A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer
A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer
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DOI：
10.1158/1078-0432.ccr-04-1453
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发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Fujisawa, T
中科院分区：
文献类型：
--
作者：
Ishikawa, A;Motohashi, S;Fujisawa, T
目的：携带不变的 Valpha24JalphaQ 抗原受体的人 Valpha24 自然杀伤 T (NKT) 细胞（鼠 Valpha14 NKT 细胞的对应物）被特定配体 α-半乳糖基酰胺 (alphaGalCer, KRN7000) 以 CD1d 依赖性方式激活。 1.v.给予 otGalCer 脉冲的树突状细胞 (DC) 会诱导肺部 Valpha14 NKT 细胞的显着激活和扩增，从而在小鼠肿瘤转移模型中产生有效的抗肿瘤活性。我们在肺癌患者中使用 αGalCer 脉冲 DC 进行了一项 I 期剂量递增研究。实验设计：患有晚期非小细胞肺癌或复发性肺癌的患者接受静脉注射。注射 alphaGalCer 拉制的 DC（1 级：5 x 10(7)/m(2)；2 级：2.5 x 10(8)/m(2)；3 级：1 X 10(9)/m(2)）以测试安全性、可行性和临床反应。所有已完成的病例均进行了免疫监测。结果：11 名患者参加了本研究。在本研究期间，没有在任何患者中观察到严重的不良事件。在第一次和第二次注射 alphaGalCerpulsed DC 后，在一个病例中观察到外周血 Valpha24 NKT 细胞急剧增加，在接受 3 级剂量的两个病例中观察到显着反应。没有发现患者符合部分或完全缓解的标准，而 3 级组中的 2 例患者在一年多的时间里没有变化，生活质量良好。结论：在这项临床试验中，αGalCer 脉冲 DC 给药耐受性良好，即使在晚期疾病患者中也可以安全地进行。
Purpose: Human Valpha24 natural killer T (NKT) cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-galactosyleeramide (alphaGalCer, KRN7000), in a CD1d-dependent manner. 1.v. administration of otGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Valpha14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with alphaGalCer-pulsed DCs in lung cancer patients.Experimental Design: Patients with advanced non-small cell lung cancer or recurrent lung cancer received i.v. injections of alphaGalCer-pullsed DCs (level 1: 5 x 10(7)/m(2); level 2: 2.5 x 10(8)/m(2); and level 3: 1 X 10(9)/m(2)) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases.Results: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of alphaGalCerpulsed DCs, dramatic increase in peripheral blood Valpha24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life.Conclusions: In this clinical trial, alphaGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.