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Efficacy of Dendritic Cell Vaccines Targeting CMV in Glioblastoma (phase 2 DC vaccine)

针对胶质母细胞瘤中 CMV 的树突状细胞疫苗的功效（2 期 DC 疫苗）

基本信息

批准号：
9752239
负责人：
DUANE A. MITCHELL
金额：
$ 67.73万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-11 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752239
关键词：
Adjuvant Affect Antigens Autologous Autologous Dendritic Cells Biological Biological Markers Brain CCL3 gene Cells Cellular Immunity Clinical Clinical Research Clinical Trials Cytomegalovirus Data Dendritic Cell Vaccine Dendritic Cells Diagnosis Diphtheria Toxoid Disease Doctor of Medicine Doctor of Philosophy Dose Double-Blind Method Enrollment Glioblastoma Granulocyte-Macrophage Colony-Stimulating Factor Human Humoral Immunities Immune response Immunologics Immunotherapeutic agent In Vitro Inflammatory Intervention Laboratories Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Minor Modality Mus Nature Newly Diagnosed Outcome Patients Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Phase II Clinical Trials Physiologic pulse Placebos Preparation Progression-Free Survivals Public Health Quality of life RNA Radiolabeled Randomized Recovery Research Residual state Safety Serological Serum Site Skin Stimulus System T cell response Tetanus Tetanus Toxoid Therapeutic Transgenic Mice Treatment Efficacy Vaccinated Vaccination Vaccines Validation Viral Antigens Work X-Ray Computed Tomography cancer therapy cell motility chemokine clinical effect clinical efficacy cohort conditioning cytokine editorial effector T cell flu immunogenic immunogenicity improved improved outcome in vivo lymph nodes migration mouse model neoplastic cell novel novel therapeutics patient response pilot trial pre-clinical prospective public health relevance response single photon emission computed tomography survival outcome temozolomide trafficking treatment strategy trial design tumor

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) antigens have been shown by ten independent laboratories to be expressed in a high proportion of malignant gliomas. We have recently completed a phase I clinical trial exploring the safety, immunogenicity, and potential clinical efficacy of autologous pp65 RNA pulsed DC vaccines in patients with newly- diagnosed GBM. This trial explored the capacity to enhance DC migration to vaccine-site draining lymph nodes (VDLNs) using inflammatory skin preparations administered prior to pp65 RNA-loaded DC vaccines in a randomized pilot trial design (n=12 patients). The results of these studies demonstrated the capacity to safely expand CMV-specific cellular and humoral immunity in patients with GBM using autologous RNA-pulsed DC vaccines and demonstrated a strong correlation with successful DC migration to VDLNs and clinical outcomes (R=0.73, P=0.007; Pearson correlation coefficient). Strikingly, patients randomized to receive a tetanus toxoid booster as an inflammatory stimulus at the vaccine-site showed an increased migration of DCs to VDLNs (P=0.04) and a corresponding increased progression-free and overall survival (P=0.01 Logrank analysis). These results suggested that successful DC trafficking in vivo is associated with improved outcomes in patients with GBM receiving pp65 RNA-pulsed DC vaccines and that inflammatory stimuli that enhance DC migration improve the efficacy of this treatment modality. In support of this hypothesis, we found increased levels of chemokines that facilitate DC migration in patients randomized to the tetanus group. Additionally, we have corroborated these findings using a transgenic mouse model employing GFP+ mice to evaluate DC migration. Pp65 RNA-pulsed DCs are a novel and promising therapeutic modality for patients with GBM, and our studies indicate that DC migration to VDLNs constitutes a major biological axis for potential clinical intervention in order to enhance the efficacy of this treatment strategy. In this proposal, we aim to prospectively validate DC migration as a functional biomarker for survival outcomes in a randomized, double-blinded phase 2 clinical trial, and identify serologic mediators of DC migratory activity. Project Description Page 6

描述（由申请方提供）：10个独立实验室已证明人巨细胞病毒（CMV）抗原在高比例的恶性胶质瘤中表达。我们最近完成了一项I期临床试验，探索了自体pp 65 RNA脉冲DC疫苗在新诊断GBM患者中的安全性、免疫原性和潜在临床疗效。该试验探索了在随机初步试验设计（n=12名患者）中使用在pp 65 RNA负载的DC疫苗之前施用的炎性皮肤制剂增强DC迁移至疫苗部位引流淋巴结（VDLN）的能力。这些研究的结果证明了使用自体RNA脉冲的DC疫苗在GBM患者中安全地扩增CMV特异性细胞和体液免疫的能力，并且证明了与成功的DC迁移到VDLN和临床结果的强相关性（R=0.73，P=0.007; Pearson相关系数）。引人注目的是，随机接受破伤风类毒素加强剂作为疫苗部位的炎症刺激的患者显示出DC向VDLN迁移的增加（P=0.04）和相应的无进展生存和总生存的增加（P=0.01对数秩分析）。这些结果表明，成功的DC体内运输与接受pp 65 RNA脉冲DC疫苗的GBM患者的结局改善相关，并且增强DC迁移的炎症刺激改善了这种治疗方式的疗效。为了支持这一假设，我们发现在随机分配到破伤风组的患者中，促进DC迁移的趋化因子水平增加。此外，我们已经证实了这些发现使用转基因小鼠模型采用GFP+小鼠来评估DC迁移。Pp 65 RNA脉冲的DC是GBM患者的一种新的和有前途的治疗方式，我们的研究表明，DC迁移到VDLN构成了潜在的临床干预，以提高这种治疗策略的疗效的主要生物学轴。在这项研究中，我们的目标是前瞻性地验证DC迁移作为一个功能性生物标志物的生存结果在随机，双盲2期临床试验，并确定DC迁移活动的血清学介质。项目描述第6页