Regulatory T Cells and Oncolytic Virotherapy of Glioma

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是最常见的原发性脑癌形式，最佳治疗后两年生存率约为26%。因此，推进这种疾病进程的能力在很大程度上取决于我们设计和测试新疗法的能力。我们的团队一直专注于条件复制腺病毒（CRAds）的开发。crad被设计成通过使用转导修饰来选择性地在肿瘤细胞内复制并杀死肿瘤细胞，以增强病毒的传染性和肿瘤选择性启动子元件，这些启动子元件在转录上限制病毒复制所必需的基因的表达。然而，基于腺病毒的病毒治疗的潜在成功在实践中受到限制。临床前研究表明，溶瘤病毒促进免疫反应，在介导抗肿瘤功效方面超过直接溶瘤。事实上，溶瘤学的主要挑战在于理解如何在预先存在的抗病毒免疫的情况下刺激有益的抗肿瘤免疫。目前的临床数据支持临床前观察，即抗肿瘤免疫反应对溶瘤病毒治疗的长期疗效很重要。因此，阐明中枢神经系统（CNS）中驱动抗病毒免疫与抗肿瘤免疫之间平衡的机制将是介导成功的抗GBM溶瘤病毒治疗的关键。当我们进入项目的下一阶段时，我们面临着对脑肿瘤病毒治疗领域具有根本性影响的几个重要问题：(1)是否需要克服抗病毒免疫？(2)抗肿瘤免疫比溶瘤更重要吗？(3)能否量化并持续操纵宿主对颅内肿瘤的免疫反应？这三个问题是我们续期申请的基础，也是我们三个具体目标的基础，它们共同验证了“在GBM溶瘤病毒治疗的背景下，调节性T细胞抑制促进病毒溶瘤和长期抗肿瘤反应”的中心假设。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) represents the most common form of primary brain cancer with a two- year survival rate of ~ 26% following the best therapy. The capacity to advance the course of this disease therefore very much depends on our abilities to design and test novel therapies. Our group has been focused on the development of conditionally replicative adenoviruses (CRAds). CRAds are engineered to selectively replicate within and kill tumor cells through the use of transductional modifications t enhance viral infectivity and tumor-selective promoter elements that transcriptionally restrict expression of genes essential for viral replication. The potential success of adenoviral-based virotherapy has, however, been limited in practice. Preclinical work suggests that oncolytic viruses promote immune responses, which outweigh direct oncolysis in mediating anti-tumor efficacy. In fact, the major challenge of oncolytics lies in the difficult task of understanding ho to stimulate profitable anti-tumor immunity in the context of preexisting antiviral immunity. Present clinical data support preclinical observations that anti-tumor immune responses are important to long- term oncolytic virotherapy efficacy. Consequently, elucidating the mechanisms which drive the balance between anti-viral immunity vs. anti-tumor immunity in the central nervous system (CNS) will be key in mediating successful oncolytic virotherapy against GBM. As we look into the next phase of our project, we face several important questions with fundamental implications for the field of brain tumor virotherapy: (1) is it desirable to overcome anti-viral immunity? (2) is anti-tumor immunity more important than oncolysis? and (3) can one quantify this and consistently manipulate the host immune response against intracranial tumors? These three problems serve as the basis for our renewal application and for our three specific aims that together test the central hypothesis "Regulatory T cell inhibition promotes vira oncolysis and long-term anti-tumor response in the context of oncolytic virotherapy of GBM".