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

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.

项目概要诊断为胶质母细胞瘤 (GBM) 的患者的中位总生存期甚至不到两年接受多模式治疗后，多种因素导致了这种治疗抵抗，包括：1）无能力。穿过血脑屏障到达入侵细胞的治疗方法；2) GBM 的分子异质性和 3）渲染GBM的规避机制因此，针对 GBM 治疗方法的需求尚未得到满足。多重抵抗机制。晚期糖基化终末产物 (RAGE) 受体是免疫球蛋白的成员超家族被发现作为非酶糖化产物的跨膜受体 RAGE 由神经胶质瘤细胞表达，并被 GBM 肿瘤中存在的配体激活。 RAGE 的激活可刺激促进 GBM 的多种信号通路。最近，我们证明神经胶质瘤中细胞内 RAGE 的遗传进展消融抑制了多种致癌途径不仅调节神经胶质瘤的生长和侵袭，而且还提高了疗效通过促进免疫学上“允许的”TME 进行免疫疗法我们还发现了 RAGE 消融。基于这些观察，我们建议评估 RAGE。抑制作为 GBM 的多方面疗法。我们的中心假设是，RAGE 失活不仅会抑制致癌途径，对于 GBM 生长和侵袭很重要，而且还增强对免疫治疗的反应三个独立的。提出目标1将确定RAGE消融增强抗肿瘤免疫的机制。该目标的发现将揭示可能的新策略。增强这些耐药肿瘤的免疫治疗效果，目标 2 将测量小型药物的协同效应。分子RAGE抑制剂与免疫疗法的结合，我们将进行临床前研究以优化。未来 GBM 临床试验的 RAGE 抑制剂的给药方案最后，目标 3 将确定其机制。免疫疗法对 RAGE 消融的抵抗该目标将确定 RAGE 配体的机制。例如 S100A9 减弱肿瘤免疫反应。这些目标的任何一个的成功，都有令人信服的初步数据的支持，预计将导致开发新颖且急需的 GBM 疗法。