α-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial.
α-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial.
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DOI：
10.1186/1471-2407-12-623
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发表时间：
2012-12-27
期刊：
影响因子：
3.8
通讯作者：
Nakasu Y
中科院分区：
文献类型：
--
作者：
Akiyama Y;Oshita C;Kume A;Iizuka A;Miyata H;Komiyama M;Ashizawa T;Yagoto M;Abe Y;Mitsuya K;Watanabe R;Sugino T;Yamaguchi K;Nakasu Y
包括多形性胶质母细胞瘤（GBM）在内的高级别胶质瘤是最恶性和侵袭性的肿瘤之一，并且尽管使用基于替莫唑胺的强化治疗，但预后非常差。因此，需要一种新的治疗方法来控制复发。在本研究中，我们研究了基于活化树突状细胞（DC）（α-type-1极化DC）的免疫治疗对HLA-A2或A24基因型高级别胶质瘤患者的影响。9例复发性高级别胶质瘤患者（包括7例符合资格标准的GBM患者）入选单核细胞衍生DC免疫治疗的I期研究。HLA-A*0201型1例，A*2402型8例。在第1天使用OptiPrepTM从白细胞分离产品中获得的富集单核细胞与GM-CSF和IL-4在封闭的无血清系统中孵育，并在第6天使用TNF-α、IL-1β、IFN-α、IFN-γ和poly I/C活化。在用限制于HLA-A2或A24和KLH的5种合成肽（WT-1、HER 2、MAGE-A3和MAGE-A1或gp 100）的混合物脉冲后，将细胞冷冻保存直至使用。将解冻的DC以每个队列1.0、2.0和5.0× 107/体的剂量皮内注射到后颈部。CD 14+单核细胞的比例从11.9%增加到44.6%。与细胞因子孵育7天后，患者中被评定为lin-HLA-DR+的DC的平均百分比为56.2 ± 19.1%。大多数DC表达高水平的成熟标记物、共刺激分子和1型表型（CD 11 c +HLA-DR+），DC 1/2比率为35.6。从活化的DC产生的IL-12的量为1025 ± 443 pg/ml/105个细胞。所有76次DC注射均耐受良好，但一过性肝功能障碍II级除外。6例患者在ELISPOT试验中显示对肽的免疫反应阳性，4例患者对肽脉冲DC和KLH的皮肤试验阳性。对DC注射的临床应答如下：1例SD和8例PD。有趣的是，给予24次DC注射的SD患者显示出长期无复发和免疫阳性反应期。这些结果表明，肽混合物处理的活化α-1型DC免疫疗法是一种潜在的治疗工具，主要针对HLA-A*2402复发性高级别胶质瘤。当前非随机研究试验UMIN-CTR UMIN ID：000000914。
High-grade gliomas including glioblastoma multiforme (GBM) are among the most malignant and aggressive of tumors, and have a very poor prognosis despite a temozolomide-based intensive treatment. Therefore, a novel therapeutic approach to controlling recurrence is needed. In the present study, we investigated the effect of activated dendritic cell (DC) (α-type-1 polarized DC)-based immunotherapy on high-grade glioma patients with the HLA-A2 or A24 genotype. Nine patients with recurrent high-grade gliomas including 7 with GBMs who fulfilled eligibility criteria were enrolled into a phase I study of monocyte-derived DC-based immunotherapy. HLA-genotyping revealed 1 case of HLA-A*0201 and 8 cases of A*2402. Enriched monocytes obtained using OptiPrepTM from leukapheresis products on day1, were incubated with GM-CSF and IL-4 in a closed serum-free system, and activated on day6 with TNF-α, IL-1β, IFN-α, IFN-γ, and poly I/C. After pulsing with a cocktail of 5 synthetic peptides (WT-1, HER2, MAGE-A3, and MAGE-A1 or gp100) restricted to HLA-A2 or A24 and KLH, cells were cryopreserved until used. Thawed DCs were injected intradermally in the posterior neck at a dose per cohort of 1.0, 2.0 and 5.0× 107/body. The frequency of CD14+ monocytes increased to 44.6% from 11.9% after gradient centrifugation. After a 7-day-incubation with cytokines, the mean percentage of DCs rated as lin-HLA-DR+ in patients was 56.2 ± 19.1%. Most DCs expressed high levels of maturation markers, co-stimulatory molecules and type-1 phenotype (CD11c+HLA-DR+) with a DC1/2 ratio of 35.6. The amount of IL-12 produced from activated DCs was 1025 ± 443 pg/ml per 105 cells. All 76 DC injections were well tolerated except for transient liver dysfunction with grade II. Six patients showed positive immunological responses to peptides in an ELISPOT assay, and positive skin tests to peptide-pulsed DC and KLH were recognized in 4 cases. The clinical response to DC injections was as follows :1 SD and 8 PD. Interestingly, the SD patient, given 24 DC injections, showed a long-term recurrence-free and immunological positive response period. These results indicate peptide cocktail-treated activated α-type-1 DC-based immunotherapy to be a potential therapeutic tool against recurrent high-grade glioma with mainly HLA-A*2402. Current non-randomized investigational trial UMIN-CTR UMIN ID: 000000914.
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