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发表于 2020-3-28 20:44 |只看该作者 |倒序浏览 |打印
Checkpoint Inhibitors for the Treatment of Advanced Hepatocellular Carcinoma
Laura A. Huppert M.D.
John D. Gordan M.D., Ph.D.
Robin Kate Kelley M.D.
First published: 26 March 2020
https://doi.org/10.1002/cld.879
Potential conflict of interest: J.D.G. advises Genentech. R.K.K. advises Genentech and Roche.
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Abbreviations

APC
    antigen‐presenting cell
ASCO
    American Society of Clinical Oncology
BSC
    best supportive care
CPI
    checkpoint inhibitor
CTLA‐4
    cytotoxic T lymphocyte–associated protein 4
FDA
    US Food and Drug Administration
HBV
    hepatitis B virus
HCC
    hepatocellular carcinoma
IRAE
    immune‐related adverse event
MHC
    major histocompatibility complex
MKI
    multikinase inhibitor
ORR
    objective response rate
OS
    overall survival
PD‐1
    programmed cell death protein 1
PD‐L1
    programmed death‐ligand 1
PFS
    progression‐free survival
TACE
    transarterial chemoembolization
VEGFR
    vascular endothelial growth factor receptor

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer‐related deaths worldwide.1 In the United States, HCC is the fastest rising cause of cancer death, owing in part to the obesity epidemic.2 The high rate of mortality has been attributed to an aggressive tumor biology, comorbid underlying liver disease in a majority of patients, late stage of disease at diagnosis in many cases, and a lack of effective systemic therapy options. For more than a decade, the multikinase inhibitor (MKI) sorafenib has been the only systemic therapy to improve survival in advanced HCC, although median survival prolongation from sorafenib is less than 3 months and fewer than 5% of patients achieve objective response rate (ORR) in the pivotal sorafenib trials.3, 4 Since 2017, multiple new drugs, including lenvatinib, regorafenib, and cabozantinib, have demonstrated noninferiority to sorafenib in the treatment of advanced HCC, leading to regulatory approvals and dramatically expanding the treatment landscape for advanced HCC. Despite these advances, the median overall survival (OS) remains only about 1 year after the start of systemic therapy, the duration of treatment response is limited, and new treatment strategies are still urgently needed.

Cancer immunotherapy with checkpoint inhibitors (CPIs) is an exciting and rapidly evolving area of oncology that has dramatically increased survival in patients with many types of cancer.5 HCC arises in the setting of proinflammatory conditions, such as hepatitis B/C infections and liver cirrhosis, and demonstrates an immunosuppressive microenvironment. These features are associated with response to immunotherapy in other cancer types, suggesting that CPI may have potential benefit in HCC as well. In this review, we will first discuss the basic principles of cancer immunology and mechanisms of immunotherapy. Then, we will highlight key clinical trials that demonstrate the therapeutic potential of immunotherapy in the treatment of advanced HCC. Finally, we will comment on challenges and future directions in this field.


Conclusion

Immune CPIs have established the potential for durable, robust, and meaningful responses across agents and subgroups of patients with advanced HCC. Ongoing clinical trial biomarker analyses aim to define features associated with response to CPI monotherapy. In addition, combination approaches are underway to determine whether the addition of tyrosine kinase inhibition, the anti–vascular endothelial growth factor antibody bevacizumab, or additional immune CPIs can augment the proportion of patients with response to PD‐1 or PD‐L1 inhibition. The unprecedented activity of CPI in patients with advanced stage HCC has prompted a new generation of clinical trials in early and intermediate stages of disease in hopes of improving the proportion of patients who achieve disease cure.

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发表于 2020-3-28 20:45 |只看该作者
检查点抑制剂治疗晚期肝细胞癌
劳拉·胡珀特医学博士
约翰D.戈登医学博士
罗宾·凯特·凯利医学博士
首次发布:2020年3月26日
https://doi.org/10.1002/cld.879
潜在的利益冲突:J.D.G。为Genentech提供建议。 R.K.K.为Genentech和Roche提供建议。
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装甲运兵车
    抗原呈递细胞
阿斯科
    美国临床肿瘤学会
平衡计分卡
    最佳支持治疗
消费物价指数
    检查点抑制剂
CTLA‐4
    细胞毒性T淋巴细胞相关蛋白4
美国食品药品管理局
    美国食品药品监督管理局
乙肝病毒
    乙型肝炎病毒
肝癌
    肝细胞癌
伊拉伊
    免疫相关不良事件
MHC
    主要组织相容性复合体
MKI
    多激酶抑制剂
ORR
    客观回应率
操作系统
    总体生存
PD-1
    程序性细胞死亡蛋白1
PD‐L1
    程序化死亡配体1
PFS
    无进展生存
泰斯
    经动脉化疗栓塞
血管内皮生长因子
    血管内皮生长因子受体

肝细胞癌(HCC)是全球第五大流行癌症,是与癌症相关的死亡的第二大主要原因。1在美国,HCC是癌症死亡人数上升最快的原因,部分原因是肥胖病流行2。死亡率的高低归因于侵略性的肿瘤生物学,大多数患者并存的潜在肝病,许多情况下诊断出疾病的晚期以及缺乏有效的全身治疗选择。十多年来,尽管索拉非尼的中位生存期延长不到3个月,且少于5%的患者达到客观缓解率(ORR),但多激酶抑制剂(MKI)索拉非尼是提高晚期HCC生存率的唯一全身疗法3,4自2017年以来,包括lenvatinib,regorafenib和Cabozantinib在内的多种新药在晚期HCC的治疗中均显示出不逊于索拉非尼,从而获得了监管部门的批准并大大扩展了晚期HCC的治疗范围。尽管取得了这些进展,但全身治疗的中位总生存期(OS)仍仅在开始治疗后约1年,治疗反应的持续时间有限,仍然迫切需要新的治疗策略。

带有检查点抑制剂(CPI)的癌症免疫疗法是令人兴奋且迅速发展的肿瘤学领域,可显着提高患有多种类型癌症的患者的生存率。5HCC出现在诸如B / C肝炎感染和肝硬化等促炎性疾病中,并展示了一种免疫抑制性微环境。这些特征与其他癌症类型对免疫疗法的反应有关,这表明CPI也可能对HCC有潜在益处。在这篇综述中,我们将首先讨论癌症免疫学的基本原理和免疫疗法的机制。然后,我们将重点介绍可证明免疫疗法在晚期HCC治疗中具有治疗潜力的关键临床试验。最后,我们将评论该领域的挑战和未来方向。

结论

免疫CPI已建立了在晚期HCC患者的病原体和亚组中实现持久,稳健和有意义的反应的潜力。 正在进行的临床试验生物标志物分析旨在定义与CPI单药治疗反应相关的特征。 此外,目前正在采用组合方法来确定是否添加酪氨酸激酶抑制,抗血管内皮生长因子抗体贝伐单抗或其他免疫CPI可以增加对PD-1或PD-1L抑制反应的患者比例。 晚期肝癌患者中CPI的空前活动促使了在疾病早期和中期进行新一代临床试验,以期提高治愈疾病的患者比例。

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