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

癌症仍然是发病率和死亡率的重要原因，尽管管理这种疾病的技术已经得到改进。化疗、放射治疗和根治性手术等干预措施可以将患者带到可以容忍的副作用的极限，以便提供适度的生存优势，这在晚期癌症中具有特殊性。免疫疗法是一种不同的方法，旨在扩大药物的有效性和耐受性之间的差距，在一些患者中导致完全和持久的缓解。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摧毁癌细胞，同时刺激免疫系统。癌症通常通过掩盖免疫系统来识别任何异常细胞和过程的证据，从而逃避身体自身对疾病组织的排斥。然而，当一种癌症选择性病毒开始在肿瘤细胞中复制并通过一种称为裂解的过程摧毁它们时，由此产生的促炎环境会引起免疫系统的注意，即可以认识到患病组织的真实情况。第一个成功的溶瘤病毒癌症疫苗的例子最近被批准用于治疗转移性黑色素瘤，在病毒的影响下，免疫系统能够清除几名表现出持久(而且通常是持续的)反应的患者的疾病。目前的提案旨在这一早期开发的基础上，使用一种强大的溶瘤病毒疫苗(基于新城疫病毒)，该疫苗应该更有能力引导免疫系统识别和摧毁癌细胞。我们的方法将包括表达细胞因子，免疫系统的信息信号，从新城疫溶瘤癌症疫苗，以鼓励更强大的免疫反应。通过这种方式，我们希望在免疫治疗迄今难以奏效的癌症适应症上取得疗效，比如结直肠癌。虽然这个项目将只涉及最初的概念验证阶段，但它将以一种能够支持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老牌研究小组之间强有力的、充满活力的合作。马来西亚的合作伙伴在开发基于新城疫病毒的溶瘤病毒方面拥有世界级的专业知识和多年的实践经验。英国团队已经开发出一种以腺病毒为基础的溶瘤病毒，通过临床前研究和一系列临床试验成功。这里建议的伙伴关系将结合两个中心的关键专业知识，通过基础科学研究和临床前开发促进溶瘤新城疫病毒的快速和合乎道德的发展，并将使其准备进入结直肠癌的临床试验。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，为这种毁灭性疾病的潜在治疗创造一种新的治疗方法。

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.