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

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。

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.