Second Department of Oncology, Cangzhou Central Hospital, NO.16 Xinhua West Road, Cangzhou, 061000, Hebei, China.
Medical Oncology, Cangzhou Central Hospital Hejian Branch, NO.32 Jingkai South Street, Hejian, 062450, Hebei, China.
Lung. 2023 Oct;201(5):489-497. doi: 10.1007/s00408-023-00648-0. Epub 2023 Oct 12.
Chimeric antigen receptor T cell (CAR-T) therapy stands as a precise and targeted approach in the treatment of malignancies. In this study, we investigated the feasibility of targeting Cadherin 17 (CDH17) with CDH17 CAR-T cells as a therapeutic modality for small cell lung cancer (SCLC).
CDH17 expression levels were assessed in human SCLC tumor tissues and cell lines using qPCR and Western blot. Subsequently, we established CDH17 CAR-T cells and assessed their cytotoxicity by co-culturing them with various SCLC cell lines at different effector-to-target (E:T) ratios, complemented by ELISA assays. To ascertain the specificity of CDH17 CAR-T cells, we conducted experiments on SCLC cells with and without CDH17 expression (shRNAs). Furthermore, we employed an SCLC xenograft model to evaluate the in vivo efficacy of CDH17 CAR-T cells.
Our results revealed a significant upregulation of CDH17 in both SCLC tissues and cell lines. CDH17 CAR-T cells exhibited robust cytotoxic activity against SCLC cells in vitro, while demonstrating no cytotoxicity towards CDH17-deficient SCLC cells and HEK293 cells that lack CDH17 expression. Importantly, the production of IFN-γ and TNF-α by CDH17 CAR-T cells correlated with their cytotoxic potency. Additionally, treatment with CDH17 CAR-T cells significantly decelerated the growth rate of SCLC-derived xenograft tumors in vivo. Remarkably, no significant difference in body weight was observed between the control group and the group treated with CDH17 CAR-T cells.
The preclinical data open further venues for the clinical use of CDH17 CAR-T cells as an immunotherapeutic strategy for SCLC treatment.
嵌合抗原受体 T 细胞（CAR-T）疗法是治疗恶性肿瘤的一种精确而靶向的方法。在这项研究中，我们研究了用靶向 Cadherin 17（CDH17）的 CDH17 CAR-T 细胞作为治疗小细胞肺癌（SCLC）的治疗方法的可行性。
使用 qPCR 和 Western blot 评估人 SCLC 肿瘤组织和细胞系中 CDH17 的表达水平。随后，我们建立了 CDH17 CAR-T 细胞，并通过与不同 E:T 比例的各种 SCLC 细胞系共培养，通过 ELISA 测定评估其细胞毒性。为了确定 CDH17 CAR-T 细胞的特异性，我们在有和没有 CDH17 表达（shRNAs）的 SCLC 细胞上进行了实验。此外，我们使用 SCLC 异种移植模型来评估 CDH17 CAR-T 细胞的体内疗效。
我们的结果显示，CDH17 在 SCLC 组织和细胞系中均显著上调。CDH17 CAR-T 细胞在体外对 SCLC 细胞具有强大的细胞毒性活性，而对缺乏 CDH17 的 SCLC 细胞和缺乏 CDH17 表达的 HEK293 细胞没有细胞毒性。重要的是，CDH17 CAR-T 细胞产生的 IFN-γ 和 TNF-α与其细胞毒性效力相关。此外，用 CDH17 CAR-T 细胞治疗显著减缓了体内 SCLC 衍生异种移植肿瘤的生长速度。值得注意的是，在对照组和用 CDH17 CAR-T 细胞治疗的组之间，体重没有观察到显著差异。
临床前数据为 CDH17 CAR-T 细胞作为治疗 SCLC 的免疫治疗策略的临床应用开辟了进一步的途径。
