Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin
Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin
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DOI：
10.1158/1078-0432.ccr-04-0482
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Livingston, PO
中科院分区：
文献类型：
--
作者：
Krug, LM;Ragupathi, G;Livingston, PO
目的：针对细胞表面抗原的免疫治疗可能为根除小细胞肺癌（SCLC）患者的耐药微转移性疾病提供一种新的方法。在SCLC细胞系和人体组织中的研究表明，神经节苷脂岩藻糖基GM 1是一个丰富而特异的靶标。先前的临床研究表明，岩藻糖基GM-1来自牛甲状腺，共轭钥孔血蓝蛋白（KLH）和管理与QS-21 adjuvant.Experimental设计：我们测试了三种不同剂量的岩藻糖基-GM-1的合成版本的免疫原性与SCLC患者的主要反应后，最初的治疗。主要终点是建立能够诱导抗体production.Results的最低有效剂量：五名患者在30-马克杯剂量和三名患者在10-马克杯剂量安装1：80或更高的IgM反应。这些抗体被证实。流式细胞仪检测8例中的7例。在3-mug剂量下，没有患者的滴度超过1：80。一名患者在30 μ g剂量下出现IgG应答，滴度为1：80。从六个的八个应答者的血清诱导有效的补体介导的细胞毒性的肿瘤cytokes.Conclusions：与合成的岩藻糖基GM 1-KLH缀合物的疫苗接种诱导IgM抗体反应岩藻糖基GM 1和表达facosyl GM 1的肿瘤细胞，与牛衍生物诱导的反应。我们计划将30 μ g剂量的联合收割机合成法可西GM 1疫苗与针对其他三种抗原--GM 2、Globo H和聚唾液酸的疫苗联合使用，以在初始化疗后的SCLC患者中进行测试。
Purpose: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicify of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant.Experimental Design: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production.Results: Five of six patients at the 30-mug dose and three of five patients at the 10-mug dose mounted lgM responses of 1:80 or greater. These antibodies were confirmed by. flow cytometry in seven of eight cases. None of the patients at the 3-mug dose had titers above 1:80. One patient at the 30-mug dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complementmediated cytotoxicity of tumor cells.Conclusions: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing facosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic facosyl GMI vaccine at a dose of 30 mug with vaccines against three other antigens-GM2, Globo H, and polysialic acid-to test in patients with SCLC after initial chemotherapy.