy Receptor Activation Receptor Inhibition Regimen Reporting Resistance Role S100A9 gene Secondary to Signal Pathway Signal Transduction T cell infiltration T-Lymphocyte Testing Tumor Cell Invasion WNT Signaling Pathway anti-tumor immune response blood-brain barrier crossing cytokine exhaust exhaustion glycation immune checkpoint blockade improved inflammatory milieu inhibitor member novel novel strategies novel therapeutics oxidation permissiveness preclinical study programmed cell death protein 1 receptor receptor for advanced glycation endproducts resistance mechanism response small molecule success synergism targeted treatment therapy resistant transcription factor tumor tumor growth tumor microenvironment

Ablation Address Age Alzheimer&apos s disease patient Attenuated Cells Chronic Clinical Trials Combined Modality Therapy Data Development Diagnosis Dose Down-Regulation Effector Cell Endothelial Cells Functional disorder Future Genetic Glioblastoma Glioma Goals Growth Heterogeneity Human Immune Immune response Immunoglobulins Immunologics Immunotherapy Infiltration Inflammation Inflammatory Invaded Knockout Mice Ligands Macrophage Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Membrane Mesenchymal Modeling Molecular Mus Oncogenic Pathway interactions Patients Pattern recognition receptor Pharmaceutical Preparations Process Proteins Radiation therapy Receptor Activation Receptor Inhibition Regimen Reporting Resistance Role S100A9 gene Secondary to Signal Pathway Signal Transduction T cell infiltration T-Lymphocyte Testing Tumor Cell Invasion WNT Signaling Pathway anti-tumor immune response blood-brain barrier crossing cytokine exhaust exhaustion glycation immune checkpoint blockade improved inflammatory milieu inhibitor member novel novel strategies novel therapeutics oxidation permissiveness preclinical study programmed cell death protein 1 receptor receptor for advanced glycation endproducts resistance mechanism response small molecule success synergism targeted treatment therapy resistant transcription factor tumor tumor growth tumor microenvironment

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项目摘要

PROJECT SUMMARY Patients diagnosed with glioblastoma (GBM) have a median overall survival of less than two years even after receiving multimodal therapies. Multiple factors account for this treatment resistance including: 1) Inability of therapies to cross the blood-brain barrier to reach invading cells; 2) GBM’s molecular heterogeneity and overlapping escape mechanisms that overcome targeted therapies; 3) Evasive mechanisms that render GBMs resistant to immunotherapy. Therefore, there is an unmet need for GBM treatment approaches that address multiple resistance mechanisms. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily which was discovered as a transmembrane receptor for the products of nonenzymatic glycation and oxidation of proteins. RAGE is expressed by glioma cells and is activated by its ligands present in GBM tumor microenvironment (TME). Activation of RAGE stimulates multiple signaling pathways that promote GBM progression. Recently, we demonstrated that genetic ablation of intracellular RAGE in gliomas inhibited multiple oncogenic pathways that not only regulated glioma growth and invasion, but also, improved the efficacy of immunotherapies by promoted an immunologically “permissive” TME. We also discovered that RAGE ablation in TME enhances the efficacy of immunotherapy. Based on these observations, we propose to evaluate RAGE inhibition as a multifaceted therapy for GBM. Our central hypothesis is that RAGE inactivation will not only suppress oncogenic pathways that are important for GBM growth and invasion, but also, enhance responses to immunotherapy. Three independent aims are proposed. Aim 1 will determine the mechanism of RAGE ablation on enhancing the anti-tumor immune responses in syngeneic mouse GBM models. Findings from this Aim will uncover novel strategies that could enhance immunotherapy efficacy in these resistant tumors. Aim 2 will measure the synergistic effects of small molecule RAGE inhibitors with immunotherapy. In this Aim, we will perform the pre-clinical studies to optimize the dosing regimen of RAGE inhibitors for future GBM clinical trials. Finally, Aim 3 will Identify mechanisms of immunotherapy resistance to RAGE ablation. This Aim will identify the mechanisms by which RAGE ligands such as S100A9 attenuate tumor immune responses. Success of any of these aims, which are supported by compelling preliminary data, is expected to lead to the development of novel and critically needed GBM therapies.

项目摘要被诊断为胶质母细胞瘤（GBM）的患者中位总生存期甚至不到两年接受多模式疗法后。多个因素解释了这种治疗抗性，包括：1）无法跨越血脑屏障的疗法到达入侵细胞； 2）GBM的分子异质性和克服目标疗法的重叠逃生机制； 3）呈现GBM的回避机制对免疫疗法有抵抗力。因此，对GBM治疗方法的需求未满足多重电阻机制。高级糖基终端产品（RAGE）的接收器是免疫球蛋白的成员超家族被发现是一种非酶糖化产物的跨膜受体和蛋白质的氧化。愤怒用神经胶质瘤细胞表达，并被GBM肿瘤中存在的配体激活微环境（TME）。愤怒的激活刺激促进GBM的多种信号通路进展。最近，我们证明了神经胶质瘤中细胞内愤怒的遗传消融抑制了多个不仅调节神经胶质瘤生长和侵袭的致癌途径，而且还提高了通过促进免疫学上的“允许” TME的免疫疗法。我们还发现愤怒消融在TME中提高了免疫疗法的效率。基于这些观察，我们建议评估愤怒作为GBM的多面疗法抑制作用。我们的中心假设是，愤怒失活不仅会抑制对于GBM的生长和入侵而言，重要的是增强对免疫疗法的反应。三个独立提出了目标。 AIM 1将决定增强抗肿瘤免疫的愤怒消融机制合成小鼠GBM模型中的响应。这个目标的发现将发现可能的新策略在这些抗性肿瘤中增强免疫疗法的有效性。 AIM 2将衡量小的协同作用通过免疫疗法的分子抑制剂。在此目标中，我们将进行临床前研究以优化对未来GBM临床试验的愤怒抑制剂的给药方案。最后，AIM 3将确定免疫疗法抵抗愤怒消融。这个目标将确定愤怒配体的机制例如S100A9减弱肿瘤免疫调查。这些目标的成功，这些目标得到了引人入胜的初步数据的支持，预计将导致开发新颖和急需的GBM疗法。