Perales Miguel-Angel, Yuan Jianda, Powel Sarah, Gallardo Humilidad F, Rasalan Teresa S, Gonzalez Christina, Manukian Gregor, Wang Jian, Zhang Yan, Chapman Paul B, Krown Susan E, Livingston Philip O, Ejadi Samuel, Panageas Katherine S, Engelhorn Manuel E, Terzulli Stephanie L, Houghton Alan N, Wolchok Jedd D
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mol Ther. 2008 Dec;16(12):2022-9. doi: 10.1038/mt.2008.196. Epub 2008 Sep 16.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances immune responses by inducing proliferation, maturation, and migration of dendritic cells (DCs) as well as expansion and differentiation of B and T lymphocytes. The potency of DNA vaccines can be enhanced by the addition of DNA encoding cytokines, acting as molecular adjuvants. We conducted a phase I/II trial of human GM-CSF DNA in conjunction with a multipeptide vaccine (gp100 and tyrosinase) in stage III/IV melanoma patients. Nineteen human leukocyte antigen (HLA)-A*0201+ patients were treated. Three dose levels were studied: 100, 400, and 800 microg DNA/injection, administered subcutaneously every month with 500 microg of each peptide. In the dose-ranging study, three patients were treated at each dose level. The remaining patients were then treated at the highest dose. Most toxicities were grade 1 injection-site reactions. Eight patients (42%) developed CD8+ T-cell responses, defined by a > or =3 SD increase in baseline reactivity to tyrosinase or gp100 peptide in tetramer or intracellular cytokine staining (ICS) assays. There was no relationship between dose and T-cell response. Responding T cells had an effector memory cell phenotype. Polyfunctional T cells were also demonstrated. At a median of 31 months follow-up, median survival has not been reached. Human GM-CSF DNA was found to be a safe adjuvant.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过诱导树突状细胞（DC）的增殖、成熟和迁移以及B淋巴细胞和T淋巴细胞的扩增和分化来增强免疫反应。DNA疫苗的效力可通过添加编码细胞因子的DNA来增强，这些细胞因子起到分子佐剂的作用。我们对III/IV期黑色素瘤患者进行了一项人GM-CSF DNA与多肽疫苗（gp100和酪氨酸酶）联合使用的I/II期试验。19名人类白细胞抗原（HLA）-A*0201+患者接受了治疗。研究了三个剂量水平：100、400和800微克DNA/注射，每月皮下注射，每种肽500微克。在剂量范围研究中，每个剂量水平治疗3名患者。其余患者随后接受最高剂量治疗。大多数毒性为1级注射部位反应。8名患者（42%）出现了CD8+T细胞反应，在四聚体或细胞内细胞因子染色（ICS）试验中，对酪氨酸酶或gp100肽的基线反应性增加≥3标准差即定义为出现该反应。剂量与T细胞反应之间没有关系。反应性T细胞具有效应记忆细胞表型。还证实了多功能T细胞。在中位随访31个月时，尚未达到中位生存期。发现人GM-CSF DNA是一种安全的佐剂。
