Reconstruction of an oncolytic HSV vector for systemic delivery

重建用于全身递送的溶瘤 HSV 载体

基本信息

批准号：
9891964
负责人：
SHAUN XIAOLIU ZHANG
金额：
$ 34.63万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-22 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891964
关键词：
Address Affect Affinity Antibodies Antiviral Agents Benign Binding Blood Blood Circulation Blood Volume CD47 gene Cancer Patient Cells Chimeric Proteins Clinic Clinical Clinical Trials Collagen Data Development Disease ERBB2 gene Eating Extracellular Domain Fc Immunoglobulins Fc Receptor Focal Infection Future Gene Delivery Glycoproteins Goals Grant HSV vector Herpesvirus 1 Human Herpesvirus 2 Immune Immunoglobulin G In Vitro Legal patent Modeling Mononuclear Mus Natural Killer Cells Neoplasms in Vascular Tissue Oncolytic Oncolytic viruses Phagocytes Phase Property Route Series Signaling Molecule Simplexvirus Site Solid System T-Lymphocyte Testing Therapeutic Translating Tumor Antigens Vertebral column Viral Viral Antibodies Virotherapy Virus Virus Diseases arm base bench to bedside cancer cell cancer therapy chimeric antigen receptor clinical application design experimental study in vivo nanoparticle neoplastic cell neovasculature neutralizing antibody novel novel strategies oncolytic virotherapy particle peptidomimetics public health relevance receptor reconstruction response tumor vector

项目摘要

DESCRIPTION: Cancer virotherapy is a pragmatic approach with a simple, yet practical, therapeutic mechanism - purposeful conversion of the intrinsic cytolytic property of a virus into targeted killing of malignant cells. Although significant progress has recently been made in this field, a remaining major obstacle is the lack of an efficient means to deliver oncolytic viruses by the systemic route, which is hampering its application in treating metastatic diseases. Key components that affect the delivery efficiency of oncolytic viruses by the systemic route include engulfment of viral particles by the mononuclear phagocyte system (MPS), clearance of virus infection by natural killer (NK) cells, and neutralization of virus infectivity by antiviral antiboies. Additionally, as the systemically delivered viral particles are instantly diluted by the large bloo volume, a delivery strategy that can actively enrich viruses to the tumor site may need to be developed and applied. This project is purposefully designed to develop a series of novel strategies to overcome these major obstacles; primarily, it will use a unique oncolytic virus (FusOn-H2) that was originally constructed in our lab. In aim 1, we will test our hypothesis that genetically coating FusOn-H2 with a "don't eat me" signal molecule allows the virus to escape the clearance of MPS during systemic delivery. CD47 is a major "don't eat me" signal molecule. We plan to fuse the extracellular domain of CD47 with a viral glycoprotein to coat the virus and will conduct a series of in vivo experiments to show that genetically coating the virus with CD47 can indeed enhance systemic delivery of virotherapy against metastatic disease. In aim 2, we will test the idea that a chimeric molecule, HER2-Col-Fc, once incorporated into FusOn-H2, can redirect NK cells to attack tumor cells instead of clearing the virus. HER2-Col-Fc contains three key domains: the single chain antibody specific for the tumor antigen HER2, the Fc fragment from IgG and the trimerization domain from collagen. When expressed as a secreted form, this molecule self multimerizes and attaches to HER2-expressing tumor cells as aggregates, which can then efficiently bind to the low affinity Fc receptor (FcγRIIIA) on NK cells to activate them o kill tumor cells. This simultaneously diverts NK cells from clearing oncolytic virus. In aim 3, we will demonstrate that a novel cell carrier can protect FusOn-H2 as well as actively deliver the virus to tumor sites by the systemic route. In our recent studies, we have generated a novel chimeric antigen receptor that specifically targets tumor neovasculature. T cells engrafted with this receptor (T-eCAR) can specifically attach to and destroy tumor blood vessels. We will test our hypothesis that T-eCAR can function as a perfect cell carrier for systemic delivery of FusOn-H2, as they can protect the virus from the neutralizing antibodies and actively send the virus payload to the tumor site. Although this project is mainly designed to address the obstacles associated with systemic delivery of an oncolytic HSV, most of the strategies can be applied to other oncolytic viruses or to gene delivery vectors in general.

描述：癌症病毒疗法是一种务实的方法，具有简单但实用的热机制 - 有目的的转化病毒的内在细胞溶性转化为靶向杀害恶性细胞的杀害。尽管最近在该领域取得了重大进展，但剩下的主要障碍是缺乏通过通过系统的路线正在阻碍其在治疗转移性疾病中的应用。通过全身途径影响溶瘤病毒输送效率的关键成分包括通过单核吞噬细胞系统（MPS）吞噬病毒颗粒，自然杀伤（NK）细胞对病毒感染的清除以及抗病毒抗体对病毒感染中和病毒感染的清除率。此外，由于大型血液体积会立即稀释系统递送的病毒颗粒，因此可能需要开发和应用一种可以主动富集病毒到肿瘤部位的传递策略。该项目旨在制定一系列新型策略来克服这些主要障碍。主要，它将使用最初在我们实验室中构建的独特溶瘤病毒（Fuson-H2）。在AIM 1中，我们将测试我们的假设，即用“不要吃我”信号分子涂层fuson-h2允许病毒在全身传递过程中逃脱MPS的清除率。 CD47是主要的“不要吃我”信号分子。我们计划将CD47的细胞外域与病毒糖蛋白融合以覆盖该病毒，并将进行一系列体内实验，以表明遗传在遗传上用CD47涂抹病毒确实可以增强针对转移性疾病的系统性递送。在AIM 2中，我们将测试以下想法：嵌合分子Her2-Col-FC曾经掺入Fuson-H2中，可以重定向NK细胞以攻击肿瘤细胞而不是清除病毒。 HER2-COL-FC包含三个关键结构域：针对肿瘤抗原HER2的单链抗体，来自IgG的FC片段和胶原蛋白的三聚体化结构域。当以分泌形式表达时，该分子自我将其作为聚集体的表达HER2表达的肿瘤细胞，然后可以在NK细胞上有效地与低亲和力FC受体（FCγRIIIA）结合，以激活它们O杀死肿瘤细胞。这只是将NK细胞转移到清除溶瘤病毒的情况下。在AIM 3中，我们将证明一种新型的细胞载体可以保护Fuson-H2，并通过全身途径积极地将病毒传递到肿瘤部位。在最近的研究中，我们产生了一种新型的嵌合抗原受体，该受体专门针对肿瘤新生血管。用该受体（T-ECAR）植入的T细胞可以特异性地附着并破坏肿瘤血管。我们将测试我们的假设，即T-ECAR可以充当全身递送Fuson-H2的理想细胞载体，因为它们可以保护病毒免受中和抗体的影响并积极地将病毒有效载荷发送到肿瘤部位。尽管该项目主要旨在解决与全身交付癌HSV相关的障碍，但大多数策略都可以应用于其他溶瘤病毒或一般的基因递送向量。