评估HER2/neu衍生肽GP2在基于肽的乳腺癌疫苗试验中的应用。

Evaluation of the HER2/neu-derived peptide GP2 for use in a peptide-based breast cancer vaccine trial.

作者信息

Mittendorf Elizabeth A, Storrer Catherine E, Foley Rebecca J, Harris Katie, Jama Yusuf, Shriver Craig D, Ponniah Sathibalan, Peoples George E

机构信息

Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA.

出版信息

Cancer. 2006 Jun 1;106(11):2309-17. doi: 10.1002/cncr.21849.

DOI:10.1002/cncr.21849

PMID:16596621

Abstract

BACKGROUND

E75 and GP2 are human leukocyte antigen (HLA)-A2-restricted immunogenic peptides derived from the HER2/neu protein. In a E75 peptide-based vaccine trial, preexisting immunity and epitope spreading to GP2 was detected. The purpose of this study was to further investigate GP2 for potential use in vaccination strategies. Importantly, a naturally occurring polymorphism (I-->V at position 2, 2VGP2) associated with increased breast cancer risk was addressed.

METHODS

Prevaccination peripheral blood samples (PBMC) from HLA-A2 breast cancer patients and CD8+ T cells from HLA-A2 healthy donors were stimulated with autologous dendritic cells (DC) pulsed with GP2 and tested in standard cytotoxicity assays with HER2/neu+ tumor cells or GP2- or 2VGP2-loaded T2 targets. Additional cytotoxicity experiments used effectors stimulated with DC pulsed with E75, GP2, or the combination of E75+GP2.

RESULTS

GP2-stimulated prevaccination PBMC from 28 patients demonstrated killing of MCF-7, SKOV3-A2, and the HLA-A2- control target SKOV3 of 28.8+/-3.7% (P<.01), 29.5+/-4.0% (P<.01), and 16.9+/-2.7%, respectively. When compared with E75, GP2-stimulated CD8+ T cells lysed HER2/neu+ targets at 43.8+/-5.2% versus 44.2+/-5.7% for E75 (P=.87). When combined, an additive effect was noted with 58.6+/-5.4% lysis (P=.05). GP2-stimulated CD8+ T cells specifically recognized both GP2-loaded (19.6+/-5.7%) and 2VGP2-loaded T2 targets (17.7+/-5.2%).

CONCLUSIONS

GP2 is a clinically relevant HER2/neu-derived peptide with immunogenicity comparable to that of E75. Importantly, GP2-specific effectors recognize 2VGP2-expressing targets; therefore, a GP2 vaccine should be effective in patients carrying this polymorphism. GP2 may be most beneficial used in a multiepitope vaccine.

摘要

背景

E75和GP2是源自HER2/neu蛋白的人类白细胞抗原（HLA）-A2限制性免疫原性肽段。在一项基于E75肽段的疫苗试验中，检测到了预先存在的免疫反应以及表位扩展至GP2的情况。本研究的目的是进一步研究GP2在疫苗接种策略中的潜在用途。重要的是，研究了一种与乳腺癌风险增加相关的自然发生的多态性（第2位I→V，2VGP2）。

方法

用负载GP2的自体树突状细胞（DC）刺激来自HLA-A2乳腺癌患者的接种前外周血样本（PBMC）以及来自HLA-A2健康供体的CD8⁺T细胞，并在标准细胞毒性试验中用HER2/neu⁺肿瘤细胞或负载GP2或2VGP2的T2靶细胞进行检测。另外的细胞毒性实验使用了用负载E75、GP2或E75 + GP2组合的DC刺激的效应细胞。

结果

来自28例患者的接种前受GP2刺激的PBMC对MCF-7、SKOV3-A2和HLA-A2对照靶细胞SKOV3的杀伤率分别为28.8±3.7%（P<0.01）、29.5±4.0%（P<0.01）和16.9±2.7%。与E75相比，受GP2刺激的CD8⁺T细胞对HER2/neu⁺靶细胞的裂解率为43.8±5.2%，而E75为44.2±5.7%（P = 0.87）。两者联合时，观察到加成效应，裂解率为58.6±5.4%（P = 0.05）。受GP2刺激的CD8⁺T细胞特异性识别负载GP2的（19.6±5.7%）和负载2VGP2的T2靶细胞（17.7±5.2%）。