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。它是全球癌症死亡的第七大常见原因，5年生存率一直很低，只有3%。如果不进行积极治疗，转移性PDAC患者的平均生存期为3-5个月。即使在潜在的治愈性切除后，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，目前在手术、辅助和姑息治疗方面的进展未能提高总体生存率。因此，不与传统化疗交叉耐药的新治疗策略势在必行。有效治疗PDAC的一个主要障碍是肿瘤无法获得治疗。此外，患者通常表现为已经转移到远处部位的晚期疾病。肿瘤靶向溶瘤病毒（tov）是一类新的治疗方法，在许多不同癌症的临床试验中显示出巨大的希望，并为PDAC治疗方法的开发提供了一个有希望的平台。tov不仅通过直接裂解杀死肿瘤细胞，而且还通过多种其他机制起作用，通过靶向参与致癌的分子途径，以及破坏免疫抑制肿瘤微环境并诱导持久的肿瘤特异性免疫。此外，随着病毒在恶性细胞内的复制，tov可以特异性地将治疗蛋白递送到肿瘤中，其水平不断提高。尽管各种tov的临床试验已经产生了反应的证据，但许多最终都令人失望，特别是对于PDAC。牛痘病毒（VV）有几个特点，使其成为一种很有前途的治疗剂，特别是因为一种这样的病毒（JX594）最近被证明在静脉输注后能有效地靶向肿瘤，使VV成为治疗胰腺癌等难以接近的肿瘤的理想TOV。我们最近发现，欧洲疫苗株李斯特牛痘病毒是开发新一代溶瘤性VV治疗癌症的一个有吸引力的平台，特别是用于PDAC。基于lister菌株，我们最近开发了新一代的VV （VVTKN1L，由QMUL创新有限公司申请的专利），它更具有肿瘤特异性，并且具有更高的抗肿瘤功效。此外，我们还构建了一组表达免疫调节基因VV-IL10、VV-GMCSF、VV-IL12、VV-IL15/IL15R和VV-IL-21的VVTKN1L载体。vvtkn1l - il - 21在治疗腹膜播散性胰腺癌中显示出最高的治疗指数。在这个项目中，我们将开发一种优化的治疗方案，将我们的新病毒与一种新的肿瘤靶向药物结合起来，这种药物可以调节宿主免疫反应，也可以用于治疗晚期胰腺癌的常规化疗（吉西他滨）。

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.