Creation of Immuno-Oncolytic Viruses for Cancer Therapy

创造用于癌症治疗的免疫溶瘤病毒

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：对于癌症治疗的使用癌症病毒的兴趣是最近的正当恢复，这主要是由于高度有希望的II期数据具有至少三种不同的病毒菌株以及最近的III期早期数据。值得注意的是，当前正在进行随机试验的多个向量表达了细胞因子以增强其治疗作用，并据报道诱导抗肿瘤免疫。但是，该平台的免疫治疗潜力仍然不足。我们在临床前模型和诊所都证明了溶瘤疫苗可以提高对肿瘤抗原的保护性免疫。实际上，在某些情况下，溶瘤疫苗完全通过免疫治疗机制提供了有效的抗肿瘤作用。然而，尽管疫苗的强大免疫原性受到人们的理解，并且从用作疫苗的使用中相对众所周知，但尚未设计目前的溶瘤菌株来利用这一潜力。因此，我们建议开发起作用的下一代媒介，以充当有效和特定的免疫治疗剂。重要的是，我们将尝试这样做，而不会有害影响其直接的溶瘤能力。据认为，病毒载体对在癌细胞中有选择地复制的逻辑下降又指导针对肿瘤的特定和靶向免疫反应将显着提高其治疗潜力，并代表我们称为免疫 - 凝集溶解病毒（IOV）的新型治疗平台。通过在全球水平和免疫反应的多个步骤中作用的相关方法，将实现免疫治疗效应的优化。最初，我们将纳入开发疫苗疗法的技术，以选择性调节TLR激活和先天免疫反应，并将其应用于溶瘤疫苗。通过重新指导，而不是简单地激活先天免疫途径，可以调节整体免疫反应而不会有害影响病毒性溶瘤活性。其次，我们将操纵由离甲酸编码的免疫调节性毒力基因，以重新指导vaccinia对潜在更有益的Th1部门产生的自然th2加权免疫反应。最后，特异性抗原的表达将用于增强肿瘤内大体肿瘤和特定细胞亚群的免疫靶向，特别是肿瘤引发细胞。这项工作中产生的载体将成为下一代治疗药，具有预定义的动作免疫治疗机制，并显着增强了抗肿瘤作用。他们将在与这项工作的同一时间范围内经过（独立资助）GMP制造，因此，通过完成本研究的完成，并准备好立即进行临床测试，并将其纳入本应用程序中开发的治疗方案。