Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer.
Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in Patients with Nonmetastatic Castrate-Resistant Prostate Cancer.
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DOI：
10.1158/2326-6066.cir-15-0189
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发表时间：
2016-10
影响因子：
10.1
通讯作者：
Foley R
中科院分区：
文献类型：
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作者：
Scheid E;Major P;Bergeron A;Finn OJ;Salter RD;Eady R;Yassine-Diab B;Favre D;Peretz Y;Landry C;Hotte S;Mukherjee SD;Dekaban GA;Fink C;Foster PJ;Gaudet J;Gariepy J;Sekaly RP;Lacombe L;Fradet Y;Foley R
MUC1是一种表达于导管上皮细胞顶端表面的糖蛋白。恶性转化导致极化缺失和低糖基化MUC1的过表达，MUC1携带截断的碳水化合物，称为T或Tn肿瘤抗原。肿瘤MUC1携带Tn碳水化合物（Tn-MUC1）是免疫治疗的潜在靶点。在恒河猴MUC1的不同糖基化形式的临床前研究之后，我们在人类I/II期临床试验中评估了n-MUC1糖肽的安全性，恒河猴的MUC1与人类MUC1高度同源。将未糖基化的恒河猴MUC1肽（rmMUC1）或n-rmMUC1糖肽与佐剂混合，或负载于自体树突状细胞（DCs），并比较反应。与n-rmMUC1糖肽相比，未糖基化的rmMUC1肽诱导的体液或细胞反应可忽略不计。负载在dc上的n- rmmuc1诱导了最高的抗rmmuc1 t细胞反应，无临床毒性。在I/II期临床研究中，17例非转移性去势抵抗性前列腺癌（nmCRPC）患者接受了aTn-MUC1糖肽- dc疫苗的检测。患者接受多次皮内和结内剂量的自体dc治疗，这些dc装载了n- muc1糖肽（KLH作为免疫反应性的阳性对照）。16例可评估患者中有11例PSA倍增时间（PSADT）显著改善（P = 0.037）。免疫反应分析检测到7名患者中有5名患者有显著的n- muc1特异性CD4+和/或CD8+ t细胞细胞因子反应。总之，在nmCRPC患者中接种携带tn - muc1的dc似乎是安全的，能够诱导显著的t细胞反应，并且通过接种后PSADT的增加来测量其生物活性。
MUC1 is a glycoprotein expressed on the apical surface of ductal epithelial cells. Malignant transformation results in loss of polarization and overexpression of hypoglycosylated MUC1 carrying truncated carbohydrates known as T or Tn tumor antigens. Tumor MUC1 bearing Tn carbohydrates (Tn-MUC1) represent a potential target for immunotherapy. We evaluated the Tn-MUC1 glycopeptide in a human phase I/II clinical trial for safety that followed a preclinical study of different glycosylation forms of MUC1 in rhesus macaques, whose MUC1 is highly homologous to human MUC1. Either unglycosylated rhesus macaque MUC1 peptide (rmMUC1) or Tn-rmMUC1 glycopeptide were mixed with an adjuvant, or loaded on autologous dendritic cells (DCs), and responses compared. Unglycosylated rmMUC1 peptide induced negligible humoral or cellular responses compared to the Tn-rmMUC1 glycopeptide. Tn-rmMUC1 loaded on DCs induced the highest anti-rmMUC1 T-cell responses and no clinical toxicity. In the phase I/II clinical study, 17 patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) were tested with aTn-MUC1 glycopeptide-DC vaccine. Patients were treated with multiple intradermal and intranodal doses of autologous DCs, which were loaded with the Tn-MUC1 glycopeptide (and KLH as a positive control for immune reactivity). PSA doubling time (PSADT) improved significantly in 11 of 16 evaluable patients (P = 0.037). Immune response analyses detected significant Tn-MUC1-specific CD4+ and/or CD8+ T-cell intracellular cytokine responses in 5 out of 7 patients evaluated. In conclusion, vaccination with Tn-MUC1-loaded DCs in nmCRPC patients appears to be safe, able to induce significant T-cell responses, and have biological activity as measured by the increase in PSADT following vaccination.