Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models
Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models
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EpCAM 特异性 CAR-T 细胞在免疫活性小鼠模型中产生的潜在肺部攻击和致死率
DOI：
10.1080/2162402x.2020.1806009
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Li, Qi-Jing
中科院分区：
文献类型：
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作者：
Qin, Diyuan;Li, Dan;Li, Qi-Jing
摘要 人类 CAR-T 细胞的杀瘤效率通常使用免疫缺陷小鼠模型进行评估；然而，由于它们的免疫功能低下和目标抗原的物种特异性反应性，这些模型在临床上模拟 CAR-T 引起的不良反应时存在问题。上皮细胞粘附分子（EpCAM）是一种明显存在于各种癌症细胞表面的肿瘤相关抗原，使其成为 CAR-T 疗法的有吸引力的靶点。在这里，我们开发了一种抗小鼠 EpCAM CAR，以评估其在免疫功能正常的小鼠模型中的安全性和有效性。正如之前报道的人类同类细胞一样，鼠 EpCAM CAR-T 细胞在体外和体内表现出有希望的抗肿瘤功效。然而，输注 CAR-T 后，在荷瘤小鼠和无瘤小鼠中均观察到各种剂量依赖性毒性，包括体重减轻、细胞因子释放综合征 (CRS) 和死亡。病理检查显示由于正常肺中基础 EpCAM 表达导致意外且严重的肺部免疫病理学变化。虽然我们的研究验证了 EpCAM CAR-T 的强大抗肿瘤功效，但它也揭示了用于治疗实体瘤的 EpCAM CAR-T 细胞可能会引起致命毒性，因此应谨慎对患者进行评估。
ABSTRACT The tumoricidal efficiency of human CAR-T cells is generally evaluated using immune-deficient mouse models; however, due to their immune-incompetency and the species-specific reactivity of a target antigen, these models are problematic to imitate CAR-T-induced adverse effects in the clinic. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen overtly presented on the cell surface of various carcinomas, making it an attractive target for CAR-T therapy. Here, we developed an anti-mouse EpCAM CAR to evaluate its safety and efficacy in immunocompetent mouse models. As previously reported for their human equivalents, murine EpCAM CAR-T cells exhibit promising anti-tumor efficacy in vitro and in vivo. However, after CAR-T infusion, various dose-depended toxicities including body weight loss, cytokine-release syndrome (CRS), and death were observed in both tumor-bearing and tumor-free mice. Pathological examination revealed unexpected and severe pulmonary immunopathology due to basal EpCAM expression in normal lung. While our study validates EpCAM CAR-T’s potent anti-tumor efficacy, it also reveals that EpCAM CAR-T cells used for the treatment of solid tumors may cause lethal toxicity and should, therefore, be evaluated in patients with caution.