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（应用程序提供）：十个独立的实验室已显示出人类巨细胞病毒（CMV）抗原，以高比例的恶性神经胶质瘤表达。我们最近完成了一项I期临床试验，该试验探讨了新诊断的GBM患者的自体PP65 RNA脉冲DC疫苗的安全性，免疫原性和潜在的临床效率。该试验探讨了在随机试验试验设计中使用PP65 RNA负载的DC疫苗之前给予的炎症皮肤制剂，以增强直流迁移到疫苗位置排水淋巴结（VDLN）的能力（n = 12患者）。这些研究的结果表明，使用自体RNA脉冲DC疫苗在GBM患者中安全扩展CMV特异性细胞和体液免疫学的能力与成功的DC迁移到VDLN和临床结果（r = 0.73，P = 0.007; Pearson coreff coreff coreff coreff coreff and vdLN和临床结果）具有很强的相关性。令人惊讶的是，在疫苗部位，随机将其作为炎症刺激的患者随机接受毒素促进性，表明DC迁移到VDLN（p = 0.04），并且相应的无进展和总生存率增加（P = 0.01 Logrank分析）。这些结果表明，在体内成功运输的DC运输与接受PP65 RNA脉冲脉冲DC疫苗的GBM患者的预后改善有关，并且增强DC迁移的炎症刺激提高了这种治疗方式的效率。为了支持这一假设，我们发现趋化因子的水平增加，这些趋化因子促进了随机分为Tetanius组的患者的直流迁移。此外，我们使用使用GFP+小鼠评估DC迁移的转基因小鼠模型证实了这些发现。 PP65 RNA脉冲DC是针对GBM患者的一种新颖且承诺的治疗方式，我们的研究表明，DC迁移到VDLNS构成了潜在的临床干预措施的主要生物轴，以增强该治疗策略的有效性。在该提案中，我们旨在在随机的，双盲阶段2临床试验中前瞻性地验证DC迁移作为生存结果的功能生物标志物，并确定DC迁移活性的血清学介体。项目说明第6页