Oncolytic VSV for Hepatocellular Carcinoma

溶瘤 VSV 治疗肝细胞癌

• 批准号: 7258999
• 负责人: Savio L Woo
• 金额: $ 33.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258999
• 关键词: 5' Untranslated Regions; Aftercare; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Antiviral Response; Attenuated; Binding Proteins; Brain; Cancer Etiology; Cell physiology; Cells; Cessation of life; Chemotaxis; Class; Development; Disease regression; Dose; Elements; Engineering; Enhancing Antibodies; Exhibits; Facility Construction Funding Category; Future; Gene Expression; Genes; Genetic Translation; Genome; Giant Cells; Glycoproteins; Hepatic artery; Hepatocyte; Human; Immune; Infiltration; Inflammatory; Inflammatory Response; Internal Ribosome Entry Site; Lead; Lesion; Limb structure; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Membrane Glycoproteins; Messenger RNA; Minor; Modeling; Molecular; Natural Killer Cells; Neurons; Oncolytic; Oncolytic viruses; Paralysed; Pathology; Patients; Phase; Polymerase; Primary carcinoma of the liver cells; RNA Viruses; Rattus; Recombinants; Refractory; Research; Research Personnel; Research Project Grants; Safety; Secondary to; Site; Specificity; Spinal Cord; Time; Toxic effect; Translations; Treatment Efficacy; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Replication; artery infusion; attenuation; cancer therapy; chemokine; day; dosage; improved; killings; macrophage; neoplastic cell; neurotoxicity; neutralizing antibody; neutrophil; novel; oncolysis; preclinical study; programs; translational clinical trial; tumor; vector

DESCRIPTION (provided by applicant): Hepatocellular Carcinoma (HCC) is the third leading cause of cancer deaths in the world with a median survival time of only 7.8 months in untreated patients. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents for cancer treatment. Vesicular Stomatitis Virus (VSV) is a cytoplasmic RNA virus with inherent specificity for replication in tumor cells due to their attenuated anti- viral responses. We demonstrated robust VSV replication and cytopathic effects in cultured rat and human HCC cells, while normal rat and human hepatocytes were refractory. We have constructed a fusogenic rVSV vector and showed that through hepatic artery infusion, it reached and replicated in large multi-focal HCC lesions in the livers of syngeneic and immune-competent rats that led to massive tumor destruction and survival prolongation, and without liver pathology. While encouraging, intratumoral virus replication peaked after only one day and long-term survival was achieved in only a minor fraction of the treated animals. The logarithmic decline in intratumoral virus titers beyond one-day was co-incidental with the infiltration and accumulation of NK cells, neutrophils and macrophages at the tumor sites, and oncolysis was substantially enhanced by antibody-mediated depletion of these inflammatory cells prior to virus treatment. We hypothesize that the oncolytic potency VSV can be significantly elevated by vector-mediated expression of genes from heterologous viruses that suppress NK cell activity and chemotaxis of inflammatory cells, so that intratumoral virus replication will be extended from one to several days needed by the host to mount a neutralizing antibody response, which will lead to robust oncolysis and substantially prolonged survival. Additionally, at virus dosages above the maximum tolerated dose some treated rats exhibited signs of neuro-pathology manifested by limb paralysis, and virus was detected in neurons in the brain and spinal cord. We hypothesize that neuronal virus replication and spread can be inhibited by molecularly engineering the VSV genome so that the translation of pertinent viral mRNAs will be under the direction of internal ribosome entry sites of heterologous viruses that are non-functional in neurons but active in HCC cells. The successful conduct of the proposed research may lead to the future development of potent and neuro-attenuated rVSV vectors as effective and safe oncolytic agents to treat patients with advanced HCC and other cancers.

描述（由申请人提供）：肝细胞癌（HCC）是世界上第三大癌症死亡原因，未经治疗的患者中位生存时间仅为 7.8 个月。针对肿瘤的条件复制病毒正在被开发为一类用于癌症治疗的新型溶瘤剂。水泡性口炎病毒（VSV）是一种细胞质RNA病毒，由于其抗病毒反应减弱，因此具有在肿瘤细胞中复制的固有特异性。我们在培养的大鼠和人 HCC 细胞中证明了强大的 VSV 复制和细胞病变效应，而正常大鼠和人肝细胞则难以抵抗。我们构建了一种融合性 rVSV 载体，并表明，通过肝动脉输注，它可以到达同基因和免疫功能正常的大鼠肝脏中的大型多灶性 HCC 病灶并在其中复制，从而导致大量肿瘤破坏和生存延长，并且没有肝脏病理学改变。尽管令人鼓舞，但瘤内病毒复制仅在一天后就达到顶峰，并且只有一小部分接受治疗的动物实现了长期存活。超过一天后肿瘤内病毒滴度的对数下降与肿瘤部位的 NK 细胞、中性粒细胞和巨噬细胞的浸润和积累同时发生，并且在病毒治疗之前抗体介导的这些炎症细胞的消耗大大增强了溶瘤作用。我们假设，通过载体介导的异源病毒基因表达，抑制NK细胞活性和炎症细胞趋化性，可以显着提高VSV的溶瘤效力，从而使瘤内病毒复制从宿主所需的一天延长到几天。产生中和抗体反应，这将导致强大的溶瘤作用并显着延长生存期。此外，当病毒剂量高于最大耐受剂量时，一些接受治疗的大鼠表现出以肢体麻痹为代表的神经病理学迹象，并且在大脑和脊髓的神经元中检测到了病毒。我们假设可以通过对 VSV 基因组进行分子改造来抑制神经元病毒的复制和传播，从而使相关病毒 mRNA 的翻译将在异源病毒的内部核糖体进入位点的指导下进行，这些病毒在神经元中无功能，但在 HCC 细胞中活跃。拟议研究的成功进行可能会导致未来开发出有效的神经减毒 rVSV 载体，作为有效且安全的溶瘤剂来治疗晚期 HCC 和其他癌症患者。