HSV VECTORS FOR THE DESTRUCTION OF BRAIN TUMORS

用于破坏脑肿瘤的 HSV 载体

• 批准号: 6479158
• 负责人: NIGEL William FRASER
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479158
• 关键词: angiogenesis inhibitors; biotechnology; brain neoplasms; defective virus; disease /disorder model; gene targeting; gene therapy; genetic manipulation; herpes simplex virus 1; host organism interaction; laboratory mouse; melanoma; metastasis; microorganism immunology; mutant; neoplasm /cancer immunology; nonhuman therapy evaluation; technology /technique development; transfection /expression vector; virus load; virus replication

DESCRIPTION(Adapted from applicant's abstract): Malignant brain tumors, both metastatic and primary, occur frequently, and only palliative therapy is available at present. CNS tumors are particularly devastating to the quality of life of patients, as they frequently result in severe and debilitating neurological complications including headache, paralysis, seizures, and impaired cognition. We have performed experiments in a mouse intracranial melanoma model that demonstrate the viability of a tumor therapy approach based on the use of replication competent neuroattenuated Herpes Simplex Virus-1 (HSV-1) mutants. The rationale for this approach, is that these genetically mutant viruses cannot replicate within the generally post mitotic cells of the nervous system, yet do replicate in cancer cells, which are mitotically active. Thus, they can be used to selectively lyse cancer cells within the CNS. We have developed straightforward, reproducible, clinically relevant syngeneic mouse models in which to study brain tumor therapy. The presence, progression, or regression of tumors can be assessed by non-invasive magnetic resonance imaging, histology, immunohistochemistry, RNA in situ hybridization, and viral titration studies, allowing detailed examination of viral induced effects on the tumor and the brain. Outcome experiments indicate that HSV-1 mutant 1716 can slow progression of pre-formed tumors, and even lead to complete regression of tumors in some animals. Successful Phase 1 clinical trials have been performed with HSV-1 strain 1716 in Scotland, and with a similar virus in the US. The experiments outlined in this proposal will critically examine several important aspects of the tumor-virus host relationship. Specifically, we will i) extend our data on the role of the immune response in control of viral replication and tumor recognition by determining the differences in response in the brain and flank; ii) examine the role of innate and adaptive antiviral and ant-tumor immunity in this model; iii) explore strategies to augment the effectiveness of HSV-1 based tumor destruction by engineering HSV-1 mutants that will express biological response modifiers, such as an angiogenesis inhibitor specifically within tumors cells. Other mutants will be engineered with melanoma specific promoters replacing key viral promoters, in order to increase the viral specificity for tumor cells. This project will allow us to use insights gained from molecular virology and cancer biology to develop viable innovative therapies for patients with brain (and other) tumors.

描述（根据申请人的摘要改编）： 转移性和原发性的恶性脑肿瘤经常发生，仅发生 目前可以接受姑息治疗。中枢神经系统肿瘤特别是 毁灭性的患者生活质量，因为他们经常导致 严重而令人衰弱的神经系统并发症，包括头痛， 瘫痪，癫痫发作和认知受损。 我们已经在小鼠颅内黑色素瘤模型中进行了实验 根据使用的使用证明肿瘤治疗方法的生存 复制能干的神经肌肉单纯疱疹病毒-1 （HSV-1）突变体。这种方法的理由是这些 遗传性突变病毒无法在通常的有丝分裂后复制 神经系统的细胞，但确实在癌细胞中复制， 有丝分裂活动。因此，它们可用于选择性地裂解癌细胞 在中枢神经系统内。 我们已经开发了直接，可重复的，临床上相关的同步 小鼠模型研究脑肿瘤疗法。存在，进展， 或可以通过非侵入性磁性评估肿瘤的回归 共振成像，组织学，免疫组织化学，RNA原位杂交， 和病毒滴定研究，允许对病毒诱导的详细检查 对肿瘤和大脑的影响。结果实验表明 HSV-1突变体1716可以减缓预形成肿瘤的进展，并且 甚至导致某些动物的肿瘤完全消退。成功的阶段1 苏格兰的HSV-1菌株1716已进行了临床试验， 并在美国有类似的病毒。 该提案中概述的实验将严格检查一些 肿瘤病毒宿主关系的重要方面。具体来说，我们 i）是否会扩展有关免疫反应控制病毒的作用的数据 通过确定反应差异的复制和肿瘤识别 大脑和侧面； ii）检查先天和适应性抗病毒的作用 该模型中的蚂蚁肿瘤免疫力； iii）探索策略来增加 通过工程HSV-1对基于HSV-1的肿瘤破坏的有效性 将表达生物反应修饰符的突变体，例如 血管生成抑制剂特别是在肿瘤细胞中。其他突变体将是 由黑色素瘤特定启动子替代关键病毒启动子的设计 为了增加肿瘤细胞的病毒特异性。 该项目将使我们能够利用从分子病毒学和 癌症生物学，为大脑患者开发可行的创新疗法 （和其他）肿瘤。