Induction of CD8+ T-Cell Responses Against Novel Glioma-Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma
Induction of CD8+ T-Cell Responses Against Novel Glioma-Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma
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DOI：
10.1200/jco.2010.30.7744
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发表时间：
2011-01-20
影响因子：
45.3
通讯作者：
Lieberman, Frank S.
中科院分区：
文献类型：
--
作者：
Okada, Hideho;Kalinski, Pawel;Lieberman, Frank S.
目的进行 I/II 期试验，以评估新型疫苗接种的安全性和免疫原性，该疫苗使用装载有神经胶质瘤相关抗原 (GAA) 表位的合成肽的 α-1 型极化树突状细胞 (α DC1)，并施用由赖氨酸和稳定的聚肌苷-聚胞苷酸 [poly(I:C)]。 羧甲基纤维素（聚-ICLC）治疗复发性恶性神经胶质瘤的 HLA-A2（+）患者。这些肽的 GAA 为 EphA2、白介素 (IL)-13 受体-α 2、YKL-40 和 gp100。 患者和方法 22 名患者（13 名多形性胶质母细胞瘤 [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 名间变性少突胶质细胞瘤患者） 少突星形细胞瘤 [AOA]）接受了至少一次疫苗接种，19 名患者以 2 周的间隔在结内接受了至少 4 次疫苗接种，剂量为 2 α DC1 剂量水平（1 x 或 3 x 10(7)/剂）。患者还接受每周两次20μg/kg聚-ICLC肌肉注射。表现出阳性放射学反应或疾病稳定且无重大不良事件的患者被允许接受加强疫苗。通过酶联免疫吸附斑点和 HLA 四聚体测定评估 T 淋巴细胞针对 GAA 表位的反应。结果该方案耐受性良好。前四种疫苗在 58% 的患者中诱导了针对外周血单核细胞中至少一种疫苗接种目标 GAA 的阳性免疫反应。外周血样本显示 1 型细胞因子和趋化因子（包括干扰素-α 和 CXCL10）显着上调。 9 例（4 例 GBM、2 例 AA、2 例 AO 和 1 例 AOA）达到持续至少 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。 α DC1 产生的 IL-12 水平与进展时间呈正相关。 结论 这些数据支持基于聚 ICLC 增强的 α DC1 疫苗的安全性、免疫原性和初步临床活性。
PurposeA phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with alpha-type 1 polarized dendritic cells (alpha DC1) 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-alpha 2, YKL-40, and gp100.Patients and MethodsTwenty-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 alpha DC1 dose levels (1 x or 3 x 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 mu g/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.ResultsThe 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-alpha 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 alpha DC1 positively correlated with time to progression.Conclusion These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted alpha DC1-based vaccines.