Kershaw Michael H, Westwood Jennifer A, Hwu Patrick
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Biotechnol. 2002 Dec;20(12):1221-7. doi: 10.1038/nbt756. Epub 2002 Nov 4.
An effective immune response against cancer requires the activation and expansion of specific T cells. Tumor antigens, however, are generally poor immunogens. To achieve expansion of tumor-reactive T cells in vivo, we used a strategy of generating dual-specific T cells that could respond to a powerful immunogen while also possessing tumor reactivity. We generated dual-specific T cells by genetic modification of alloreactive T cells with a chimeric receptor recognizing folate-binding protein, an ovarian cancer-associated antigen. Mouse dual-specific T cells responded in vitro to both allogeneic antigen and tumor cells expressing folate-binding protein, and expanded in number in vivo in response to immunization with allogeneic cells. Most importantly, the combination of dual-specific T cells and immunization had an antitumor effect in vivo. We also generated human dual-specific T cells and characterized the dual-specific nature of individual clones. Assigning the tasks of expansion and tumor reactivity to different receptors within the same lymphocyte may help to overcome the problem of poor immunogenicity of tumor antigens.
针对癌症的有效免疫反应需要特定T细胞的激活和扩增。然而，肿瘤抗原通常是弱免疫原。为了在体内实现肿瘤反应性T细胞的扩增，我们采用了一种策略，即生成双特异性T细胞，使其既能对强免疫原做出反应，又具备肿瘤反应性。我们通过用识别叶酸结合蛋白（一种卵巢癌相关抗原）的嵌合受体对同种异体反应性T细胞进行基因改造，从而生成双特异性T细胞。小鼠双特异性T细胞在体外对同种异体抗原和表达叶酸结合蛋白的肿瘤细胞均有反应，并在体内因同种异体细胞免疫而数量增加。最重要的是，双特异性T细胞与免疫的联合在体内具有抗肿瘤作用。我们还生成了人类双特异性T细胞，并对单个克隆的双特异性特性进行了表征。将扩增和肿瘤反应性的任务分配给同一淋巴细胞内的不同受体，可能有助于克服肿瘤抗原免疫原性差的问题。
