Combination therapy with immunotherapy and chemotherapy for pancreatic cancer. -Aim at the standardization of clinical trial for immuno-chemotherapy-

在这个项目中，我们试图寻找免疫治疗和化疗联合治疗胰腺癌的临床有效治疗方法。我们在本项目期间报告了MUC1肽疫苗接种和个性化肽疫苗接种的两项I期试验。我们给9名患者接种了300、1000或3000毫克的105个氨基酸的MUC1肽。除接种部位出现轻度红肿外，无不良事件发生。在符合临床评价条件的8例患者中，7例病情进展，1例病情稳定，接种疫苗后循环抗muc1 IgG抗体有升高趋势。其次，我们将另一项I期研究应用于11名胰腺癌患者的个性化肽疫苗接种。即，在体外筛选预接种的外周血单个核细胞对HLA-A24^+或-A2^+患者的14或16种候选肽的反应性，然后仅在体内接种反应性肽。该方案总体耐受性良好，无血液学毒性，尽管在7例患者中观察到注射部位的炎症反应。在8名患者中的4名和10名患者中的4名接种后的pbmc和血清中，分别观察到对用于疫苗接种的至少一种肽的细胞和体液免疫反应增加。接种3次以上疫苗（n=10）的患者的6个月和12个月生存率分别为80%和20%。在两个I期研究的基础上，我们开展了一项使用GEM进行个性化肽免疫治疗和化疗联合治疗胰腺癌的I期试验。我们给13名患者接种了1、2或3毫克的活性肽。没有不良事件，推荐剂量为3mg。在这个项目之后，需要进行一项使用GEM进行个性化肽免疫治疗和化疗联合治疗胰腺癌的II期研究。

On this project, we attempted to find clinically effective therapy against pancreatic cancer using the combination with immunotherapy and chemotherapy. We reported two phase I trials of MUC1 peptide vaccination and personalized peptide vaccination within the term of this project. We vaccinated 9 patients with 300,1000,or 3000 mg of the 105 amino acid MUC1 peptide. There were no adverse events, except for mild reddening and swelling at the vaccination site. In 8 patients eligible for clinical evaluation,7 had progressive disease and 1 stable disease with a tendency for increased circulating anti-MUC1 IgG antibody after vaccination. Secondary we applied another phase I study with personalized peptide vaccination to 11 patients with pancreatic cancer. Namely, pre-vaccinated peripheral blood mononuclear cells were screened for the reactivity in vitro to each of 14 or 16 peptide candidates in HLA-A24^+ or -A2^+ patients, and then only the reactive peptides were vaccinated in vivo. This regimen was generally well tolerated without hematological toxicity, although inflammatory reactions at the injection site were observed in 7 patients. Increased cellular and humoral immune responses to at least one of peptides used for vaccination were observed in the post-vaccination PBMCs and sera from 4 of 8 patients and 4 of 10 patients tested, respectively. The 6- and 12-month survival rates for patients who received more than 3 vaccinations (n=10) were 80% and 20%, respectively. On the base of two phase I study, we conducted a phase I trial of combination therapy with personalized peptide immunotherapy and chemotherapy using GEM for pancreatic cancer. We vaccinated 13 patients with 1,2,or 3 mg of the reactive peptides. There were no adverse events, and a dose of 3 mg was recommended. After this project, a phase II study of combination therapy with personalized peptide immunotherapy and chemotherapy using GEM for pancreatic cancer is warranted.