Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-10-23 DOI:10.1186/s12943-024-02154-0
Chaoting Zhang, Ting Liu, Shance Li, Xia Teng, Yuge Zhu, Guanyu Zhang, Huimin Xie, Kang Sun, Jiaxin Tu, Wenjun Yang, Zheming Lu
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Abstract

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.
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由 CD8 跨膜区固定的膜结合 IL-7 可提高 CD19 CAR-T 细胞疗法的疗效
提高 CD19 CAR-T 细胞疗法的疗效可以降低 CD19 + B 细胞恶性肿瘤的复发率,从而显著改善患者的预后。外源性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,但会带来严重的毒性风险。解决这些局限性的一种可行方法是利用跨膜(TM)锚域将细胞因子固定在 CAR-T 细胞表面。鉴于 IL-7 可增强 T 细胞增殖和抗肿瘤活性,我们的研究开发了使用不同 TM 锚定域(CD8、CD28 和 B7-1)的膜结合 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,带有 CD8 TM(IL7/CD8)的 IL-7 构建物能增强幼稚 T 细胞的增殖和效应功能,提高 CD19 CAR-T 细胞的体外和体内抗肿瘤活性。重要的是,虽然IL7/CD8能促进T细胞增殖,但不能维持长期自主扩增,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。总之,IL7/CD8构建体是提高CD19 CAR-T细胞治疗潜力的一种有前途的策略。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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