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。大多数胰管 腺癌（PDAC）患者在疾病的晚期被诊断出，并且在这些晚期阶段的治疗 后期是非常具有挑战性的。治疗晚期PDAC的新疗法迫切需要 needed. 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-γ）的联合治疗。 OAd）和放化疗治疗局部晚期和不可切除的胰腺癌（LAPC）， 可切除的胰腺癌（BRPC），占PDAC患者的50%以上。治疗局部 这些组中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（OAds）作为癌症治疗药物。OAD旨在 选择性地在肿瘤内复制和扩散，导致由杀细胞因子介导的强烈溶瘤作用。 导致免疫原性细胞死亡的病毒功能。OAds还可以诱导大量的选择性表达 在病毒复制发生的靶癌细胞中的转基因。 因此，OAd系统将被利用来克服基于IFN的治疗的当前障碍， 在肿瘤区域选择性表达大量IFN。在我们的初步实验中，IFN- 表达OAd（IFN-OAd）的小鼠在同基因PDAC模型中显示出令人印象深刻的肿瘤消退， 免疫活性仓鼠，与化放疗结合时，其效果大大增强。我们有 也报道了表达IFN的Ad不仅在注射的肿瘤中而且在未治疗的肿瘤中诱导的收缩。 对侧肿瘤刺激引起的全身免疫。这表明这种新的组合 治疗可以实现对局部晚期和转移性疾病的更有效的治疗。 为了实现这一目标，我们将首先分析联合治疗在人PDAC细胞系中的作用， 组织切片培养系统。然后，我们将优化放化疗方案，以最大限度地提高效果 在免疫活性同系仓鼠模型中与IFN-OAd的联合治疗。免疫 还将严格检查联合治疗的效果和毒性。最后， 将在LAPC模型中分析IFN-OAd与放化疗新组合方法， 患者来源的肿瘤异种移植物。 本项目将建立一种基于新型IFN-OAd的放化疗治疗方案， 开始在LAPC和BRPC患者中进行临床翻译。我们拥有一支强大的团队，在以下领域取得了成功： 将这种疗法带给患者，一旦实施，治疗/治疗将提供一个极好的 改善目前胰腺癌的毁灭性临床结果的机会。

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.