Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model
Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model
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DOI：
10.1016/j.omto.2020.05.013
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发表时间：
2020-09-25
影响因子：
5.7
通讯作者：
Nakazawa, Yozo
中科院分区：
文献类型：
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作者：
Tanaka, Kuniaki;Kato, Itaru;Nakazawa, Yozo
抗CD 19嵌合抗原受体（CAR）T细胞在临床试验中显示出对骨髓（BM）中的急性淋巴细胞白血病（ALL）的优异效果。然而，CD 19 CART细胞疗法是否对中枢神经系统（CNS）中的ALL细胞有效仍有待阐明，因为患有孤立或晚期CNS疾病的患者被排除在全身静脉内（i. v.）CAR T细胞的递送。因此，临床前评估CAR T细胞疗法对CNS中ALL细胞的疗效对于临床应用至关重要。我们使用异种移植小鼠模型，通过i. v.或脑室内（i. c. v.）CAR T细胞的递送。通过i. v.注射piggyBac CD 19 CAR T细胞具有部分作用，而所有CAR T i. c. v.递送的小鼠已经消除了CNS中的ALL。虽然一些CART i. c. v. -递送的小鼠在治疗后的最初几天内显示出临床症状的短暂变化，CAR T i.递送的小鼠显示出致命的不良事件。在这项研究中，我们证明了将CAR T细胞直接递送到CNS中是异种移植小鼠模型的一种可能的治疗方法。
The anti-CD19 chimeric antigen receptor (CAR) T cells showed excellent effect against acute lymphoblastic leukemia (ALL) in bone marrow (BM) in clinical trials. However, it remains to be elucidated whether the CD19 CART cell therapy is effective for ALL cells in central nervous system (CNS) because the patients with isolated or advanced CNS disease were excluded from clinical trials of systemic intravenous (i.v.) delivery of CAR T cells. Therefore, the preclinical evaluation for the efficacy of CAR T cell therapy against ALL cells in CNS is essential for clinical application. We evaluated the effect and adverse reaction of CD19 CART cells against ALL in CNS using a xenograft mouse model by i.v. or intra-cerebroventricular (i.c.v.) delivery of CAR T cells. Injection of piggyBac CD19 CAR T cells by i.v. had partial effects, whereas all CAR T i.c.v.-delivered mice had eliminated ALL in CNS. Although some CART i.c.v.-delivered mice showed transient changes of clinical symptoms during the first few days after treatment, none of CAR T i.c.v.-delivered mice displayed fatal adverse events. In this study, we demonstrated that direct delivery into CNS of CAR T cells is a possible therapeutic approach with the xenograft mouse model.