Wei Wei-Zen, Jacob Jennifer, Radkevich-Brown Olga, Whittington Paula, Kong Yi-chi M
Karmanos Cancer Institute and Department of Immunology and Microbiology, Wayne State University, 110 E. Warren Ave, Detroit, MI 48201, USA.
Cancer Immunol Immunother. 2008 Nov;57(11):1711-7. doi: 10.1007/s00262-008-0464-y. Epub 2008 Feb 14.
The development of Her-2 DNA vaccine has progressed through three phases that can be categorized as phase "A": the pursuit of Her-2 as a tumor-associated "antigen", phase "B": tilting the "balance" between tumor immunity and autoimmunity and phase "C": the on-going "clinical trials".
In phase "A", a panel of human ErbB-2 or Her-2 plasmids were constructed to encode non-transforming Her-2 derivatives. The immunogenicity and anti-tumor activity of Her-2 DNA vaccines were tested in human Her-2 transgenic mice with or without the depletion of regulatory T cells (Tregs). However, Treg depletion or other immune modulating regimens may increase the risk of autoimmunity. In phase "B", the balance between tumor immunity and autoimmunity was assessed by monitoring the development of experimental autoimmune thyroiditis (EAT). To test the efficacy of Her-2 DNA vaccines in cancer patients, clinical trials have been initiated in phase "C".
Significant anti-Her-2 and anti-tumor activity was observed when Her-2 transgenic mice were electro-vaccinated after Treg depletion. Susceptibility to EAT was also enhanced by Treg depletion and there was mutual amplification between Her-2 immunity and EAT development. Although Tregs regulate both EAT and Her-2 immunity, their effector mechanisms may differ. It may be possible to amplify tumor immunity with improved strategies that can by-pass undue autoimmunity. Critical information will be revealed in the next decade to expedite the development of cancer vaccines.
Her-2 DNA疫苗的研发已历经三个阶段，可归类为“A期”：将Her-2作为肿瘤相关“抗原”进行探索；“B期”：调节肿瘤免疫与自身免疫之间的“平衡”；“C期”：正在进行的“临床试验”。
在“A期”，构建了一组人ErbB-2或Her-2质粒以编码非转化性Her-2衍生物。在有或没有去除调节性T细胞（Tregs）的人Her-2转基因小鼠中测试了Her-2 DNA疫苗的免疫原性和抗肿瘤活性。然而，去除Tregs或其他免疫调节方案可能会增加自身免疫的风险。在“B期”，通过监测实验性自身免疫性甲状腺炎（EAT）的发展来评估肿瘤免疫与自身免疫之间的平衡。为了测试Her-2 DNA疫苗在癌症患者中的疗效，“C期”已启动临床试验。
在去除Tregs后对Her-2转基因小鼠进行电穿孔接种疫苗时，观察到显著的抗Her-2和抗肿瘤活性。去除Tregs也增强了对EAT的易感性，并且Her-2免疫与EAT发展之间存在相互放大作用。尽管Tregs调节EAT和Her-2免疫，但它们的效应机制可能不同。通过能够避免过度自身免疫的改进策略来增强肿瘤免疫可能是可行的。未来十年将揭示关键信息，以加速癌症疫苗的研发。
