T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells
T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells
复制标题
DOI：
10.1182/blood-2006-04-017061
复制
发表时间：
2006-12-01
期刊：
影响因子：
20.3
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
--
作者：
Vera, Juan;Savoldo, Barbara;Dotti, Gianpietro
人们对产生表达靶向CD 19/CD 20抗原的嵌合人工受体（汽车）的T细胞以治疗B细胞淋巴瘤感兴趣。然而，如果成功，这种方法可能会损害体液免疫，因为T细胞可能会长期存在。大多数低度淋巴瘤和慢性淋巴细胞白血病（B-CLL）细胞表达携带κ或λ轻链的单克隆免疫球蛋白。因此，我们探讨了是否可以通过基因修饰T淋巴细胞以靶向肿瘤相关轻链，而不影响表达相互轻链的B淋巴细胞，从而减少体液免疫的损害。我们发现表达抗K轻链CAR的T淋巴细胞在体外和体内均显示出对IG kappa（+）肿瘤细胞系和B-CLL细胞的细胞毒性活性。我们还发现，在CAR内掺入CD 28胞内结构域增强了肿瘤相关抗原刺激后转基因T细胞的体外和体内扩增。游离IG kappa（+）不会损害重定向T淋巴细胞消除IG kappa（+）肿瘤的能力，因为这些游离免疫球蛋白用于维持CAR-CD 28转基因T细胞的增殖。因此，过继转移的T淋巴细胞靶向适当的轻链可能是一个有用的免疫治疗方法来治疗B淋巴细胞恶性肿瘤，克隆表达免疫球蛋白，而不完全损害体液免疫。
There has been interest in generating T cells expressing chimeric artificial receptors (CARs) targeting CD19/CD20 antigens to treat B-cell lymphomas. If successful, however, this approach would likely impair humoral immunity because T cells may persist long-term. Most low-grade lymphoma and chronic lymphocytic leukemia (B-CLL) cells express monoclonal immunoglobulins carrying either kappa or lambda light chains. We, therefore, explored whether T lymphocytes could be genetically modified to target the tumor-associated light chain, sparing B lymphocytes expressing the reciprocal light chain, and consequently reduce impairment of humoral immunity. We found that T lymphocytes expressing the anti-K light chain CAR showed cytotoxic activity against Ig kappa(+) tumor cell lines and B-CLL cells both in vitro and in vivo. We also found that the incorporation of the CD28 endodomain within the CAR enhanced the in vitro and in vivo expansion of transgenic T cells after tumor-associated antigen stimulation. Free Ig kappa(+) did not compromise the ability of redirected T lymphocytes to eliminate Ig kappa(+) tumors be-cause these free immunoglobulins served to sustain proliferation of CAR-CD28 transgenic T cells. Thus, adoptive transfer of T lymphocytes targeting the appropriate light chain could be a useful immunotherapy approach to treat B-lymphocyte malignancies that clonally express immunoglobulin without entirely compromising humoral immunity.