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，我们试图找到临床上有效的治疗胰腺癌的联合免疫治疗和化疗。在本项目期间，我们报告了MUC 1肽疫苗接种和个性化肽疫苗接种的两个I期试验。我们用300、1000或3000 mg的105个氨基酸的MUC 1肽对9名患者进行了疫苗接种。除接种部位轻度发红和肿胀外，未发生不良事件。在符合临床评价条件的8例患者中，7例疾病进展，1例疾病稳定，接种疫苗后循环抗MUC 1 IgG抗体有增加的趋势。其次，我们对11名胰腺癌患者进行了另一项I期研究，采用个性化肽疫苗接种。也就是说，在HLA-A24^+或-A2^+患者中筛选预先接种的外周血单核细胞对14或16种候选肽的体外反应性，然后仅对反应性肽进行体内接种。尽管在7例患者中观察到注射部位的炎症反应，但该方案通常耐受良好，无血液学毒性。在分别来自4/8名受试患者和4/10名受试患者的疫苗接种后PBMC和血清中观察到对用于疫苗接种的至少一种肽的细胞和体液免疫应答增加。接受3次以上疫苗接种的患者（n=10）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，我们进行了一个I期试验，联合治疗与个性化的肽免疫治疗和化疗，使用吉西他滨胰腺癌。我们用1、2或3 mg的反应性肽接种了13名患者。没有不良事件，推荐剂量为3 mg。在该项目之后，有必要进行一项针对胰腺癌的个性化肽免疫疗法和使用GEM的化疗的联合疗法的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.