HSV Amplicon Activation of Innate and Adaptive Immunity

HSV 扩增子激活先天性和适应性免疫

• 批准号: 7474033
• 负责人: Joseph David Rosenblatt
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-23 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474033
• 关键词: Adenocarcinoma; B-Cell Neoplasm; Biological Assay; CCL21 gene; Cells; Chronic Lymphocytic Leukemia; Clinical; Dendritic Cells; Development; Funding; Goals; Helper Viruses; Human; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Lead; Ligands; Malignant lymphoid neoplasm; Mediating; Modeling; Mus; Mutation; Natural Killer Cells; Nature; Ovalbumin; Receptor Signaling; Recruitment Activity; Role; Signal Transduction; Simplexvirus; Splenocyte; System; T-Lymphocyte; TNFSF5 gene; Testing; Transgenic Organisms; chemokine; cytokine; human study; immunogenicity; insight; lymphoid neoplasm; novel; response; tumor; vector

DESCRIPTION (provided by applicant): We are requesting continuing support for years 04-09. Our accomplishments during the previous funding period include studying the role of HSV amplicon mediated chemokine delivery alone or in combination with the co-stimulatory ligand CD40L in the murine pre B-cell tumor model A20, and the CT26 adenocarcinoma model. We demonstrated the utility of transducing tumors with the chemokines SLC alone and in combination with CD40L in eliciting recruitment of naive T-cells and dendritic cells, and facilitating development of a systemic adaptive immune response. We also demonstrated the potential utility of helper virus free HSV amplicons for transduction of human lymphoid malignancies. HSV amplicons encoding chemokines and/or costimulatory ligands elicit an unusually vigorous response resulting in eradication of multicentric tumors and the establishment of long lasting immunity. This suggests a particularly productive interplay between the innate and adaptive immune systems. We propose to continue studies of HSV amplicon mediated immunotherapy in murine tumors and human lymphoid tumors, with new emphasis on the role of the innate immune response. The overall goal is to understand the nature of the innate response to HSV amplicon transduction, and the role of the innate response in priming a subsequent adaptive response. Aim I, will focus on HSV amplicon engagement of the innate immune system. The chemokine/cytokine profile generated in response to vector transduction in normal splenocytes in vitro will be studied. We will study TLR receptor signaling in response to HSV amplicons. In Aim II we will compare the anti-tumor response mediated by SLC delivered using HSV amplicon vectors to that seen with nonviral delivery systems. Next we will study the effect of HSV amplicons encoding effector molecules that will selectively recruit and activate the innate system on anti-tumor response. HSV amplicons encoding chemokines that can recruit NK cells and/or NKG2D ligands will be delivered to augment the innate response in the mouse tumor models CT26, and A20. Using Ovalbumin expressing EG.7 cells, and OVA specific TCR transgenic T-cells from OT-1 mice, we will study how signals from within the innate system impact subsequent development of an adaptive response. Mice with genetic defects in key components of the innate response and the innate/adaptive transition will be tested for ability to support OT-1 activation and expansion following amplicon transduction. In Aim III we will study HSV amplicon capacity to induce NKG2D ligands on human Chronic Lymphocytic Leukemia (CLL) cells. We will also assay effects of direct transduction using HSV amplicons encoding NKG2D ligands on the immunogenicity of CLL cells. Insights gained from murine and human studies proposed will afford a better understanding of the innate contribution to development of an adaptive anti tumor response, and may lead to novel clinical approaches.

描述（由申请人提供）：我们请求 04-09 年继续提供支持。我们在上一个资助期间取得的成就包括研究HSV扩增子介导的趋化因子递送单独或与共刺激配体CD40L联合在小鼠前B细胞肿瘤模型A20和CT26腺癌模型中的作用。我们证明了单独使用趋化因子 SLC 以及与 CD40L 组合转导肿瘤在诱导幼稚 T 细胞和树突状细胞的募集以及促进全身适应性免疫反应的发展方面的效用。我们还证明了无辅助病毒 HSV 扩增子在人类淋巴恶性肿瘤转导中的潜在用途。编码趋化因子和/或共刺激配体的 HSV 扩增子会引发异常强烈的反应，从而消除多中心肿瘤并建立持久的免疫力。这表明先天免疫系统和适应性免疫系统之间存在特别有效的相互作用。我们建议继续研究 HSV 扩增子介导的小鼠肿瘤和人类淋巴肿瘤的免疫疗法，新的重点是先天免疫反应的作用。总体目标是了解 HSV 扩增子转导的先天反应的本质，以及先天反应在引发后续适应性反应中的作用。目标 I 将重点关注先天免疫系统中 HSV 扩增子的参与。将研究体外正常脾细胞中响应载体转导而产生的趋化因子/细胞因子谱。我们将研究响应 HSV 扩增子的 TLR 受体信号传导。 在目标 II 中，我们将比较使用 HSV 扩增子载体传递的 SLC 介导的抗肿瘤反应与使用非病毒传递系统所观察到的抗肿瘤反应。接下来，我们将研究编码效应分子的 HSV 扩增子的作用，这些效应分子将选择性地招募和激活先天系统对抗肿瘤反应的影响。编码可招募 NK 细胞和/或 NKG2D 配体的趋化因子的 HSV 扩增子将被递送，以增强小鼠肿瘤模型 CT26 和 A20 中的先天反应。使用表达卵清蛋白的 EG.7 细胞和来自 OT-1 小鼠的 OVA 特异性 TCR 转基因 T 细胞，我们将研究先天系统内的信号如何影响适应性反应的后续发展。将测试先天反应和先天/适应性转变的关键组成部分存在遗传缺陷的小鼠在扩增子转导后支持 OT-1 激活和扩增的能力。 在目标 III 中，我们将研究 HSV 扩增子在人类慢性淋巴细胞白血病 (CLL) 细胞上诱导 NKG2D 配体的能力。我们还将测定使用编码 NKG2D 配体的 HSV 扩增子直接转导对 CLL 细胞免疫原性的影响。 从小鼠和人类研究中获得的见解将有助于更好地理解适应性抗肿瘤反应发展的先天贡献，并可能带来新的临床方法。