Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Oncol Rep. 2013 Mar;29(3):951-9. doi: 10.3892/or.2013.2231. Epub 2013 Jan 10.
Recently, analysis of tumor antigens using micro-arrays has revealed upregulation of cancer-testis antigens RNF43 and TOMM34 and vascular endothelial growth factor receptors VEGFR1 and VEGFR2 in colorectal cancer. A phase I clinical trial of peptide vaccine therapy together with oral anticancer drugs was conducted to treat advanced colorectal cancer using synthesized peptides of these tumor antigens in order to confirm the safety, immunogenicity and activity of this treatment. The subjects were patients with a human leukocyte antigen (HLA) type of A2402 who had inoperable colorectal cancer but had failed to respond to or were unable to undergo standard chemotherapy. Four peptides (RNF43, TOMM34, VEGFR1 and VEGFR2) were emulsified with incomplete Freund's adjuvant (Montanide), and the resulting solution was administered subcutaneously once a week. Patients received the oral anticancer drug tegafur-uracil plus leucovorin for four weeks continuously as part of one course followed by one week of rest. The primary endpoint of the trial was observation of adverse events as determined by the NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the number of cytotoxic T lymphocytes (CTLs) in the peripheral blood after treatment. Vaccine therapy was administered 148 times to 10 patients from July 2008 to December 2009. The adverse events were grade 1 redness and induration, a grade 2 skin ulcer at the vaccination site and grade 1 pyrexia. All patients tolerated treatment. Tumor imaging revealed that after 1 course of treatment 1 patient had partial response (PR), 7 had stable disease (SD) and 2 had progressive disease. A CTL assay of 10 patients revealed an increase in peptide-specific CTLs in patients with PR and SD, and the clinical responses of those patients were observed. Kaplan‑Meier analysis indicated that patients who had a strong CTL reaction had a tendency to have longer progression‑free survival and overall survival.
最近，利用微阵列对肿瘤抗原进行分析显示，结直肠癌中癌症睾丸抗原 RNF43 和 TOMM34 以及血管内皮生长因子受体 VEGFR1 和 VEGFR2 上调。为了确认这种治疗的安全性、免疫原性和活性，进行了一项使用这些肿瘤抗原合成肽的肽疫苗治疗联合口服抗癌药物的 I 期临床试验，以治疗晚期结直肠癌。该试验的受试者是 HLA-A2402 型的无法手术的结直肠癌患者，但对标准化疗无反应或无法接受。将四种肽（RNF43、TOMM34、VEGFR1 和 VEGFR2）与不完全弗氏佐剂（Montanide）乳化，每周一次皮下给药。患者接受替加氟-尿嘧啶加亚叶酸连续四周作为一个疗程，然后休息一周。该试验的主要终点是根据 NCI-CTCAE 标准观察不良事件，次要终点是治疗后外周血中肿瘤的大小和细胞毒性 T 淋巴细胞（CTL）的数量。2008 年 7 月至 2009 年 12 月，对 10 名患者进行了 148 次疫苗治疗。不良事件为 1 级发红和硬结、接种部位 2 级皮肤溃疡和 1 级发热。所有患者均耐受治疗。肿瘤成像显示，在 1 个疗程后，1 名患者有部分缓解（PR），7 名患者有稳定疾病（SD），2 名患者有进展性疾病。对 10 名患者的 CTL 检测显示 PR 和 SD 患者的肽特异性 CTL 增加，观察到这些患者的临床反应。Kaplan-Meier 分析表明，具有强烈 CTL 反应的患者无进展生存期和总生存期延长的趋势。
