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

新型可全身给药的溶瘤牛痘病毒用于治疗胰腺癌的 IND 应用的临床前开发

• 批准号: MR/V006053/1
• 负责人: Yaohe Wang
• 金额: $ 420.29万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV006053%2F1
• 关键词: Pre; clinical; development; IND; application

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.

胰腺导管腺癌(PDAC)是一种几乎一致致命的疾病。仅在英国，每年报告的病例就有10,000例，预计到2035年，发病率将进一步上升6%。虽然许多癌症对包括疫苗接种和检查点阻断在内的新的免疫治疗方案有良好的反应，但这些策略未能影响PDAC的存活率，因为PDAC能够有效地阻止控制癌症进展的宿主免疫系统。因此，迫切需要设计新的治疗方法来克服传统治疗的障碍。我们已经开发出新型的肿瘤靶向溶瘤病毒(TOV)，这是一种有吸引力的癌症治疗选择。通过在肿瘤组织中选择性复制，这些药物可以放大输入剂量，并通过多种机制杀死肿瘤，包括直接细胞杀伤，更重要的是通过在患者体内诱导系统性抗肿瘤免疫反应，可以针对原发肿瘤、转移沉积和防止复发。此外，TOV还可以作为递送载体，递送免疫刺激剂来放大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和杀伤肿瘤细胞。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的微环境，促进多种免疫细胞在胰腺肿瘤内的渗透。值得注意的是，这种新的药物可以提高已获批准的免疫治疗药物抗PD1的疗效，这些药物共同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。在这个项目中，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批准这种新病毒治疗胰腺癌的I期临床试验，为改善胰腺癌患者的预后提供希望。

项目成果

Ferroptosis-Related Genes Are Potential Therapeutic Targets and the Model of These Genes Influences Overall Survival of NSCLC Patients.

• DOI: 10.3390/cells11142207
• 发表时间: 2022-07-15
• 期刊: CELLS
• 影响因子: 6
• 作者: Zhang, Na;Wu, Yangyang;Wu, Yifan;Wang, Lihong;Chen, Jingfei;Wang, Xiaosa;Dunmall, Louisa S. Chard;Cheng, Zhenguo;Wang, Yaohe
• 通讯作者: Wang, Yaohe

Characterization of the Intra-tumoral B Cell Immunoglobulin Repertoire Is of Prognostic Value for Esophageal Squamous Cell Carcinoma.

肿瘤内B细胞免疫球蛋白库的表征对食管鳞状细胞癌具有预后价值。

• DOI: 10.3389/fimmu.2022.896627
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

An effective therapeutic regime for treatment of glioma using oncolytic vaccinia virus expressing IL-21 in combination with immune checkpoint inhibition.

• DOI: 10.1016/j.omto.2022.05.008
• 发表时间: 2022-09-15
• 期刊: MOLECULAR THERAPY ONCOLYTICS
• 作者: Sun, Yijie;Zhang, Zhe;Zhang, Chenglin;Zhang, Na;Wang, Pengju;Chu, Yongchao;Dunmall, Louisa S. Chard;Lemoine, Nicholas R.;Wang, Yaohe
• 通讯作者: Wang, Yaohe

Natural products targeting glycolysis in cancer.

• DOI: 10.3389/fphar.2022.1036502
• 发表时间: 2022
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6

Remodeling the tumor microenvironment by oncolytic viruses: beyond oncolysis of tumor cells for cancer treatment.

• DOI: 10.1136/jitc-2021-004167
• 发表时间: 2022-05
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9