Improving the Pharmacology of Oncolytic Adenovirus

描述（由申请人提供）：一种理想的癌症治疗剂应该专门针对恶性细胞杀死这些细胞，同时避开正常组织。溶瘤病毒是一种通过感染、复制并最终杀死肿瘤细胞而选择性杀死肿瘤细胞的病毒。这些药物具有“自我放大”药物的吸引力，因为每个被感染的肿瘤细胞会产生1万个以上的病毒，以扩大被杀死的肿瘤细胞的数量。溶瘤病毒已在临床前和临床试验中显示出前景，在这些试验中，它们已被证明在直接肿瘤内注射时最有用。虽然这可能有助于肿瘤的缩小，但这种方法不能解决远处转移。通过利用某些癌细胞类型的特定特征或利用肿瘤发生固有的分子变化，腺病毒已被设计为实现癌症特异性。虽然这些病毒具有更高的癌症特异性，但静脉注射到肝脏的剂量减少了90%，减少了可用于杀死肿瘤转移的病毒数量。这种损失也会造成剂量限制，有时甚至是致命的肝损伤。除了这些药理学问题外，临床转化的另一个重大障碍是患者体内存在或高水平的Ad5中和抗体。这些抗体会耗尽大部分注射剂量，显著降低药效。鉴于这些问题，本项目将应用临床相关的干预措施，试图提高腺病毒溶瘤剂用于全身癌症治疗的药理学和免疫原性。该项目将通过基因和化学工程将溶瘤病毒从肝脏中分离出来，并保护它们免受免疫系统的攻击。梅奥诊所的分子医学项目之前已经将其他溶瘤病毒转化为临床癌症应用。如果这个项目取得成功，它将为将这些腺病毒溶瘤学转化为梅奥诊所和其他地方的癌症患者的治疗奠定基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Successful pursuit of this project will enable more specific and less dangerous oncolytic adenoviruses for cancer therapy. This project will work to improve the ability of these cancer killing viruses to be used for systemic therapy to find and kill distant tumor sites in metastatic disease. This work will lay the foundation for future testing in humans.