Advancing Systematic Delivery of Oncolytic Adenovirus for Pancreatic Cancer

推进溶瘤腺病毒治疗胰腺癌的系统递送

• 批准号: 10734709
• 负责人: Julia Davydova
• 金额: $ 48.08万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734709
• 关键词: Acinar Cell; Address; Adenovirus Vector; Adenoviruses; Anatomy; Animal Model; Binding; Biodistribution; Body Size; Bystander Effect; CD46 Antigen; Cancer Biology; Cancer Etiology; Cancer Model; Cells; Cessation of life; Clinical; Clinical Trials; Data; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disadvantaged; Disease; Disseminated Malignant Neoplasm; Drug Kinetics; Duct (organ) structure; Ductal Epithelial Cell; Engineering; Enterobacteria phage P1 Cre recombinase; Evaluation; Excision; Family suidae; Fostering; Generations; Genes; Genetic; Goals; Human; Image; Imaging technology; Immunity; Immunocompetent; Industrialization; Intravenous; KRAS2 gene; KRASG12D; Lesion; Malignant neoplasm of pancreas; Mediating; Metabolism; Methods; Modeling; Monitor; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncolytic; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Pathologist; Patient Selection; Patient imaging; Patients; Pattern; Phase I Clinical Trials; Physiology; Preclinical Testing; Radiation therapy; Radioactive Iodine; Radioisotopes; Recording of previous events; Reporting; Rodent; Rodent Model; SLC5A5 gene; Safety; Serotyping; Survival Rate; System; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Translating; Translations; Treatment Protocols; Unresectable; Virus; Work; X-Ray Computed Tomography; Xenograft Model; anticancer treatment; cancer cell; cancer therapy; canine model; carcinogenesis; clinical development; clinical translation; clinically relevant; collaborative environment; curative treatments; design; desmoglein 2; detection sensitivity; effective therapy; experience; gene function; immunogenicity; improved; mouse model; neoplastic; neoplastic cell; novel; novel diagnostics; novel therapeutic intervention; oncolysis; oncolytic adenovirus; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; permissiveness; porcine model; pre-clinical; preclinical study; prevent; radioiodine imaging; radioiodine therapy; radiologist; receptor; safety study; screening; single photon emission computed tomography; success; surgical service; theranostics; tool; tumor; tumor progression; tumorigenesis; uptake; vector

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

摘要 该项目的目标是使临床翻译系统交付溶瘤腺病毒 （OAds）用于胰腺导管腺癌（PDAC）的联合诊断成像和治愈性治疗， 如果没有有效的治疗方法，PDAC没有有效的筛查方法，其传播和 转移很难评估。这种表达钠碘同向转运体（OAd 5/3-OAd 5）的新一代OAds， NIS载体）在Davydova实验室开发，诱导胰腺癌细胞摄取放射性碘， 因此便于SPECT/CT成像和131 I放射治疗。我们已经展示了惊人的预- 支持OAd 5/3-NIS平台促进放射性碘成像的适用性的临床数据， PDAC的治疗然而，静脉给药的OAD的临床转化已经停滞， 缺乏允许OAd复制的动物模型。小鼠组织不支持人类的复制 腺病毒，防止使用小鼠来研究全身递送的腺病毒的生物分布和脱靶效应。 OAD。此外，所有啮齿动物系统都缺乏结合基于Ad 3的腺病毒所必需的3型腺病毒（Ad 3）受体。 载体（包括我们的OAd 5/3-NIS）。对可靠的动物模型的需求至关重要。低于5%的抗癌 在鼠模型中有希望的治疗在人类临床试验中是成功的。因此，为了解决这个问题， 迫切需要，我们正在开发一种新的PDAC转译猪模型。猪作为一种动物， 癌症建模的替代平台，因为它们在解剖学，代谢， 肿瘤发生、遗传、免疫和体型。此外，正如我们最近报道的那样，与啮齿动物和 在犬模型中，猪允许5型腺病毒和3型腺病毒载体在水平上复制 类似于人类。在我们的猪胰腺炎模型中验证OAd 5/3-NIS的全身施用 癌症是临床试验的下一步。在这项工作中，我们将1）生产一种新的转基因 PDAC的KrasG 12 D/+/TP 53 R167 H/+猪模型; 2）监测和表征PDAC肿瘤发展;和3） 进行临床前研究，以评估静脉内给予OAd 5/3-NIS促进 在猪PDAC模型中使用131 I进行放射性碘成像和放射治疗。完成本提案 将能够临床转化全身注射的OAd 5/3-NIS载体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、清除率、脱靶效应和总体治疗潜力的基本信息 临床相关的腺病毒复制允许的免疫活性模型中的OAds。此外，我们的小说 猪模型将克服啮齿类动物固有的许多缺点，特别是在大小，遗传， 癌症生物学，代谢和免疫，导致翻译更安全，更有效的癌症治疗， PDAC患者，这是一种没有有效治疗方法的令人沮丧的疾病。 1