Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma
Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma
复制标题
DOI：
10.1182/blood-2011-05-354449
复制
发表时间：
2011-12-01
期刊：
影响因子：
20.3
通讯作者：
Brenner, Malcolm K.
中科院分区：
文献类型：
--
作者：
Louis, Chrystal U.;Savoldo, Barbara;Brenner, Malcolm K.
我们产生了针对神经母细胞瘤肿瘤细胞表达的GD2抗原的MHC非依赖性嵌合抗原受体(CARS)，并用于治疗这种疾病。这种CAR的两种不同形式表达于EBV特异性细胞毒性T淋巴细胞(EBV-CTL)和激活的T细胞(ATCs)。我们先前已经证明，表达GD2-CARS的EBV-CTL(CAR-CTL)在输注后早期循环的水平高于GD2-CAR ATCs(CAR-ATCs)，但到6周时，这两个亚群都变得很低或检测不到。我们现在报告了19例高危神经母细胞瘤患者输液的长期临床和免疫学后果：8例输液后缓解，11例活动性疾病。11例活动性疾病患者中有3例获得完全缓解，持续6周以上的CAR-ATCs或CAR-CTL与较好的临床结局相关。我们观察到CAR-ATCs持续时间长达192周，CAR-CTL持续时间长达96周，并且持续时间与输注产物中CD_4(+)细胞和中枢记忆细胞(CD45RO(+)CD62L(+))的百分比高度一致。总之，GD2-CAR T细胞可以在活动期神经母细胞瘤患者中诱导完全的肿瘤反应；这些CAR T细胞在患者中可能具有延长的、低水平的持久性，并且这种持久性与更长的生存期相关。这项研究在www.clinialtrials.gov上注册为#NCT00085930。(血。2011；118(23)：6050-6056)
We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4(+) cells and central memory cells (CD45RO(+) CD62L(+)) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930. (Blood. 2011;118(23):6050-6056)