肝癌，治疗，免疫治疗，检查点抑制剂

StephenW

Article Outline

• Conflict of interest
• Authors’ contributions
• References
  

Keywords:                Liver cancer, Therapy, Immunotherapy, Checkpoint inhibitors

During the last years, new immune-modulatory agents were introduced for oncological treatment, eventually leading to the clinical breakthrough of checkpoint inhibitors (CPI) targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) and programmed death-1 ligand (PD-1L) [[url=][1][/url], [url=][2][/url], [url=][3][/url], [url=][4][/url], [url=][5][/url]]. Under physiological conditions these molecules resolve T cell activation to maintain inflammatory homeostasis, protect tissue integrity and prevent unwanted auto-immunity [[url=]6[/url]]. CPI administration in tumor patients, however, unleashes tumor-directed cytotoxic T cells specific against an unknown spectrum of tumor-associated antigens (TAA). This results in a robust multi-targeted immune response even capable of inducing durable oncological remission in some patients. The expectations are high that these novel drugs may also contribute to the developmental need of more effective treatment for hepatocellular carcinoma (HCC). Different trials are currently underway to investigate the safety and efficacy of CPI in primary liver cancer (Table 1).

Table 1Current trials on checkpoint inhibitors in HCC.Tumor entityInvestigated regimenTrial identifier
Solid tumors⁎Durvalumab (anti PD-1L Ab) plus ramucirumab (anti-VEGF-R2 Ab)NCT02572687
Solid tumors⁎Durvalumab (anti PD-1L Ab) plus AZD4635 (adenosine A2A receptor antagonist)NCT02740985
Solid tumors⁎Ipilimumab (anti CTLA-4 Ab) plus stereotactic body radiationNCT02239900
Solid tumors⁎Ipilimumab (anti CTLA-4 Ab) plus MGN1703 (Toll-like receptor agonist)NCT02668770
HCCNivolumab (anti PD-1 Ab)NCT02576509
HCCNivolumab (anti PD-1 Ab) plus CC-122 (immunostimulatory pathway modifier)NCT02859324
HCCNivolumab (anti PD-1 Ab) plus LRT (Yttrium 90Y glass microspheres)NCT02837029
HCCNivolumab (anti PD-1 Ab) plus ipilimumab (anti CTLA-4 Ab)NCT01658878
Solid tumors⁎Nivolumab (anti PD-1 Ab) plus galunisertib (TGF-β inhibitor)NCT02423343
HCCPDR001 (anti PD-1 Ab) plus INC280 (c-Met inhibitor)NCT02795429
Solid tumors⁎PDR001 (anti PD-1 Ab) plus NIS793 (anti TGF-β Ab)NCT02947165
HCCPrembrolizumab (anti PD-1 Ab)NCT02702401
HCCPrembrolizumab (anti PD-1 Ab)NCT02940496
HCCPrembrolizumab (anti PD-1 Ab) plus dendritic cells, cytokine-induced killer cellsNCT02886897
HCCTremelimumab (anti CTLA-4 Ab)NCT01853618 (Duffy et al.)
HCCTremelimumab (anti CTLA-4 Ab) plus durvalumab (anti PD-1L Ab)NCT02519348
HCCTremelimumab (anti CTLA-4 Ab), durvalumab (anti PD-1L Ab) plus LRTNCT02821754Ab, antibody; c-Met, hepatocyte growth factor receptor; CTLA-4, cytotoxic T lymphocyte antigen-4; HCC, hepatocellular carcinoma; LRT, loco-regional therapy; PD-1, programmed death-1; PD-1L, programmed death 1-ligand; TGF-ß, transforming growth factor-beta; VEGF-R2, vascular endothelial growth factor receptor-2.

Including HCC.

StephenW

文章概要

    利益冲突
    作者的贡献
    参考文献

关键词：
肝癌，治疗，免疫治疗，检查点抑制剂

在最近几年，引入新的免疫调节剂用于肿瘤治疗，最终导致靶向细胞毒性T淋巴细胞抗原-4（CTLA-4），程序性死亡-1（PD-1）的检查点抑制剂（CPI）和程序性死亡-1配体（PD-1L）[[1]，[2]，[3]，[4]，[5]]。在生理条件下，这些分子解决T细胞活化以维持炎症性体内平衡，保护组织完整性和防止不必要的自身免疫[6]。然而，肿瘤患者中的CPI施用释放对未知光谱的肿瘤相关抗原（TAA）特异性的肿瘤定向的细胞毒性T细胞。这导致稳健的多靶点免疫应答，甚至能够在一些患者中诱导持久的肿瘤学缓解。期望很高，这些新型药物也可能有助于更有效治疗肝细胞癌（HCC）的发展需要。目前正在进行不同的试验来研究CPI在原发性肝癌中的安全性和有效性（表1）。
表1 HCC中检查点抑制剂的临床试验肿瘤实体研究方案试验标识符
实体瘤Durvalumab（抗PD-1L Ab）加雷莫单抗（抗VEGF-R2 Ab）NCT02572687
实体瘤Durvalumab（抗PD-1L Ab）加AZD4635（腺苷A2A受体拮抗剂）NCT02740985
实体瘤Ipilimumab（抗CTLA-4 Ab）加立体定向体辐射NCT02239900
实体瘤Ipilimumab（抗CTLA-4 Ab）加MGN1703（Toll样受体激动剂）NCT02668770
HCC Nivolumab（抗PD-1 Ab）NCT02576509
HCC Nivolumab（抗PD-1 Ab）加CC-122（免疫刺激途径调节剂）NCT02859324
HCC Nivolumab（抗PD-1 Ab）加LRT（钇90Y玻璃微球）NCT02837029
HCC Nivolumab（抗PD-1 Ab）加上易普利姆玛（抗CTLA-4 Ab）NCT01658878
实体肿瘤Nivolumab（抗PD-1 Ab）加上galunisertib（TGF-β抑制剂）NCT02423343
HCC PDR001（抗PD-1 Ab）加INC280（c-Met抑制剂）NCT02795429
实体肿瘤PDR001（抗PD-1 Ab）加NIS793（抗TGF-βAb）NCT02947165
HCC Prembrolizumab（抗PD-1 Ab）NCT02702401
HCC Prembrolizumab（抗PD-1 Ab）NCT02940496
HCC Prembrolizumab（抗PD-1 Ab）加树突细胞，细胞因子诱导的杀伤细胞NCT02886897
HCC Tremelimumab（抗CTLA-4 Ab）NCT01853618（Duffy等人）
HCC Tremelimumab（抗CTLA-4 Ab）加durvalumab（抗PD-1L Ab）NCT02519348
HCC Tremelimumab（抗CTLA-4 Ab），durvalumab（抗PD-1L Ab）加LRT NCT02821754

Ab，抗体; c-Met，肝细胞生长因子受体; CTLA-4，细胞毒性T淋巴细胞抗原-4; HCC，肝细胞癌; LRT，局部区域治疗; PD-1，程序性死亡-1; PD-1L，程序性死亡1-配体; TGF-β，转化生长因子-β; VEGF-R2，血管内皮生长因子受体-2。
低星号包括HCC。

StephenW

http://www.journal-of-hepatology ... seases%7CHepatology