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，我们试图通过联合免疫治疗和化疗来寻找治疗胰腺癌的临床有效方法。在本项目期间，我们报道了MUC1多肽疫苗和个性化多肽疫苗的两个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多肽。除了接种部位轻微发红和肿胀外，没有任何不良反应。在符合临床评价的8例患者中，7例为进展型，1例为稳定期，免疫后循环抗MUC1Ig G抗体有升高趋势。其次，我们对11名胰腺癌患者进行了个性化多肽疫苗接种的I期研究。即对免疫前的外周血单个核细胞进行筛选，检测其对14或16个候选多肽的体外反应性，然后在体内仅接种反应性多肽。该方案一般耐受性良好，没有血液毒性，尽管在7名患者中观察到注射部位的炎症反应。8例受试者中有4例免疫后PBMC和10例受试者中有4例对至少一种免疫多肽的细胞免疫应答和体液免疫应答增强。接种3次以上疫苗(n=10)的患者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，我们进行了胰腺癌个体化多肽免疫联合化疗的I期试验。我们给13名患者接种了1、2或3毫克的反应肽。未见不良反应，推荐剂量为3 mg。本项目完成后，对胰腺癌进行个体化多肽免疫治疗和GEM化疗的II期研究是有必要的。

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.