Combination therapy with immunotherapy and chemotherapy for pancreatic cancer

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。在免疫治疗方面，我们进行了MUC1肽疫苗接种和个性化肽疫苗接种的两项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并诱导MUC1特异性细胞毒性T淋巴细胞，不受HLA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肽。MUC1疫苗在所有患者中耐受性良好，没有产生任何副作用。在9例患者中，1例肿瘤标志物下降，但在其他患者中，他们的疾病出现进展。其次，我们应用了另一项I期研究，对10名胰腺癌患者进行个性化肽疫苗接种。即，预先接种的外周血单个核细胞在体外对HLA-A24^+的14或16个候选肽中的每一个进行反应性筛选，然后在体内只接种反应性肽。该方案通常耐受性良好，无血液学毒性，尽管在注射部位观察到炎症反应。病人。3例出现发热，1例出现厌食，1例出现疲劳。在接受3次以上疫苗接种并符合临床评价条件的10例患者中，3例在第6次疫苗接种时病情稳定，7例病情进展。3例病情稳定的患者中有1例在初次治疗后存活了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，我们建立了一种新的人类胰腺癌细胞系，命名为YPK-1。吉西他滨对YPK-1的50%抑制浓度（IC50）为0.0063 ug/ml。顺铂和5-氟尿嘧啶的IC50分别为1.26和3.16 ug/ml。这些数据表明GEM可能在化疗药物中对胰腺癌有临床疗效。总之，进一步发展以个性化肽为基础的免疫治疗和化疗联合使用GEM治疗胰腺癌是值得的

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