利用car靶修饰的细胞外囊泡,通过靶向细胞因子递送系统改善car - t细胞功能。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Yuanyuan Zhang, Meijuan Huang, Shujia Zhang, Tianjiao Liu, Shanwei Ye, Yuhang Cheng, Yang Cao, Liting Chen, Li Zhu, Xueyan Sun, Kefeng Shen, Qian Xu, Tongjuan Li, Dengju Li, Liang Huang, Wei Mu, Lei Zhao, Jue Wang
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引用次数: 0

摘要

嵌合抗原受体(CAR)- t细胞疗法在治疗b细胞恶性肿瘤方面取得了显著的临床成功;然而,在某些情况下,其疗效可能受到t细胞持久性差和抗肿瘤活性不足的限制。此外,白细胞介素-12 (IL-12)是癌症免疫治疗中的重要药物,但其临床应用受到全身暴露相关的严重毒性的限制。在这项研究中,我们开发了一种基于CAR靶向修饰的细胞源性细胞外囊泡(ev)的新型细胞因子递送平台,该平台优先结合CAR- t细胞以改善CAR- t细胞的功能。HEK-293T细胞成功生成表面显示CD19和/或IL-12的电动汽车。与同等浓度的rhIL-12相比,IL-12 ev在体外显著增强抗cd19 CAR-T细胞的效应功能,导致干扰素γ (IFN-γ)和TNF-α分泌增加,细胞溶解活性增加,t细胞扩增。此外,流式细胞术显示,与单独表达IL-12的ev相比,共表达IL-12和CD19 (CD19/IL-12 ev)的ev与CAR-T细胞的结合效率更高,而与T细胞的结合效率不高。在携带CD19 + Raji肿瘤的异种移植模型小鼠中,瘤内注射CD19/IL-12 ev可产生持久的抗肿瘤反应,并增强CAR-T细胞的体内扩增,优于CD19 ev、IL-12 ev和对照ev,且不会引起全身毒性。对ev刺激的CAR-T细胞的RNA测序(RNA-seq)分析表明,提高的疗效是由IL-12信号驱动的。这些数据表明,car靶向修饰的ev可以作为CAR-T细胞的靶向细胞因子递送系统,为增强CAR-T细胞功能提供了一种安全有效的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Improving CAR-T cell function through a targeted cytokine delivery system utilizing car target-modified extracellular vesicles.

Chimeric antigen receptor (CAR)-T-cell therapy has achieved remarkable clinical success in the treatment of B-cell malignancies; however, its efficacy can be limited by poor T-cell persistence and insufficient antitumor activity in certain cases. Moreover, interleukin-12 (IL-12) is a prominent agent in cancer immunotherapy, but its clinical application is constrained by severe toxicity associated with systemic exposure. In this study, we developed a novel cytokine delivery platform based on CAR target-modified cell-derived extracellular vesicles (EVs) that preferentially bind CAR-T cells to improve CAR-T-cell function. EVs with surface-displayed CD19 and/or IL-12 were successfully generated from HEK-293T cells. Compared with an equivalent concentration of rhIL-12, IL-12 EVs significantly enhanced the effector function of anti-CD19 CAR-T cells in vitro, resulting in increased Interferon-γ (IFN-γ) and TNF-α secretion, cytolytic activity, and T-cell expansion. Additionally, compared with EVs expressing IL-12 alone, EVs co-expressing IL-12 and CD19 (CD19/IL-12 EVs) exhibited superior binding efficiency to CAR-T cells but not to T cells, as indicated by flow cytometry. In xenograft model mice bearing CD19 + Raji tumors, intratumoral injection of CD19/IL-12 EVs resulted in durable antitumor responses and enhanced the in vivo expansion of CAR-T cells, outperforming CD19 EVs, IL-12 EVs and control EVs, without causing systemic toxicity. RNA sequencing (RNA-seq) analysis of CAR-T cells stimulated with EVs suggested that the increased efficacy was driven by IL-12 signaling. These data demonstrate that CAR-targeted modified EVs may serve as targeted cytokine delivery systems for CAR-T cells, offering a safe and effective strategy to augment CAR-T-cell function.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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