Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy.

中文翻译：

---

CD8 跨膜区域固定的膜结合 IL-7 提高了 CD19 CAR-T 细胞疗法的疗效


提高 CD19 CAR-T 细胞疗法的疗效可以通过降低 CD19 + B 细胞恶性肿瘤的复发率来显着改善患者的预后。外源或转基因细胞因子通常用于促进 CAR-T 细胞的扩增和持久性，但存在严重毒性的风险。解决这些限制的一种有前途的方法是使用跨膜 （TM） 锚定结构域将细胞因子固定在 CAR-T 细胞表面。鉴于 IL-7 可以增强 T 细胞增殖和抗肿瘤活性，我们的研究使用不同的 TM 锚定结构域 （CD8、CD28 和 B7-1） 开发了膜结合的 IL-7 构建体。我们主要发现，与 CD28 和 B7-1 相比，CD8 TM 为 IL-7 提供了更好的锚定。此外，具有 CD8 TM （IL7/CD8） 的 IL-7 构建体增强了初始 T 细胞增殖和效应功能，并提高了 CD19 CAR-T 细胞的体外和体内抗肿瘤活性。重要的是，虽然 IL7/CD8 可以促进 T 细胞增殖，但它不能维持长期的自主扩增，这可以确保表达 IL7/CD8 的 CD19 CAR-T 细胞在临床应用中的安全性。总的来说，IL7/CD8 构建体代表了增强 CD19 CAR-T 细胞疗法治疗潜力的一种有前途的策略。