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.



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