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

基本信息

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
项目类别：
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

项目摘要

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

抽象的该项目的目标是实现系统递送的溶瘤腺病毒的临床转化（OAds）用于胰腺导管腺癌（PDAC）的联合诊断成像和治疗治疗，没有有效治疗方法的毁灭性疾病。 PDAC尚无有效的筛查方法，其传播和传播转移很难评估。新一代 OAd 表达碘化钠同向转运体 (OAd5/3- NIS 载体）由 Davydova 实验室开发，诱导胰腺癌细胞摄取放射性碘，从而促进 SPECT/CT 成像和 131I 放射治疗。我们已经展示了卓越的预临床数据支持 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，静脉注射 OAd 的临床转化却因以下原因而陷入停滞：缺乏允许 OAd 复制的动物模型。小鼠组织不支持人类复制腺病毒，阻止使用小鼠来研究系统递送的生物分布和脱靶效应 OA广告。此外，所有啮齿动物系统都缺乏与基于 Ad3 的腺病毒结合所必需的 3 型腺病毒 (Ad3) 受体。载体（包括我们的 OAd5/3-NIS）。对可靠的动物模型的需求至关重要。抗癌效果低于5% 在小鼠模型中具有前景的治疗方法在人体临床试验中取得了成功。因此，为了解决这个问题为了满足迫切需要，我们正在开发一种新型的PDAC转化猪模型。猪作为一种动物一直很有吸引力癌症建模的替代平台，因为它们在解剖学、新陈代谢、肿瘤发生、遗传、免疫和体型。此外，正如我们最近报道的那样，与啮齿动物和在犬科动物模型中，猪允许在水平上复制 5 型腺病毒和 3 型腺病毒载体与人类相似。在我们的猪胰腺模型中验证 OAd5/3-NIS 的全身给药癌症是临床试验之前的下一步。在这项工作中，我们将 1) 生产一种新型转基因 KrasG12D/+/TP53R167H/+ PDAC猪模型； 2) 监测和表征PDAC肿瘤的发展；和 3) 进行临床前研究以评估静脉注射 OAd5/3-NIS 的潜力，以促进在猪 PDAC 模型中进行基于放射性碘的成像和 131I 放射治疗。完成本提案将实现系统注射 OAd5/3-NIS 载体的临床转化，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，这些研究将产生有关其他药物的生物分布、清除率、脱靶效应和整体治疗潜力的重要信息临床相关、腺病毒复制许可、免疫活性模型中的 OAd。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、癌症生物学、代谢和免疫为人类带来更安全、更有效的癌症治疗方法 PDAC 患者是一种令人沮丧的疾病，没有有效的治疗方法。 1