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: 6732448
• 负责人: Joseph David Rosenblatt
• 金额: $ 33.68万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732448
• 关键词: Alphaherpesvirinae; CD40 molecule; T lymphocyte; adenocarcinoma; biological signal transduction; chemokine; chronic lymphocytic leukemia; clinical research; cytotoxic T lymphocyte; gene delivery system; genetic transduction; genetically modified animals; human subject; immune tolerance /unresponsiveness; laboratory mouse; lymphoma; natural killer cells; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; patient oriented research; tissue /cell culture; toll like receptor; transfection /expression 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）：我们正在申请04-09年度的持续支持。在之前的资助期间，我们的成就包括研究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。我们证明了用SLC趋化因子单独或与CD40L联合转导肿瘤在诱导幼稚t细胞和树突状细胞募集和促进系统性适应性免疫反应发展方面的效用。我们也证明了无辅助病毒的HSV扩增子在人类淋巴细胞恶性肿瘤转导中的潜在效用。编码趋化因子和/或共刺激配体的HSV扩增子引发异常强烈的反应，导致多中心肿瘤的根除和持久免疫的建立。这表明先天免疫系统和适应性免疫系统之间有一种特别有效的相互作用。我们建议继续研究HSV扩增子介导的免疫治疗在小鼠肿瘤和人淋巴样肿瘤中的作用，新的重点是先天免疫反应的作用。总体目标是了解对HSV扩增子转导的先天反应的本质，以及先天反应在引发随后的适应性反应中的作用。目的1，将重点关注HSV扩增子与先天免疫系统的接合。我们将在体外研究正常脾细胞响应载体转导而产生的趋化因子/细胞因子谱。我们将研究TLR受体信号对HSV扩增子的反应。