Combination therapy with IFN expressing oncolytic adenovirus for pancreatic cancer

表达 IFN 的溶瘤腺病毒联合治疗胰腺癌

• 批准号: 10333308
• 负责人: Julia Davydova
• 金额: $ 34.52万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333308
• 关键词: Adenoviruses; Adjuvant Therapy; Affect; Blood Vessels; Cancer Diagnostics; Cancer Etiology; Cell Line; Cessation of life; Chemotherapy and/or radiation; Clinical; Combined Modality Therapy; Contralateral; Development; Diagnosis; Disease; Dropout; Excision; Goals; Hamsters; Human; Immune; Immunity; Immunocompetent; Immunologics; Immunotherapy; Impairment; In Vitro; Induction of Apoptosis; Interferon-alpha; Interferons; Investigational Drugs; Location; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nodule; North America; Oncolytic; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Phase I Clinical Trials; Principal Investigator; Prognosis; Recording of previous events; Regimen; Reporting; Resectable; Site; Slice; System; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Transgenes; Tumor Antigens; Tumor Debulking; Tumor Immunity; Tumor-Derived; Unresectable; Virus; Virus Replication; Work; advanced pancreatic cancer; anti-tumor immune response; antitumor effect; base; cancer cell; chemoradiation; clinical application; clinical translation; cytokine; design; effective therapy; experimental study; immunogenic cell death; immunoregulation; improved; interferon therapy; new combination therapies; novel; novel therapeutics; oncolysis; oncolytic adenovirus; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient prognosis; selective expression; success; systemic toxicity; transgene expression; tumor; tumor xenograft

Pancreatic cancer is the 3rd leading cause of cancer-related death in North America. Most pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed at an advanced stage of the disease, and treatment at these late stages is extremely challenging. Novel therapeutics for the treatment of advanced PDAC are desperately needed. In this project, we plan to develop combination therapy with interferon-expressing oncolytic adenovirus (IFN- OAd) and chemoradiation for locally advanced and unresectable pancreatic cancer (LAPC) including borderline resectable pancreatic cancer (BRPC), which constitute more than 50% of the PDAC patients. Treatment of local disease in these groups will benefit the resectability and prognosis. We have been developing oncolytic adenoviruses (OAds) as cancer therapeutics. OAds are designed to selectively replicate and spread within the tumor, resulting in a strong oncolytic effect mediated by the cytocidal function of the virus leading to immunogenic cell death. OAds can also induce massive and selective expression of a transgene in the target cancer cells where viral replication is taking place. Therefore, OAd system will be exploited to overcome the current obstacles of IFN-based therapy by selectively expressing a massive amount of IFN in the tumor region. In our preliminary experiments, IFN- expressing OAd (IFN-OAd) showed impressive tumor regression in a syngeneic PDAC model in immunocompetent hamsters, and its effect was greatly enhanced when combined with chemoradiation. We have also reported shrinkage induced by IFN-expressing Ad not only in the injected tumor but also in the untreated contralateral tumor caused by the stimulation of systemic immunity. These suggest that this new combination therapy may realize a more effective treatment of locally advanced and metastatic diseases. Toward this goal, we will first analyze the effects of the combination therapy in human PDAC cell lines and the tissue-slice culture system. We then will optimize chemoradiation regimens in order to maximize the effect of the combination therapy with IFN-OAd in an immunocompetent syngeneic hamster model. The immunological effect and toxicity of the combination therapy will also be examined rigorously. Finally, the therapeutic benefit of the novel combination approach of IFN-OAd with chemoradiaion will be analyzed in LAPC models as well as with patient-derived tumor xenografts. This project will establish a therapeutic regimen of the novel IFN-OAd-based chemoradiation in order to commence clinical translation in LAPC and BRPC patients. We have a strong team with a history of success in bringing such therapeutics to patients, andonce implemented, the therapeutic/treatment will provide an excellent opportunity to improve the current devastating clinical outcome of pancreatic cancers.

胰腺癌是北美与癌症相关死亡的第三主要原因。大多数胰管导管 腺癌（PDAC）患者在疾病的晚期诊断出来，并在这些疾病中进行治疗 晚期非常具有挑战性。用于治疗高级PDAC的新型治疗方法拼命 需要。 在这个项目中，我们计划通过表达干扰素的溶瘤腺病毒（IFN- OAD）和局部晚期和不可切除的胰腺癌（LAPC）的化学放疗包括边界 可切除的胰腺癌（BRPC）占PDAC患者的50％以上。局部治疗 这些群体中的疾病将有益于切除性和预后。 我们一直在开发溶瘤腺病毒（OAD）作为癌症治疗剂。 OAD被设计为 选择性地复制并扩散在肿瘤内，从而产生了由细胞粘附介导的强瘤作用 导致免疫原性死亡的病毒的功能。 OAD还可以诱导大量和选择性的表达 发生病毒复制的目标癌细胞中的转基因。 因此，将利用OAD系统来克服当前基于IFN的治疗的障碍 在肿瘤区域有选择地表达大量的IFN。在我们的初步实验中， 表达OAD（IFN-OAD）在同步PDAC模型中显示出令人印象深刻的肿瘤消退 免疫能力仓鼠及其与化学放疗相结合时的作用大大增强。我们有 还报道了由表达IFN的AD引起的收缩，不仅在注射的肿瘤中，而且在未处理的肿瘤中也 由全身免疫力刺激引起的对侧肿瘤。这些表明这种新组合 治疗可能会对局部晚期和转移性疾病进行更有效的治疗方法。 为了实现这一目标，我们将首先分析组合疗法在人类PDAC细胞系中的影响和 组织片培养系统。然后，我们将优化化学放疗方案，以最大化效果 在免疫能力的合成仓鼠模型中与IFN-OD的组合疗法的组合疗法。免疫学 联合疗法的效果和毒性也将进行严格检查。最后，的治疗益处 IFN-OAD与化学处理的新型组合方法将在LAPC模型以及 与患者衍生的肿瘤异种移植物。 该项目将建立一种基于IFN-OAD的新型化学放疗的治疗方案，以便为了 从LAPC和BRPC患者开始临床翻译。我们有一个坚强的团队，拥有成功的历史 将这种治疗剂带给患者，Andonce实施，治疗/治疗将提供出色的 改善胰腺癌当前毁灭性临床结果的机会。