Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma.
Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma.
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2009
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通讯作者：
Jianda Yuan;G. Ku;H. Gallardo;F. Orlandi;G. Manukian;T. Rasalan;Yinyan Xu;Hao-Kang Li;S. Vyas;Z. Mu;P. Chapman;S. Krown;K. Panageas;S. Terzulli;L. Old;A. Houghton;J. Wolchok
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作者：
Jianda Yuan;G. Ku;H. Gallardo;F. Orlandi;G. Manukian;T. Rasalan;Yinyan Xu;Hao-Kang Li;S. Vyas;Z. Mu;P. Chapman;S. Krown;K. Panageas;S. Terzulli;L. Old;A. Houghton;J. Wolchok
Gp100是黑色素瘤细胞常见表达的分化抗原，是T细胞侵袭的靶点。我们对黑色素瘤患者进行了I期随机交叉试验，分别以三种剂量(100、500或1500微克)肌肉注射异种(小鼠)或人gp100质粒DNA，共三次。在前三次注射后，患者接受了来自其他物种的gp100免疫三次。用多参数流式细胞仪分析gp100多肽培养10d后不同时间点的外周血标本。共有19名患者入选，其中18名患者的免疫功能和生存期可评估。14例(74%)为男性，中位年龄56岁(20-82岁)。所有患者均无疾病迹象；10例(53%)为III期疾病，3例(16%)为IIB和IV期疾病，2例(11%)为脉络膜病变，1例(5%)为肛门黏膜受累。中位随访时间为30个月，中位无进展生存(PFS)为44个月。未达到中位存活率。无3/4级毒性；最常见的1/2级毒性是12例患者的注射部位反应(63%，均为1级)。5例患者出现CD8+细胞结合gp100(280-288)人类白细胞抗原A2限制性四聚体。1例患者CD8+干扰素-γ+细胞增多。这种异种免疫策略是安全的，毒性最小。也有免疫反应的证据。
A differentiation antigen commonly expressed on melanoma cells, gp100 is the target of infiltrating T cells. We conducted a phase I randomized cross-over trial of melanoma patients with either xenogeneic (mouse) or human gp100 plasmid DNA injected intramuscularly at three dosages (100, 500 or 1,500 microg) every three weeks for three doses. After the first three injections, patients were then immunized three times with gp100 from the other species. Peripheral blood samples were analyzed at various time points following 10-day culture with gp100 peptides using multi-parametric flow cytometry. A total of 19 patients were enrolled, with 18 assessable for immune function and survival. 14 (74%) were male, with a median age of 56 years (range, 20-82). All patients had no evidence of disease; 10 (53%) had stage III disease, 3 each (16%) had stage IIB and IV disease, 2 (11%) had choroidal and 1 (5%) had anal mucosal involvement. With a median follow-up of 30 months, median progression-free survival (PFS) is 44 months. Median survival is not reached. There was no grade 3/4 toxicity; the most common grade 1/2 toxicity was an injection site reaction in 12 patients (63%, all grade 1). Five patients developed CD8+ cells binding gp100(280-288) HLA-A2-restricted tetramer. One patient had an increase in CD8+ IFN-gamma+ cells. This xenogeneic immunization strategy was safe and associated with minimal toxicity. There was also evidence of immune response.