HSV VECTORS FOR THE DESTRUCTION OF BRAIN TUMORS

用于破坏脑肿瘤的 HSV 载体

• 批准号: 6363919
• 负责人: NIGEL William FRASER
• 金额: $ 26.71万
• 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 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363919
• 关键词: brain neoplasms; defective virus; ganciclovir; gene therapy; herpes simplex virus 1; host organism interaction; interleukin 2; laboratory mouse; melanoma; microorganism immunology; neoplasm /cancer immunology; nonhuman therapy evaluation; recombinant proteins; recombinant virus; tissue /cell culture; transfection /expression vector

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. The applicants have performed preliminary experiments in a mouse intracranial melanoma model, that demonstrate the viability of a tumor therapy approach based on the use of replication competent neuro-attenuated 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. The applicants have developed a straightforward, reproducible, clinically relevant model in which to study brain tumor therapy. The presence, progression, or regression of tumors can be assessed by non-invasive magnetic resonance imaging, and histology, immunohistochemistry, RNA in situ hybridization, and viral titration studies allow detailed examination of viral induced effects on tumor and 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. No deaths or untoward effects attributable to HSV-1 have been observed. The experiments outlined in this proposal will critically examine several important aspects of the tumor-virus-host relationship that is occurring. Specifically, the applicants will i) extend their preliminary data to other promising HSV-1 mutants and examine the viral and tumor cell factors that influence therapy; ii) examine the role of primary and secondary antiviral immunity in this model; iii) explore strategies to augment the effectiveness of HSV-1 based tumor therapy by combining viral therapy with ganciclovir treatment, and engineering HSV-1 mutants that will express biological response modifiers, such as IL-2, specifically within tumor cells.

描述（改编自申请人的摘要）：恶性脑肿瘤， 转移性和原发性经常发生，只有姑息治疗是 目前可用。 中枢神经系统肿瘤特别毁灭了 患者的生活质量，因为他们经常会导致严重和 神经系统并发症，包括头痛，麻痹， 癫痫发作和认知受损。 申请人进行了初步 在小鼠颅内黑色素瘤模型中进行的实验，证明了 基于复制的使用，肿瘤治疗方法的生存能力 有能力的神经衰减的单纯疱疹病毒-1（HSV-1）突变体。 这 这种方法的理由是这些遗传突变病毒不能 在神经系统的一般后有丝分裂细胞内复制，但 在有丝分裂活性的癌细胞中进行复制。 因此，他们可以 用于选择性地裂解中枢神经系统内的癌细胞。 申请人在临床上开发了直接，可重复的，可重复的 研究脑肿瘤疗法的相关模型。 存在， 可以通过非侵入性评估肿瘤的进展或肿瘤的回归 磁共振成像和组织学，免疫组织化学，原位RNA 杂交和病毒滴定研究允许对 病毒诱导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，甚至铅 完成某些动物肿瘤的回归。 没有死亡或不幸 已经观察到归因于HSV-1的效果。 该提案中概述的实验将严格检查一些 正在发生的肿瘤病毒宿主关系的重要方面。 具体而言，申请人将i）将他们的初步数据扩展到其他 有希望的HSV-1突变体，并检查病毒和肿瘤细胞因子 影响疗法； ii）检查原发性和继发性抗病毒的作用 该模型的免疫力； iii）探索提高有效性的策略 通过将病毒疗法与ganciclovir结合起来的基于HSV-1的肿瘤疗法 处理和工程HSV-1突变体，将表达生物学 响应修饰符，例如IL-2，特别是在肿瘤细胞中。