Tanaka Kuniaki, Kato Itaru, Tanaka Miyuki, Morita Daisuke, Matsuda Kazuyuki, Takahashi Yoshiyuki, Nakahata Tatsutoshi, Umeda Katsutsugu, Hiramatsu Hidefumi, Adachi Souichi, Takita Junko, Nakazawa Yozo
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
Mol Ther Oncolytics. 2020 May 26;18:37-46. doi: 10.1016/j.omto.2020.05.013. eCollection 2020 Sep 25.
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 CAR T 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 CAR T 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 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 CAR T 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.
在临床试验中，抗CD19嵌合抗原受体（CAR）T细胞对骨髓中的急性淋巴细胞白血病（ALL）显示出优异疗效。然而，由于患有孤立性或进展性中枢神经系统（CNS）疾病的患者被排除在CAR T细胞全身静脉注射（i.v.）临床试验之外，CD19 CAR T细胞疗法对CNS中的ALL细胞是否有效仍有待阐明。因此，对CAR T细胞疗法针对CNS中ALL细胞的疗效进行临床前评估对于临床应用至关重要。我们通过静脉注射或脑室内（i.c.v.）递送CAR T细胞，使用异种移植小鼠模型评估了CD19 CAR T细胞对CNS中ALL的作用及不良反应。静脉注射CD19 CAR T细胞有部分效果，而所有经脑室内递送CAR T细胞的小鼠在CNS中均清除了ALL。尽管一些经脑室内递送CAR T细胞的小鼠在治疗后的头几天出现了临床症状的短暂变化，但没有经脑室内递送CAR T细胞的小鼠出现致命不良事件。在本研究中，我们证明了在异种移植小鼠模型中，将CAR T细胞直接递送至CNS是一种可行的治疗方法。
