Chu Jianhong, He Shun, Deng Youcai, Zhang Jianying, Peng Yong, Hughes Tiffany, Yi Ling, Kwon Chang-Hyuk, Wang Qi-En, Devine Steven M, He Xiaoming, Bai Xue-Feng, Hofmeister Craig C, Yu Jianhua
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Clin Cancer Res. 2014 Aug 1;20(15):3989-4000. doi: 10.1158/1078-0432.CCR-13-2510. Epub 2014 Mar 27.
Our goal is to test whether CS1 could be targeted by chimeric antigen receptor (CAR) T cells to treat multiple myeloma (MM).
We generated a retroviral construct of a CS1-specific CAR and engineered primary human T cells expressing the CAR. We then tested the capacity of CS1-CAR T cells to eradicate human MM tumor cells in vitro, ex vivo, and in vivo using orthotopic MM xenograft mouse models.
In vitro, compared with mock-transduced T cells, upon recognizing CS1-positive MM cells, CS1-CAR-transduced T cells secreted more IFN-γ as well as interleukin (IL)-2, expressed higher levels of the activation marker CD69, showed higher capacity for degranulation, and displayed enhanced cytotoxicity. Ectopically forced expression of CS1 in MM cells with low CS1 expression enhanced recognition and killing by CAR T cells. Ex vivo, CS1-CAR T cells also showed similarly enhanced activities when responding to primary MM cells. More importantly, in orthotopic MM xenograft mouse models, adoptive transfer of human primary T cells expressing CS1-CAR efficiently suppressed the growth of human MM.1S and IM9 myeloma cells and significantly prolonged mouse survival.
CS1 is a promising antigen that can be targeted by CAR-expressing T cells for treatment of MM.
我们的目标是测试嵌合抗原受体（CAR）T细胞是否可以靶向CS1来治疗多发性骨髓瘤（MM）。
我们构建了一种CS1特异性CAR的逆转录病毒载体，并对表达该CAR的原代人T细胞进行工程改造。然后，我们使用原位MM异种移植小鼠模型，测试了CS1-CAR T细胞在体外、离体和体内根除人MM肿瘤细胞的能力。
在体外，与模拟转导的T细胞相比，识别CS1阳性MM细胞后，转导CS1-CAR的T细胞分泌更多的干扰素-γ以及白细胞介素（IL）-2，表达更高水平的活化标志物CD69，显示出更高的脱颗粒能力，并表现出增强的细胞毒性。在低CS1表达的MM细胞中异位强制表达CS1可增强CAR T细胞的识别和杀伤能力。在离体实验中，CS1-CAR T细胞在对原代MM细胞作出反应时也表现出类似的增强活性。更重要的是，在原位MM异种移植小鼠模型中，表达CS1-CAR的人原代T细胞的过继转移有效地抑制了人MM.1S和IM9骨髓瘤细胞的生长，并显著延长了小鼠的生存期。
CS1是一种有前景的抗原，可被表达CAR的T细胞靶向用于治疗MM。
