Improving the Pharmacology of Oncolytic Adenovirus

描述(申请人提供)：理想的癌症治疗药物应该是专门针对肿瘤细胞来杀死这些细胞，同时避开正常组织。溶瘤病毒是一种病毒，通过感染、复制并最终杀死肿瘤细胞来选择性地杀死这些细胞。这些药物具有“自我放大”药物的吸引力，因为每个被感染的肿瘤细胞产生10,000多个病毒来放大被杀死的肿瘤细胞的数量。溶瘤病毒已经在临床前和临床试验中显示出希望，在这些试验中，通过直接瘤内注射被证明是最有用的。虽然这可能对清除肿瘤有用，但这种方法不能解决远处转移。腺病毒已经被设计成通过利用某些癌细胞类型的特定特征或通过利用肿瘤发生所固有的分子变化来实现癌症特异性。虽然这些病毒具有更高的癌症特异性，但失去90%的肝脏静脉注射剂量会减少可用于杀死肿瘤转移的病毒数量。这种损失还会造成剂量限制，有时还会造成致命的肝脏损伤。除了这些药理学问题，临床翻译的另一个重大障碍是患者中存在或高水平的抗Ad5的中和抗体。这些抗体耗尽了注射剂量的大部分，显着降低了疗效。鉴于这些问题，该项目将应用与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。该项目将从肝脏中去除溶瘤病毒的目标，并通过基因和化学工程保护它们免受免疫系统的攻击。梅奥诊所的分子医学计划此前曾将其他溶瘤病毒翻译到临床用于癌症应用。如果该项目成功，将为将这些腺病毒溶瘤剂转化为治疗梅奥诊所和其他地点的癌症患者奠定基础。 公共卫生相关性：该项目的成功实施将使溶瘤腺病毒用于癌症治疗的特异性更强、危险性更小。该项目将致力于提高这些致癌病毒的能力，用于系统治疗，以发现和杀死转移疾病中的远程肿瘤部位。这项工作将为未来的人体试验奠定基础。

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.