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

使用新型免疫治疗剂开发治疗晚期胰腺癌的有效治疗方案

• 批准号: MR/N027655/1
• 负责人: Nick Lemoine
• 金额: $ 74.74万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN027655%2F1
• 关键词: Development; effective; therapeutic; regimen; treatment

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.

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，五年生存率始终保持在3%的低水平。如果不积极治疗，转移性PDAC患者的平均生存期为3-5个月。即使在潜在的根治性切除术后，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生存率。因此，新的治疗策略，不交叉耐药与传统的化疗为基础的制度是必要的。PDAC有效治疗的主要障碍是肿瘤无法接受治疗。肿瘤靶向溶瘤病毒（TOV）是一类新型的治疗药物，在临床试验中显示出对多种不同癌症的巨大前景，并为PDAC的治愈性疗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，而且还通过靶向参与致癌作用的分子途径，以及破坏免疫抑制肿瘤微环境和诱导持久的肿瘤特异性免疫，通过多种其他作用机制发挥作用。此外，TOV可以在恶性细胞内病毒复制后以增加的水平特异性地将治疗性蛋白质递送到肿瘤中。虽然各种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）具有使其成为有希望的治疗剂的几个特征，特别是因为一种这样的病毒（JX 594）最近已被证明在静脉输注后有效地靶向肿瘤，使得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牛痘病毒是开发新一代溶瘤VV用于癌症治疗（尤其是PDAC）的有吸引力的平台。基于lister菌株，我们最近开发了新一代VV（VVTKN 1 L，由QMUL Innovation Ltd申请的专利），该产品更具肿瘤特异性，并提高了抗肿瘤疗效。此外，我们已经创建了一组表达免疫调节基因的VVTKN 1 L载体，所述免疫调节基因包括VV-IL 10、VV-GMCSF、VV-IL 12、VV-IL 15/IL 15 R和VV-IL-21。VVTKN 1 L-IL 21已被证明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新的肿瘤靶向药物相结合，该药物可调节宿主免疫反应以及常规化疗（吉西他滨），用于治疗晚期胰腺癌。

项目成果

A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer.

• DOI: 10.1136/jitc-2020-001624
• 发表时间: 2021-01
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Marelli G;Chard Dunmall LS;Yuan M;Di Gioia C;Miao J;Cheng Z;Zhang Z;Liu P;Ahmed J;Gangeswaran R;Lemoine N;Wang Y
• 通讯作者: Wang Y

Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent.

• DOI: 10.1038/s41467-017-01385-8
• 发表时间: 2017-11-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wang P;Li X;Wang J;Gao D;Li Y;Li H;Chu Y;Zhang Z;Liu H;Jiang G;Cheng Z;Wang S;Dong J;Feng B;Chard LS;Lemoine NR;Wang Y
• 通讯作者: Wang Y

Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.

• DOI: 10.3389/fonc.2017.00195
• 发表时间: 2017
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Howells A;Marelli G;Lemoine NR;Wang Y
• 通讯作者: Wang Y

Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer.

溶瘤病毒疗法和免疫系统：对抗癌症的双刃剑

• DOI: 10.3389/fimmu.2018.00866
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Marelli G;Howells A;Lemoine NR;Wang Y
• 通讯作者: Wang Y

A novel vaccinia virus enhances anti-tumor efficacy and promotes a long-term anti-tumor response in a murine model of colorectal cancer.

一种新型疫苗病毒在小鼠结直肠癌模型中增强了抗肿瘤疗效并促进了长期抗肿瘤反应。

• DOI: 10.1016/j.omto.2020.11.002
• 发表时间: 2021-03-26
• 期刊: Molecular therapy oncolytics
• 作者: Wang N;Wang J;Zhang Z;Cao H;Yan W;Chu Y;Chard Dunmall LS;Wang Y
• 通讯作者: Wang Y