Tuning Biomaterials-immune cell interactions for treatment of glioblastoma multiforme

摘要 尽管在手术、化疗和放疗方面取得了进展，但多形性胶质母细胞瘤（GBM）患者仍有 预后很差，只有不到10%的患者存活超过5年。最近的研究表明 T和B细胞对GBM的反应潜力。然而，现有的技术未能引起强有力的水平， 抗GBM免疫应答与治疗功效。因此，迫切需要一种替代品， 有效策略，可以实现针对GBM的强T和B细胞应答。我们的长期研究目标是 以表征生物材料控制免疫激活的结构/功能关系。我们的目标 是了解基于生物材料的疫苗平台的物理化学性质 影响材料与淋巴组织的相互作用，特别强调（i）体内抗原（Ag） 淋巴结中的积累，（ii）抗原呈递细胞的Ag呈递，和（iii）细胞毒性的诱导 CD 8 + T淋巴细胞（CTL）和抗体（Ab）对GBM的反应。为此，我们开发了一种新的 基于脂质的系统，称为双层间交联多层囊泡（ICMV）。我们发现ICMV（1） 有效地将Ag转运至局部引流淋巴结，（2）促进抗原呈递细胞对Ag的呈递， (3)产生比其他常规佐剂更强的CTL应答，包括油包水佐剂中的CpG， Montanide（可以说是临床试验中最强的CTL佐剂系统之一），和（4）发挥有效的 在鼠肿瘤模型中的治疗功效，包括颅内GBM。在这里，我们将合成一系列 具有不同材料特性的新型ICMV，并确定生物材料对免疫激活的影响 以及诱导CTL和Ab应答。我们将在小鼠模型中评估它们的治疗效果， 可移植的GBM以及遗传诱导的GBM。我们还将评估我们的战略， 旨在刺激GBM内免疫功能的疗法。总的来说，这些研究将改善我们的 了解生物材料界面，并可能导致生物材料的新设计原则 工程设计以引发强大的免疫应答水平，延迟肿瘤生长，并防止复发。更 总的来说，拟议的工作将解决疫苗技术目前的技术限制， 为GBM患者提供了一种新的治疗选择。

Abstract Despite advances in surgery, chemo- and radiation-therapy, patients with glioblastoma multiforme (GBM) have a grim prognosis with less than 10% of patients surviving more than 5 years. Recent studies have shown potential of T and B-cell responses against GBM. However, existing technologies fail to elicit robust levels of anti-GBM immune responses with therapeutic efficacy. Therefore, there is a critical need for an alternative and effective strategy that can achieve strong T and B-cell responses against GBM. Our long-term research goal is to characterize the structure/function relationship governing immune activation with biomaterials. Our objective in this application is to understand how physicochemical properties of biomaterial-based vaccine platforms impact materials interactions with lymphoid tissues, with particular emphasis on (i) in vivo antigen (Ag) accumulation in lymph nodes, (ii) Ag presentation by antigen-presenting cells, and (iii) induction of cytotoxic CD8+ T lymphocyte (CTL) and antibody (Ab) responses against GBM. To that end, we have developed a novel lipid-based system, called interbilayer-crosslinked multilamellar vesicles (ICMVs). We show that ICMVs (1) efficiently transport Ag to local draining lymph nodes, (2) promote Ag presentation by antigen-presenting cells, (3) generate stronger CTL responses than other conventional adjuvants, including CpG in water-in-oil adjuvant, Montanide (arguably one of the strongest CTL adjuvant systems in clinical trials), and (4) exert potent therapeutic efficacy in murine tumor models, including intracranial GBM. Here, we will synthesize a series of new ICMVs with varying materials properties and determine the effects of biomaterials on immune activation and induction of CTL and Ab responses. We will evaluate their therapeutic efficacy in murine models of transplantable GBM as well as genetically induced GBM. We will also assess our strategy in combination with therapies designed to stimulate immune functions within GBM. Overall, these studies will improve our understanding of the biology-materials interfaces and may lead to new design principles for biomaterials engineered to elicit robust levels of immune responses, delay tumor growth, and prevent relapse. More broadly, the work proposed will address current technical limitations in vaccine technologies and potentially lead to a new treatment option for GBM patients.