Mayanagi Shuhei, Kitago Minoru, Sakurai Toshiharu, Matsuda Tatsuo, Fujita Tomonobu, Higuchi Hajime, Taguchi Junichi, Takeuchi Hiroya, Itano Osamu, Aiura Koichi, Hamamoto Yasuo, Takaishi Hiromasa, Okamoto Masato, Sunamura Makoto, Kawakami Yutaka, Kitagawa Yuko
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Cancer Sci. 2015 Apr;106(4):397-406. doi: 10.1111/cas.12621. Epub 2015 Mar 9.
This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).
本研究旨在评估在晚期胰腺癌患者中，将威尔姆斯瘤基因1（WT1）肽脉冲树突状细胞疫苗联合吉西他滨（DCGEM）作为一线治疗的可行性及免疫反应。10例HLA - A*2402患者在第8天和第22天接受WT1肽脉冲树突状细胞疫苗接种（1×10⁷个细胞），并在第1天、第8天和第15天接受吉西他滨（1000mg/m²）治疗。使用迟发型超敏反应（DTH）皮肤试验、干扰素 - γ酶联免疫斑点试验和HLA四聚体分析以及各种免疫因子分析来评估WT1特异性免疫反应的诱导情况。DCGEM耐受性良好，吉西他滨的相对剂量强度为87%。在所有3例DTH阳性患者中均观察到与低中性粒细胞/淋巴细胞比值相关的疾病控制；这也与预处理外周血中粒细胞性髓源性抑制细胞的低百分比相关（P = 0.017）。有肝转移且炎症标志物如C反应蛋白和白细胞介素 - 8（IL - 8）水平高的患者，即使诱导出了WT1特异性免疫反应，其生存期也较差。WT1肽脉冲DCGEM在诱导抗肿瘤T细胞反应方面是可行且有效的。我们的结果支持对非肝转移且免疫条件良好的胰腺癌患者进行进一步研究。本试验已在大学医院医学信息网络（UMIN）临床试验注册中心注册（http://www.umin.ac.jp/ctr/编号：UMIN - 000004855）。
