用小格式免疫细胞因子靶向 PD-1+ T 细胞可增强 IL-12 的抗肿瘤活性。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Noelia Silva-Pilipich, Uxue Beloki, Patricia Apaolaza, Ana Igea, Laura Salaberry, Laura Prats-Mari, Eric Rovira, Marina Ondiviela, Marta Gorraiz, Juan José Lasarte, Lucía Vanrell, Cristian Smerdou
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引用次数: 0

摘要

免疫刺激细胞因子和免疫检查点抑制剂有望成为癌症治疗药物;然而,它们的使用往往因疗效降低和毒性显著而受到限制。在这项研究中,我们开发了基于白细胞介素-12(IL-12)的小分子免疫细胞因子(ICK),以及针对小鼠和人类 PD-1 和 PD-L1 的阻断纳米抗体。与单独使用IL-12相比,PD-1和PD-L1靶向的ICK在体外表现相似,都能显著增加IL-12与免疫细胞的系留,提高T细胞的细胞毒活性。ICKs 的抗肿瘤功效是通过使用基于 RNA 的自扩增载体或作为重组蛋白在小鼠体内进行瘤内递送来评估的。尽管PD-L1介导的肿瘤锚定有效且体外结果良好,但只有当通过抗PD-1纳米抗体实现对瘤内T细胞的特异性靶向时,IL-12的抗肿瘤活性才会显著增强。通过电穿孔 DNA/RNA 分层载体递送 PD-1 特异性 ICK 时,也能观察到这种效果。我们的研究结果表明,在IL-12疗法中,靶向肿瘤微环境中适当类型的细胞可能优于肿瘤锚定策略。我们还开发了这些ICK的人类版本,它们在人类免疫细胞中显示出活性,为临床转化提供了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting PD-1+ T cells with small-format immunocytokines enhances IL-12 antitumor activity.

Immunostimulatory cytokines and immune checkpoint inhibitors hold promise as cancer therapeutics; however, their use is often limited by reduced efficacy and significant toxicity. In this study, we developed small-format immunocytokines (ICKs) based on interleukin-12 (IL-12) and blocking nanobodies (Nbs) targeting mouse and human programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). Both PD-1- and PD-L1-targeted ICKs demonstrated similar in vitro performance, significantly increasing IL-12 tethering to immune cells and enhancing T cell cytotoxic activity compared with IL-12 alone. The antitumor efficacy of ICKs was evaluated by intratumoral delivery using self-amplifying RNA-based vectors or as recombinant proteins in mice. Despite effective PD-L1-mediated tumor anchoring and promising in vitro results, IL-12 antitumor activity was significantly enhanced only when specific targeting to intratumoral T cells was achieved via anti-PD-1 Nb. This effect was also observed when the PD-1 specific ICK was delivered by electroporation of a DNA/RNA layered vector. Our findings suggest that targeting the appropriate type of cell within the tumor microenvironment could outperform tumor-anchoring strategies in the context of IL-12 therapy. Human versions of these ICKs were also developed, which showed to be active in human immune cells, opening an opportunity for clinical translation.

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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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