PDF(Pubmed)
Abstract：
In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.
摘要：
在这项随机II期临床试验中，我们评估了添加TLR激动剂的有效性，聚-ICLC或瑞喹莫特，对新诊断或复发的WHOIII-IV级恶性神经胶质瘤患者进行自体肿瘤裂解物脉冲树突状细胞（ATL-DC）疫苗接种。主要终点是评估疫苗和佐剂的最有效组合，以增强免疫效力，还有安全。ATL-DC疫苗和TLR激动剂的组合是安全的，并且发现可以增强全身免疫反应。如干扰素基因表达增加和免疫细胞活化变化所示。具体来说,PD-1表达在CD4+T细胞上增加，而CD38和CD39在CD8+T细胞上的表达减少，伴随着单核细胞的增加。Poly-ICLC处理放大了单核细胞和T淋巴细胞中干扰素诱导的基因的诱导。表现出较高干扰素应答基因表达的患者表现出延长的生存期和延迟的疾病进展。这些发现表明，ATL-DC与poly-ICLC的结合可以诱导循环单核细胞和CD8+T细胞的极化干扰素应答，这可能是该患者人群中免疫疗法的重要血液生物标志物。试用注册：ClinicalTrials.gov标识符：NCT01204684。
