Combination therapy with IFN expressing oncolytic adenovirus for pancreatic cancer

胰腺癌是北美癌症相关死亡的第三大原因。最大胰管 腺癌(PDAC)患者在疾病的晚期被诊断出来，并在这些阶段进行治疗 后期阶段是极具挑战性的。治疗晚期PDAC的新疗法迫在眉睫 需要的。 在这个项目中，我们计划开发干扰素表达溶瘤腺病毒(干扰素-1)的联合治疗。 OAD)和放化疗治疗局部晚期不能切除的胰腺癌(LAPC) 可切除胰腺癌(BRPC)，占PDAC患者的50%以上。对局部的治疗 这些组的疾病将有利于手术的可切除性和预后。 我们一直在开发溶瘤腺病毒(OAD)作为癌症治疗药物。OAD的设计目的是 选择性地在肿瘤内复制和扩散，导致由细胞杀伤剂介导的强大的溶瘤作用 病毒的功能导致免疫原性细胞死亡。OAD还可以诱导大量和选择性的表达 在病毒复制发生的目标癌细胞中的转基因。 因此，将通过开发OAD系统来克服目前基于干扰素的治疗的障碍 在肿瘤区域选择性地表达大量的干扰素。在我们的初步实验中，干扰素- 表达OAD(干扰素-OAD)在同基因PDAC模型中显示出令人印象深刻的肿瘤消退 免疫活性仓鼠，与放化疗联合应用效果显著。我们有 还报道了表达干扰素的Ad不仅在注射的肿瘤中而且在未治疗的肿瘤中引起萎缩 对侧肿瘤是由全身免疫刺激引起的。这些都表明，这种新的组合 治疗可能实现对局部晚期和转移性疾病的更有效治疗。 为了达到这一目标，我们将首先分析联合治疗对人PDAC细胞株和 组织切片培养系统。然后，我们将优化化疗方案，以最大限度地发挥作用 在具有免疫功能的同基因仓鼠模型中联合应用干扰素-OAD。免疫学 联合治疗的效果和毒性也将得到严格的检验。最后，它的治疗益处 将在LAPC模型中分析干扰素-OAD与化疗相结合的新方法 患者来源的肿瘤异种移植。 该项目将建立一种以干扰素-OAD为基础的新型化疗方案，以便 开始在LAPC和BRPC患者中进行临床翻译。我们有一支强大的团队，在 将这种疗法带给患者，一旦实施，治疗/治疗将提供极好的 有机会改善目前胰腺癌毁灭性的临床结果。

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.