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

• 批准号: 8403539
• 负责人: KAH-WHYE PENG
• 金额: $ 34.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403539
• 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

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（由申请方提供）：内皮层是一种屏障，循环溶瘤病毒和病毒感染的细胞载体必须穿过该屏障才能进入肿瘤细胞。我们建议，在溶瘤麻疹病毒（或病毒感染的细胞载体）的表面上添加血管结合基序，使它们能够识别并结合到内衬肿瘤新血管的内皮细胞的内腔表面上的独特抗原标记物，从而增强它们在肿瘤部位的定位/逮捕。使用多功能麻疹病毒展示平台，我们已经产生了双嗜性麻疹病毒（血管结合性和肿瘤嗜性），并证明在血管内给药后，麻疹病毒显示？3整合素结合基序，而不是亲本病毒，可以与新生血管中的内皮细胞的内腔表面相互作用。结合的病毒可以通过内皮细胞之间的穿孔外渗，通过或感染内皮细胞以穿过内皮屏障并感染下面的肿瘤细胞。我们现在准备测试以下假设：1）具有添加的血管结合基序的嵌合MV（和被这些病毒感染的细胞载体）将在肿瘤生长位点具有增强的定位，和2）与不能与肿瘤新血管相互作用的亲本病毒相比，这种双嗜性血管结合MV（和病毒感染的细胞载体）将具有增强的抗肿瘤功效。