Selvaraj Periasamy, Yerra Archana, Tien Linda, Shashidharamurthy Rangaiah
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Hum Vaccin. 2008 Sep-Oct;4(5):384-8. doi: 10.4161/hv.4.5.5866. Epub 2008 Sep 3.
Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals result in an antigenic profile that varies from patient to patient. Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host's own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a method by which therapeutic vaccines may be custom-designed to treat cancers case by case. Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both experimental models and also in human clinical trials. Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings.
研发针对人类抵御诸如病毒和细菌等入侵病原体的疫苗已取得了巨大成功。针对这些病原体研发疫苗的过程因它们含有对人类而言完全陌生的抗原而得到极大助力。尽管为设计针对这些微生物的疫苗所积累的知识和策略可能有助于开发癌症疫苗，但癌症的低抗原性和免疫抑制能力给疫苗研发带来了重大障碍。已形成的肿瘤不仅经受住了免疫筛选和选择压力，使其难以刺激免疫反应，还通过营造免疫抑制环境来适应并继续逃避免疫监视机制。此外，个体对一种抗原的免疫反应存在基因差异，导致不同患者的抗原谱各不相同。癌症与体内正常细胞极为相似，以至于在分子层面，癌细胞与非癌细胞之间的差异微乎其微。因此，使用宿主自身肿瘤组织研发疫苗存在打破对肿瘤组织中自身抗原耐受性的风险。需要研发在免疫抑制条件下能最佳地刺激免疫系统对抗肿瘤特异性抗原的疫苗接种策略。实际上，这就需要一种方法，据此可针对不同病例定制治疗性癌症疫苗。在实验模型和人体临床试验中，都在测试对树突状细胞的体外操作以及在体外扩增的肿瘤中进行免疫刺激分子的基因转移。其中一些已取得了有限的成功。诸如蛋白质转移等新兴技术使得在肿瘤细胞膜上表达免疫刺激分子成为可能，为开发高效、简便、快速且易于在人类患者中储存和施用的肿瘤疫苗提供了途径。这些技术的进展将使癌症疫苗领域朝着在人类临床环境中实现定制化癌症疫苗的目标迈进一大步。
