Li Sujun, Xue Lei, Wang Min, Qiang Ping, Xu Hui, Zhang Xuhan, Kang Wenyao, You Fengtao, Xu Hanying, Wang Yu, Liu Xin, Yang Lin, Wang Xingbing
Department of Hematology of Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Onco Targets Ther. 2019 Jul 12;12:5627-5638. doi: 10.2147/OTT.S198567. eCollection 2019.
CD19-directed chimeric antigen receptor (CAR) T cells have substantial benefit in the treatment of patients with B-cell malignancies. However, despite encouraging therapeutic efficiency, there is limited overall response rate when anti-CD19 CAR-T cells are used to treat patients with relapsed and refractory (R/R) B cell lymphomas. Therefore, it further investigation is urgently needed to improve treatment efficacy. A combined treatment protocol of CAR-T cell with decitabine (DAC) to treat B cell lymphoma was developed and tested on lymphoma cell lines first, and then efficacy and the underlying mechanism were investigated. After ethical approval was granted, the combined treatment protocol was applied to treat two patients with R/R B-cell lymphomas. CAR-T cells were prepared successfully, and they recognized CD19 antigen expressed on lymphoma cell lines specifically. Cell-line studies also showed that CD19 antigen expression was increased by DAC pretreatment, and the function of CAR-T cells was not compromised. The cell-line study further demonstrated that lymphoma cells pretreated by DAC responded more to the treatment of CAR-T cells. Two patients with R/R B cell lymphoma were pretreated with DAC then treated with CAR-T, and both achieved complete remission (CR). The epigenetic modifying drug DAC increases expression of the surface antigen CD19 on lymphoma cells. The DAC pretreatment protocol may lead patients with B cell lymphoma to be more susceptible to adoptive transfer of anti-CD19 CAR-T cells treKeywordsatment.
靶向CD19的嵌合抗原受体（CAR）T细胞在治疗B细胞恶性肿瘤患者方面具有显著益处。然而，尽管治疗效果令人鼓舞，但使用抗CD19 CAR-T细胞治疗复发难治性（R/R）B细胞淋巴瘤患者时，总体缓解率仍然有限。因此，迫切需要进一步研究以提高治疗效果。开发了一种CAR-T细胞与地西他滨（DAC）联合治疗B细胞淋巴瘤的方案，并首先在淋巴瘤细胞系上进行测试，然后研究其疗效和潜在机制。在获得伦理批准后，该联合治疗方案应用于治疗两名R/R B细胞淋巴瘤患者。成功制备了CAR-T细胞，它们能特异性识别淋巴瘤细胞系上表达的CD19抗原。细胞系研究还表明，DAC预处理可增加CD19抗原表达，且不损害CAR-T细胞的功能。细胞系研究进一步证明，经DAC预处理的淋巴瘤细胞对CAR-T细胞治疗的反应更强。两名R/R B细胞淋巴瘤患者先接受DAC预处理，然后接受CAR-T治疗，均实现完全缓解（CR）。表观遗传修饰药物DAC可增加淋巴瘤细胞表面抗原CD19的表达。DAC预处理方案可能使B细胞淋巴瘤患者更易接受抗CD19 CAR-T细胞的过继性转移治疗。
