Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Cancer Immunol Immunother. 2011 Feb;60(2):249-60. doi: 10.1007/s00262-010-0942-x. Epub 2010 Nov 11.
Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide-MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1(+) melanoma patients were vaccinated intravenously (on average 25 × 10(6) DC) and intradermally (on average 11 × 10(6) DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses.
树突状细胞（DC）为基础的免疫疗法在癌症患者中正在进行全球探索。已经采用了几种策略来负载 DC 抗原，包括肽负载。为了提高肽的免疫原性，可以通过修饰氨基酸序列来提高 MHC Ⅰ类结合亲和力和肽-MHC 复合物在细胞表面的稳定性。在这项研究中，我们比较了负载野生型和具有更高结合亲和力的修饰型 gp100 肽的 DC 的能力，以诱导晚期黑色素瘤患者的免疫和临床反应。转移性 HLA-A2.1(+)黑色素瘤患者接受静脉内（平均 25×10(6)DC）和皮内（平均 11×10(6)DC）接种成熟的负载钥孔血蓝蛋白（KLH）的 DC，以及酪氨酸酶肽和野生型（15 例患者）或修饰型（12 例患者）gp100 肽。所有接种疫苗的患者均对 KLH 表现出明显的增殖性 T 细胞或体液反应。通过四聚体和功能分析在治疗后迟发型超敏反应（DTH）皮肤活检中监测 gp100 特异性 T 细胞反应。在接种野生型 gp100 负载 DC 的 15 例患者中有 2 例，在接种修饰肽负载 DC 的 12 例患者中有 1 例发现了抗原特异性 T 细胞。这三名患者也有最好的临床反应，两名患者均为完全缓解，且缓解时间>8 年。我们得出结论，负载肽的 DC 疫苗接种可导致少数转移性黑色素瘤患者的长期临床反应，并且与野生型 gp100 肽相比，使用修饰型 gp100 肽负载 DC 不会导致相关的增强免疫反应。
