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: 10000856
• 负责人: Jamie N Bakkum-Gamez
• 金额: $ 54.37万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000856
• 关键词: Adjuvant Therapy; 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; Infection; Innovative Therapy; Interferon-beta; Interferons; Intravenous; Iodine Isotopes; Kinetics; Lesion; Letters; 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; Time; Toxic effect; Tumor Antigens; 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; first-in-human; gene panel; genetic signature; human subject; imaging study; immunogenicity; intravenous administration; laboratory experiment; lead candidate; neoantigens; 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; 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，我们试图了解的影响，系统管理水泡性口炎病毒（VSV）， 人类和转移性子宫内膜癌。该项目包括首次人体临床试验， VSV经改造以编码人干扰素β（hIFNβ）和钠碘同向转运体（NIS）。hIFNβ编码 干扰素（IFN）保护正常细胞免受VSV的影响，NIS使肿瘤细胞感染VSV， 病毒浓缩各种碘同位素，这可以允许对感染病毒的肿瘤进行成像。的 本项目所测试的病毒为VSV-hIFNβ-NIS。我们选择VSV作为本研究的平台病毒 因为：1）VSV是一种非致命的非人（牲畜）病毒，在自然人中具有轻微症状（如果有的话） 感染，2）VSV暴露在美国是罕见的，<5%的人口是血清阳性，3）VSV 作为HIV和埃博拉病毒疫苗的平台病毒，已安全接种超过7500人 4）临床前研究表明，VSV有效和快速地杀死子宫内膜癌细胞， 肿瘤，5）晚期和高级别子宫内膜癌已经显示表达来自 VSV用于细胞感染的低密度脂蛋白受体（LDLR）家族，6）小鼠和犬 研究已经确定了VSV-hIFNβ-NIS在这些哺乳动物中的安全性和最大耐受剂量（MTD）， 7)小鼠研究表明，VSV-hIFNβ-NIS定位于癌症，并可通过SPECT/CT检测 8）一种类似的病毒株VSV-hIFNβ的I期试验目前正在人体中进行 科目该项目已纳入实时评估毒性，肿瘤感染性，和全身 对病毒和子宫内膜癌的免疫反应。总体目标是产生一个 全面了解病毒全身给药对免疫活性 并确定病毒感染对肿瘤特异性影响。这三个具体目标是要调查的， 项目有：1.确定VSV-hIFNβ-NIS给药时的安全性、毒性和肿瘤特异性 转移性子宫内膜癌的患者静脉注射。2.确定VSV-hIFNβ-NIS复制 病毒给药后的药代动力学和脱落，并对病毒进行RNAseq和外显子组测序。 肿瘤和正常组织，以测试一种新的基因面板作为肿瘤对病毒反应的生物标志物。3. 确定静脉内VSV-hIFNβ-NIS对针对病毒的适应性免疫应答的影响， 子宫内膜癌抗原和免疫抑制介质。