Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides
Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides
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DOI：
10.1097/cji.0b013e318133451c
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发表时间：
2007-10-01
影响因子：
3.9
通讯作者：
Fong, Lawrence
中科院分区：
文献类型：
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作者：
Kavanagh, Brian;Ko, Andrew;Fong, Lawrence
开发一种产生适用于多中心试验的树突状细胞（DC）的方法将有助于癌症疫苗的开发。此外，用这种疫苗策略靶向多种抗原可以增强这种治疗方法的功效。我们进行了一项1/2期临床试验，向晚期结直肠癌（CRC）患者施用靶向多种肿瘤相关抗原的DC疫苗。使用经鉴定的生产工艺，使用粒细胞巨噬细胞集落刺激因子和IL-13从血液单核细胞生成DC，并使用克雷伯氏菌衍生的细胞壁组分和干扰素-γ（IFN-γ）成熟6小时。DC还负载有源自癌胚抗原（CEA）、法师和HER 2/neu的6种HLA-A*0201结合肽，以及钥孔血蓝蛋白和泛DR表位肽。每3周皮内给予4次计划剂量的35 x 10（6）个细胞。通过IFN-γ酶联免疫吸附斑点（ELISPOT）评估免疫应答。成熟的DC具有活化的表型，可以在体外引发T细胞。在该试验中，21名HLA-A2 +患者接受了单采，13名接受了疫苗治疗，I I患者可进行评估。未报告显著的给药相关毒性。在3例患者中通过ELISPOT检测对CEA衍生肽的T细胞应答。CEA诱导的T细胞具有高亲和力的T细胞受体。体外再刺激后的ELISPOT检测到2例患者对多种肽的应答。所有患者均显示疾病进展。在晚期CRC患者中的这项初步研究表明，DC产生的粒细胞巨噬细胞集落刺激因子和IL-13与克雷伯氏菌衍生的细胞壁组分和IFN-γ一起成熟，可以诱导晚期CRC患者对多种肿瘤相关抗原的免疫应答。
Developing a process to generate dendritic cells (DCs) applicable for multicenter trials would facilitate cancer vaccine development. Moreover, targeting multiple antigens with such a vaccine strategy could enhance the efficacy of such a treatment approach. We performed a phase 1/2 clinical trial administering a DC-based vaccine targeting multiple tumor-associated antigens to patients with advanced colorectal cancer (CRC). A qualified manufacturing process was used to generate DC from blood monocytes using granulocyte macrophage colony-stimulating factor and IL-13, and matured for 6 hours with Klebsiella-derived cell wall fraction and interferon-gamma (IFN-gamma). DCs were also loaded with 6 HLA-A*0201 binding peptides derived from carcinoembryonic antigen (CEA), MAGE, and HER2/neu, as well as keyhole limpet hemocyanin protein and pan-DR epitope peptide. Four planned doses of 35 x 10(6) cells were administered intradermally every 3 weeks. Immune response was assessed by IFN-gamma enzyme-linked immunosorbent spot (ELISPOT). Matured DC possessed an activated phenotype and could prime T cells in vitro. In the trial, 21 HLA-A2 + patients were apheresed, 13 were treated with the vaccine, and I I patients were evaluable. No significant treatment-related toxicity was reported. T-cell responses to a CEA-derived peptide were detected by ELISPOT in 3 patients. T cells induced to CEA possessed high avidity T-cell receptors. ELISPOT after in vitro restimulation detected responses to multiple peptides in 2 patients. All patients showed progressive disease. This pilot study in advanced CRC patients demonstrates DC-generated granulocyte macrophage colony-stimulating factor and IL-13 matured with Klebsiella-derived cell wall fraction and IFN-gamma can induce immune responses to multiple tumor-associated antigens in patients with advanced CRC.