CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients
CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients
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DOI：
10.1172/jci46110
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
--
作者：
Savoldo, Barbara;Ramos, Carlos Almeida;Dotti, Gianpietro
使用表达肿瘤导向嵌合抗原受体(CARS)的工程T淋巴细胞的靶向T细胞免疫疗法旨在使癌症患者受益。尽管在这些CARS中加入共刺激内域增加了CAR重定向T淋巴细胞的增殖，但由于缺乏与只有一个信号域的T细胞的并列比较，关于共刺激内域对CAR重定向T细胞在人体内的扩张、持久性和抗肿瘤有效性的具体影响，已被证明很难得出明确的结论。因此，我们设计了一项研究，使我们能够直接测量向CAR重定向的T细胞添加共刺激内域的后果。B细胞淋巴瘤患者同时输注两种自体T细胞产品，表达CD19抗原的CARS与大多数B细胞恶性肿瘤存在相同的特异性。一个CAR同时编码共刺激CD28和Zeta-内域，而另一个CAR只编码Zeta-内域。与不含CD28内区的CAR(+)T细胞相比，含有CD28内区的CAR(+)T细胞的扩张性和持久性显著增强。这些结果证明了具有双重信号域的CARS的优越性，并证实了一种在单个患者中比较CAR修饰的T细胞的方法，从而避免了患者之间的差异，并加速了最佳T细胞免疫疗法的发展。
Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARS increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARS with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the zeta-endodomains, while the other encoded only the zeta-endodomain. CAR(+) T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR(+) T cells lacking this endodomain. These results demonstrate the superiority of CARS with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell imtnunotherapies.