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

项目摘要 媒介中和免疫是诱导细胞免疫反应的主要障碍。 使用基于微生物的疫苗。一种新型重组单核细胞增多性李斯特菌的正在进行的试验 我们机构的癌症疫苗产生了很差的肿瘤抗原特异性免疫反应。这个结果是 与其他以LM为基础的疫苗的临床试验一致。重要的是，我们观察到 每个受试者体内都有γδT细胞。这一发现与小鼠模型形成了直接对比，在小鼠模型中，基于LM的疫苗 对内源性LM抗原和肿瘤抗原产生强烈的抗肿瘤αβT细胞反应。一个 这种效应由特定的不变γδT细胞群负责，靶标已确定--人类 Vγ9Vδ2 T细胞对(E)-4-羟基-3-甲基-2-烯基焦磷酸的反应 MEP(或非甲氧戊酸)类异戊二烯合成途径。我们假设缺乏HMBPP的LM不会 激活人类主要的γδT细胞反应，是产生αβT细胞的优越疫苗平台 与目前处于临床开发中的载体相比，对人类免疫疗法的反应。我们建议 这些γδT细胞有助于在2℃免疫期间快速清除LM，最大限度地减少炎症和 抗原呈递给αβT细胞的数量和质量。这项研究的具体目的是：1：测试 假设单核细胞增多性李斯特氏菌感染的抗原提呈细胞快速清除γδT细胞可预防 产生αβT细胞反应；和2：检验HMBPP缺陷的单核细胞增多性李斯特菌的假设 是治疗αβT细胞反应的优越和安全的疫苗，不会产生γδT细胞反应。我们的研究 设计结合了小鼠和人源化的小鼠模型，以确定主导的γδT细胞 应答抑制了LM产生αβT细胞应答和评估比较的能力 HMBPP缺陷疫苗与标准LM疫苗中αβ和γδT细胞反应的激活。这项工作是一项 疫苗在患者身上进行全面试验的必要先驱。

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.