Enhancing viral oncolysis with vasculostatin gene delivery

通过血管抑素基因传递增强病毒溶瘤作用

• 批准号: 9900732
• 负责人: Balveen Kaur
• 金额: $ 37.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900732
• 关键词: Adult; Angiogenesis Inhibitors; Animals; Astrocytes; Attenuated; Back; Bortezomib; Brain; Brain Neoplasms; Clinical; Clinical Trials; Development; Engineering; G207; Gene Delivery; Generations; Genes; Genetic Transcription; Glioma; Goals; Grant; HSV vector; Herpesvirus 1; Human; Immunologics; In Vitro; Intracranial Neoplasms; Malignant Glioma; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Normal Cell; Oncolytic; Oncolytic viruses; Patients; Proteasome Inhibition; Proteasome Inhibitor; Research; Technology; Testing; Toxic effect; Transcriptional Activation; Translating; Treatment Efficacy; Tumor Immunity; United States National Institutes of Health; Vertebral column; Viral; Virotherapy; Virus; Virus Activation; Virus Replication; anti-tumor immune response; antiangiogenesis therapy; antitumor effect; bone; brain tissue; comparative efficacy; efficacy clinical trial; extracellular; improved; in vivo; neoplastic cell; nerve stem cell; nestin protein; oncolysis; oncolytic virotherapy; outcome forecast; preclinical study; programs; promoter; public health relevance; selective expression; tumor

 DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to leverage Vstat120 expressing oncolytic HSV-1 viruses (oHSV) for glioma therapy. Vstat120 is the extracellular fragment of Brain Angiogenesis Inhibitor 1 (BAI1) that has potent anti-angiogenic and anti-tumor effects. During the last cycle we created two Vstat120 expressing oncolytic viruses in different virus backbones. RAMBO, the first generation Vstat120 expressing virus, was created in a doubly attenuated virus back bone that is similar to G207, which has been tested in patients and found to be safe. RAMBO showed significantly better anti-tumor efficacy in mice with established brain tumors compared to the control virus with an identical backbone but lacking Vstat120 expression [5]. 34.5ENVE, the second generation Vstat120 expressing virus, was created in a virus backbone that is transcriptionally driven under the control of a nestin promoter. 34.5ENVE showed the best efficacy in GBM models that expressed high nestin levels. Given the significant improvement in anti-tumor efficacy of 34.5ENVE we have pursued its translational development with NIH (NCI NeXT program and NINDS CREATE program). The concern articulated by advisors at both NINDS and NCI was the fact that nestin is expressed in some normal cells, prompting us to reconsider tighter of nestin driven ICP34.5 expression. Here we propose to (Aim 1) modulate the backbone of 34.5ENVE to precisely control its replication in tumor cells and minimize toxicity to normal brain neurons and neural stem cells. We will further (Aim 2) evaluate the immunological consequences of this virus alone and (Aim 3) in conjunction with proteasome inhibition. At the conclusion of this project we will have an optimized oncolytic HSV vector that expresses Vstat120 which can be pursued for translational development with NIH.

 描述（由适用提供）：该提案的最终目标是利用VSTAT120表达癌HSV-1病毒（OHSV）进行神经胶质瘤治疗。 VSTAT120是具有潜在的抗血管生成和抗肿瘤作用的脑血管生成抑制剂1（BAI1）的细胞外片段。在最后一个周期中，我们创建了两个VSTAT120在不同病毒骨架中表达溶瘤病毒的VSTAT120。 Rambo是表达病毒的第一代VSTAT120，是在双重减毒病毒背骨中创建的，该病毒与G207相似，该病毒已在患者中进行了测试并发现安全。与对照病毒相比，RAMBO在具有固定脑肿瘤的小鼠中显示出明显更好的抗肿瘤效率，具有相同的主链，但缺乏VSTAT120表达[5]。 34.5NVE，第二代VSTAT120表达病毒，是在巢蛋白启动子控制下转录驱动的病毒主链中创建的。 34.5NVE在表达高巢素水平的GBM模型中显示出最佳效率。考虑到34.5岁的抗肿瘤效率的显着提高，我们通过NIH（NCI下一个程序和Ninds Create program）进行了转化开发。 Ninds和NCI顾问所表达的关注是，Nestin在某些正常细胞中表达，促使我们重新考虑了Nestin驱动的ICP34.5表达的更严格。在这里，我们建议（AIM 1）调节34.5岁的主链，以精确控制其在肿瘤细胞中的复制，并最大程度地减少对正常脑神经元和神经元干细胞的毒性。我们将仅（AIM 2）仅评估该病毒的免疫学后果，并与蛋白酶体抑制结合使用（目标3）。在该项目的结论中，我们将拥有一个优化的溶瘤HSV向量，该向量表达了VSTAT120，可以使用NIH进行转化开发。

项目成果

White paper on microbial anti-cancer therapy and prevention.

• DOI: 10.1186/s40425-018-0381-3
• 发表时间: 2018-08-06
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Forbes NS;Coffin RS;Deng L;Evgin L;Fiering S;Giacalone M;Gravekamp C;Gulley JL;Gunn H;Hoffman RM;Kaur B;Liu K;Lyerly HK;Marciscano AE;Moradian E;Ruppel S;Saltzman DA;Tattersall PJ;Thorne S;Vile RG;Zhang HH;Zhou S;McFadden G
• 通讯作者: McFadden G