Department of Surgery, Medicine, Division of Medical Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina, USA.
Clin Cancer Res. 2010 Mar 1;16(5):1466-77. doi: 10.1158/1078-0432.CCR-09-2549. Epub 2010 Feb 23.
Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use.
We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo.
Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo.
Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.
乳腺癌致癌基因 HER2 的过表达与不良预后相关。目前的 HER2 靶向治疗仅能带来有限的临床获益,大多数患者会出现疾病进展。由于耐药肿瘤仍强烈表达 HER2+,针对 HER2 的疫苗方法具有治疗潜力,但由于野生型(wt)HER2 是一种有效的致癌基因,因此不能在免疫原性病毒载体中安全传递。我们设计并测试了几种缺乏致癌活性的 HER2 疫苗,以开发一种安全的疫苗用于临床应用。
我们构建了表达 HER2 细胞外结构域(Ad-HER2-ECD)、ECD 加跨膜结构域(Ad-HER2-ECD-TM)和全长 HER2 的重组腺病毒载体,使其激酶功能失活(Ad-HER2-ki),并在野生型(WT)和 HER2 耐受小鼠中确定其免疫原性和抗肿瘤作用。为了评估其安全性,我们比较了它们对细胞转录组、细胞增殖、锚定依赖性生长和体内转化潜能的影响。
Ad-HER2-ki 是 WT 动物中最具免疫原性的载体,在 HER2 转基因耐受动物中保留了免疫原性,并在治疗模型中表现出强烈的治疗效果。尽管高度表达,但 HER2-ki 蛋白未被磷酸化,并且不会在原代人细胞中产生致癌基因特征。此外,与 HER2-wt 相比,过表达 HER2-ki 的细胞增殖能力较低,锚定非依赖性生长能力较低,并且在体内不会发生转化。
突变失活、非致癌性 Ad-HER2-ki 的疫苗接种可在耐受模型中引发针对 HER2 的强大多克隆免疫反应,从而在体内转化为强烈有效的抗肿瘤反应。因此,Ad-HER2-ki 是一种安全且有前途的疫苗,可在临床试验中进行评估。