Improving the Pharmacology of Oncolytic Adenovirus

描述（由申请人提供）：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，同时避开正常组织。溶瘤病毒是开发用于通过感染、复制并最终杀死肿瘤细胞来选择性杀死这些细胞的病毒。这些药物具有“自我放大”药物的吸引力，因为每个感染的肿瘤细胞会产生10，000多个病毒来放大被杀死的肿瘤细胞的数量。溶瘤病毒已在临床前和临床试验中显示出前景，其中当通过直接瘤内注射施用时，它们已被证明是最有用的。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某些癌细胞类型的特定性状或通过利用肿瘤发生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，但肝脏静脉注射剂量的90%损失减少了可用于杀死肿瘤转移的病毒量。这种损失也会产生剂量限制性，有时甚至致命的肝损伤。除了这些药理学问题之外，临床转化的另一个重要障碍是患者中存在或高水平的针对Ad5的中和抗体。这些抗体消耗大部分注射剂量，显著降低疗效。鉴于这些问题，本项目将应用临床相关的干预措施，试图改善腺病毒溶瘤药的药理学和免疫原性，用于全身癌症治疗。该项目将通过基因和化学工程将溶瘤病毒从肝脏中去除，并使其免受免疫系统的影响。马约诊所的分子医学项目先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，危险性更低。该项目将致力于提高这些癌症杀伤病毒用于全身治疗的能力，以发现和杀死转移性疾病中的远处肿瘤部位。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.