Creation of Immuno-Oncolytic Viruses for Cancer Therapy

创造用于癌症治疗的免疫溶瘤病毒

• 批准号: 8842109
• 负责人: Stephen H Thorne
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842109
• 关键词: Affect; Animal Model; Antibodies; Antigens; Area; Autoantigens; Cell Cycle Regulation; Cells; Clinic; Clinical; Clinical Trials; Data; Development; ERBB2 gene; Engineering; Equilibrium; Funding; Gene Deletion; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor Gene; Health; Human; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunocompetent; Immunosuppression; Immunotherapeutic agent; In Situ; In Vitro; Intravenous; Kinetics; Malignant Neoplasms; Mediating; Modeling; Modification; Mus; Neoplasm Metastasis; Oncolytic; Oncolytic viruses; Pathway interactions; Patients; Phase; Population; Pre-Clinical Model; Primary Neoplasm; Production; Relapse; Reporting; Residual Tumors; Role; Safety; Signal Pathway; Signal Transduction; Specimen; TK Gene; Technology; Testing; Therapeutic; Therapeutic Effect; Thymidine Kinase; Time; Treatment Protocols; Tumor Antigens; Tumor Immunity; Vaccination; Vaccine Therapy; Vaccines; Vaccinia; Vaccinia virus; Vaccinium; Vertebral column; Viral; Viral Antigens; Viral Genome; Viral Vector; Virulence; Virus; Virus Diseases; Virus Replication; Weight; Work; adaptive immunity; aldehyde dehydrogenase 1; aldehyde dehydrogenases; antitumor effect; arm; base; cancer cell; cancer therapy; cytokine; design; immunogenicity; in vitro testing; in vivo; interest; killings; mouse model; neoplastic cell; neutralizing antibody; next generation; novel; novel therapeutics; oncolysis; oncolytic vector; particle; phase I trial; pre-clinical; prevent; randomized trial; research clinical testing; therapeutic vaccine; tumor; vector

DESCRIPTION (provided by applicant): There has been a recent and justified resurgence in interest in the use of oncolytic viruses for cancer therapy, primarily due to highly promising Phase II data with at least three different viral strains and recent early Phase III data. It is noteworthy that multiple vectors currently undergoing randomized trials express a cytokine to enhance their therapeutic effects, and have been reported to induce anti-tumor immunity. However, the immunotherapeutic potential of this platform remains under-developed. We have demonstrated both in pre-clinical models and in the clinic that oncolytic vaccinia can raise protective immunity against tumor antigens. Indeed, under some circumstances oncolytic vaccinia provides potent anti-tumor effects entirely through immunotherapeutic mechanisms of action. However, while the powerful immunogenicity of vaccinia is appreciated and relatively well understood from its use as a vaccine, the current oncolytic strains have not been designed to take advantage of this potential. We therefore propose to develop next generation vectors that act as potent and specific immunotherapeutics. Importantly we will look to do this without deleteriously affecting their directly oncolytic capabilities. It is believed that the logical desin of viral vectors to both replicate selectively in cancer cells and direct a specific and targeted immune response against the tumor will significantly enhance their therapeutic potential, and represents a novel treatment platform we have termed Immuno-Oncolytic Viruses (IOV). Optimization of immunotherapeutic effects will be achieved through inter-related approaches acting at a global level and at multiple steps in the immune response. Initially, we will incorporate technologies pioneered in the development of vaccine therapies to selectively modulate TLR activation and the innate immune response and apply these to oncolytic vaccinia. By re-directing, rather than simply activating innate immune pathways it is possible to modulate the overall immune response without deleteriously affecting viral oncolytic activity. Secondly, we will manipulate immune-modulatory virulence genes encoded by vaccinia in order to re-direct the naturally Th2-weighted immune response raised by vaccinia towards the potentially more beneficial Th1 arm. Finally, the expression of specific antigens will be used to boost the immune targeting of the bulk tumor and of specific subsets of cells within the tumor, notably tumor initiating cells. The vectors produced in this work will become next generation therapeutics with predefined immunotherapeutic mechanisms of action and significantly enhanced anti-tumor effects. They will undergo (independently funded) GMP manufacture over the same time frame as this work and so be ready for immediate clinical testing by the completion of this study and incorporating treatment regimens developed within this application.

描述（由申请方提供）：最近对使用溶瘤病毒进行癌症治疗的兴趣有所回升，这主要是由于至少三种不同病毒株的非常有希望的II期数据和最近的早期III期数据。值得注意的是，目前正在进行随机试验的多种载体表达一种细胞因子以增强其治疗效果，并已报道诱导抗肿瘤免疫。然而，该平台的免疫潜力仍然未得到充分开发。我们已经在临床前模型和临床中证明了溶瘤牛痘可以提高针对肿瘤抗原的保护性免疫。事实上，在某些情况下，溶瘤牛痘完全通过免疫作用机制提供有效的抗肿瘤作用。然而，虽然牛痘的强大免疫原性被赞赏并且从其作为疫苗的用途中相对较好地理解，但目前的溶瘤菌株尚未被设计成利用这种潜力。因此，我们建议开发下一代载体，作为有效和特异性的免疫治疗剂。重要的是，我们将寻求在不对它们的直接溶瘤能力产生有害影响的情况下做到这一点。据信，病毒载体的逻辑设计既能在癌细胞中选择性复制，又能引导针对肿瘤的特异性和靶向免疫应答，这将显著增强其治疗潜力，并代表了一种我们称为免疫溶瘤病毒（IOV）的新型治疗平台。免疫效果的优化将通过在免疫应答的多个步骤中在全局水平上起作用的相互关联的方法实现。最初，我们将结合疫苗疗法开发中的技术，选择性地调节TLR激活和先天免疫应答，并将其应用于溶瘤牛痘。通过重定向，而不是简单地激活先天免疫途径，可以调节整体免疫应答而不会不利地影响病毒溶瘤活性。其次，我们将操纵免疫调节的毒力基因编码的牛痘，以重新定向的自然Th2加权的免疫反应，对潜在的更有益的Th1臂牛痘提出的。最后，特定抗原的表达将被用来提高免疫靶向的大块肿瘤和特定亚群的细胞内的肿瘤，特别是肿瘤起始细胞。在这项工作中产生的载体将成为下一代治疗剂，具有预定义的免疫作用机制和显着增强的抗肿瘤作用。它们将在与本研究相同的时间范围内进行（独立资助）GMP生产，因此在本研究完成时准备立即进行临床试验，并纳入本申请中开发的治疗方案。