Whittington Paula J, Radkevich-Brown Olga, Jacob Jennifer B, Jones Richard F, Weise Amy M, Wei Wei-Zen
Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Cancer Immunol Immunother. 2009 May;58(5):759-67. doi: 10.1007/s00262-008-0599-x. Epub 2008 Oct 3.
Direct comparison and ranking of vaccine formulations in pre-clinical studies will expedite the identification of cancer vaccines for clinical trials. Two human ErbB-2 (Her-2) vaccines, naked DNA and whole cell vaccine, were tested side-by-side in wild type and Her-2 transgenic mice. Both vaccines can induce humoral and cellular immunity to the entire repertoire of Her-2 epitopes. Mice were electro-vaccinated i.m. with a mixture of pGM-CSF and pE2TM, the latter encodes Her-2 extracellular and transmembrane domains. Alternatively, mice were injected i.p. with human ovarian cancer SKOV3 cells that have amplified Her-2. In wild type mice, comparable levels of Her-2 antibodies (Ab) were induced by these two vaccines. However, T cell immunity and protection against Her-2(+) tumors were superior in DNA vaccinated mice. In BALB Her-2 transgenic (Tg) mice, which were tolerant to Her-2, DNA and cell vaccines were administered after regulatory T cells (Treg) were removed by anti-CD25 mAb. Again, comparable levels of Her-2 Ab were induced, but DNA vaccines rendered greater anti-tumor activity. In B6xDR3 Her-2 Tg mice that expressed the autoimmune prone HLA-DR3 allele, higher levels of Her-2 Ab were induced by SKOV3 cell than by Her-2 DNA. But anti-tumor activity was still more profound in DNA vaccinated mice. Therefore, Her-2 DNA vaccine induced greater anti-tumor immunity than cell vaccine, whether mice were tolerant to Her-2 or susceptible to autoimmunity. Through such side-by-side comparisons in appropriate pre-clinical test systems, the more effective vaccine formulations will emerge as candidates for clinical trials.
在临床前研究中对疫苗制剂进行直接比较和排名将加速用于临床试验的癌症疫苗的鉴定。两种人表皮生长因子受体2（ErbB-2，即Her-2）疫苗，裸DNA疫苗和全细胞疫苗，在野生型和Her-2转基因小鼠中进行了并行测试。两种疫苗均可诱导针对Her-2表位全部组成部分的体液免疫和细胞免疫。小鼠通过肌肉注射pGM-CSF和pE2TM的混合物进行电疫苗接种，后者编码Her-2细胞外和跨膜结构域。或者，给小鼠腹腔注射已扩增Her-2的人卵巢癌SKOV3细胞。在野生型小鼠中，这两种疫苗诱导的Her-2抗体（Ab）水平相当。然而，DNA疫苗接种的小鼠的T细胞免疫和对Her-2(+)肿瘤的保护作用更强。在对Her-2耐受的BALB Her-2转基因（Tg）小鼠中，通过抗CD25单克隆抗体清除调节性T细胞（Treg）后，再接种DNA疫苗和细胞疫苗。同样，诱导的Her-2 Ab水平相当，但DNA疫苗具有更强的抗肿瘤活性。在表达自身免疫易感HLA-DR3等位基因的B6xDR3 Her-2 Tg小鼠中，SKOV3细胞诱导的Her-2 Ab水平高于Her-2 DNA诱导的水平。但DNA疫苗接种的小鼠的抗肿瘤活性仍然更强。因此，无论小鼠对Her-2耐受还是易患自身免疫，Her-2 DNA疫苗诱导的抗肿瘤免疫力均强于细胞疫苗。通过在适当的临床前测试系统中进行这种并行比较，更有效的疫苗制剂将成为临床试验的候选者。
