Advaxis Inc., New Brunswick, NJ 08902, USA.
Cancer Gene Ther. 2011 Jan;18(1):53-62. doi: 10.1038/cgt.2010.48. Epub 2010 Aug 20.
A chimeric human Her2/neu gene (ChHer2) harboring most of the known major histocompatibility complex class I epitopes of the HER2/neu oncogene was expressed as a fusion protein to a non-hemolytic fragment of listeriolysin O (LLO), by the highly attenuated Listeria vector LmddA, which lacks antibiotic selection markers and the ability to spread from cell-to-cell. This construct (ADXS31-164) was tested for immunogenicity and anti-tumor effects in mice. Despite being highly attenuated, ADXS31-164 proved to be efficacious in breaking immune tolerance toward the HER2/neu self-antigen. ADXS31-164 elicited strong T-cell immune responses in experimental animals. In tumors, ADXS31-164 caused a reduction in regulatory T cells (Treg) accompanied by an increase in the CD8(+)/Treg ratio. Comparison of this vaccine with the conventional antibiotic resistant Listeria vector (Lm-LLO-ChHer2) shows that ADXS31-164 is more efficacious in delaying tumor growth in Her2/neu transgenic animals. Because of its well-defined attenuation mechanism and independence from antibiotic selection markers, ADXS31-164 is potentially more suitable for human use. These results support the future clinical development of this vaccine for the treatment of HER2/neu-overexpressing malignancies, such as breast, colorectal and pancreatic cancers.
一种嵌合的人类 Her2/neu 基因（ChHer2），携带 Her2/neu 癌基因的大多数已知主要组织相容性复合体 I 表位，被表达为李斯特菌载体 LmddA 的非溶血片段李斯特菌溶血素 O（LLO）的融合蛋白，该载体缺乏抗生素选择标记物和细胞间传播的能力。该构建体（ADXS31-164）在小鼠中进行了免疫原性和抗肿瘤作用的测试。尽管高度减毒，ADXS31-164 被证明在打破针对 Her2/neu 自身抗原的免疫耐受方面是有效的。ADXS31-164 在实验动物中引起强烈的 T 细胞免疫反应。在肿瘤中，ADXS31-164 导致调节性 T 细胞（Treg）减少，同时 CD8(+)/Treg 比例增加。与传统的抗生素抗性李斯特菌载体（Lm-LLO-ChHer2）相比，该疫苗表明 ADXS31-164 在延迟 Her2/neu 转基因动物的肿瘤生长方面更有效。由于其明确的减毒机制和不依赖抗生素选择标记物，ADXS31-164 更适合人类使用。这些结果支持该疫苗用于治疗 Her2/neu 过表达恶性肿瘤（如乳腺癌、结直肠癌和胰腺癌）的临床开发。
