Radiation-induced targeted extracellular vesicles -based gene delivery for glioma therapy

放射诱导的基于细胞外囊泡的基因递送用于神经胶质瘤治疗

基本信息

批准号：
9902892
负责人：
BAKHOS A TANNOUS
金额：
$ 24.86万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902892
关键词：
Adaptive Immune System Affinity Animals Antibodies Brain Brain Neoplasms CD47 gene CD8-Positive T-Lymphocytes Cells Characteristics Chemotherapy and/or radiation Development Eating Excision Exhibits FDA approved Gene Delivery Glioblastoma Glioma Immune Immune checkpoint inhibitor Immune response Immunosuppression Immunotherapy Injections Innate Immune System Integrin alphaVbeta3 Intravenous Ligands Malignant neoplasm of brain Modification Mus Operative Surgical Procedures Patients Peptides Property RGD (sequence)Radiation Radiation Dose Unit Radiation therapy Signal Transduction Site Small Interfering RNA Surface Survival Rate System Therapeutic Tumor Antigens Tumor-associated macrophages Vascular Endothelial Cell Vesicle adaptive immune response base cancer type checkpoint inhibition clinical application cytotoxic CD8 T cells extracellular vesicles immune checkpoint immunogenicity improved intravenous administration mouse model nanotherapeutic nerve stem cell outcome forecast programmed cell death ligand 1 radiation effect recruit targeted delivery therapeutic transgene tumor tumor growth tumor microenvironment tumor-immune system interactions uptake

项目摘要

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with poor prognosis. Therapeutic suppression of immune checkpoint molecules elicits a tumor immune response and improves long-term survival in several types of cancers. GBM cells highly express immune checkpoint molecules including programmed death-ligand 1 (PD-L1) a critical “don’t find me” signal to the adaptive immune system, and CD47, a “don’t eat me” signal to the innate immune system as well as a regulator of the adaptive immune response. Although radiation therapy has been shown to counteracts the immunosuppressive GBM microenvironment by enhancing the presentation of normally suppressed tumor-associated antigens, promoting CD8+ T cell recruitment, radiation enhances even further the expression of PD-L1 on tumor and microenvironment. Unfortunately, little effect has been observed with checkpoint inhibitors against GBM. An effective GBM therapy requires a delivery system that reaches the tumor in the brain, with limited systemic effect. Endogenous small vesicles known as extracellular vesicles (EVs) hold a great promise as a delivery vehicle given their unique properties including low immunogenicity and innate stability. However, intravenous delivery of EVs to the brain remains a major challenge due to poor targeting of unmodified EVs, which can be improved by surface modification. Our preliminary results shows that The cyclo(Arg-Gly-Asp- D-Tyr-Lys) peptide, which exhibits high affinity to integrin αvβ3 on tumor vascular endothelial cells, could be conjugated on EVs surface (derived from FDA-approved normal neural progenitor cells), resulting in improved EV accumulation in brain tumors after intravenous administration. Furthermore, building on recent studies showing that short bursts of radiation therapy can prime tumors for enhanced accumulation and intratumoral distribution of nanotherapeutics in tumor-associated macrophages-dependent fashion, we showed that glioblastomas primed with radiation had an enhanced uptake of targeted EVs. In this proposal, we will take advantage of these unique characteristics of targeted EVs and load them with small interfering RNAs (siRNAs) against PD-L1 and CD47 to achieve enhanced immune response at the glioblastoma site, primed with radiation. We will evaluate whether radiation therapy will prime glioblastomas for enhanced uptake of these targeted EV across the BBB to deliver siRNAs to GBM, to increase CD8 T cells cytotoxic activity, thus halting tumor growth and prolonging animal survival in a syngeneic graft GBM mouse model.

抽象的胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，预后较差。抑制免疫检查点分子会引发肿瘤免疫反应并改善长期效果 GBM 细胞高度表达免疫检查点分子，包括多种癌症的存活率。程序性死亡配体 1 (PD-L1) 是向适应性免疫系统发出的关键“不要找到我”信号，以及 CD47，向先天免疫系统发出“不要吃我”的信号，也是适应性免疫系统的调节剂尽管放射治疗已被证明可以抵消免疫抑制性 GBM。通过增强正常抑制的肿瘤相关抗原的表达来改善微环境，促进 CD8+ T 细胞募集，辐射进一步增强肿瘤上 PD-L1 的表达，不幸的是，检查点抑制剂对 GBM An 的影响很小。有效的 GBM 治疗需要一个能够到达大脑肿瘤的递送系统，但系统性有限称为细胞外囊泡（EV）的内源性小囊泡作为递送具有很大的前景。然而，载体具有低免疫原性和先天稳定性等独特特性。由于未经修饰的电动汽车的靶向性较差，将电动汽车静脉输送到大脑仍然是一个重大挑战，我们的初步结果表明，环（Arg-Gly-Asp-）可以改善这一问题。 D-Tyr-Lys）肽与肿瘤血管内皮细胞上的整合素 αvβ3 表现出高亲和力，可能是结合在 EV 表面（源自 FDA 批准的正常神经祖细胞），从而产生此外，基于最近的研究，静脉注射后脑肿瘤中 EV 的积累得到改善。研究表明，短时间的放射治疗可以促进肿瘤的积累和增强纳米治疗药物以肿瘤相关巨噬细胞依赖性方式在肿瘤内分布，我们研究表明，经过放射处理的胶质母细胞瘤对目标 EV 的吸收有所增强。我们将利用目标电动汽车的这些独特特性，并为其加载小干扰针对 PD-L1 和 CD47 的 RNA (siRNA) 可增强胶质母细胞瘤部位的免疫反应，我们将评估放射治疗是否会增强胶质母细胞瘤的能力。通过 BBB 摄取这些靶向 EV，将 siRNA 递送至 GBM，从而增加 CD8 T 细胞的细胞毒性活性，从而在同基因移植 GBM 小鼠模型中阻止肿瘤生长并延长动物存活期。