Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Laboratory of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan.
Sci Rep. 2024 Aug 2;14(1):17917. doi: 10.1038/s41598-024-68779-9.
Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.
嵌合抗原受体 (CAR) T 细胞在对抗血液系统癌症方面非常有效，但在对抗非小细胞肺癌 (NSCLC) 等实体瘤方面效果较差。原因之一是仅鉴定出少数针对 NSCLC 细胞的特异性细胞表面靶标。在这里，我们报告 CD98 重链 (hc) 蛋白在 NSCLC 细胞表面过表达，是针对 NSCLC 的 CAR T 细胞的潜在靶标。对超过 10,000 个针对 NSCLC 细胞系的 mAb 克隆进行筛选后发现，mAb H2A011 与 NSCLC 细胞结合，但不与正常肺上皮细胞结合。H2A011 识别 CD98hc。尽管可能由于激活的 T 细胞中 H2A011 反应性水平较高，因此无法从 H2A011 衍生的 CAR T 细胞，但已显示缺乏与正常造血细胞和一些正常组织上表达的 CD98hc 糖型反应性的抗 CD98hc mAb R8H283 衍生的 CAR T 细胞可以成功开发。R8H283 在 15 名患者中的 6 名中与 NSCLC 细胞特异性反应。R8H283 衍生的 CAR T 细胞在体内 NSCLC 异种移植模型中发挥了显著的抗肿瘤作用。这些结果表明，尽管未来应谨慎测试脱靶反应，但 R8H283 CAR T 细胞可能成为 NSCLC 的一种新的治疗工具。
