肿瘤细胞治疗研究
英文原题：Construction of anti-HER2 affibody-directed CAR-NK and its synergistic effects with doxorubicin-loaded nanodrug against HER2-positive breast cancer.
这些发现表明，基于亲和体的 CAR-NK 细胞是传统基于 scFv 的 CAR 结构的可行替代方案。
引言：嵌合抗原受体（CAR）工程化T细胞或自然杀伤（NK）细胞，是一种有前景的癌症免疫治疗方法。CAR结构的领先区域通常是靶向肿瘤细胞表面分子的单链抗体片段（scFv），其他结构类型的报道较少。 方法：本研究利用亲和体分子作为胞外靶向结构域，替代传统scFv，开发了一种新型抗人表皮生长因子受体2（HER2）CAR-NK细胞。基于亲和体的CAR-NK细胞由NK-92细胞系制备。为增强安全性，对CAR-NK细胞进行γ射线照射，并进一步评估其与载多柔比星（DOX）纳米药物联合时的抗肿瘤活性。 结果：基于亲和体的CAR-NK细胞对HER2阳性乳腺癌细胞表现出有效细胞毒性，与抗HER2 scFv型CAR-NK细胞相当。10 Gy γ射线照射可有效抑制CAR-NK细胞的恶性增殖，但显著降低细胞毒活性。值得注意的是，加入载DOX纳米颗粒可显著增强经照射CAR-NK细胞的杀伤能力，恢复甚至进一步提高其抗肿瘤疗效。 讨论：这些发现表明，基于亲和体的CAR-NK细胞是传统scFv型CAR构建体的一种可行替代方案。此外，CAR-NK免疫疗法与化疗纳米药物联合，可有效弥补照射导致的细胞毒性减弱，为治疗HER2阳性乳腺癌提供了有前景的协同策略。
INTRODUCTION: Chimeric antigen receptor (CAR)-engineered T or natural killer (NK) cells are a promising approach for cancer immunotherapy. The leading region of the CAR structure is generally a single-chain antibody (scFv) fragment specific for a tumor cell surface molecule, and other structures are rarely reported. METHODS: In this study, we developed a novel anti-human epidermal growth factor receptor 2 (HER2) CAR-NK cell using an affibody molecule as the extracellular targeting domain instead of a conventional scFv. Affibody-based CAR-NK cells were generated from the NK-92 cell line. To enhance safety, CAR-NK cells were subjected to -irradiation, and their antitumor activity was further evaluated in combination with doxorubicin (DOX)-loaded nanoparticles. RESULTS: Affibody-based CAR-NK cells exhibited effective cytotoxicity against HER2-positive breast cancer cells, comparable to that of anti-HER2 scFv-based CAR-NK cells. -Irradiation at 10 Gy effectively inhibited malignant proliferation of CAR-NK cells but significantly reduced their cytotoxic activity. Notably, incorporation of DOX-loaded nanoparticles markedly enhanced the killing capacity of irradiated CAR-NK cells, restoring and even amplifying their antitumor efficacy. DISCUSSION: These findings demonstrate that affibody-based CAR-NK cells are a viable alternative to conventional scFv-based CAR constructs. Moreover, the combination of CAR-NK immunotherapy with chemotherapeutic nanomedicine effectively compensates for irradiation-induced cytotoxicity attenuation, offering a promising synergistic strategy for the treatment of HER2-positive breast cancer.
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