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Sci Transl Med:增加胶原蛋白亲和力可改善癌症免疫疗法

2019-09-02 佚名 细胞

基于免疫检查点抑制剂(CPI)和白细胞介素-2(IL-2)的癌症免疫疗法正变得越来越普遍,这是因为它们具有令人印象深刻的激活患者自身免疫系统以对抗肿瘤的能力。然而,全身性的免疫系统激活方法不是没有风险的,免疫疗法通常伴随着严重不良事件。

基于免疫检查点抑制剂(CPI)和白细胞介素-2(IL-2)的癌症免疫疗法正变得越来越普遍,这是因为它们具有令人印象深刻的激活患者自身免疫系统以对抗肿瘤的能力。然而,全身性的免疫系统激活方法不是没有风险的,免疫疗法通常伴随着严重不良事件。

为了解决这个问题,在一项新的研究中,来自美国芝加哥大学、瑞士洛桑理工学院和日本东京大学的研究人员鉴于肿瘤血管系统的渗漏使得肿瘤基质胶原蛋白暴露于血液成分中,通过偶联(针对抗体)或重组融合(针对细胞因子)与源自血液蛋白VWF(von Willebrand factor)A3结构域的胶原蛋白结合结构域(CBD)结合在一起,让免疫检查点抑制剂(CPI)---抗CTLA4抗体(αCTLA4)+抗PD-L1抗体(αPD-L1)---和细胞因子IL-2靶向肿瘤,从而在局部发挥作用。相关研究结果近期发表在Science Translational Medicine期刊上,论文标题为“Targeted antibody and cytokine cancer immunotherapies through collagen affinity”。

这些研究人员发现静脉注射的CBD蛋白主要堆积在肿瘤中。与CBD偶联在一起形成的CBD-CPI或与CBD融合在一起形成的CBD–IL-2降低了αCTLA4组合疗法和IL-2的全身毒性,比如,消除了免疫检查点抑制剂分子的肝毒性,减轻了IL-2引起的肺水肿。

在多种小鼠癌症模型中,相比于未修饰的CPI和IL-2,CBD-CPI和CBD-IL-2均抑制肿瘤生长,并且CBD-CPI和CBD-IL-2均增加肿瘤浸润性CD8+ T细胞的数量。

在原位乳腺癌模型中,CBD-CPI和CBD-IL-2的联合使用根除了13只动物中的9只体内的肿瘤,相比之下,未修饰的CPI和IL-2联合使用仅根除了1只动物体内的肿瘤。

由此可见,蛋白VWF的A3结构域可用于改善具有高转化潜力的全身施用的肿瘤药物的安全性和疗效。

原始出处:
Ishihara J1, Ishihara A1, Sasaki K1,et al.Targeted antibody and cytokine cancer immunotherapies through collagen affinity.Sci Transl Med. 2019 Apr 10;11(487). pii: eaau3259. doi: 10.1126/scitranslmed.aau3259.

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