Combination therapy with immunotherapy and chemotherapy for pancreatic cancer

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。在免疫治疗方面，我们进行了MUC1多肽疫苗和个性化多肽疫苗的两个I期试验。MUC1粘蛋白是一种糖蛋白，在胰腺癌细胞表面被强烈识别，可诱导MUC1特异性的细胞毒T淋巴细胞，而不受人类白细胞抗原的限制。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。所有患者对MUC1疫苗的耐受性良好，没有产生任何副作用。9例患者中，L组肿瘤标志物降低，其余患者病情进展。其次，我们对10名胰腺癌患者进行了个性化多肽疫苗接种的I期研究。也就是说，对预接种的外周血单个核细胞进行了对HLAA24^+…中14或16个候选多肽的体外反应性筛选更多或-A2^+患者，然后只接种反应性多肽。这种方案总体上耐受性良好，没有血液毒性，尽管在注射部位观察到炎症反应。病人。此外，还观察到发热、食欲不振和疲劳--分别有3名、1名和1名患者。在接受3次以上疫苗接种并符合临床评估条件的10例患者中，在第6次接种时，3例病情稳定，7例病情进展。3名病情稳定的患者中有1名在最初治疗后存活了30个月。我们证明了两种疫苗免疫疗法的可行性和安全性，然而，这些疗法并没有显示出明显的生存益处：另一方面，我们建立了一个新的人胰腺癌细胞系，命名为YPK-1。吉西他滨(GEM)对YPK-1的半数抑制浓度(IC_(50))为0.0063微克/毫升，顺铂和5-氟尿嘧啶的IC_(50)分别为1.26和3.16微克/毫升。这些数据表明，在化疗药物中，GEM对胰腺癌可能是临床有效的。综上所述，结合个体化多肽为基础的免疫治疗和使用GEM进行化疗对胰腺癌的进一步发展是不必要的。

On this project, we attempted to find clinically effective therapy against pancreatic cancer using the combination with immunotherapy and chemotherapy. For immunotherapy, we conducted two phase I trials of MUC1 peptide vaccination and personalized peptide vaccination. MUC1 mucin is glycoprotein, which is strongly recognized on the surface of pancreatic cancer cells and induces MUC1-specific cytotoxic T lymphocytes without restriction of HLA. We vaccinated 9 patients with 300, 1000, or 3000 mg of the 105 amino acid MUC1 peptide. The MUC1 vaccination was well tolerated in all patients and did not produce any side effects. In l out of 9 patients tumor markers decreased, but in the others their diseases showed progression. Secondary we applied another phase I study with personalized peptide vaccination to 10 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^+ … More 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 ? patients. Moreover fever, anorexia, and fatigue were observed -in 3, 1, and 1 patient, respectively. Of 10 patients who received more than 3 vaccinations and were eligible for clinical evaluation, 3 showed stable disease and 7 demonstrated progressive disease at the time of the 6th vaccination. One patient of 3 with stable disease has been alive for 30 months after the initial treatment. We demonstrated feasibility and safety of two vaccination immunotherapy, however, these therapy did not show a obvious survival benefit : On the other hand, we established a new human pancreatic cancer cell line, designated YPK-1. 50% inhibitory concentration (IC50) to YPK-1 of gemcitabine (GEM) was 0.0063 ug/ml. IC50 of cisplatin and 5-fluorouracil were 1.26 and 3.16 ug/ml, respectively. These data showed GEM may be clinically effective for pancreatic cancer among chemotherapeutic agents. In conclusion, further development of combination with personalized peptide based immunotherapy and chemotherapy using GEM for pancreatic cancer is warranted Less