Improving the Pharmacology of Oncolytic Adenovirus

理想的癌症治疗剂将特异性靶向恶性细胞以杀死这些细胞，同时避免 正常组织溶瘤病毒是被开发为通过感染、复制 并最终杀死这些细胞。这些药物具有“自我放大”药物的吸引力，因为每一种药物 受感染的肿瘤细胞产生10，000多个病毒，以扩大被杀死的肿瘤细胞的数量。溶瘤病毒 在临床前和临床试验中显示出了希望，在这些试验中，当应用于 直接瘤内注射。虽然这可能对肿瘤减积有用，但这种方法不能解决 远处转移 腺病毒已经被工程化以通过利用腺病毒的特定特性来实现癌症特异性。 某些癌细胞类型或通过利用肿瘤发生固有的分子变化。虽然这些 病毒具有更高的癌症特异性，90%的静脉注射剂量损失到肝脏会减少 病毒的量可用于杀死肿瘤转移。这种损失也会产生剂量限制，有时甚至是致命的 肝损伤除了这些药理学问题，临床转化的另一个重要障碍是 患者体内存在或高水平的抗Ad5中和抗体。这些抗体消耗了 注射剂量明显降低疗效。 鉴于这些问题，本项目将应用临床相关的干预措施，试图改善 用于全身癌症治疗的腺病毒溶瘤剂的药理学和免疫原性。该项目将 使溶瘤病毒脱离肝脏，并通过遗传和化学方法使其免受免疫系统的影响。 工程.马约诊所的分子医学项目先前已经翻译了其他溶瘤病毒 用于癌症治疗如果这个项目成功，它将为 在马约诊所和其他地点翻译这些腺病毒溶瘤剂用于治疗癌症患者。

An ideal cancer therapeutic agent would specifically target malignant cells to kill these cells while avoiding normal tissues. Oncolytic viruses are viruses developed to selectively kill tumor cells by infecting, replicating, and ultimately killing these cells. These agents have the appeal of being "self-amplifying" drugs, because each infected tumor cell produces 10,000 more viruses to amplify the number of killed tumor cells. Oncolytic viruses have shown promise in preclinical and clinical trials where they have proved most useful when applied by direct intratumoral injection. While this may be useful for debulking tumors, this approach cannot address distant metastases. Adenoviruses have been engineered to achieve cancer specificity by taking advantage of specific traits of certain cancer cell types or by taking advantage of molecular changes intrinsic to oncogenesis. While these viruses have higher cancer specificity, loss of 90% of the intravenously injected dose to liver reduces the amount of virus available to kill tumor metastases. This loss also produces dose-limiting and sometimes lethal liver damage. In addition to these pharmacologic problems, another significant hurdle to clinical translation is the presence or high levels of neutralizing antibodies against Ad5 in patients. These antibodies deplete most of an injected dose markedly reducing efficacy. Given these problems, this project will apply clinically-relevant interventions to attempt to improve both the pharmacology and immunogenicity of adenoviral oncolytics for systemic cancer therapy. This project will detarget oncolytic viruses from the liver and shield them from the immune system by genetic and chemical engineering. The Molecular Medicine Program at Mayo Clinic has previously translated other oncolytic viruses into the clinic for cancer applications. If this project is successful, it will therefore lay the groundwork for translating these adenovirus oncolytics for the treatment of cancer patients at Mayo Clinic and other sites.