肿瘤细胞治疗研究
英文原题：Interleukin-21 engineering enhances CD19-specific CAR-NK cell activity against B-cell lymphoma via enriched metabolic pathways.
与共表达 IL-15 的 CAR-NK 细胞相比，共表达 IL-21 的 CAR-NK 细胞在响应 CD19 + Raji 淋巴瘤细胞时，IFN-、TNF- 和 Granzyme B 的产生以及脱颗粒均显著增加，从而在反复肿瘤刺激下表现出增强的细胞毒活性。
背景：工程化表达白细胞介素 15（IL-15）和 CD19 靶向嵌合抗原受体（CAR）的 NK 细胞已用于治疗复发和/或难治性 B 细胞恶性肿瘤，显示出令人鼓舞的结局和良好安全性，但 IL-21 在 CAR-NK 细胞疗法中的作用尚不清楚。方法：构建带 4-1BB 共刺激结构域的 CD19 特异性 CAR，并将 IL-21 或 IL-15 细胞因子基因导入外周血来源 NK 细胞，分别生成 CD19-CAR-IL21 NK 细胞（CAR-21）和 CD19-CAR-IL15 NK 细胞（CAR-15）。比较 CAR-21 与 CAR-15 NK 细胞的表型、转录组特征、功能和抗肿瘤活性。结果：与共表达 IL-15 的 CAR-NK 细胞相比，共表达 IL-21 的 CAR-NK 细胞响应 CD19⁺ Raji 淋巴瘤细胞时，IFN-γ、TNF-α 和颗粒酶 B 产生显著增加，脱颗粒增强；重复肿瘤刺激下细胞毒性也提高。此外，共表达 IL-21 可改善 CAR-NK 细胞体内持久性，并在 Raji 淋巴瘤异种移植小鼠模型中显著抑制肿瘤生长，延长 CD19⁺ 肿瘤负荷小鼠的生存。RNA 测序显示，与 CAR-15 NK 或未携带细胞因子的 CAR-NK 细胞相比，CAR-21 NK 具有独特的转录组特征，细胞因子、细胞毒性和代谢相关信号富集。结论：本研究显示，工程化表达 IL-21 的 CD19 特异性 CAR-NK 细胞相较共表达 IL-15 的 CAR-NK 细胞，具有更强持久性和抗 CD19⁺ 肿瘤活性，可能成为治疗复发或难治性 B 细胞恶性肿瘤的有前景策略。
BACKGROUND: NK cells engineered to express interleukin-15 (IL-15) and a CD19-targeted chimeric antigen receptor (CAR) have been used to treat patients with relapsed and/or refractory B cell malignances, demonstrating encouraging outcomes and favorable safety profile. However, the effect of IL-21 in CAR-NK cell therapy remains unknown. METHODS: CD19-specific CAR with 4-1BB costimulatory domain and cytokine IL-21 or IL-15 was constructed and transduced into peripheral blood (PB)-derived NK cells to produce CD19-CAR-IL21 NK cells (CAR-21) or CD19-CAR-IL15 NK cells (CAR-15), respectively. The phenotypic profile, transcriptomic characteristics, functionality and anti-tumor activity of CAR-21 NK cells and CAR-15 NK cells were compared. RESULTS: Compared with CAR-NK cells co-expressing IL-15, CAR-NK cells co-expressing IL-21 exhibited significantly increased IFN- , TNF- and Granzyme B production, as well as degranulation, in response to CD19 + Raji lymphoma cells, resulting in enhanced cytotoxic activity upon repetitive tumor stimulation. Furthermore, IL-21 co-expression improved the in vivo persistence of CAR-NK cells and significantly suppressed tumor growth in a xenograft Raji lymphoma murine model, leading to prolonged survival of CD19 + tumor-bearing mice. RNA sequencing revealed that CAR-21 NK cells have a distinct transcriptomic signature characterized by enriched in cytokine, cytotoxicity, and metabolic related signaling, when compared with CAR-15 NK or CAR NK cells. CONCLUSIONS: This study demonstrated that CD19-specific CAR-NK cells engineered to express IL-21 exhibit superior persistence and anti-tumor activity against CD19 + tumor compared to CAR-NK cells co-expressing IL-15, which might be a promising therapeutic strategy for treating patients with relapse or refractory B cell malignances.
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