Nano-therapeutics Reprogramming of Immunosuppressive Myeloid Cells Potentiate Radiotherapy for Glioblastoma

免疫抑制性骨髓细胞的纳米治疗重编程可增强胶质母细胞瘤的放射治疗

基本信息

批准号：
10671715
负责人：
Peng Zhang
金额：
$ 35.87万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-26 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671715
关键词：
Address Adult Agonist Animal Model Anti-CD47 Antitumor Response Brain Brain Neoplasms CD47 gene Cancer Patient Cells Clinical Data Development Effectiveness Experimental Animal Model Gene Activation Genes Glioblastoma Human Immune Immune response Immunologic Surveillance Immunologics Immunosuppression Impairment Infiltration Inflammatory Inflammatory Response Innate Immune System Interferons Knowledge Laboratories Mainstreaming Malignant Neoplasms Malignant neoplasm of brain Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nanotechnology Nature Newly Diagnosed Pathway interactions Phagocytes Phagocytosis Phenotype Play Population Radiation therapy Research Research Support Resistance Role Route Sampling Shapes Signal Pathway Stimulator of Interferon Genes T cell infiltration T cell response T-Lymphocyte Testing Therapeutic Therapeutic Effect Toxic effect Treatment outcome Tumor Antigens Tumor Immunity Tumor Promotion Tumor-associated macrophages Work anti-tumor immune response antitumor effect cancer immunotherapy cancer infiltrating T cells cancer therapy clinical translation clinically relevant cytotoxic effectiveness evaluation effectiveness testing effector T cell genotoxicity humanized mouse immunogenic cell death in vivo interest lipid nanoparticle mouse model nanoparticle nanotherapeutic neoplastic cell novel strategies pre-clinical programs radiation effect response standard of care success targeted delivery targeted treatment temozolomide therapeutic nanoparticles therapeutic target therapy resistant treatment effect treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Radiation therapy (RT) is a key component of standard of care treatments for glioblastoma (GBM), the most common and deadly primary brain malignancy in adults. Beyond the direct cytotoxic effect on tumor itself, RT- elicited anti-tumor immune responses have recently been appreciated as a key factor to the treatment outcomes. These responses are dependent on the functionality of myeloid cells, an essential component of the innate immune system. However, within tumor microenvironment, much of the myeloid compartment is programed to be immunosuppressive, which impairs the anti-tumor immune responses and thereby therapeutic effects of RT. The objective of this proposed work is to harness and reprogram immunosuppressive tumor-associated myeloid cells (TAMCs), the most abundant immune population in GBM, to amplify the RT-elicited anti-tumor immune responses. To enable a precise and efficient therapeutic targeting of TAMC, we propose the development of a bridge-lipid nanoparticle (B-LNP) platform with the ability to actively target the GBM-induced TAMC in-vivo. Our preliminary data suggest that B-LNP tethers TAMC to GBM through a “bridging” effect and concurrently blocks the anti-phagocytic effectors used by GBM to escape immune surveillance. This platform also enables TAMC- targeted delivery of an agonist for stimulator of interferon genes (STING), a key factor in bridging innate and adaptive anti-tumor immunity, resulting in the tumor displaying a pro-inflammatory phenotype that robustly stimulates effector T cell infiltration of tumor. In preclinical animal models, our TAMC-targeted reprogramming promotes brain tumor regression, and increases the anti-tumor activity of RT. The central hypothesis of this proposal is that nanoparticle therapies that simultaneously activate TAMC phagocytic activity and interferon pathway signaling will amplify the RT-stimulated anti-tumor immunity against GBM. We will focus on two different anti-GBM mechanisms of TAMC that our nanoparticle could harness: phagocytosis of GBM (Aim 1) and activation of effector T cell responses (Aim 2). Lastly, we will determine the effectiveness of TAMC-targeted therapy in the context of standard of care treatments for GBM (Aim 3). The feasibility for clinical translation will be thoroughly evaluated using preclinical animal models, including a unique humanized animal model of GBM, and clinical GBM samples, which will test the effectiveness of a humanized version of the therapeutics. Overall, our study provides a novel approach to reshape the immunosuppressive tumor microenvironment responsible for therapy resistance, and promote current standard of care therapies for GBM.

项目概要/摘要放射治疗 (RT) 是胶质母细胞瘤 (GBM) 标准治疗的关键组成部分，也是最常见的胶质母细胞瘤 (GBM) 治疗方法。成人常见且致命的原发性脑恶性肿瘤除了对肿瘤本身有直接的细胞毒性作用外，RT- 引发的抗肿瘤免疫反应最近被认为是治疗结果的关键因素。这些反应取决于骨髓细胞的功能，骨髓细胞是先天免疫系统的重要组成部分。然而，在肿瘤微环境中，大部分骨髓区室被编程为具有免疫抑制作用，会损害抗肿瘤免疫反应，从而损害放疗的治疗效果。这项工作的目的是利用和重新编程免疫抑制性肿瘤相关骨髓细胞细胞（TAMC）是 GBM 中最丰富的免疫群体，可放大 RT 引发的抗肿瘤免疫为了实现 TAMC 的精确有效的治疗靶向，我们建议开发一种桥脂质纳米颗粒 (B-LNP) 平台能够主动靶向体内 GBM 诱导的 TAMC。初步数据表明，B-LNP 通过“桥接”效应将 TAMC 与 GBM 联系起来，同时阻断 GBM 用来逃避免疫监视的抗吞噬效应器，该平台还使 TAMC- 成为可能。靶向递送干扰素基因刺激剂 (STING) 激动剂，干扰素基因是桥接先天和干扰素基因的关键因素适应性抗肿瘤免疫，导致肿瘤表现出强烈的促炎表型在临床前动物模型中，我们的 TAMC 靶向重编程可刺激肿瘤的效应 T 细胞浸润。促进脑肿瘤消退，并增加 RT 的抗肿瘤活性。该提案的中心假设是同时激活 TAMC 的纳米颗粒疗法吞噬细胞活性和干扰素途径信号传导将增强 RT 刺激的抗肿瘤免疫力我们将重点关注我们的纳米颗粒可以利用的 TAMC 的两种不同的抗 GBM 机制： GBM 的吞噬作用（目标 1）和效应 T 细胞反应的激活（目标 2）。 GBM 护理治疗标准背景下 TAMC 靶向治疗的有效性（目标 3）。将使用临床前动物模型彻底评估临床转化的可行性，包括独特的 GBM人源化动物模型和临床GBM样本，这将测试人源化GBM的有效性总的来说，我们的研究提供了一种重塑免疫抑制的新方法。肿瘤微环境负责治疗抵抗，并促进当前的护理治疗标准 GBM。