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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：
10464904
负责人：
Marcin Kortylewski
金额：
$ 45.12万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464904
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 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 evaluation efficacy study feasibility testing human model immune checkpoint immunogenic improved in vivo in vivo Model inhibitor inhibitor therapy innovation mouse model neoplastic cell novel nuclease pharmacokinetics and pharmacodynamics potential biomarker preclinical study prevent radiation resistance 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.

尽管多模式治疗，如放射治疗，恶性胶质瘤（MG）是迅速致命的。电阻 MG的放射治疗（RT）是固有的癌细胞特性和保护性的结果。肿瘤微环境的影响。我们先前证明，RT诱导的细胞死亡导致了释放危险信号，招募Toll样受体-9（TLR 9）阳性骨髓细胞，启动肿瘤血管化和再生。TLR 9激活的促血管生成（而非免疫刺激）作用是由NF-κB/IL-6依赖的信号转导和转录激活因子（STAT 3）激活介导的。 STAT 3是一种多方面的癌基因，也是一种在癌细胞和肿瘤细胞中激活的中枢免疫检查点调节因子。 MG和其他肿瘤患者中的肿瘤相关骨髓细胞。它仍然是一个难以捉摸的目标，没有 FDA批准的直接小分子STAT 3抑制剂。为了克服这一挑战，我们以前开发了一个将STAT 3 siRNA特异性递送到TLR 9阳性骨髓细胞和神经胶质瘤细胞中的策略，将siRNA连接至TLR 9配体、CpG寡脱氧核苷酸（ODN）。我们之前的临床前研究表明使用CpG-STAT 3siRNA的局部肿瘤治疗使神经胶质瘤和其他肿瘤中的STAT 3沉默，模型，从而减少肿瘤血管再生，同时刺激全身抗肿瘤免疫。我们提出使用基于STAT 3反义寡核苷酸（CpG-STAT 3）的新一代CpG-STAT 3抑制剂（CSI）， STAT 3AS 0）或STAT 3诱饵寡脱氧核苷酸（CpG-STAT 3dODN）设计以支持针对复发性人MG。我们建议进行研究，以评估可行性、药代动力学/药效学特性，新CSI全身给药对MG的人和小鼠模型的体内有效性和安全性。我们的目标是产生临床相关的，有效的和安全的基于CSI的策略，能够克服RT 抗肿瘤免疫应答的方法，以产生长期的抗肿瘤免疫应答。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Noninvasive Delivery of Biologicals to the Brain.

将生物制品无创输送至大脑。

DOI：
10.1176/appi.focus.20210028
发表时间：
2022
期刊：
Focus (American Psychiatric Publishing)
影响因子：
0
作者：
Jordan,Sheldon;Zielinski,Margaret;Kortylewski,Marcin;Kuhn,Taylor;Bystritsky,Alexander
通讯作者：
Bystritsky,Alexander