Singh Narendra P, Yolcu Esma S, Taylor Douglas D, Gercel-Taylor Cicek, Metzinger Daniel S, Dreisbach Stephen K, Shirwan Haval
Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky 40202, USA.
Cancer Res. 2003 Jul 15;63(14):4067-73.
Malignant cells often elude the immune system by lacking costimulatory signals required for the generation of effective antitumor immunity. Immunization with tumor cells genetically modified to express costimulatory molecules is a highly promising approach to cancer immunotherapy. However, genetic modification of tumor cells is not only labor/time intensive but is also less efficient and bears safety concerns. To override these complications, we have recently developed a novel technology that allows for efficient and durable display of exogenous proteins on the surface of a cell within 2 h. This technology involves modification of the cell membrane with a biotin derivative and decoration of biotinylated cells with proteins chimeric with core streptavidin. A chimeric molecule composed of the extracellular domains of the human CD80 costimulatory molecule and core streptavidin (CD80-SA) was efficiently displayed on the cell surface, where it persisted with a t(1/2) of >10 days in vivo. Tumors from patients with advanced stage gynecologic cancers decorated with CD80-SA elicited potent ex vivo tumor-specific proliferative and cytotoxic responses in autologous lymphocytes. Immunization with tumor cells decorated with CD80-SA completely prevented tumor growth in an aggressive model of mouse lymphoma. This technology may serve as a fast, efficient, and safe alternative to gene transfer approaches for engineering tumor cells for use in immunotherapy and research.
恶性细胞常常通过缺乏产生有效抗肿瘤免疫所需的共刺激信号来逃避免疫系统。用经基因改造以表达共刺激分子的肿瘤细胞进行免疫接种是一种非常有前景的癌症免疫治疗方法。然而，肿瘤细胞的基因改造不仅耗费人力/时间，而且效率较低，还存在安全问题。为了克服这些并发症，我们最近开发了一种新技术，该技术能够在2小时内使外源蛋白在细胞表面高效且持久地展示。这项技术涉及用生物素衍生物修饰细胞膜，并用与核心链霉亲和素嵌合的蛋白质对生物素化的细胞进行修饰。由人CD80共刺激分子的胞外结构域和核心链霉亲和素组成的嵌合分子（CD80-SA）在细胞表面高效展示，在体内其半衰期>10天。用CD80-SA修饰的晚期妇科癌症患者的肿瘤在自体淋巴细胞中引发了强大的体外肿瘤特异性增殖和细胞毒性反应。用CD80-SA修饰的肿瘤细胞进行免疫接种在小鼠淋巴瘤侵袭性模型中完全阻止了肿瘤生长。这项技术可作为一种快速、高效且安全的替代方法，用于对肿瘤细胞进行工程改造以用于免疫治疗和研究，替代基因转移方法。
