Boyman Onur, Arenas-Ramirez Natalia
Department of Immunology, University Hospital Zurich, Switzerland / Faculty of Medicine, University of Zurich, Switzerland.
Department of Immunology, University Hospital Zurich, Switzerland.
Swiss Med Wkly. 2019 Jan 23;149:w14697. doi: 10.4414/smw.2019.14697. eCollection 2019 Jan 14.
Tumour immunotherapy, and particularly immue checkpoint inhibitors, have resulted in considerable response rates in patients with metastatic cancer. However, most of these approaches are limited to immunogenic tumours. Based on its ability to stimulate cytotoxic T cells, interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and metastatic kidney cancer. Clinical efficacy achieved through high doses is countered by severe adverse effects on vascular endothelial cells and various organs, a short in vivo half-life, and the stimulation of regulatory T cells that counteract antitumour immune responses. Accumulating evidence suggests that IL-2 receptor β (CD122)-biased IL-2 formulations address the shortcomings of IL-2 cancer immunotherapy. This knowledge stems from studies using CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2 complexes), which preferentially stimulate CD8+ T cells, while interaction with regulatory T cells and vascular endothelial cells is disfavoured by the anti-IL-2 antibody used. CD122-biased IL-2 complexes, when assessed in different mouse cancer models, cause stronger antitumour effects and significantly less adverse effects than high-dose IL-2. A recently developed and characterised anti-human IL-2 antibody, termed NARA1, forms human CD122-biased IL-2 complexes. Alternative strategies based on this concept, such as site-directed pegylation and mutation of IL-2, have also been pursued. Moreover, recent data have shown that a combination of CD122-biased IL-2 formulations with immune checkpoint inhibitors, antigen-specific immunotherapy and epigenetic modifying drugs results in synergistic anti-cancer effects in various tumour models. Thus, CD122-biased IL-2 approaches constitute a novel class of immunotherapy for metastatic cancer that has the potential to complement and increase the efficacy of other antitumour strategies.
肿瘤免疫疗法，尤其是免疫检查点抑制剂，已使转移性癌症患者产生了可观的缓解率。然而，这些方法大多局限于免疫原性肿瘤。基于其刺激细胞毒性T细胞的能力，白细胞介素-2（IL-2）已被用于治疗转移性黑色素瘤和转移性肾癌患者。高剂量使用IL-2所取得的临床疗效被其对血管内皮细胞和各种器官的严重不良反应、体内半衰期短以及刺激调节性T细胞从而抵消抗肿瘤免疫反应所抵消。越来越多的证据表明，偏向白细胞介素-2受体β（CD122）的IL-2制剂解决了IL-2癌症免疫疗法的缺点。这一认识源于对使用偏向CD122的IL-2/抗IL-2抗体复合物（IL-2复合物）的研究，该复合物优先刺激CD8+T细胞，而所用的抗IL-2抗体不利于其与调节性T细胞和血管内皮细胞的相互作用。在不同的小鼠癌症模型中评估时，偏向CD122的IL-2复合物比高剂量IL-2产生更强的抗肿瘤作用，且不良反应显著更少。一种最近开发并鉴定的抗人IL-2抗体，称为NARA1，可形成偏向人CD122的IL-2复合物。基于这一概念的替代策略，如IL-2的定点聚乙二醇化和突变，也已被探索。此外，最近的数据表明，偏向CD122的IL-2制剂与免疫检查点抑制剂、抗原特异性免疫疗法和表观遗传修饰药物联合使用，在各种肿瘤模型中产生协同抗癌作用。因此，偏向CD122的IL-2方法构成了一种新型的转移性癌症免疫疗法，有可能补充并提高其他抗肿瘤策略的疗效。
