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.

胰腺癌是北美癌症相关死亡的第三大原因。大多数胰管 腺癌 (PDAC) 患者在疾病晚期才被诊断出来，并在这些阶段进行治疗 后期阶段极具挑战性。治疗晚期 PDAC 的新疗法迫切需要 需要。 在这个项目中，我们计划开发与表达干扰素的溶瘤腺病毒（IFN- OAd）和放化疗治疗局部晚期和不可切除的胰腺癌（LAPC），包括边缘性胰腺癌 可切除胰腺癌（BRPC），占 PDAC 患者的 50% 以上。局部治疗 这些群体的疾病将有利于可切除性和预后。 我们一直在开发溶瘤腺病毒（OAd）作为癌症治疗药物。 OAd 旨在 选择性地在肿瘤内复制和扩散，从而产生由杀细胞介导的强溶瘤作用 病毒的功能导致免疫原性细胞死亡。 OAds 还可以诱导大量和选择性表达 发生病毒复制的目标癌细胞中的转基因。 因此，OAd系统将被用来克服目前基于IFN的治疗的障碍 在肿瘤区域选择性表达大量干扰素。在我们的初步实验中，IFN- 表达 OAd (IFN-OAd) 的同基因 PDAC 模型中显示出令人印象深刻的肿瘤消退 免疫功能健全的仓鼠，与放化疗结合时其效果大大增强。我们有 还报道了表达 IFN 的 Ad 不仅在注射的肿瘤中而且在未治疗的肿瘤中诱导收缩 对侧肿瘤是由于刺激全身免疫而引起的。这些表明这种新组合 治疗可以实现对局部晚期和转移性疾病的更有效治疗。 为了实现这一目标，我们将首先分析联合疗法在人类 PDAC 细胞系中的效果， 组织切片培养系统。然后我们将优化放化疗方案以最大化效果 在免疫功能正常的同基因仓鼠模型中与 IFN-OAd 联合治疗的研究。免疫学方面 联合疗法的效果和毒性也将受到严格检查。最后，治疗效果 IFN-OAd 与放化疗的新组合方法将在 LAPC 模型以及 患者来源的肿瘤异种移植物。 该项目将建立基于 IFN-OAd 的新型放化疗的治疗方案，以便 开始在 LAPC 和 BRPC 患者中进行临床转化。我们拥有一支强大的团队，在以下方面拥有成功的历史 将此类疗法带给患者，一旦实施，疗法/治疗将提供极好的效果 改善目前胰腺癌破坏性临床结果的机会。