Reconstruction of an oncolytic HSV vector for systemic delivery

重建用于全身递送的溶瘤 HSV 载体

• 批准号: 9076933
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 34.1万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-22 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076933
• 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; Future; Gene Delivery; Glycoproteins; Goals; Grant; HSV vector; Herpesvirus 1; Human Herpesvirus 2; Immune; Immunoglobulin G; In Vitro; Legal patent; Malignant Neoplasms; Modeling; Mononuclear; Mus; Natural Killer Cells; Neoplasms in Vascular Tissue; Oncolytic; Oncolytic viruses; Phagocytes; Phase; Property; Research Design; Route; Series; Signaling Molecule; Simplexvirus; Site; Solid; Staging; 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; in vivo; killings; nanoparticle; neoplastic cell; neovasculature; neutralizing antibody; novel; novel strategies; particle; peptidomimetics; public health relevance; receptor; reconstruction; research study; response; tumor; vector

 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实用的方法，具有简单而实用的治疗机制 - 有目的地将病毒的内在细胞溶解特性转化为对恶性细胞的靶向杀伤。尽管最近在这一领域取得了重大进展，但仍然存在的主要障碍是缺乏一种有效的方法来传递溶瘤病毒 全身途径，这阻碍了其在治疗转移性疾病中的应用。影响溶瘤病毒通过全身途径递送效率的关键因素包括单核吞噬细胞系统（MPS）吞噬病毒颗粒、自然杀伤（NK）细胞清除病毒感染以及抗病毒抗体中和病毒感染性。此外，由于系统递送的病毒颗粒会立即被大量血液稀释，因此可能需要开发和应用一种能够主动将病毒富集到肿瘤部位的递送策略。该项目旨在制定一系列新颖的策略来克服这些主要障碍；首先，它将使用最初在我们实验室构建的独特溶瘤病毒（FusOn-H2）。在目标 1 中，我们将检验我们的假设，即用“别吃我”信号分子对 FusOn-H2 进行基因包被，使病毒在全身递送过程中逃脱 MPS 的清除。 CD47 是一种主要的“别吃我”信号分子。我们计划将CD47的胞外结构域与病毒糖蛋白融合以包裹病毒，并将进行一系列体内实验以证明用CD47基因包裹病毒确实可以增强针对转移性疾病的病毒疗法的全身递送。在目标 2 中，我们将测试这样的想法：嵌合分子 HER2-Col-Fc 一旦整合到 FusOn-H2 中，可以重定向 NK 细胞攻击肿瘤细胞，而不是清除病毒。 HER2-Col-Fc 包含三个关键结构域：肿瘤抗原 HER2 特异性的单链抗体、IgG 的 Fc 片段和胶原蛋白的三聚化结构域。当以分泌形式表达时，该分子会自我多聚化并以聚集体形式附着在表达 HER2 的肿瘤细胞上，然后可以有效地与 NK 细胞上的低亲和力 Fc 受体 (FcγRIIIA) 结合，激活它们并杀死肿瘤细胞。这同时会转移 NK 细胞清除溶瘤病毒的作用。在目标 3 中，我们将证明一种新型细胞载体可以保护 FusOn-H2 并通过全身途径主动将病毒递送至肿瘤部位。在我们最近的研究中，我们产生了一种新型嵌合抗原受体，专门针对肿瘤新血管系统。植入该受体 (T-eCAR) 的 T 细胞可以特异性附着并破坏肿瘤血管。我们将测试我们的假设，即 T-eCAR 可以作为 FusOn-H2 系统递送的完美细胞载体，因为它们可以保护病毒免受中和抗体的侵害，并主动将病毒有效负载发送到肿瘤部位。尽管该项目主要旨在解决与溶瘤 HSV 系统递送相关的障碍，但大多数策略可应用于其他溶瘤病毒或一般基因递送载体。