G12.a Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213-1863, USA.
J Clin Oncol. 2011 Jan 20;29(3):330-6. doi: 10.1200/JCO.2010.30.7744. Epub 2010 Dec 13.
A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100.
Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays.
The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression.
These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.
一项 I/II 期临床试验旨在评估新型 α 型 1 极化树突状细胞 (αDC1) 疫苗接种的安全性和免疫原性，该疫苗接种使用载有针对神经胶质瘤相关抗原 (GAA) 表位的合成肽和聚肌苷酸-聚胞苷酸 [poly(I:C)] 与赖氨酸和羧甲基纤维素稳定物 (poly-ICLC)，用于 HLA-A2(+) 复发性恶性神经胶质瘤患者。这些肽的 GAA 是 EphA2、白细胞介素 (IL)-13 受体-α2、YKL-40 和 gp100。
22 名患者（13 名胶质母细胞瘤 [GBM]、5 名间变性星形细胞瘤 [AA]、3 名间变性少突胶质细胞瘤 [AO] 和 1 名间变性少突星形细胞瘤 [AOA]）至少接受了一次疫苗接种，19 名患者在 2 周间隔内接受了两种 αDC1 剂量水平（1×或 3×10(7)/剂量）的至少四次疫苗接种。患者还每周两次接受 20μg/kg poly-ICLC 肌内注射。显示出阳性影像学反应或无重大不良事件的稳定疾病的患者允许接受增强疫苗。通过酶联免疫斑点和 HLA 四聚体测定评估针对 GAA 表位的 T 淋巴细胞反应。
该方案耐受性良好。在前四次疫苗接种中，58%的患者外周血单核细胞中针对至少一种疫苗接种靶向 GAA 产生了阳性免疫反应。外周血样本显示出 1 型细胞因子和趋化因子的显著上调，包括干扰素-α和 CXCL10。9 名（4 名 GBM、2 名 AA、2 名 AO 和 1 名 AOA）实现了至少 12 个月的无进展状态。一名复发性 GBM 患者表现出持续的完全缓解。αDC1 产生的 IL-12 水平与进展时间呈正相关。
这些数据支持 poly-ICLC 增强的基于 αDC1 的疫苗的安全性、免疫原性和初步临床活性。
