Pre-clinical development for IND application of a novel systemically deliverable oncolytic Vaccinia virus for treatment of pancreatic cancer

胰腺导管腺癌（PDAC）是一种几乎一致致命的疾病。仅在英国，每年就有10，000例病例报告，预计到2035年，发病率将进一步上升6%。虽然许多癌症对新的免疫治疗方案（包括疫苗接种和检查点阻断）有良好的反应，但这些策略未能影响PDAC存活率，因为PDAC能够有效地阻止宿主免疫系统控制癌症进展。因此，迫切需要设计新型的治疗方法来克服PDAC中常规治疗的障碍。我们已经开发了新型的肿瘤靶向溶瘤病毒（TOV），这是有吸引力的癌症治疗选择。这些药剂可以通过在肿瘤组织中的选择性复制，放大输入剂量并通过多种机制杀死肿瘤，包括直接杀死细胞，重要的是通过在患者中诱导全身性抗肿瘤免疫应答，其可以靶向原发性肿瘤、转移性沉积物并防止复发。此外，TOV还可以作为递送载体，递送免疫刺激剂，以增强针对仅由肿瘤细胞表达的肿瘤特异性抗原的免疫反应，使免疫系统能够特异性识别并杀死肿瘤细胞。我们最近开发了新一代TOV，称为VVL-21。这种新的生物治疗剂可以刺激肿瘤微环境，促进胰腺肿瘤内多种免疫细胞的浸润。引人注目的是，这种新药物可以提高已批准的免疫治疗药物抗PD 1的疗效，这些药物一起为胰腺癌的治疗提供了一个强大的治疗平台。此外，我们的新治疗剂可以静脉注射，这将允许靶向转移性癌症。目前TOV的靶向效率很低，因为大多数临床先进的TOV必须在肿瘤内递送才能实现治疗效果。在本项目中，我们的目标是获得足够的实验数据，包括大规模生产符合GMP标准的病毒和毒性测试，以便获得MHRA批准进行这种新型病毒治疗胰腺癌的I期临床试验，为改善胰腺癌患者的预后提供了希望。

Pancreatic Ductal Adenocarcinoma (PDAC) is an almost uniformly lethal disease. In the UK alone, 10,000 cases are reported each year and the incidence rates are expected to rise by a further 6% by 2035. While a number of cancers are responding favourably to new immunotherapeutic treatment protocols, including vaccination and checkpoint blockade, these strategies have failed to impact PDAC survival rates, because PDAC is potently able to prevent the host immune system controlling cancer progression. Thus, there is an urgent need to design new types of therapy to overcome the barriers to conventional therapy in PDAC.We have developed novel tumour-targeting oncolytic viruses (TOVs), which are attractive therapeutic options for cancer. These agents can, through selective replication in the tumour tissue, amplify the input dose and kill tumours by multiple mechanisms, including direct cell killing and importantly by induction of systemic anti-tumour immune responses in the patient that can target primary tumour, metastatic deposits and prevent recurrence. In addition, TOVs can act as delivery vectors, delivering immune stimulants to amplify the immune response against tumour-specific antigens that are expressed only by tumour cells, allowing the immune system to specifically recognise and kill tumour cells.We have recently developed a new generation of TOVs called VVL-21. This new biological therapeutic agent can inflame the tumour micro-environment, promoting infiltration of multiple immune cells within pancreatic tumours. Strikingly this new agent can boost the efficacy of an approved immunotherapy agent anti-PD1 and together these agents provide a powerful therapeutic platform for treatment of pancreatic cancer. Additionally, our new therapeutic agent can be injected intravenously,which will allow targeting of metastatic cancers. These are currently targeted inefficiently by TOVs as most clinically advanced TOVs must be delivered intra-tumourally to achieve therapeutic benefit.In this project, we aim to to achieve sufficient experimental data, including large scale manufacture of the virus to GMP standard and toxicity testing in order to get an approval by the MHRA for a Phase I clinical trial of this novel virus to treat pancreatic cancer, providing hope for improved prognosis for pancreatic cancer patients.