A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.021
Wenqiang Shi, Wei Xu, Luyao Song, Qiongya Zeng, Gen Qi, Ying Qin, Zhikun Li, Xianglei Liu, Zheng Jiao, Yonggang Zhao, Nan Liu, Huili Lu
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Abstract

It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Rα-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-γ levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.

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一种肿瘤条件性 IL-15 可安全地与免疫疗法协同增强抗肿瘤免疫反应。
如何在激活肿瘤浸润淋巴细胞的同时不引起免疫相关不良反应是一项挑战,这也是导致癌症免疫疗法产生抗药性的主要因素。IL-15能有效促进T细胞的扩增和活化,但其临床应用一直受到剂量限制性毒性的限制。在这项研究中,我们开发了一种肿瘤条件IL-15(pro-IL-15),它利用Fc片段和IL-15Rα-sushi结构域造成的立体阻碍掩盖了IL-15。到达肿瘤部位后,它可被肿瘤相关蛋白酶裂解,释放出IL-15超拮抗剂,从而产生强大的抗肿瘤活性。全身给药的原-IL-15 毒性明显降低,但抗肿瘤疗效不受影响。原-IL-15能产生更好的效应因子,并能激活终末衰竭的CD8+ T细胞,从而克服检查点阻断剂的耐药性。此外,pro-IL-15 还能促进收养 T 细胞的趋化和活化,从而根除晚期实体瘤并实现持久治愈。此外,pro-IL-15 还能通过提高 CD8/Treg 比率和 IFN-γ 水平,与 IL-12 和溶瘤病毒等其他免疫疗法协同作用,从而使局部和转移性冷冻瘤大幅消退。总之,我们的研究结果表明,pro-IL-15 是克服对当前免疫疗法的抗药性同时避免毒性的一种令人信服的策略。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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