肿瘤细胞治疗研究
英文原题：Precision targeting of rhabdomyosarcoma by combining primary CAR NK cells and radiotherapy.
本研究为 EGFR-CAR NK 细胞作为 RMS 的一种有前景的免疫疗法提供了概念验证，尤其是与放疗联合使用时，可克服实体瘤的障碍。
背景：横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤类型，在高危和转移性患者中仍是一种治疗困难、预后不佳的癌症。本研究报道了使用靶向表皮生长因子受体（EGFR）的嵌合抗原受体（CAR）自然杀伤（NK）细胞联合放疗作为一种新型免疫治疗方法用于RMS治疗。方法：使用慢病毒转导对来自健康供体的原代人NK细胞进行工程化改造，以表达基于西妥昔单抗的EGFR特异性CAR。随后在体外评估工程化NK细胞裂解RMS细胞的能力，包括在RMS单层细胞和球状体中，以及针对化疗耐药和患者来源的原代RMS细胞。在皮下RMS异种移植模型中使用活体成像观察NK细胞的迁移特性，并分析EGFR-CAR NK细胞联合局部分次放疗的疗效。结果：原代人EGFR-CAR NK细胞在二维培养和三维球状体模型中均表现出对多种RMS细胞系增强的细胞毒性。此外，EGFR-CAR NK细胞对化疗耐药的RMS细胞和患者来源样本具有高度杀伤效率。重要的是，在体内RMS异种移植模型中，EGFR-CAR NK细胞还表现出较未转导NK细胞改善的肿瘤归巢能力。值得注意的是，EGFR-CAR NK细胞治疗与分次放疗联合进一步增强了NK细胞向肿瘤的浸润并减少了肿瘤生长。结论：本研究为EGFR-CAR NK细胞作为RMS一种有前景的免疫疗法提供了概念验证，尤其是与放疗联合以克服实体瘤的屏障时。这种联合方法可能有望改善RMS和其他表达EGFR的恶性肿瘤患者的预后。
Background: Rhabdomyosarcoma (RMS) is the most common type of soft-tissue sarcoma in children, and it remains a challenging cancer with poor outcomes in high-risk and metastatic patients. This study reports the use of epidermal growth factor receptor (EGFR)-targeted chimeric antigen receptor (CAR) natural killer (NK) cells in combination with radiotherapy as a novel immunotherapeutic approach for RMS treatment. Methods: Primary human NK cells from healthy donors were engineered using lentiviral transduction to express a cetuximab-based EGFR-specific CAR. The ability of the engineered NK cells to lyse RMS cells was then assessed in vitro in RMS monolayers and spheroids, as well as against chemotherapy-resistant and primary patient-derived RMS cells. Migratory properties of NK cells were observed in a subcutaneous RMS xenograft model using in vivo imaging, and the efficacy of EGFR-CAR NK cells in combination with localized fractionated radiotherapy was analyzed. Results: Primary human EGFR-CAR NK cells demonstrated enhanced cytotoxicity against multiple RMS cell lines in both two-dimensional culture and three-dimensional spheroid models. Furthermore, EGFR-CAR NK cells were highly efficient against chemotherapy-resistant RMS cells and patient-derived samples. Importantly, EGFR-CAR NK cells also exhibited improved tumor homing compared with non-transduced NK cells in an in vivo RMS xenograft model. Notably, the combination of EGFR-CAR NK cell therapy with fractionated radiotherapy further enhanced NK cell infiltration into the tumor and reduced tumor growth. Conclusion: This study provides a proof-of-concept for EGFR-CAR NK cells as a promising immunotherapy for RMS, particularly when combined with radiotherapy to overcome barriers of solid tumors. This combinatorial approach may hold potential to improve outcomes for patients with RMS and other EGFR-expressing malignancies.
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