肿瘤细胞治疗研究
英文原题：Interleukin 21-Armed EGFR-VHH-CAR-T Cell Therapy for the Treatment of Esophageal Squamous Cell Carcinoma.
我们的结果表明，hIL-21 装甲的、纳米抗体衍生的、EGFR 特异性 CAR-T 细胞疗法是治疗 ESCC 患者的一种极具前景的选择。
背景/目的：食管鳞状细胞癌（ESCC）是食管癌的一种常见类型，预后差且治疗选择有限。表皮生长因子受体（EGFR）在所有 ESCC 患者中均为过表达的致癌基因，是开发针对 ESCC 疗法的有吸引力的靶点。目前极其迫切需要开发靶向 EGFR 的免疫治疗工具用于 ESCC 的治疗。方法：在本研究中，我们开发了携带人白细胞介素-21（hIL-21）的、靶向 EGFR 的嵌合抗原受体修饰 T（CAR-T）细胞作为一种新的治疗手段。该 CAR 包含源自羊驼重链抗体重链可变域（VHH），也称为纳米抗体（Nbs），作为 CAR-T 开发中常用单链可变片段（ScFv）的有前景的替代物。结果：我们证明，源自纳米抗体的、靶向 EGFR 的 CAR-T 细胞在体外和动物模型中特异性杀伤 EGFR 阳性食管癌细胞。CAR-T 细胞中的人 IL-21 表达进一步改善了其扩增和抗肿瘤能力，并且在体外与 ESCC 细胞系共培养时观察到分泌更多的干扰素-γ（IFN-）、肿瘤坏死因子α（TNF-）和白细胞介素-2（IL-2）。在表达 hIL-21 的 CAR-T 细胞中检测到更多的 CD8 + CAR-T 细胞和 CD3 + CD8 + CD45RO + CD62L + 中枢记忆 T 细胞。值得注意的是，表达 hIL-21 的 CAR-T 细胞在 KYSE-150 异种移植小鼠模型中显示出更优越的体内抗肿瘤活性。结论：我们的结果表明，携带 hIL-21 的、源自纳米抗体的、EGFR 特异性 CAR-T 细胞疗法是治疗 ESCC 患者极具前景的选择。
Background/Objectives: Esophageal squamous cell carcinoma (ESCC) is a common form of esophageal cancer with a poor prognosis and limited treatment options. Epidermal growth factor receptor (EGFR), an overexpressed oncogenic gene in all ESCC patients, is an attractive target for developing therapies against ESCC. There is an extremely urgent need to develop immunotherapy tools targeting EGFR for the treatment of ESCC. Methods: In this study, we developed human Interleukin-21 (hIL-21)-armed, chimeric-antigen-receptor-modified T (CAR-T) cells targeting EGFR as a new therapeutic approach. The CAR contains a variable domain of the llama heavy chain of heavy-chain antibodies (VHHs), also known as nanobodies (Nbs), as a promising substitute for the commonly used single-chain variable fragment (ScFv) for CAR-T development. Results: We show that nanobody-derived, EGFR-targeting CAR-T cells specifically kill EGFR-positive esophageal cancer cells in vitro and in animal models. Human IL-21 expression in CAR-T cells further improved their expansion and antitumor ability and were observed to secrete more interferon-gamma (IFN- ), tumor necrosis factor alpha (TNF- ), and Interleukin-2 (IL-2) when co-cultured with ESCC cell lines in vitro. More CD8 + CAR-T cells and CD3 + CD8 + CD45RO + CD62L + central memory T cells were detected in CAR-T cells expressing hIL-21 cells. Notably, hIL-21-expressing CAR-T cells showed superior antitumor activity in vivo in a KYSE-150 xenograft mouse model. Conclusions: Our results show that hIL-21-armed, nanobody-derived, EGFR-specific CAR-T cell therapy is a highly promising option for treating ESCC patients.
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