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

 描述(申请人提供)：十个独立的实验室已经证明人类巨细胞病毒(CMV)抗原在很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，探索自体pp65RNA脉冲DC疫苗在新诊断的GBM患者中的安全性、免疫原性和潜在的临床疗效。这项试验采用随机先导试验设计(n=12名患者)，探讨了在pp65 RNA负载DC疫苗之前使用炎性皮肤制剂增强DC向疫苗部位引流淋巴结(VDLN)迁移的能力。这些研究的结果表明，使用自体核糖核酸冲击的DC疫苗可以安全地扩大基底膜患者的巨细胞病毒特异性细胞和体液免疫，并与DC向VDLN的成功迁移和临床结果密切相关(R=0.73，P=0.007；皮尔森相关系数)。值得注意的是，随机接受破伤风类毒素增强剂作为疫苗部位炎症刺激的患者显示，DC向VDLN迁移增加(P=0.04)，相应地增加了无进展和总存活率(P=0.01 LOGRANK分析)。这些结果表明，在体内成功的DC运输与接受pp65 RNA脉冲DC疫苗的GBM患者的结果改善有关，并且促进DC迁移的炎性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，在随机分为破伤风组的患者中，促进DC迁移的趋化因子水平增加。此外，我们还用转基因小鼠模型证实了这些发现，该模型使用GFP+小鼠来评估DC迁移。Pp65RNA冲击的DC是治疗GBM的一种新的有前景的治疗方法，我们的研究表明DC向VDLN的迁移构成了潜在的临床干预的主要生物学轴，以提高这一治疗策略的有效性。在这项提案中，我们的目标是在一项随机、双盲的2期临床试验中，前瞻性地验证DC迁移作为预测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质。项目说明第6页

 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