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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：
9265809
负责人：
SHAUN XIAOLIU ZHANG
金额：
$ 34.42万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265809
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 Injectable Legal patent Malignant Neoplasms 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 killings nanoparticle neoplastic cell neovasculature neutralizing antibody novel novel strategies 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.