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.

摘要 尽管在手术、化疗和放射治疗方面取得了进展，但多形性胶质母细胞瘤(GBM)的患者 预后不佳，不到10%的患者存活超过5年。最近的研究表明 T和B细胞对基底膜的潜在反应。然而，现有技术未能引发强劲的 抗GBM免疫应答具有治疗效果。因此，迫切需要一种替代方案和 有效的策略，可以实现强大的T和B细胞对GBM的反应。我们的长期研究目标是 描述生物材料免疫激活的结构/功能关系。我们的目标 在这方面的应用是为了了解基于生物材料的疫苗平台的物理化学性质 冲击材料与淋巴组织的相互作用，特别强调(I)体内抗原(Ag) (2)抗原提呈细胞的抗原提呈；(3)诱导细胞毒作用 抗GBM的CD8+T淋巴细胞(CTL)和抗体(Ab)反应。为此，我们开发了一部小说 以脂质为基础的系统，称为双层间交联多层囊泡(ICMV)。我们证明了ICMV(1) 有效地将Ag输送到局部引流淋巴结，(2)通过抗原提呈细胞促进Ag提呈， (3)产生比其他常规佐剂更强的CTL反应，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)，以及(4)发挥效力 在小鼠肿瘤模型中的治疗效果，包括颅内基底膜。在这里，我们将综合一系列 具有不同材料性质的新型ICMV和确定生物材料对免疫激活的影响 诱导CTL和抗体应答。我们将在小鼠模型上评估它们的治疗效果。 可移植的基底膜以及基因诱导的基底膜。我们还将结合以下方面评估我们的战略 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 对生物-材料界面的理解并可能导致生物材料的新设计原则 经改造后可激发强大的免疫反应水平，延缓肿瘤生长，防止复发。更多 总的来说，拟议的工作将解决疫苗技术目前的技术限制，并可能 为GBM患者提供了一种新的治疗选择。