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.

项目摘要/摘要放射治疗（RT）是胶质母细胞瘤（GBM）护理标准治疗标准的关键组成部分，这是最多的成人常见和致命的原发性大脑恶性肿瘤。除了对肿瘤本身的直接细胞毒性作用之外，RT- 最近，人们对引起的抗肿瘤免疫调查剂被认为是治疗结果的关键因素。这些响应取决于髓样细胞的功能，这是先天的重要组成部分免疫系统。但是，在肿瘤微环境中，大部分髓样室被编程为进行免疫抑制作用，会损害抗肿瘤的免疫调查，从而损害RT的治疗作用。这项提议的工作的目的是利用和重编程免疫抑制肿瘤相关的髓样 GBM中最丰富的免疫种群的细胞（TAMCS），以扩增RT引起的抗肿瘤免疫回答。为了实现TAMC的精确，有效的治疗靶向，我们提出了A的发展桥脂纳米颗粒（B-LNP）平台具有积极靶向GBM诱导的TAMC体内的能力。我们的初步数据表明，B-LNP将TETHERS TAMC通过“桥接”效果和同时阻止 GBM用于避免免疫监测的抗吞噬作用。该平台还可以使TAMC- 针对干扰素基因刺激剂（Sting）的激动剂的针对性递送，这是弥合先天和的关键因素自适应抗肿瘤免疫，导致肿瘤表现出促炎的表型刺激肿瘤的效应T细胞浸润。在临床前动物模型中，我们的TAMC靶向重编程促进脑肿瘤回归，并增加RT的抗肿瘤活性。该提议的中心假设是，纳米颗粒疗法只是激活TAMC 吞噬活性和干扰素途径信号传导将放大RT刺激的抗肿瘤免疫力 GBM。我们将专注于我们纳米颗粒可以利用的两种不同的TAMC的抗GBM机制： GBM的吞噬作用（AIM 1）和效应T细胞反应的激活（AIM 2）。最后，我们将确定在GBM的护理标准治疗标准的背景下，TAMC靶向治疗的有效性（AIM 3）。这将使用临床前动物模型对临床翻译的可行性进行彻底评估，其中包括独特的 GBM的人性化动物模型和临床GBM样品，该模型将测试人源化的有效性治疗剂的版本。总体而言，我们的研究提供了一种新颖的方法来重塑免疫抑制负责治疗耐药性的肿瘤微环境，并促进当前的护理疗法标准 GBM。