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Cell-Selective CpG-STAT3 Inhibitors for Radioimmunotherapy of Malignant Glioma

用于恶性胶质瘤放射免疫治疗的细胞选择性 CpG-STAT3 抑制剂

基本信息

批准号：
9768413
负责人：
Marcin Kortylewski
金额：
$ 42.87万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768413
关键词：
Agonist Animals Antibodies Antisense Oligonucleotides Biodistribution Cause of Death Cell Death Cell Survival Cells Combined Modality Therapy Cyclic GMP Dose Drug Kinetics FDA approved Flow Cytometry Generations Glioma Growth Human Immune Immunotherapeutic agent Immunotherapy In Vitro Interleukin-6 Intravenous Label Ligands Link Malignant Glioma Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Target Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Oligonucleotides Oncogenes Oncogenic Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Preclinical Testing Property Radiation therapy Radioimmunotherapy Radioresistance Reagent Recurrence Regimen Resistance Route STAT protein STAT3 gene Safety Schedule Signal Transduction Small Interfering RNA TLR9 gene Technology Testing Therapeutic Effect TimeLine Toxicology Tumor Immunity Vascularization anti-tumor immune response base cGMP production cancer cell clinical candidate clinically relevant comparative efficacy cytotoxic design efficacy study human model immune checkpoint immunogenic improved in vivo in vivo Model inhibitor/antagonist innovation mouse model neoplastic cell novel nuclease pharmacokinetics and pharmacodynamics potential biomarker preclinical study prevent recruit small molecule success therapeutic siRNA transcription factor tumor tumor microenvironment tumorigenic

项目摘要

Despite multimodal treatments, such as radiation therapy, malignant gliomas (MG) are rapidly fatal. Resistance of MG to radiation therapy (RT) is a consequence of both intrinsic cancer cell properties and protective influence of the tumor microenvironment. We previously demonstrated that RT-induced cell death causes the release of danger signals recruiting Toll-like Receptor-9 (TLR9)-positive myeloid cells which jump-start tumor vascularization and regrowth. The proangiogenic (rather than immunostimulatory) effects of TLR9 activation are mediated by NF-κB/IL-6-dependent activation of Signal Transducer and Activator of Transcription (STAT3). STAT3 is a multifaceted oncogene and a central immune checkpoint regulator activated in cancer cells and in tumor-associated myeloid cells in patients with MG and with other tumors. It remains an elusive target, with no FDA-approved direct small molecule STAT3 inhibitors. To overcome this challenge, we previously developed a strategy to deliver STAT3 siRNA specifically into TLR9-positive myeloid cells and glioma cells, by physically linking siRNA to TLR9 ligands, CpG oligodeoxynucleotides (ODNs). Our previous preclinical studies demonstrated that local tumor treatment using CpG-STAT3siRNA silences STAT3 in glioma and other tumor models, thereby reducing tumor revascularization while stimulating systemic antitumor immunity. We propose to use a new generation of CpG-STAT3 inhibitors (CSIs) based on STAT3 antisense oligonucleotide (CpG- STAT3ASO) or STAT3 decoy oligodeoxynucleotide (CpG-STAT3dODN) design to support RT against recurrent human MG. We propose studies to assess feasibility, pharmacokinetic/pharmacodynamic properties, efficacy and safety of systemic administration of new CSIs against human and mouse models of MG in vivo. Our aim is to produce clinically relevant, effective and safe CSI-based strategies capable of overcoming RT resistance in MG in order to generate long term antitumor immune responses.

尽管有多种治疗方法，如放射治疗，恶性胶质瘤（MG）是迅速致命的。电阻