Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours.,Nature Biomedical Engineering

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Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours.
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2020-04-13 , DOI: 10.1038/s41551-020-0549-2
Aslan Mansurov ₁ , Jun Ishihara ₁ , Peyman Hosseinchi ₁ , Lambert Potin ₁ , Tiffany M Marchell _{1,

2} , Ako Ishihara ₁ , John-Michael Williford ₁ , Aaron T Alpar ₁ , Michal M Raczy ₁ , Laura T Gray ₁ , Melody A Swartz _{1,

2,

3} , Jeffrey A Hubbell _{1,

2}

Affiliation

Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.

中文翻译：

胶原蛋白结合 IL-12 增强肿瘤炎症并促使已建立的免疫冷小鼠肿瘤完全缓解。

检查点抑制剂（CPI）免疫疗法在临床上取得了显着的成功，但其对“免疫冷”肿瘤的疗效一直有限。白介素 12 (IL-12) 是一种强大的细胞因子，可激活免疫系统的先天性和适应性臂；然而，IL-12 的给药与免疫相关的不良事件有关。在这里，我们发现，在患有侵袭性小鼠肿瘤的小鼠中静脉注射与 IL-12 融合的胶原蛋白结合结构域（CBD-IL-12）后，由于紊乱中的胶原蛋白暴露，CBD-IL-12 在肿瘤基质中积聚。肿瘤血管系统。与施用未修饰的IL-12相比，CBD-IL-12诱导持续的肿瘤内干扰素-γ水平，显着降低其全身水平以及器官损伤，并提供卓越的抗癌功效，引发CPI无反应的乳腺肿瘤的完全消退。此外，CBD-IL-12 与 CPI 有效协同作用，在基因工程小鼠黑色素瘤模型中根除大型黑色素瘤、诱导抗原特异性免疫记忆并控制肿瘤生长。 CBD-IL-12 可能会增强免疫冷肿瘤的 CPI 免疫治疗。

更新日期：2020-04-24

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