Sabha Youssef, Kim Sang Hoon, Tseng Hsiang-Chi, Byrne Maeve Elizabeth, Tsao Wei-Chung, Lee Sang Hoon, Zhou Zhongren, Jang Mi-Hyeon, Liu Dongfang
Department of Pathology, Immunology and Laboratory Medicine, Rutgers University New Jersey Medical School, 180 South Orange Avenue, Newark, NJ 07103, USA.
Department of Neurosurgery, Robert Wood Johnson Medical School, The State University of New Jersey, 661 Hoes Lane West, Piscataway, NJ 08854, USA.
Mol Ther Oncol. 2025 Feb 26;33(1):200957. doi: 10.1016/j.omton.2025.200957. eCollection 2025 Mar 20.
The toxicity of chimeric antigen receptor-natural killer (CAR-NK) therapy has not been tested in solid tumors, compared with CAR-T therapy side by side. To address this, we investigated the CD147-CAR-NK "on-target/off-tumor" toxicity and neurotoxicity in human CD147-transgenic (hCD147TG) mice with hepatocellular carcinoma (HCC). We first tested the cytotoxicity of CD147-CAR-NK against CD147 tumor and CD147 healthy cells. Both CD147-CAR-NK cells and CD147-IL15-CAR-NK (autocrine expressing interleukin [IL]-15) can kill tumor cells specifically but not CD147 healthy lung and spleen tissue from hCD147TG mice. assays show minimal systemic toxicities against CD147 healthy tissues but 1-week-longer persistence times in tumor than non-tumor tissues. To evaluate neurotoxicity, we compared the expression of ionized calcium-binding adaptor protein 1 (IBA1), glial fibrillary acidic protein (GFAP), and inducible nitric oxide synthase (iNOS) between CD147-CAR-T- and CD147-CAR-NK-treated hCD147TG mice with HCC. Both CD147-CAR-T- and CD147-CAR-NK-treated mice exhibited higher GFAP and IBA1 expression than control groups. CD147-CAR-T-treated mice showed an increase in iNOS compared to the control groups. The behavioral studies testing spatial memory showed that mice treated with CD147-CAR-NK exhibit better memory function than CD147-CAR-T-treated mice. This study provides a deeper understanding of the CD147-CAR-NK systemic toxicities and neurotoxicity of CD147-CAR-NK relative to CD147-CAR-T therapy.
与嵌合抗原受体T细胞（CAR-T）疗法相比，嵌合抗原受体自然杀伤细胞（CAR-NK）疗法在实体瘤中的毒性尚未得到测试。为了解决这一问题，我们在患有肝细胞癌（HCC）的人CD147转基因（hCD147TG）小鼠中研究了CD147-CAR-NK的“靶向/脱瘤”毒性和神经毒性。我们首先测试了CD147-CAR-NK对CD147肿瘤细胞和CD147健康细胞的细胞毒性。CD147-CAR-NK细胞和CD147-IL15-CAR-NK（自分泌表达白细胞介素[IL]-15）都能特异性杀死肿瘤细胞，但不会杀死来自hCD147TG小鼠的CD147健康肺组织和脾脏组织。检测显示，对CD147健康组织的全身毒性极小，但在肿瘤组织中的持续时间比非肿瘤组织长1周。为了评估神经毒性，我们比较了CD147-CAR-T和CD147-CAR-NK治疗的hCD147TG HCC小鼠之间离子钙结合衔接蛋白1（IBA1）、胶质纤维酸性蛋白（GFAP）和诱导型一氧化氮合酶（iNOS）的表达。CD147-CAR-T和CD147-CAR-NK治疗的小鼠均表现出比对照组更高的GFAP和IBA1表达。与对照组相比，CD147-CAR-T治疗的小鼠iNOS增加。测试空间记忆的行为研究表明，CD147-CAR-NK治疗的小鼠比CD147-CAR-T治疗的小鼠表现出更好的记忆功能。这项研究更深入地了解了CD147-CAR-NK相对于CD147-CAR-T疗法的全身毒性和神经毒性。
