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Spherical Nucleic Acid nano-architectures as first-in-class cGAS agonists for the immunotherapeutic treatment of Glioblastoma.

球形核酸纳米结构作为一流的 cGAS 激动剂，用于胶质母细胞瘤的免疫治疗。

基本信息

批准号：
10709540
负责人：
CHAD A. MIRKIN
金额：
$ 42.56万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-09-23 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709540
关键词：
3-Dimensional Adaptor Signaling Protein Address Adenosine Advanced Malignant Neoplasm Agonist Animals Antigen-Presenting Cells Antisense DNA Architecture Binding Biochemical Biological Biological Availability Brain CXCL10 gene Cancer Model Cancer Patient Cells Characteristics Clinical Clinical Trials Combined Modality Therapy Credentialing Cyclic GMP DNA Data Development Diagnosis Dinucleoside Phosphates Dose Enzymes Formulation Gene Activation Gene Expression Generations Genetic Engineering Genetic Transcription Glioblastoma Glioma Histopathology Human IRF3 gene Immune Immune response Immune system Immunocompetent Immunologic Stimulation Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory Innate Immune Response Interferons Intranasal Administration Knowledge acquisition Lead Libraries Macrophage Malignant Neoplasms Malignant neoplasm of brain Mediating Modality Modeling Mus Myelogenous Myeloid-derived suppressor cells NK Cell Activation Nanoconjugate Natural Killer Cells Nuclear Nucleic Acids Nucleosome Core Particle Oligonucleotides PD-1 inhibitors Pathway interactions Patients Periodicity Pharmaceutical Preparations Phase I Clinical Trials Phenotype Production Property Radial Regulator Genes Research Signal Transduction Small Interfering RNA Solid Solid Neoplasm Spherical Nucleic Acids Stimulator of Interferon Genes Structure Surface Survival Analysis T-Lymphocyte TLR9 gene Testing Toll-like receptors Toxic effect Transcriptional Activation Treatment Protocols Tumor-Derived Vaccines adaptive immune response antitumor effect bioluminescence imaging cancer type clinical application delivery vehicle density dimer ds-DNA early phase clinical trial immune checkpoint blockade immunoregulation improved outcome in vivo innate immune sensing mouse model nanoGold nanoarchitecture nanoparticle neuro-oncology novel nuclease nucleic acid structure nucleic acid-based therapeutics personalized immunotherapy pharmacologic response sensor small molecule tumor tumor growth uptake

项目摘要

Vaccines, drugs, and modified human cells that activate the immune system against tumor can improve the outcomes and prolong the lives of patients diagnosed with some type of cancers, but have failed to provide survival benefits for patients with glioblastoma (GBM). Activation of the Stimulator of Interferon Genes (STING) pathway represents one of the main innate immune sensing pathway to enable natural killer (NK) and T cell priming against tumor. Intratumoral administration of STING agonists, in particular cyclic dinucleotides (CDNs), was shown to have significant anti-tumor effects in multiple cancer models, including orthotopic GBM models, and is currently being tested in a phase 1 clinical trial in advanced cancer patients (NCT0267754339). Limited bioavailability and stability, however, are limiting factors for clinical CDN development. We have shown that the formulation of oligonucleotides into SNA structures, i.e., the presentation of oligonucleotides at high density on the surface of nanoparticles, leads to biochemical and biological properties that are radically different from those of linear (“free”) oligonucleotides. These include the cellular uptake of SNAs by a wide variety of cells, the gene regulatory activity of SNAs functionalized with siRNA or antisense DNA oligonucleotides, and the TLR-agonistic activity of SNAs conjugated with immunostimulatory oligonucleotides. Importantly, clinical trials with first generation siRNA-based SNAs (NCT03020017; GBM), and toll-like receptor 9 (TLR9)-agonsitic SNAs (NCT03086278; solid cancers) have recently been completed. Our proposed research is to develop a first-in-class immunotherapy by targeting cGAS – the sensor of cytosolic dsDNA upstream of STING – with SNAs presenting interferon-stimulating DNA (ISD) oligonucleotides at high surface density, and to evaluate the potential of SNAcGAS for use in clinical neuro-oncology. This approach is distinct from other current approaches that target the STING pathway with CDNs and small molecules. By targeting cGAS, the strategy of using SNAsISD exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. Our use of SNAs addresses the challenges of delivery of therapeutic nucleic acids through the enhanced uptake of nucleic acids formulated as SNAs, and furthermore, exploits the polyvalent presentation of oligonucleotides at high density on a nanoparticle template. Here, the binding of closely-spaced, neighboring dsDNA molecules on the surfaces of SNAs should enhance the formation of 2:2 dimers of cGAS:DNA and thus lead to potent cGAS activation. In three Specific Aims, we will optimize the SNA platform for maximum cGAS-STING pathway activation in vitro and in vivo (Aim 1), assess anti-tumor effect of our lead SNAcGAS architectures together with additional high-activity SNA constructs in vivo (Aim 2), and evaluate treatment regimens combining SNAcGAS with prioritized immunotherapies, including check point blockade and pharmacological strategies to inhibit adenosine signaling (Aim 3).

激活免疫系统对抗肿瘤的疫苗、药物和修饰的人类细胞可以改善结果并延长被诊断患有某种癌症的患者的生命，但未能提供胶质母细胞瘤（GBM）患者的生存获益。干扰素基因刺激剂 (STING) 的激活途径代表了使自然杀伤 (NK) 和 T 细胞发挥作用的主要先天免疫传感途径之一启动对抗肿瘤。 STING 激动剂的瘤内给药，特别是环状二核苷酸（CDN），在多种癌症模型中被证明具有显着的抗肿瘤作用，包括原位 GBM 模型，目前正在晚期癌症患者中进行一期临床试验（NCT0267754339）。有限的然而，生物利用度和稳定性是临床 CDN 开发的限制因素。我们已经证明，将寡核苷酸配制为 SNA 结构，即纳米颗粒表面高密度的寡核苷酸，导致生化和生物学特性与线性（“游离”）寡核苷酸完全不同。其中包括 SNA 的细胞摄取通过多种细胞，SNA 的基因调控活性通过 siRNA 或反义 DNA 进行功能化寡核苷酸，以及与免疫刺激寡核苷酸缀合的 SNA 的 TLR 激动活性。重要的是，第一代基于 siRNA 的 SNA（NCT03020017；GBM）和 Toll 样受体的临床试验 9 (TLR9)-agonsitic SNA（NCT03086278；实体癌）最近已完成。我们提出的研究是通过靶向 cGAS（细胞质传感器）来开发一流的免疫疗法 STING 上游的 dsDNA – SNA 呈现高浓度的干扰素刺激 DNA (ISD) 寡核苷酸表面密度，并评估 SNAcGAS 在临床神经肿瘤学中的应用潜力。这种方法是与目前其他利用 CDN 和小分子靶向 STING 通路的方法不同。经过针对 cGAS，使用 SNASISD 的策略利用了 cGAS 通过传递来提高 STING 响应的能力 dsDNA 并诱导内源 CDN 的催化生产。我们使用 SNA 应对挑战通过增强配制为 SNA 的核酸的摄取来递送治疗性核酸，以及此外，利用纳米颗粒模板上高密度寡核苷酸的多价呈现。在这里，SNA 表面上紧密排列的相邻 dsDNA 分子的结合应该会增强 cGAS:DNA 2:2 二聚体的形成，从而导致有效的 cGAS 激活。在三个具体目标中，我们将优化 SNA 平台，以在体外和体内最大限度地激活 cGAS-STING 通路（目标 1），评估我们的领先 SNAcGAS 架构与其他高活性 SNA 构建体在体内的抗肿瘤作用（目标 2），并评估 SNAcGAS 与优先免疫疗法相结合的治疗方案，包括检查点阻断和抑制腺苷信号传导的药理学策略（目标 3）。