Nishida Naoshi, Kudo Masatoshi
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Hepatol Res. 2018 Jul;48(8):622-634. doi: 10.1111/hepr.13191. Epub 2018 Jun 6.
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high recurrence rate. Currently, tyrosine kinase inhibitors (TKIs) are the first-line treatment for cases refractory to conventional therapies. However, the acquisition of somatic mutations can result in TKI resistance. Clinical evidence suggests that acquired immunity contributes to the suppression of tumor recurrence, indicating the potential of induced antitumor immune reaction for the treatment of HCC. Recently, immune checkpoint inhibitors have become available for the treatment of malignancies. They are effective regardless of the response to prior therapies and a durable effect can be expected, which should be attributed to an adaptive immunity to HCC components. The results of phase I/II trials of nivolumab, an anti-programmed cell death-1 antibody, showed that 20% of patients showed objective response and that nivolumab was effective regardless of prior sorafenib treatment and viral status. Nivolumab received expedited Food and Drug Administration approval in 2017 for the treatment of advanced HCC after failure or intolerance to sorafenib. However, the majority of the patients remain refractory, likely due to the solid immune suppressive status, which involves many stromal cells, humoral mediators, and suppressive checkpoint molecules. Therefore, current clinical trials are focusing on how immunosuppressive conditions in HCC might be overcome using immune checkpoint inhibitors in combination with different types of immune checkpoint blockades, TKIs, and other conventional treatments. The development of immune checkpoint inhibitors is rapidly progressing and these inhibitors are likely to be key agents for HCC treatment in the near feature.
肝细胞癌（HCC）是最常见的癌症之一，复发率很高。目前，酪氨酸激酶抑制剂（TKIs）是对传统疗法难治病例的一线治疗方法。然而，体细胞突变的获得可导致TKI耐药。临床证据表明，获得性免疫有助于抑制肿瘤复发，这表明诱导抗肿瘤免疫反应在治疗HCC方面具有潜力。最近，免疫检查点抑制剂已可用于治疗恶性肿瘤。它们无论对先前治疗的反应如何均有效，并且可以预期有持久的效果，这应归因于对HCC成分的适应性免疫。抗程序性细胞死亡-1抗体纳武单抗的I/II期试验结果表明，20%的患者出现客观反应，并且纳武单抗无论先前是否接受索拉非尼治疗及病毒状态如何均有效。纳武单抗于2017年获得美国食品药品监督管理局加速批准，用于治疗索拉非尼治疗失败或不耐受后的晚期HCC。然而，大多数患者仍然难治，可能是由于坚实的免疫抑制状态，这涉及许多基质细胞、体液介质和抑制性检查点分子。因此，目前的临床试验集中在如何使用免疫检查点抑制剂与不同类型的免疫检查点阻断剂、TKIs和其他传统治疗联合来克服HCC中的免疫抑制状况。免疫检查点抑制剂的开发正在迅速推进，这些抑制剂可能在不久的将来成为HCC治疗的关键药物。
