Translational development of oncolytic Newcastle Disease Virus for treatment of colorectal cancer

溶瘤新城疫病毒治疗结直肠癌的转化开发

• 批准号: MR/P012795/1
• 负责人: Leonard Seymour
• 金额: $ 25.78万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP012795%2F1
• 关键词: Translational; development; oncolytic; Newcastle; Disease

Cancer remains an important cause of morbidity and mortality despite the refinement of techniques used to manage the disease. Interventions like chemotherapy, radiotherapy and radical surgery can take patients to the limits of tolerable side effects in order to provide a modest survival advantage, particularity in advanced carcinomas. Immunotherapy is a different approach that aims to widen the margin between efficacy and tolerability of drugs and in some patients induce a full and lasting remission. Oncolytic viruses are an interesting emerging class of therapies that utilise vaccine-like viruses to replicate selectively within and destroy cancer cells whilst simultaneously stimulating the immune system. Cancer often evades the body's own attempt to reject disease tissue, by masking the immune system from recognising any evidence of abnormal cells and processes. However, when a cancer-selective virus begins to replicate in tumour cells and destroys them through a process called lysis, the resulting pro-inflammatory environment attracts the attention of the immune system the reality of the diseased tissue can be recognised. The first example of a successful oncolytic virus cancer vaccine was approved recently for the treatment of metastatic melanoma, where the immune system, influenced by the virus was able to clear the disease in several of the patients who showed durable (and often ongoing) responses. The current proposal aims to build on this early development, using a powerful oncolytic virus vaccine (based on Newcastle Disease Virus, NDV) that should be even more capable of directing the immune system towards identifying and destroying cancer cells. Our approach will involve expressing cytokines, the messaging signals of the immune system, from the NDV oncolytic cancer vaccine in order to encourage a more robust immune response. In this way we hope to achieve efficacy in cancer indications that have have thus far been refractory to immunotherapy such as colorectal cancer. Although this project will address only the initial proof of concept stage, it will be conducted in a way that will enable future development and clinical trials. We have structured the proposal as a strong and dynamic collaboration between established research groups in Malaysia and the UK. The Malaysian partner has world class expertise, and many years practical experience, in developing oncolytic viruses based upon NDV. The UK team has already developed an oncolytic virus based on adenovirus, successfully through preclinical studies to a series of clinical trials. The partnership proposed here will combine the key expertise form both centres in fostering rapid and ethical development of oncolytic NDV through basic scientific study, through preclinical development and will position it ready to enter clinical trial for colorectal cancer. In this way we aim to use the academic and translational strengths in both centres in creating a new therapeutic for potential treatment of this devastating disease.

癌症仍然是发病率和死亡率的一个重要原因，尽管用于管理这种疾病的技术得到了改进。化疗、放疗和根治性手术等干预措施可以使患者达到可耐受副作用的极限，以提供适度的生存优势，特别是在晚期癌症中。免疫疗法是一种不同的方法，旨在扩大药物疗效和耐受性之间的差距，并在某些患者中诱导完全和持久的缓解。溶瘤病毒是一种有趣的新兴疗法，它利用疫苗样病毒在癌细胞内选择性复制并破坏癌细胞，同时刺激免疫系统。癌症通常会掩盖免疫系统识别异常细胞和过程的任何证据，从而逃避身体自身拒绝疾病组织的尝试。然而，当癌症选择性病毒开始在肿瘤细胞中复制并通过一种称为溶解的过程破坏它们时，产生的促炎环境会引起免疫系统的注意，从而可以识别出患病组织的真实情况。最近，第一个成功的溶瘤病毒癌症疫苗的例子被批准用于治疗转移性黑色素瘤，其中受病毒影响的免疫系统能够在几个表现出持久（通常是持续）反应的患者中清除疾病。目前的建议旨在建立在这一早期发展的基础上，使用一种强大的溶瘤病毒疫苗（基于纽卡斯尔病病毒，NDV），该疫苗应该更有能力指导免疫系统识别和摧毁癌细胞。我们的方法将涉及表达细胞因子，免疫系统的信息传递信号，从NDV溶瘤癌症疫苗，以鼓励更强大的免疫反应。通过这种方式，我们希望在迄今为止免疫疗法难以治疗的癌症适应症（如结直肠癌）中获得疗效。虽然该项目将只解决概念阶段的初步证明，但它将以一种能够实现未来开发和临床试验的方式进行。我们将该提案构建为马来西亚和英国现有研究小组之间强大而充满活力的合作。马来西亚合作伙伴在开发基于NDV的溶瘤病毒方面拥有世界一流的专业知识和多年的实践经验。英国团队已经开发出一种基于腺病毒的溶瘤病毒，成功地通过临床前研究到一系列临床试验。这里提出的合作伙伴关系将联合收割机的关键专业知识，从两个中心在促进快速和道德的发展溶瘤新城疫病毒通过基础科学研究，通过临床前开发，并将定位它准备进入临床试验结直肠癌。通过这种方式，我们的目标是利用这两个中心的学术和翻译优势来创造一种新的治疗方法，以潜在地治疗这种毁灭性的疾病。