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

尽管进行了多种治疗，如放射治疗，恶性胶质瘤(MG)很快就会致命。抵抗力 MG的放射治疗(RT)既是癌细胞固有特性的结果，也是保护性的结果 肿瘤微环境的影响。我们先前证明了RT诱导的细胞死亡导致 释放危险信号招募Toll样受体-9(TLR9)阳性髓系细胞启动肿瘤 血管化和再生。TLR9激活的促血管生成(而非免疫刺激)作用 通过依赖于信号转导和转录激活因子(STAT3)的核因子-κB/IL-6的激活而介导。 STAT3是一个多方面的癌基因，是一种中枢免疫检查点调节因子，在癌细胞和肿瘤细胞中被激活。 MG和其他肿瘤患者的肿瘤相关髓系细胞。它仍然是一个难以捉摸的目标，没有 FDA批准的直接小分子STAT3抑制剂。为了克服这一挑战，我们以前开发了一种 通过物理方法将STAT3 siRNA特异性地传递到TLR9阳性的髓系细胞和胶质瘤细胞的策略 将siRNA连接到TLR9配体，CpG寡脱氧核苷酸(ODN)。我们之前的临床前研究 证明使用CpG-STAT3siRNA的局部肿瘤治疗可以沉默胶质瘤和其他肿瘤中的STAT3 模型，从而减少肿瘤血管重建，同时刺激全身抗肿瘤免疫。我们建议 使用基于STAT3反义寡核苷酸的新一代CpG-STAT3抑制剂(CSI) STAT3ASO)或STAT3诱骗寡核苷酸(CpG-STAT3dODN)设计以支持RT 复发性人类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、 新型CSIS体内全身给药对人和小鼠MG模型的有效性和安全性。 我们的目标是产生临床相关的、有效的和安全的基于CSI的能够克服RT的策略 在MG中耐药，以产生长期的抗肿瘤免疫反应。

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.