Clinical & Regulatory Affairs, Nevro Corp, 1800 Bridge Parkway, Redwood City, CA, 94065, USA.
J Exp Clin Cancer Res. 2019 Jun 13;38(1):255. doi: 10.1186/s13046-019-1259-z.
Targeting checkpoints of immune cell activation has been demonstrated to be the most effective approach for activation of anti-tumor immune responses. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), both inhibitory checkpoints commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its ligand PD-L1 and one drug targeting CTLA-4 have been approved for treatment of different types of cancers and several others are in advanced stages of development. The drugs when administered as monotherapy had dramatic increase in durable response rates and had manageable safety profile, but more than 50% of patients failed to respond to treatment. Combination of CTLA-4 and PD-1 blockers was then evaluated to increase the response rates in patients, and ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) combination was shown to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer with MMR/MSI-H aberrations. The success of combination encouraged multiple clinical studies in other cancer types. Efficacy of the combination has been shown in a number of published studies and is under evaluation in multiple ongoing studies. This review aims to support future research in combination immunotherapy by discussing the basic details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated combination of CTLA-4 and PD-1/PD-L1 blockers.
靶向免疫细胞激活的检查点已被证明是激活抗肿瘤免疫反应最有效的方法。细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）和程序性细胞死亡蛋白 1（PD-1），这两种在激活的 T 细胞上常见的抑制性检查点，已被发现是治疗癌症最可靠的靶点。六种针对 PD-1 或其配体 PD-L1 的药物和一种针对 CTLA-4 的药物已被批准用于治疗不同类型的癌症，还有几种药物处于开发的后期阶段。这些药物作为单药治疗时，持久缓解率显著增加，且安全性可控，但超过 50%的患者对治疗无反应。然后评估了 CTLA-4 和 PD-1 抑制剂联合使用以提高患者的反应率，伊匹单抗（抗 CTLA-4）加纳武单抗（抗 PD-1）联合治疗转移性黑色素瘤患者的疗效显著提高。随后，伊匹单抗联合纳武单抗被批准用于治疗转移性黑色素瘤、晚期肾细胞癌和伴有 MMR/MSI-H 异常的转移性结直肠癌。联合治疗的成功鼓励了其他癌症类型的多项临床研究。该联合治疗的疗效已在多项已发表的研究中得到证实，并正在多项正在进行的研究中进行评估。本文旨在通过讨论 CTLA-4 和 PD-1 通路的基本细节以及评估 CTLA-4 和 PD-1/PD-L1 抑制剂联合治疗的临床研究结果，为联合免疫治疗的未来研究提供支持。
