Targeted Recombinant VSV Virus to Treat Breast Cancer

靶向重组 VSV 病毒治疗乳腺癌

• 批准号: 6967367
• 负责人: IRA BERGMAN
• 金额: $ 27.77万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-03 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967367
• 关键词: Vesiculovirus; breast neoplasms; cytotoxic T lymphocyte; helper T lymphocyte; macrophage; natural killer cells; neoplasm /cancer immunotherapy; protooncogene; recombinant virus; therapy design /development

DESCRIPTION (provided by applicant): The goal of this project is to develop a replicating recombinant vesicular stomatitis virus (rrVSV) that targets specifically to breast cancer cells and treats cancer by two mechanisms: 1) direct infection and killing of tumor cells and 2) stimulation of the immune system to recognize and kill breast cancer cells. Therapy for breast cancer is currently inadequate with approximately 40,000 women dying from metastatic disease each year. VSV is an efficient cell killer with a rapid replication rate. VSV is safe. It is endemic in certain human populations but is not pathogenic. We have created an rrVSV that preferentially infects breast cancer cells based on viral binding to the Her2/neu receptor. This rrVSV was highly effective in eliminating peritoneal implants of Her2/neu expressing tumor. Cured animals rejected rechallenge with Her2/neu expressing tumor and with parental tumors that did not express Her2/neu. Specific Aim 1 (SA1) will optimize the therapeutic efficacy of rrVSV. We will determine the maximum size tumor that can be eradicated, the optimal dose of virus, the effect of multiple viral administrations, the duration of viral persistence, the therapeutic effect of using a virus that expresses either GM-CSF or IL-12, the bystander effect on tumor cells that do not express Her2/neu and the toxicity of virus administration. SA2 will identify the immune cells that eradicate tumor following treatment with rrVSV. Successful therapy will be re-assessed in animals that are depleted in one of the following immune components: NK cells, macrophages, CD4 and/or CD-8 T-cells. SA3 will determine whether rrVSV treatment generates anti-tumor T-cells which find and eradicate tumors distant from the site of rrVSV therapy. SA4 will improve rrVSV by engineering mutations that enhance potency and specificity. This proposal uses new capabilities in constructing rrVSV to create an innovative, unique, flexible and theoretically sound treatment for a common, frequently incurable disease. The proposal focuses on breast cancer but could be equally applied to many other cancers for which suitable cell surface targets exist.

描述（由申请人提供）：该项目的目的是开发复制的重组囊泡病毒病毒（RRVSV），该病毒（RRVSV）专门针对乳腺癌细胞，并通过两种机制治疗癌症：1）直接感染和杀死肿瘤细胞和2）刺激免疫系统以识别和杀死乳腺癌细胞。目前，治疗乳腺癌的治疗不足，每年约有40,000名因转移性疾病而死的妇女。 VSV是具有快速复制速率的有效细胞杀手。 VSV是安全的。它在某些人类人群中是地方性的，但不是致病性的。我们创建了一个RRVSV，该RRVSV优先根据病毒结合与HER2/NEU受体感染乳腺癌细胞。该RRVSV在消除HER2/NEU表达肿瘤的腹膜植入物方面非常有效。治愈的动物用HER2/NEU表达肿瘤和未表达HER2/neu的父母肿瘤拒绝了补给。特定的目标1（SA1）将优化RRVSV的治疗功效。我们将确定可以消除的最大尺寸肿瘤，病毒的最佳剂量，多种病毒施用的作用，病毒持续性的持续时间，使用表达GM-CSF或IL-12的病毒的治疗作用，对不表达HER2/NEU的旁观者效果的GM-CSF或IL-12，对旁观者的效果表达HER2/NEU和VIRUS IDASSICOMTION。 SA2将确定用RRVSV治疗后消除肿瘤的免疫细胞。成功的治疗将在以下免疫成分之一中耗尽的动物中重新评估：NK细胞，巨噬细胞，CD4和/或CD-8 T细胞。 SA3将确定RRVSV处理是否会产生抗肿瘤T细胞，这些T细胞发现并消除远离RRVSV治疗部位的肿瘤。 SA4将通过提高效力和特异性的工程突变来改善RRVSV。该提案在构建RRVSV方面使用了新的功能来创建一种创新，独特，灵活和理论上的合理处理，以治疗常见的，经常无法治愈的疾病。该提案的重点是乳腺癌，但可以同样地应用于许多其他适合细胞表面靶标的癌症。