Creation of Immuno-Oncolytic Viruses for Cancer Therapy

描述（由申请人提供）：最近对溶瘤病毒用于癌症治疗的兴趣有了合理的复苏，主要是由于至少有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细胞因子以增强其治疗效果，并已报道可诱导抗肿瘤免疫。然而，该平台的免疫治疗潜力仍未得到充分开发。我们已经在临床前模型和临床中证明，溶瘤痘苗可以提高对肿瘤抗原的保护性免疫。事实上，在某些情况下，溶瘤痘苗完全通过免疫治疗机制提供有效的抗肿瘤作用。然而，虽然牛痘强大的免疫原性得到了认可，并且从其作为疫苗的使用中得到了相对较好的理解，但目前的溶瘤菌株尚未被设计为利用这一潜力。因此，我们建议开发下一代载体，作为有效的和特异性的免疫疗法。重要的是，我们希望这样做不会对它们的直接溶瘤能力造成有害影响。我们相信，病毒载体的逻辑设计既可以在癌细胞中选择性复制，又可以指导针对肿瘤的特异性和靶向免疫反应，这将显著增强其治疗潜力，并代表了一种新的治疗平台，我们称之为免疫溶瘤病毒（IOV）。免疫治疗效果的优化将通过相互关联的方法在全球层面和免疫反应的多个步骤中发挥作用来实现。最初，我们将采用在疫苗疗法开发中率先采用的技术，选择性地调节TLR激活和先天免疫反应，并将这些技术应用于溶瘤性痘苗。通过重新定向，而不是简单地激活先天免疫途径，有可能在不有害地影响病毒溶瘤活性的情况下调节整体免疫反应。其次，我们将操纵由牛痘编码的免疫调节毒力基因，以便将牛痘引起的自然th2加权免疫反应重新导向可能更有益的Th1臂。最后，特异性抗原的表达将用于增强对肿瘤和肿瘤内特定细胞亚群的免疫靶向，特别是肿瘤起始细胞。本工作产生的载体将成为具有预定义的免疫治疗作用机制和显著增强的抗肿瘤作用的新一代治疗药物。它们将在与本研究相同的时间框架内进行（独立资助的）GMP生产，因此，在本研究完成并纳入本应用程序中开发的治疗方案后，可以立即进行临床试验。

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.