Kirkwood John M, Lee Sandra, Moschos Stergios J, Albertini Mark R, Michalak John C, Sander Cindy, Whiteside Theresa, Butterfield Lisa H, Weiner Louis
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2584, USA.
Clin Cancer Res. 2009 Feb 15;15(4):1443-51. doi: 10.1158/1078-0432.CCR-08-1231.
No therapy has ever shown prolongation of survival in stage IV metastatic melanoma. The association of cytokine-induced autoimmunity with improved prognosis led us to investigate the effect of multi-epitope melanoma vaccines alone and in combination with cytokines in this Eastern Cooperative Oncology Group multicenter phase II trial.
Eligible patients were required to have failed prior therapies and to be HLA-A2 positive. Three HLA class I-restricted lineage antigen epitopes were administered in a factorial 2x2 design. Peptide vaccine alone (arm A), or combined with granulocyte-monocyte colony-stimulating factor (GM-CSF; Immunex) 250 microg/d subcutaneously for 14 of 28 days each month (arm B), or combined with IFN-alpha2b (Intron A; Schering-Plough) 10 million units/m2 three times a week (arm C), or combined with both IFN-alpha2b and GM-CSF (arm D). The primary endpoint was immune response measured by enzyme-linked immunospot assay; secondary endpoints were clinical antitumor response, disease-free survival, and overall survival.
One hundred twenty patients enrolled and 115 patients were analyzed. Immune responses to at least one melanoma antigen were observed in 26 of 75 (35%) patients with serial samples. Neither IFN-alpha2b nor GM-CSF significantly improved immune responses. Six objective clinical responses were documented. At a median follow-up of 25.4 months, the median overall survival of patients with vaccine immune response was significantly longer than that of patients with no immune response (21.3 versus 13.4 months; P=0.046).
Immune response to vaccination correlates with prolonged survival in patients with metastatic melanoma and is not enhanced by immunomodulatory cytokines as tested in this trial.
既往尚无治疗手段可延长IV期转移性黑色素瘤患者的生存期。细胞因子诱导的自身免疫与预后改善之间的关联促使我们在东部肿瘤协作组的这项多中心II期试验中，研究多表位黑色素瘤疫苗单独使用以及与细胞因子联合使用的效果。
符合条件的患者需先前治疗失败且为HLA - A2阳性。采用析因2×2设计给予三种HLA I类限制性谱系抗原表位。单独使用肽疫苗（A组），或与粒细胞 - 单核细胞集落刺激因子（GM - CSF；Immunex）联合使用，每月皮下注射250μg/d，共28天中的14天（B组），或与干扰素 - α2b（Intron A；先灵葆雅）联合使用，每周三次，每次1000万单位/m²（C组），或与干扰素 - α2b和GM - CSF两者联合使用（D组）。主要终点是通过酶联免疫斑点试验测量的免疫反应；次要终点是临床抗肿瘤反应、无病生存期和总生存期。
120例患者入组，115例患者接受分析。在75例有系列样本的患者中，26例（35%）观察到对至少一种黑色素瘤抗原的免疫反应。干扰素 - α2b和GM - CSF均未显著改善免疫反应。记录到6例客观临床反应。在中位随访25.4个月时，有疫苗免疫反应的患者的中位总生存期显著长于无免疫反应的患者（21.3个月对13.4个月；P = 0.046）。
在转移性黑色素瘤患者中，对疫苗的免疫反应与生存期延长相关，且如本试验所测试，免疫调节细胞因子并不能增强这种反应。
