Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan.
J Transl Med. 2014 Mar 10;12:63. doi: 10.1186/1479-5876-12-63.
To evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor-II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.
Eighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund's adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of "the cocktail of 5 peptides" on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks.
The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of "peptides cocktail" did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032).
Our cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.
UMIN-CTR number UMIN000004948.
为评估多种肽联合疫苗治疗的安全性，对 18 例标准治疗失败的 HLA-A2402 阳性晚期结直肠癌患者进行了 I 期临床试验，使用了 5 种新型 HLA-A2402 限制性肽，3 种来自癌抗原的肽，环指蛋白 43（RNF43）、34 kDa 外线粒体膜转位酶（TOMM34）和胰岛素样生长因子-II mRNA 结合蛋白 3（KOC1），其余 2 种来自血管生成因子，血管内皮生长因子受体 1（VEGFR1）和 VEGFR2。
将 18 例 HLA-A*2402 阳性的标准治疗失败的结直肠癌患者纳入本研究。将每种 0.5mg、1.0mg 或 3.0mg 的肽与不完全弗氏佐剂混合，然后每周一次皮下注射于 5 个分开的部位。我们还检查了单点注射“5 肽鸡尾酒”对免疫反应的可能影响。ELISPOT 检测在每 4 周的方案中于接种前后进行。
使用多种肽的疫苗治疗耐受性良好，无任何严重的治疗相关全身不良事件。观察到剂量依赖性诱导的肽特异性细胞毒性 T 淋巴细胞。单点注射“肽鸡尾酒”不会降低免疫反应。关于临床结果，1 例患者达到完全缓解，6 例患者稳定疾病 4 至 7 个月。中位总生存期（MST）为 13.5 个月。检测到 3 种或 3 种以上肽特异性细胞毒性 T 淋巴细胞的患者预后明显更好（MST：27.8 个月），而免疫反应较差的患者（MST：3.7 个月）（p=0.032）。
我们使用多种肽的癌症疫苗治疗对晚期结直肠癌是一种有前途的方法，具有最小的全身不良反应风险。
UMIN-CTR 编号 UMIN000004948。
