Phase I Study of Multiple Epitope Peptide Vaccination in Patients With Recurrent or Persistent Cervical Cancer
Phase I Study of Multiple Epitope Peptide Vaccination in Patients With Recurrent or Persistent Cervical Cancer
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DOI：
10.1097/cji.0000000000000214
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发表时间：
2018-05-01
影响因子：
3.9
通讯作者：
Fujiwara, Keiichi
中科院分区：
文献类型：
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作者：
Hasegawa, Kosei;Ikeda, Yuji;Fujiwara, Keiichi
癌症免疫疗法现已被确立为癌症患者子集的领先标准治疗选择。在这项研究中，我们进行了一项I期剂量递增试验，使用5种肽的混合物给宫颈癌患者接种HLA-A*2402。主要终点是安全性和推荐疫苗剂量的确定，次要终点是免疫应答和临床疗效的评价。所有患者都有复发性或持续性疾病，对既往标准化疗无效或不耐受。在3名患者队列设计中，向9名患者施用源自叉头盒蛋白M1（FOXM 1）、母体胚胎亮氨酸拉链激酶（MELK）、霍利迪连接识别蛋白和血管内皮生长因子受体1和2的肽，剂量为0.5、1或2 mg的每种单独的肽与不完全弗氏佐剂的混合物。主要不良事件为贫血和注射部位反应，发生率分别为77.8%（7/9）和66.7%（6/9）。在1例患者中观察到3级贫血。未观察到疫苗的剂量限制性毒性。7例（78%）患者病情稳定，中位无进展生存期为3.3个月（102天）。5种抗原的干扰素-酶联免疫斑点试验显示，分别有8名（89%）和7名（78%）患者对FOXM 1和MELK具有高T细胞应答。总之，我们证明了这种5肽疫苗是可耐受的，并且FOXM 1和MELK可能是宫颈癌患者免疫治疗的有希望的靶点。
Cancer immunotherapy has now been established as a leading standard therapeutic option in a subset of patients with cancer. In this study, we conducted a phase I dose-escalation trial using a mixture of 5 peptides to vaccinate cervical cancer patients with HLA-A*2402. The primary endpoints were safety and determination of a recommended vaccine dose, and the secondary endpoints were evaluations of immunologic responses and clinical efficacy. All patients had recurrent or persistent disease and had failed to respond to or were intolerant to prior standard chemotherapy. Peptides derived from forkhead box protein M1 (FOXM1), maternal embryonic leucine zipper kinase (MELK), Holliday junction-recognition protein, and vascular endothelial growth factor receptors 1 and 2 were administered to 9 patients in a 3 patient-cohort design, with doses of 0.5, 1, or 2mg of each of the individual peptides in a mixture with incomplete Freund's adjuvant. The major adverse events were anemia and injection site reactions, which were seen in 77.8% (7/9) and 66.7% (6/9) of patients, respectively. Grade 3 anemia was observed in 1 patient. No dose-limiting toxicity of the vaccine was observed. Seven (78%) patients achieved stable disease, and the median progression-free survival was 3.3 months (102d). Interferon- enzyme-linked immunospot assays for each of the 5 antigens showed that 8 (89%) and 7 (78%) patients had high T-cell responses to FOXM1 and MELK, respectively. In conclusion, we demonstrated that this 5-peptide vaccine was tolerable, and that FOXM1 and MELK could be promising targets for immunotherapy in patients with cervical cancer.