Increasing the potency of Listeria monocytogenes-based vaccines by eliminating vaccine-related gamma delta T cell responses.

通过消除疫苗相关的 γ δ T 细胞反应来提高基于单核细胞增生李斯特氏菌的疫苗的效力。

• 批准号: 9167982
• 负责人: Marka Crittenden
• 金额: $ 24.75万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167982
• 关键词: Affect; Anabolism; Antigen Presentation; Antigen-Presenting Cells; Antigens; Astrocytoma; Cancer Vaccines; Clinical; Clinical Research; Clinical Trials; Complex; Data; Development; Diphosphates; Dose; Effector Cell; GVAX Cancer Vaccine; Generations; Growth; Human; Immune response; Immunity; Immunization; Immunotherapy; In Vitro; Inflammation; Institution; Interleukin 2 Receptor Gamma; Knock-out; Listeria monocytogenes; Malignant neoplasm of pancreas; Memory; Mesothelium; Metabolic Clearance Rate; Monitor; Mus; Outcome; Pancreas; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Population; Property; Publishing; Recombinant Vaccines; Recombinants; Reporting; Research Design; Role; Secondary Immunization; T cell response; T-Lymphocyte; Testing; Time; Tumor Antigens; Vaccine Antigen; Vaccines; Work; adaptive immunity; base; butyrophilin; comparative; cytotoxic; humanized mouse; isoprenoid; mesothelin; microbial; mouse model; nonhuman primate; novel; prevent; prospective; reconstitution; response; tumor; vaccine trial; vector

Project Summary Vector-neutralizing immunity represents a major impediment to the induction of cellular immune responses using microbial-based vaccines. An ongoing trial of a novel recombinant Listeria monocytogenes (Lm) –based cancer vaccine at our institution has yielded poor tumor antigen-specific immune responses. This result is consistent with other clinical trials with Lm-based vaccines. Importantly, we observed the marked expansion of γδ T cells in every subject. This finding is in direct contrast to murine models, where Lm-based vaccines generate a strong anti-tumor αβ T cell response to both endogenous Lm antigens and the tumor antigen. A particular invariant γδ T cell population is responsible for this effect and the target has been identified – human Vγ9Vδ2 T cells respond to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate of the MEP (or non-mevalonate) isoprenoid synthesis pathway. We hypothesize that HMBPP-deficient Lm does not activate the dominant human γδ T cell response and is a superior vaccine platform to generate αβ T cell responses for human immunotherapy when compared to vectors currently in clinical development. We propose that these γδ T cells facilitate the rapid clearance of Lm during 2º immunization, minimizing inflammation and the quantity and quality of antigen presentation to αβ T cells. The specific aims of this study are: 1: Test the hypothesis that rapid γδ T cell clearance of Listeria monocytogenes infected antigen presenting cells prevents generation of a αβ T cell response; and 2: Test the hypothesis that HMBPP-deficient Listeria monocytogenes is superior and safe vaccine for αβ T cell responses and does not generate γδ T cell responses. Our study design incorporates murine and humanized mouse models to determine whether a dominant γδ T cell response suppresses the capacity of Lm to generate αβ T cell responses and to evaluate comparative activation of αβ and γδ T cell responses in HMBPP-deficient versus standard Lm vaccines. This work is a necessary precursor to full trials of the vaccine in patients.

项目摘要 载体中和免疫是诱导细胞免疫应答的主要障碍 使用微生物疫苗。正在进行的一项基于新型重组单核细胞增生李斯特菌（Lm）的试验 我们研究所的癌症疫苗产生了较差的肿瘤抗原特异性免疫应答。这一结果 与其他基于Lm的疫苗的临床试验一致。重要的是，我们观察到， 每个受试者体内的γδ T细胞。这一发现与小鼠模型形成直接对比，在小鼠模型中，基于Lm的疫苗 产生对内源性Lm抗原和肿瘤抗原两者的强抗肿瘤αβ T细胞应答。一 特定的不变γδ T细胞群体负责这种效应，并且已经确定了靶点-人 Vγ 9VS 2 T细胞响应于（E）-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP），HMBPP是V γ 9VS 2 T细胞的中间体。 MEP（或非甲羟戊酸）类异戊二烯合成途径。我们假设HMBPP缺陷型Lm不 激活显性人γδ T细胞应答，是产生αβ T细胞的上级疫苗平台 与目前临床开发中的载体相比，我们提出 这些γδ T细胞在2º免疫期间促进Lm的快速清除，最大限度地减少炎症， 抗原呈递给αβ T细胞的数量和质量。本研究的具体目的是：1：检验 单核细胞增生李斯特菌感染抗原呈递细胞快速γδ T细胞清除阻止 产生αβ T细胞应答;和2：检验HMBPP缺陷型单核细胞增生李斯特菌 是用于αβ T细胞应答的上级且安全的疫苗，并且不产生γδ T细胞应答。我们的研究 设计结合了鼠和人源化小鼠模型，以确定显性γδ T细胞是否 反应抑制Lm产生αβ T细胞反应的能力，并评估比较性的 HMBPP缺陷型与标准Lm疫苗中αβ和γδ T细胞应答的活化。这项工作是一个 这是在病人身上进行全面疫苗试验的必要前提。