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

尽管治疗癌症的技术有所改进，但癌症仍然是造成发病率和死亡率的一个重要原因。化疗、放疗和根治性手术等干预措施可以使患者达到可容忍的副作用的极限，以提供适度的生存优势，特别是在晚期癌症中。免疫治疗是一种不同的方法，旨在扩大药物的疗效和耐受性之间的差距，并在一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地复制并摧毁癌细胞，同时刺激免疫系统。癌症常常通过掩盖免疫系统，使其无法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破坏它们时，由此产生的促炎环境吸引了免疫系统的注意，从而可以识别病变组织的真实情况。溶瘤病毒癌症疫苗的第一个成功案例最近被批准用于治疗转移性黑色素瘤，在这种情况下，受病毒影响的免疫系统能够清除一些患者的疾病，这些患者表现出持久的（通常是持续的）反应。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（基于新城疫病病毒，NDV），这种疫苗应该更有能力引导免疫系统识别和摧毁癌细胞。我们的方法将涉及表达来自NDV溶瘤性癌症疫苗的免疫系统信息信号细胞因子，以促进更强大的免疫反应。通过这种方式，我们希望在迄今为止免疫疗法难以治愈的癌症适应症（如结直肠癌）中取得疗效。虽然这个项目将只解决最初的概念验证阶段，但它将以一种有利于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已建立的研究小组之间的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，并成功地通过临床前研究到一系列临床试验。此次合作将结合两家中心的关键专业知识，通过基础科学研究和临床前开发，促进溶瘤性NDV的快速和合乎伦理的发展，并使其准备好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.