Tuning Biomaterials-immune cell interactions for treatment of glioblastoma multiforme

调整生物材料-免疫细胞相互作用治疗多形性胶质母细胞瘤

• 批准号: 9348653
• 负责人: James J Moon
• 金额: $ 42.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348653
• 关键词: Address; Adjuvant; Alpha Cell; Antibody Response; Antibody Therapy; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; B-Lymphocytes; Benchmarking; Biocompatible Materials; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Communication; Cessation of life; Chitosan; Clinical Trials; Clonal Expansion; Combined Modality Therapy; Cross Presentation; Cross-Priming; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Effector Cell; Engineering; Formulation; Generations; Glioblastoma; Glioma; Goals; Human; Immune; Immune response; Immunity; Immunologic Memory; Immunosuppression; Immunosuppressive Agents; Infiltration; Intracranial Neoplasms; Lead; Ligands; Lipase; Lipids; Location; Lymphoid Tissue; Malignant - descriptor; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; Oils; Operative Surgical Procedures; Patients; Property; Public Health; Radiation therapy; Relapse; Research; Research Proposals; Series; Serum; Structure; Structure-Activity Relationship; Suppressor-Effector T-Lymphocytes; System; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic; Transplantation; Treatment Efficacy; Vaccination; Vaccines; Vesicle; Water; Work; base; cell killing; crosslink; cytotoxic; design; immune activation; immune function; improved; in vivo; lymph nodes; mortality; mouse model; nanoparticle; neoplastic cell; next generation; novel; novel vaccines; outcome forecast; prevent; receptor; response; targeted treatment; therapy design; trafficking; tumor; tumor growth; vaccine efficacy

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.

抽象的 尽管手术进展，化学疗法和放射治疗，但多形胶质母细胞瘤患者（GBM）患有 不到10％的患者的严峻预后超过5年。最近的研究表明 T和B细胞对GBM的反应的潜力。但是，现有技术无法引起强大的水平 具有治疗功效的抗GBM免疫反应。因此，对替代方案有迫切需要 有效的策略可以实现针对GBM的强烈T和B细胞反应。我们的长期研究目标是 表征与生物材料免疫激活的结构/功能关系。我们的目标 在此应用中，是要了解基于生物材料的疫苗平台的物理化学特性 影响材料与淋巴组织的相互作用，特别强调（i）体内抗原（Ag） 在淋巴结中积累，（II）通过抗原呈递细胞的AG表现，（iii）诱导细胞毒性 CD8+ T淋巴细胞（CTL）和针对GBM的抗体（AB）反应。为此，我们开发了一本小说 基于脂质的系统，称为Interbilayer-Crosslinked Multilamellar囊泡（ICMVS）。我们表明ICMVS（1） 有效地将Ag转运到局部排水淋巴结，（2）促进抗原呈递细胞的Ag表示， （3）比其他常规佐剂产生更强的CTL响应，包括在油中佐剂中的CpG， Montanide（可以说是临床试验中最强的CTL辅助系统之一），（4）发挥有效性 包括颅内GBM在内的鼠肿瘤模型中的治疗功效。在这里，我们将合成一系列 具有不同材料特性的新ICMV，并确定生物材料对免疫激活的影响 以及CTL和AB响应的诱导。我们将在鼠模型中评估它们的治疗功效 可移植的GBM以及遗传诱导的GBM。我们还将评估我们的策略与 旨在刺激GBM内免疫功能的疗法。总体而言，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理 设计以引起强大的免疫反应水平，延迟肿瘤生长并防止复发。更多的 广泛地，提出的工作将解决疫苗技术的当前技术局限 为GBM患者提供新的治疗选择。