Background

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).

Methods

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.

Results

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.

Conclusions

The preclinical data open further venues for the clinical use of CDH17 CAR-T cells as an immunotherapeutic strategy for SCLC treatment.

中文翻译：

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在小细胞肺癌中使用嵌合抗原受体重定向 T 细胞靶向 CDH17

背景

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且有针对性的方法。在这项研究中，我们研究了用 CDH17 CAR-T 细胞靶向钙粘蛋白 17 (CDH17) 作为小细胞肺癌 (SCLC) 治疗方式的可行性。

方法

使用 qPCR 和蛋白质印迹评估人 SCLC 肿瘤组织和细胞系中的 CDH17 表达水平。随后，我们建立了 CDH17 CAR-T 细胞，并通过将其与各种 SCLC 细胞系以不同的效应物与靶标 (E:T) 比例共培养来评估其细胞毒性，并辅以 ELISA 测定。为了确定 CDH17 CAR-T 细胞的特异性，我们对表达和不表达 CDH17（shRNA）的 SCLC 细胞进行了实验。此外，我们采用 SCLC 异种移植模型来评估 CDH17 CAR-T 细胞的体内功效。

结果

我们的结果揭示了 SCLC 组织和细胞系中 CDH17 的显着上调。CDH17 CAR-T 细胞在体外对 SCLC 细胞表现出强大的细胞毒活性，同时对 CDH17 缺陷的 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，CDH17 CAR-T 细胞治疗显着降低了体内 SCLC 衍生异种移植肿瘤的生长速度。值得注意的是，对照组和 CDH17 CAR-T 细胞治疗组之间没有观察到体重的显着差异。

结论

临床前数据为 CDH17 CAR-T 细胞作为 SCLC 治疗的免疫治疗策略的临床应用开辟了进一步的途径。