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Enhancing localization of therapeutic viruses and cells to tumor sites

增强治疗性病毒和细胞对肿瘤部位的定位

基本信息

批准号：
8600868
负责人：
KAH-WHYE PENG
金额：
$ 26.05万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600868
关键词：
Affinity Amino Acids Animal Model Antibodies Antiviral Agents Binding Biodistribution Blood Vessels CD19 gene CD46 Antigen Cell Line Cell-Matrix Junction Cells Clinical Trials Confocal Microscopy Cytotoxic T-Lymphocytes Data Dose Dose-Limiting ERBB2 gene Electron Microscopy Endothelial Cells Endothelium Engineering Epidermal Growth Factor Receptor Fluorescence Microscopy Gene Expression Genetic Engineering Giant Cells Glioma Glutamate Carboxypeptidase II Grant Harvest Hemagglutinin Human Immune Immunohistochemistry Infection Integrin Binding Integrins Label Life Ligand Binding Ligands Literature Location MS4A1 gene Malignant neoplasm of ovary Measles Measles virus Mediating Messenger RNA Monitor Multiple Myeloma Mus Nucleocapsid Oncolytic Oncolytic viruses PECAM1 gene Patients Pattern Peptides Phase I Clinical Trials Positioning Attribute Proteins RGD (sequence)Recombinants Recovery Reporter Genes Reporting Resolution SCID Mice Safety Site Structure Surface T-Lymphocyte Testing Therapeutic Toxic effect Transgenic Organisms Tropism Vascular Endothelial Growth Factor Receptor-2 Viral Viral Antibodies Viral Genes Viral Vector Viral load measurement Virion Virus Virus Diseases Xenograft Model Xenograft procedure attenuated measles virus bioluminescence imaging cancer cell chorioallantoic membrane comparative efficacy echistatin epidermal growth factor receptor VIII human FOLR1 protein improved neoplastic cell neovasculature overexpression particle polypeptide public health relevance receptor subcutaneous transcytosis tumor tumor growth tumor xenograft uptake vector

项目摘要

DESCRIPTION (provided by applicant): The endothelial layer is a barrier through which circulating oncolytic viruses and virus-infected cell carriers must cross to access tumor cells. We propose that addition of vascular binding motifs on the surfaces of oncolytic measles viruses (or virus-infected cell carriers) allows them to recognize and bind to unique antigenic markers on the lumenal surface of endothelial cells that line the tumor neovasculature, thereby enhancing their localization/arrest at the tumor site. Using the versatile measles virus display platform, we have generated dual tropic measles viruses (vascular binding and tumor tropic) and demonstrated that after intravascular administration, measles viruses displaying a?¿3 integrin binding motifs, but not parental virus, can interact with the lumenal surface of endothelial cells in the neovessels. The bound viruses can extravasate through fenestrations between endothelial cells, transcytose through or infect the endothelial cell to cross the endothelial barrier and infect underlying tumor cells. We are now poised to test the hypotheses that 1) chimeric MV with added vascular binding motifs (and cell carriers infected with these viruses) will have enhanced localization at sites of tumor growth and 2) such dual tropic vascular binding MV (and virus-infected cell carriers) will have enhanced anti-tumor efficacy compared to parental viruses that cannot interact with tumor neovessels.

描述（由申请人提供）：内皮层是一个屏障，循环溶瘤病毒和病毒感染的细胞载体必须穿过它才能进入肿瘤细胞。我们提出，在溶瘤性麻疹病毒（或病毒感染的细胞载体）表面添加血管结合基序，使它们能够识别并结合肿瘤新生血管内皮细胞管腔表面的独特抗原标记，从而增强其在肿瘤部位的定位/抑制。利用多功能麻疹病毒展示平台，我们产生了双回归线麻疹病毒（血管结合和肿瘤回归线），并证明在血管内给药后，麻疹病毒显示？整合素结合基序可与新生血管内皮细胞的管腔表面相互作用，而不是亲本病毒。结合的病毒可通过内皮细胞间的间隙外渗，通过或感染内皮细胞，越过内皮屏障，感染下层肿瘤细胞。我们现在准备测试以下假设：1)添加血管结合基序的嵌合MV（以及被这些病毒感染的细胞载体）将增强肿瘤生长位点的定位；2)与不能与肿瘤新血管相互作用的亲本病毒相比，这种双热带血管结合MV（以及病毒感染的细胞载体）将增强抗肿瘤功效。