Advancing Systematic Delivery of Oncolytic Adenovirus for Pancreatic Cancer

摘要 该项目的目标是实现系统递送的溶瘤腺病毒的临床翻译 (OADs)用于胰腺导管腺癌(PDAC)的综合诊断和治疗 如果没有有效的治疗，就会导致毁灭性的疾病。PDAC没有有效的筛查方法，其传播和 转移是很难评估的。表达钠-碘转运体(OAd5/3-)的新一代OAD 由Davydova实验室开发的NIS载体)，诱导胰腺癌细胞摄取放射性碘， 从而方便了SPECT/CT成像和131I放射治疗。我们已经展示了非凡的Pre 临床数据支持OAd5/3-NIS平台的适用性，以促进基于放射性碘的成像和 PDAC的治疗。然而，静脉给药的OADs的临床翻译因 缺乏允许OAD复制的动物模型。小鼠组织不支持复制人类 腺病毒，防止利用小鼠研究生物分布和系统递送的脱靶效应 OADS。此外，所有啮齿动物系统都缺乏与基于AD3的腺病毒受体结合所必需的AD3受体 载体(包括我们的OAd5/3-NIS)。需要可靠的动物模型是至关重要的。不到5%的抗癌药物 在小鼠模型中前景看好的治疗方法在人类临床试验中也取得了成功。因此，要解决这个问题， 迫切需要，我们正在开发一种新的猪PDAC平移模型。猪一直是一种有吸引力的 癌症模型的替代平台，因为它们在解剖学、新陈代谢、 肿瘤发生、遗传学、免疫力和身体大小。此外，正如我们最近报道的那样，与啮齿动物和 犬模型，猪允许在水平上复制5型和3型腺病毒载体 与人类的情况相似。OAd5/3-NIS全身给药在猪胰腺模型中的验证 癌症是临床试验前的下一步。在这项工作中，我们将1)产生一种新的转基因 KrasG12D/+/TP53R167H/+PDAC猪模型；2)监测和表征PDAC肿瘤的发展；3) 进行临床前研究以评估静脉注射OAd5/3-NIS以促进 猪PDAC模型的放射性碘显像和131I放射治疗。完成本建议书 将实现系统注射的OAd5/3-NIS载体的临床翻译，用于治疗和诊断成像 PDAC患者，包括转移性癌症患者。重要的是，这些研究将产生 关于其他药物的生物分布、清除、偏离靶点效应和总体治疗潜力的基本信息 OADs是一种临床相关的、腺病毒复制允许的、免疫活性模型。另外，我们的小说 猪模型将克服啮齿动物固有的许多缺点，特别是在体型、遗传学、 癌症生物学、新陈代谢和免疫导致更安全、更有效的癌症治疗方法 患有PDAC的患者，是一种没有有效治疗方法的令人沮丧的疾病。 1

ABSTRACT The goal of this project is to enable the clinical translation of systemically delivered Oncolytic Adenoviruses (OAds) for combined diagnostic imaging and curative therapy of Pancreatic Ductal Adenocarcinoma (PDAC), a devastating disease without effective therapies. PDAC has no effective screening methods, and its spread and metastases are difficult to assess. This new generation of OAds expressing Sodium-Iodide Symporter (OAd5/3- NIS vectors) developed in the Davydova lab, induces uptake of radioactive iodine by pancreatic cancer cells, thus facilitating both SPECT/CT imaging and radiotherapy with 131I. We have demonstrated remarkable pre- clinical data to support the applicability of the OAd5/3-NIS platform to facilitate radioiodine-based imaging and treatment of PDAC. However, the clinical translation of intravenously administrated OAds has been stalled by the lack of an animal model that allows OAd replication. Murine tissues do not support replication of human adenovirus, preventing the use of mice to study biodistribution and off target effects of systemically delivered OAds. Moreover, all rodent systems lack Adenovirus type 3 (Ad3) receptors necessary to bind to Ad3-based vectors (including our OAd5/3-NIS). The need for reliable animal models is critical. Less than 5% of anti-cancer treatments that are promising in murine models are successful in human clinical trials. Therefore, to address this urgent need, we are developing a novel translational swine model of PDAC. Pigs have been attractive as an alternative platform for cancer modeling because of their similarity with humans in terms of anatomy, metabolism, tumorigenesis, genetics, immunity, and body size. Furthermore, as we have recently reported, unlike rodent and canine models, pigs permit replication of both Adenovirus type 5 and Adenovirus type 3 vectors on the level similar to that in humans. Validating systemic administration of OAd5/3-NIS in our swine model of pancreatic cancer is the next step before clinical trials. In this work, we will 1) Produce a novel transgenic KrasG12D/+/TP53R167H/+ swine model of PDAC; 2) Monitor and characterize PDAC tumor development; and 3) Conduct the preclinical studies to evaluate the potential of intravenously administrated OAd5/3-NIS to facilitate both radioiodine-based imaging and radiotherapy with 131I in swine PDAC models. Completion of this proposal will enable clinical translation of systemically injected OAd5/3-NIS vectors for treatment and diagnostic imaging of patients with PDAC, including patients with metastatic cancer. Importantly, these studies will generate essential information on biodistribution, clearance, off target effects, and overall therapeutic potential of other OAds in a clinically relevant, adenovirus replication permissive, immunocompetent model. In addition, our novel pig model will overcome many of the disadvantages inherent in rodents, particularly with respect to size, genetics, cancer biology, metabolism, and immunity leading to translation of safer, more effective cancer treatments for patients with PDAC, a dismal disease with no effective treatments available. 1