Goydos J S, Elder E, Whiteside T L, Finn O J, Lotze M T
University of Pittsburgh School of Medicine, Department of Surgery, Pennsylvania 15261, USA.
J Surg Res. 1996 Jun;63(1):298-304. doi: 10.1006/jsre.1996.0264.
We tested a 105 amino acid synthetic mucin MUC-1 peptide that has 5 repeated immunodominant epitopes to evaluate toxicity and detect mucin-specific immune responses in patients with adenocarcinoma. We also studied the enhancement of these responses by vaccinating patients with the synthetic mucin peptide admixed with BCG. Mucins are glycoproteins present on the luminal surface of ductal epithelial cells and on tumors derived from them. The MUC-1 mucin is hypoglycosylated and nonpolarized on tumors and this exposes epitopes that can stimulate cytotoxic T-Cells (CTL). We vaccinated 63 patients with 100 micrograms of the 105aa mucin peptide mixed with BCG. Two additional vaccinations were given at 3-week intervals. All patients were able to tolerate vaccination, with most experiencing local ulceration at the vaccination site. All patients underwent hypersensitivity (DTH) testing with the 105aa and shorter mucin peptides, prior to vaccination. DTH responses were evaluated at 48 hr and the sites of highest peptide concentration were biopsied. Only 3 patients had a strong skin response to the long peptide. Examination of 55 biopsies showed intense T-Cell infiltration in 37 patients and lesser infiltration in 7. Seven of 22 patients tested had a 2- to 4-fold increase in mucin-specific CTLp. Serum levels of IL-6 were measured sequentially using the B9 hybridoma bioassay. Increasing serum levels of IL-6 correlated with constitutional symptoms (significance 0.001) and hypoalbuminemia (significance 0.007) but not with the extent of skin breakdown at vaccination sites. We conclude that mucin vaccination is safe and might serve to enhance specific responses to tumor antigens. IL-6 may be responsible for the constitution symptoms and hypoalbuminemia in these patients.
我们测试了一种含有5个重复免疫显性表位的105个氨基酸的合成粘蛋白MUC-1肽，以评估其毒性并检测腺癌患者中粘蛋白特异性免疫反应。我们还研究了通过用与卡介苗混合的合成粘蛋白肽对患者进行疫苗接种来增强这些反应。粘蛋白是存在于导管上皮细胞腔表面及其衍生肿瘤上的糖蛋白。MUC-1粘蛋白在肿瘤上是低糖基化且非极化的，这暴露出可刺激细胞毒性T细胞（CTL）的表位。我们用100微克与卡介苗混合的105aa粘蛋白肽对63名患者进行了疫苗接种。每隔3周进行另外两次接种。所有患者都能耐受疫苗接种，大多数患者在接种部位出现局部溃疡。所有患者在接种前均用105aa和较短的粘蛋白肽进行了超敏反应（DTH）测试。在48小时时评估DTH反应，并对肽浓度最高的部位进行活检。只有3名患者对长肽有强烈的皮肤反应。对55份活检样本的检查显示，37名患者有强烈的T细胞浸润，7名患者浸润较轻。在22名接受测试的患者中，7名患者的粘蛋白特异性CTLp增加了2至4倍。使用B9杂交瘤生物测定法依次测量血清IL-6水平。血清IL-6水平升高与全身症状（显著性0.001）和低白蛋白血症（显著性0.007）相关，但与接种部位皮肤破损程度无关。我们得出结论，粘蛋白疫苗接种是安全的，可能有助于增强对肿瘤抗原的特异性反应。IL-6可能是这些患者全身症状和低白蛋白血症的原因。
