RNA-encoded Interleukin 2 with Extended Bioavailability Amplifies RNA Vaccine-Induced Antitumor T-cell Immunity.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Daniel Peters, Lena M Kranz, David Eisel, Mustafa Diken, Sebastian Kreiter, Özlem Türeci, Ugur Sahin, Mathias Vormehr
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引用次数: 0

Abstract

Interleukin 2 (IL-2) is a crucial cytokine in T-cell immunity, with a promising potential in cancer vaccines. However, therapeutic application of IL-2 is hampered by its short half-life and substantial toxicity. This study reports preclinical characterization of a mouse serum albumin-IL-2 fusion protein (Alb-IL2) encoded on nucleoside-modified RNA that is delivered via a nanoparticle formulation (Alb-IL2 RNA-NP) mediating prolonged cytokine availability. Alb-IL2 RNA-NP was combined with RNA-lipoplex (RNA-LPX) vaccines to evaluate its effect on the expansion of vaccine-induced antigen specific T-cell immunity. In mice dosed with Alb-IL2 RNA-NP, translated protein was shown to be systemically available up to 2 days, with an albumin-dependent preferred presence in the tumor and tumor-draining lymph node. Alb-IL2 RNA-NP administration prolonged serum availability of the cytokine compared with murine recombinant IL-2. In combination with RNA-LPX vaccines, Alb-IL2 RNA-NP administration highly increased the expansion of RNA-LPX vaccine-induced CD8+ T cells in the spleen and blood. The combination enhanced and sustained the fraction of IL-2 receptor (IL-2R) α-positive antigen-specific CD8+ T cells and ameliorated the functional capacity of the CD8+ T-cell population. Alb-IL2 RNA-NP strongly improved the antitumor activity and survival of concomitant RNA-LPX vaccination and PD-L1 blockade in a subcutaneous mouse tumor model. The favorable pharmacokinetic properties of Alb-IL2 RNA-NP render it an attractive modality for rationally designed combination immunotherapy. RNA vaccines that induce tumor-specific T-cell immunity for Alb-IL2 RNA-NP to further amplify are particularly attractive combination partners.

具有扩展生物利用度的 RNA 编码白细胞介素-2 可增强 RNA 疫苗诱导的抗肿瘤 T 细胞免疫力。
白细胞介素-2(IL-2)是 T 细胞免疫中的一种重要细胞因子,也是一种很有希望提高癌症疫苗疗效的组合伙伴。然而,IL-2 的半衰期短、毒性大,阻碍了它的治疗应用。在此,我们报告了一种小鼠血清白蛋白-IL-2融合蛋白(Alb-IL2)的临床前特征,该蛋白由核苷修饰的RNA编码,通过纳米颗粒制剂(Alb-IL2 RNA-NP)递送,可延长细胞因子的可用性。Alb-IL2 RNA-NP 与 RNA-脂质体(RNA-LPX)疫苗结合使用,以评估其对扩大疫苗诱导的抗原特异性 T 细胞免疫的影响。研究表明,在服用 Alb-IL2 RNA-NP 的小鼠体内,翻译蛋白可在两天内全身存在,肿瘤和肿瘤引流淋巴结中的白蛋白依赖性较强。与小鼠重组IL-2(rIL-2)相比,Alb-IL2 RNA-NP可延长细胞因子在血清中的存在时间。Alb-IL2 RNA-NP与RNA-LPX疫苗联合使用,可显著提高RNA-LPX疫苗诱导的CD8+T细胞在脾脏和血液中的扩增。联合用药可提高并维持 IL-2 受体(IL-2R)α 阳性的抗原特异性 CD8+ T 细胞的比例,并改善 CD8+ T 细胞群的功能能力。在小鼠皮下肿瘤模型中,Alb-IL2 RNA-NP能显著提高同时接种RNA-LPX疫苗和PD-L1阻断剂的抗肿瘤活性和存活率。Alb-IL2 RNA-NP 良好的药代动力学特性使其成为合理设计联合免疫疗法的一种有吸引力的模式。能诱导肿瘤特异性 T 细胞免疫,使 Alb-IL2 RNA-NP 进一步放大的 RNA 疫苗是特别有吸引力的组合伙伴。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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