Phase I trial of intravenous vesicular stomatitis virus for treatment of metastatic endometrial cancer

静脉内水泡性口炎病毒治疗转移性子宫内膜癌的 I 期试验

• 批准号: 9308083
• 负责人: Jamie N Bakkum-Gamez
• 金额: $ 47.26万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-04 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308083
• 关键词: Adjuvant Therapy; Antigens; Antiviral Agents; Biological Assay; Blood; Cancer cell line; Canis familiaris; Cells; Cessation of life; Client; Clinical; Clinical Trials; Code; Cyclic GMP; Cytolysis; Data; Deposition; Digit structure; Disease; Disease remission; Distant; Dose; Dose-Limiting; Drug Kinetics; Ebola Vaccines; Endometrial Carcinoma; Engineering; Enrollment; Family; Future; Generations; Genes; Goals; Grant; HIV; Human; Human body; Image; Immune response; Immunity; Immunocompetent; Immunosuppressive Agents; Infection; Innovative Therapy; Interferon-beta; Interferons; Intravenous; Iodine Isotopes; Kinetics; Lead; Lesion; Letters; Lipoprotein Receptor; Livestock; Low Density Lipoprotein Receptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mammals; Maximum Tolerated Dose; Measles; Measures; Mediating; Mediator of activation protein; Metastatic Endometrial Carcinoma; Multiple Myeloma; Mus; Nature; Normal Cell; Normal tissue morphology; Oncolytic; Patients; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Population; Predisposition; Probability; Proteins; Randomized Controlled Trials; Recombinants; Recurrence; Recurrent disease; Reporter Genes; Research; SLC5A5 gene; Safety; Serum; Somatic Mutation; Survival Rate; Symptoms; Systemic Therapy; T cell response; Technetium 99m; Testing; Therapeutic; Therapy trial; Time; Toxic effect; Tumor Immunity; Tumor Markers; Tumor Tissue; United States; Urine; Vesicular stomatitis Indiana virus; Veterinarians; Viremia; Virotherapy; Virus; Virus Diseases; Virus Replication; Virus Shedding; X-Ray Computed Tomography; adaptive immune response; cancer cell; cancer imaging; cancer therapy; chemotherapy; design; exome sequencing; farmer; gene panel; genetic signature; human subject; imaging study; immunogenicity; intravenous administration; killings; laboratory experiment; neoplastic cell; neurotoxicity; non-invasive imaging; novel; objective response rate; oncolysis; phase I trial; preclinical study; receptor; respiratory; response; serial imaging; seropositive; single photon emission computed tomography; sobriety; success; theranostics; transcriptome sequencing; tumor; tumor specificity; vaccine development

Here we seek to understand the effect of systemically administered Vesicular Stomatitis Virus (VSV) on humans and against metastatic endometrial cancer. This project includes the first-in-human clinical trial of VSV engineered to encode human interferon β (hIFNβ) and the sodium iodide symporter (NIS). hIFNβ codes for interferon (IFN) which protects normal cells from VSV effects and NIS enables tumor cells infected with the virus to concentrate various iodine isotopes which can allow for imaging of tumors infected with the virus. The virus being tested in this project is VSV-hIFNβ-NIS. We selected VSV as the platform virus for this study because: 1) VSV is a non-lethal, non-human (livestock) virus with mild, if any, symptoms in natural human infections, 2) VSV exposure in the United States is rare with <5% of the population being seropositive, 3) VSV has been safely administered to >7500 humans as the platform virus for HIV and Ebola virus vaccine development, 4) preclinical studies have shown that VSV potently and rapidly kills endometrial cancer cells and tumors, 5) advanced stage and high grade endometrial cancers have been shown to express receptors from the low density lipoprotein receptor (LDLR) family that VSV utilizes for cell infection, 6) mouse and canine studies have established the safety and maximum tolerated dose (MTD) of VSV-hIFNβ-NIS in those mammals, 7) mouse studies have shown that VSV-hIFNβ-NIS localizes to cancer and can be detected via SPECT/CT imaging, and 8) a phase I trial of a similar virus strain, VSV-hIFNβ, is currently being performed in human subjects. This project has incorporated real-time assessments of toxicity, tumor infectivity, and systemic immune responses to the virus and against endometrial cancer. The overarching goal is to generate a comprehensive understanding of the impact of systemic administration of the virus on the immunocompetent human and determine tumor-specific effects of virus infection. The three specific aims to be investigated in this project are: 1. Determine the safety, toxicity and tumor specificity of VSV-hIFNβ-NIS when administered intravenously to patients with metastatic endometrial cancer. 2. To determine VSV-hIFNβ-NIS replication pharmacokinetics, and shedding after virus administration and perform RNAseq and exome sequencing on tumor and normal tissues to test a novel gene panel as a biomarker for tumor response to the virus. 3. Determine the impact of intravenous VSV-hIFNβ-NIS on adaptive immune responses against the virus, endometrial cancer antigens, and immunosuppressive mediators.

在这里，我们试图了解全身注射水泡性口炎病毒(VSV)对 对人类和转移性子宫内膜癌的治疗。该项目包括首个人类临床试验 Vsv被设计成编码人干扰素β(h干扰素β)和钠碘转运体(Nis)。人干扰素β编码 对于保护正常细胞免受VSV影响的干扰素(干扰素)和NIS使感染了 病毒可以浓缩各种碘同位素，从而可以对感染病毒的肿瘤进行成像。这个 本项目正在测试的病毒是vsv-h干扰素β-NIS。我们选择VSV作为本研究的平台病毒 因为：1)VSV是一种非致命性、非人类(家畜)病毒，在自然人身上有轻微的症状。 感染，2)VSV接触在美国很少见，5%的人口血清阳性，3)VSV 已经作为HIV和埃博拉病毒疫苗的平台病毒安全地接种到7500人身上 发展，4)临床前研究表明，VSV有效而快速地杀死子宫内膜癌细胞和 肿瘤、晚期和高级别子宫内膜癌已被证明表达以下受体 VSV用于细胞感染的低密度脂蛋白受体(LDLR)家族，6)小鼠和狗 研究已经确定了vsv-h干扰素β-nis在这些哺乳动物中的安全性和最大耐受量。 7)小鼠研究表明，vsv-h干扰素β-nis定位于癌症，并可通过SPECT/CT检测到 成像，以及类似病毒株vsv-h干扰素β的I期试验目前正在人类身上进行。 研究对象。该项目包含了对毒性、肿瘤传染性和系统性的实时评估。 对病毒和子宫内膜癌的免疫反应。首要目标是生成一个 全面了解全身注射病毒对机体免疫功能的影响 并确定病毒感染对肿瘤的特异性影响。这三个具体目标是要调查的 项目包括：1.确定β-nis的安全性、毒性和肿瘤特异性。 静脉注射给转移性子宫内膜癌患者。2.检测vsv-h干扰素β-nis的复制 药物动力学和病毒给药后的脱落，并进行RNAseq和外显子组测序 测试一种新的基因组合，作为肿瘤对病毒反应的生物标记物。3. 确定静脉注射vsv-hIFNβ-nis对针对病毒的获得性免疫反应的影响， 子宫内膜癌抗原和免疫抑制介质。