Development of an effective therapeutic regimen for treatment of advanced pancreatic cancer using a novel immunotherapeutic agent

胰腺导管腺癌(PDAC)是最具侵袭性的肿瘤类型之一，预后极差。它是全球第七大最常见的癌症死亡原因，五年存活率一直保持在3%的低水平。如果没有积极的治疗，转移性PDAC患者的平均生存时间为3-5个月。即使在可能的根治性切除后，超过80%的患者最终死于局部复发和/或远处转移。自20世纪70年代以来，目前手术、辅助和姑息治疗的进展未能提高总体存活率。因此，不与传统化疗方案交叉耐药的新治疗策略势在必行。PDAC有效治疗的一个主要障碍是肿瘤无法获得治疗。此外，患者通常患有已转移到远处的晚期疾病。肿瘤靶向溶瘤病毒(TOV)是一种新的治疗方法，在许多不同癌症的临床试验中显示出巨大的前景，并为PDAC的治疗方法的开发提供了一个有前途的平台。TOVS不仅通过直接裂解杀死肿瘤细胞，还通过多种其他作用机制发挥作用，靶向参与致癌的分子途径，以及破坏免疫抑制的肿瘤微环境，诱导持久的肿瘤特异性免疫。此外，TOVS可以在病毒在肿瘤细胞内复制后，以更高的水平将治疗性蛋白特异性地输送到肿瘤中。尽管各种TOV的临床试验已经产生了有效的证据，但许多最终都令人失望，特别是对PDAC。痘苗病毒(VV)有几个特点使其成为一种有前途的治疗剂，特别是因为最近有证据表明，其中一种病毒(JX594)在静脉注射后能有效地靶向肿瘤，使VV成为治疗难以接近的肿瘤(如胰腺癌)的理想TOV。我们最近发现欧洲疫苗株Lister Vapinia Virus是开发新一代溶瘤VV的有吸引力的平台，用于癌症治疗，特别是PDAC。基于列斯特菌株，我们最近开发了新一代VV(VVTKN1L，由QMUL创新有限公司申请的专利)，它更具肿瘤特异性，并导致更好的抗肿瘤效果。此外，我们还构建了一组表达免疫调节基因的VVTKN1L载体，包括VV-IL10、VV-GMCSF、VV-IL12、VV-IL15/IL15R和VV-IL-21。VVTKN1L-IL21是治疗腹膜播散性胰腺癌的最高治疗指数。在这个项目中，我们将开发一种优化的治疗方案，将我们的新型病毒与一种调节宿主免疫反应的新型肿瘤靶向药物以及用于治疗晚期胰腺癌的常规化疗(吉西他滨)相结合。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumour types, with an extremely poor prognosis. It is the 7th most common cause of cancer death worldwide and the five-year survival rate remains consistently low at 3%. Without active treatment, patients with metastatic PDAC have a mean survival of 3-5 months. Even following potential curative resection, more than 80% of patients ultimately die of the disease due to local recurrence and/or distant metastasis. Current advances in surgical, adjuvant and palliative treatments have failed to improve the overall survival rate since the 1970s. Thus, new treatment strategies that are not cross-resistant with conventional chemotherapy-based regimes are imperative. A major barrier to the effective treatment of PDAC is the inaccessibility of the tumour to treatment. Furthermore, patients usually present with advanced disease that has metastasised to distant sites.Tumour-targeting oncolytic viruses (TOVs) are a new class of therapeutic that are showing immense promise in clinical trials for a number of different cancers and provide a promising platform for development of curative therapies for PDAC. TOVs not only kill the tumour cells by direct lysis but also act through multiple other mechanisms of action by targeting molecular pathways involved in carcinogenesis, as well as breaking down the immuno-suppressive tumour microenvironment and inducing a long-lasting tumour-specific immunity. Furthermore, TOVs can specifically deliver therapeutic proteins into tumours at increasing levels following viral replication within the malignant cells. Although clinical trials with various TOVs have produced evidence of response, many have ultimately disappointed, especially for PDAC. Vaccinia virus (VV) has several features that make it a promising therapeutic agent, especially since one such virus (JX594) has recently been shown to target tumours effectively after intravenous infusion, making VV an ideal TOV for treatment of inaccessible tumours such as pancreatic cancer. We have recently identified the European vaccine strain Lister vaccinia virus is an attractive platform for development of new generation of oncolytic VV for cancer treatment, especially for PDAC. Based on the lister strain, we recently developed a new generation of VV (VVTKN1L, a patent filed by QMUL Innovation Ltd), which is more tumour-specific and results in an improved antitumour efficacy. Furthermore, we have created a set of VVTKN1L vectors expressing immunomodulatory genes including VV-IL10, VV-GMCSF, VV-IL12, VV-IL15/IL15R and VV-IL-21. VVTKN1L-IL21 has demonstrated the highest therapeutic index for treatment of peritoneally disseminated pancreatic cancer. In this project we will develop an optimised therapeutic regimen by combining our novel virus with a new tumour targeted drug that regulates host immune responses as well as conventional chemotherapy (gemcitabine) for treatment of advanced pancreatic cancer.