Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells
Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells
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DOI：
10.1007/s00262-003-0491-7
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发表时间：
2004-07-01
影响因子：
5.8
通讯作者：
Yamaue, H
中科院分区：
文献类型：
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作者：
Matsuda, K;Tsunoda, T;Yamaue, H
癌胚抗原（CEA）在绝大多数胃肠道肿瘤中强表达。最近，CEA的表位肽被鉴定。我们已经证明了HLA-A24限制性肽CEA 652 [9]（TYACFVSNL）能够引发特异性细胞毒性T淋巴细胞（CTL），其可以裂解表达HLA-A24和CEA的肿瘤细胞。HLA-A24是日本人群中最适用的MHC I类等位基因。在这项初步研究中，我们使用了肽脉冲树突状细胞（DC）从外周血单核细胞（PBMC）补充GM-CSF和IL-4作为疫苗的来源。8例晚期CEA表达胃肠道恶性肿瘤患者每2或3周接受皮下注射。通过ELISpot（酶联免疫吸附斑点）测定进行免疫监测以测量CTL的前体频率及其在体外引发抗肿瘤CTL的能力。7名患者中有4名在接种疫苗后产生了CTL反应。在DC注射部位的8例患者中有1例观察到DTH反应。注射部位皮肤活检显示淋巴细胞浸润。此外，A24/CEA肽四聚体测定揭示了接种疫苗的患者中肽特异性T细胞前体频率的增加。除1例在接种3次疫苗后出现轻度腹泻外，未观察到明显的毒副作用。三名患者在接种疫苗后病情稳定。总之，我们的结果清楚地表明，我们的疫苗接种方案是安全的，并可能在癌症患者中产生CEA特异性CTL应答。
Carcinoembryonic antigen (CEA) is strongly expressed in a vast majority of gastrointestinal carcinomas. Recently, epitope peptides of CEA were identified. We have demonstrated HLA-A24-restricted peptide, CEA652[9] (TYACFVSNL), was capable of eliciting specific cytotoxic T lymphocytes (CTLs) which could lyse tumor cells expressing HLA-A24 and CEA. HLA-A24 is the most applicable MHC class I allele in the Japanese population. In this pilot study, we have used the peptide-pulsed dendritic cells (DCs) generated from peripheral blood mononuclear cells (PBMCs) supplemented with GM-CSF and IL-4 as the source of the vaccine. Eight patients with advanced CEA-expressing gastrointestinal malignancies received subcutaneous injections every 2 or 3 weeks. Immunomonitoring was performed by ELISpot (enzyme-linked immunosorbent spot) assay to measure the precursor frequency of CTLs and their capacity to elicit antitumor CTLs in vitro. Four of seven patients have developed their CTL response after vaccinations. DTH reaction was observed in one of eight patients at the DC-injected site. Skin biopsy at the injected site showed the infiltration of the lymphocytes. Furthermore, A24/CEA peptide tetramer assay revealed an increase in peptide-specific T-cell precursor frequency in vaccinated patients. No significant toxic adverse effects were observed, except for mild diarrhea in one case after three vaccinations. Three patients have shown stabilization of the disease after vaccinations. In conclusion, our results clearly demonstrated that our vaccination protocol was safe and might develop a CEA-specific CTL response in cancer patients.