Targeting tumorigenic pathways in glioblastoma with oncolytic HSV

胶质母细胞瘤是最恶性的原发性脑肿瘤， 并且几乎一致致命，中位生存期约为15个月。的承诺 在胶质母细胞瘤中的免疫治疗尚未实现，部分原因是由于在胶质母细胞瘤中改变了免疫活性。 脑和胶质母细胞瘤的免疫抑制微环境。近期分离的胶质母细胞瘤 干细胞（GSC）被认为在肿瘤逃避治疗的能力中很重要。此外该 它们在小鼠体内产生的脑肿瘤保留了患者肿瘤的许多特征，因此它们提供了一种新的治疗方法。 用于测试新疗法的代表性肿瘤模型，这是已建立的细胞系所没有的。我们， 和其他人已经开发了溶瘤单纯疱疹病毒（oHSV）载体， 杀死癌细胞，而不伤害周围的正常组织或引起疾病，并诱导抗- 肿瘤免疫反应。oHSV的安全性已在胶质母细胞瘤的临床试验中得到证实; 然而，尽管临床反应非常有希望，但用于大脑的批准还没有。 发生，并改进这种治疗策略是必要的。 我们的研究计划的总体目标是开发oHSV作为治疗剂，并阐明 联合治疗胶质母细胞瘤。在上一次筹资取得进展的基础上 周期，我们建议通过以下方式改进oHSV治疗：（i）创建有效复制的新oHSV载体 在GSC中，在脑中是安全的，并且是最佳免疫的;（ii）开发新的oHSV 与靶向GSC的DNA损伤反应抑制剂的组合策略，并利用 oHSV破坏DNA修复;和（iii）通过组合DNA增强胶质母细胞瘤免疫疗法 损伤反应抑制剂与oHSV和免疫检查点抑制剂。这些研究的核心是 使用代表性肿瘤模型;免疫缺陷小鼠中的原发性和复发性患者源性GSC 和免疫活性小鼠中的小鼠同基因GSC。这些研究应确定新的协同增效措施， 药物/ oHSV组合也促进免疫病毒疗法。我们预计， 在拟议的研究中证明，将可用于胶质母细胞瘤和其他脑肿瘤的临床治疗。 周围的肿瘤和实体瘤。

Glioblastoma, the most malignant primary brain tumor, has remained largely refractory to all forms of therapy, and is almost uniformly lethal with a median survival of approximately 15 months. The promise of immunotherapy in glioblastoma has yet to be realized, in part due to altered immune activities in the brain and the immunosuppressive microenvironment of glioblastoma. Recently isolated glioblastoma stem cells (GSCs) are thought to be important in the tumor's ability to evade therapy. In addition, the brain tumors they generate in mice retain many of the features of the patient tumors, so they provide a representative tumor model for testing new therapies, something that established cell lines do not. We, and others have developed oncolytic herpes simplex virus (oHSV) vectors that selectively replicate in and kill cancer cells, without harming the surrounding normal tissue or causing disease, and induce anti- tumor immune responses. The safety of oHSV has been demonstrated in clinical trials for glioblastoma; however, while clinical responses have been very promising, approval for use in the brain has not yet occurred, and improvements to this therapeutic strategy are warranted. The overall goal of our research program is to develop oHSV as therapeutic agents and elucidate combination strategies with them that will cure glioblastoma. Building on the progress in the last funding cycle, we propose to improve oHSV therapy by: (i) Creating new oHSV vectors that replicate efficiently in GSCs, are safe in the brain, and are optimally immunotherapeutic; (ii) Developing new oHSV combination strategies with inhibitors of DNA damage responses to target GSCs and take advantage of oHSV disruption of DNA repair; and (iii) Enhancing glioblastoma immunotherapy by combining DNA damage response inhibitors with oHSV and immune checkpoint inhibitors. Central to these studies is the use of representative tumor models; primary and recurrent patient-derived GSCs in immunodeficient mice and mouse syngeneic GSCs in immunocompetent mice. These studies should identify new synergistic drug / oHSV combinations that also promote immunovirotherapy. We anticipate that therapies demonstrated in the proposed studies will be translatable to the clinic for glioblastoma, and other brain tumors and solid tumors in the periphery.