权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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).

疫苗、药物和改良的人体细胞可以激活免疫系统对抗肿瘤