Single injection of IL-12 coacervate as an effective therapy against B16-F10 melanoma in mice.,Journal of Controlled Release

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Single injection of IL-12 coacervate as an effective therapy against B16-F10 melanoma in mice.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.jconrel.2019.12.035
Mintai P Hwang ₁ , Ronald J Fecek ₂ , Tianyue Qin ₁ , Walter J Storkus ₃ , Yadong Wang ₁

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Melanoma is the deadliest type of skin cancer with one of the fastest increasing incidence rates among solid tumors. The use of checkpoint inhibitors (e.g. αPD-1 antibody) has recently emerged as a viable alternative to conventional modes of therapy. However, increasing evidence points towards the need for a tumor priming step to improve intratumoral immune cell infiltration. IL-12 is an immune-activating cytokine with such potential and was explored in earlier clinical trials as a highly concentrated systemic infusion. This unfortunately led to severe adverse effects. From this perspective, the localization and gradual release of such a potent immunotherapeutic agent in the tumor microenvironment is desired. This manuscript reports the use of a heparin-based complex coacervate to deliver IL-12, in which heparin-binding motifs on IL-12 allow for its effective encapsulation. IL-12-encapsulated complex coacervates significantly improved the bioactivity of IL-12 and provided protection from proteolytic cleavage in-vitro. Indeed, a single injection of IL-12 coacervate significantly inhibits the in-vivo growth of treated and untreated, contralateral tumor growth in a syngeneic B16F10 mouse melanoma model. Furthermore, tumors in mice receiving IL-12 complex coacervate treatment displayed increased infiltration by natural killer (NK) cells and CD8α+ T cells, and a decreased presence of CD4+Foxp3+ regulatory T cells. This study provides proof-of-concept data supporting the use of complex coacervates for sustained delivery of immunostimulatory proteins as an effective therapeutic strategy against disseminated tumors.

中文翻译：

单次注射 IL-12 凝聚物可有效治疗小鼠 B16-F10 黑色素瘤。

黑色素瘤是最致命的皮肤癌类型，是实体瘤中发病率增长最快的癌症之一。检查点抑制剂（例如αPD-1抗体）的使用最近已成为传统治疗模式的可行替代方案。然而，越来越多的证据表明需要肿瘤启动步骤来改善瘤内免疫细胞浸润。 IL-12 是一种具有这种潜力的免疫激活细胞因子，并在早期临床试验中作为高度浓缩的全身输注进行了探索。不幸的是，这导致了严重的不利影响。从这个角度来看，需要在肿瘤微环境中定位并逐渐释放这种有效的免疫治疗剂。该手稿报道了使用基于肝素的复合凝聚层来递送 IL-12，其中 IL-12 上的肝素结合基序允许其有效封装。 IL-12 封装的复合物凝聚层显着提高了 IL-12 的生物活性，并提供了体外免受蛋白水解裂解的保护。事实上，在同系 B16F10 小鼠黑色素瘤模型中，单次注射 IL-12 凝聚层可显着抑制已治疗和未治疗的对侧肿瘤的体内生长。此外，接受 IL-12 复合物凝聚层治疗的小鼠肿瘤中自然杀伤 (NK) 细胞和 CD8α+ T 细胞的浸润增加，并且 CD4+Foxp3+ 调节性 T 细胞的存在减少。这项研究提供了概念验证数据，支持使用复杂凝聚层持续递送免疫刺激蛋白作为对抗播散性肿瘤的有效治疗策略。

更新日期：2019-12-19

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