不可切除肝细胞癌的双重检查点封锁：临床试验中出现的机

StephenW

不可切除肝细胞癌的双重检查点封锁：临床试验中出现的机会
安东内拉·卡马罗塔
ORCID 偶像，瓦伦蒂娜·扎努索
ORCID 偶像，安东尼奥·达莱西奥
ORCID 图标，Tiziana Pressiani
ORCID 偶像，西尔维娅·博扎雷利
ORCID 图标，Nicola Personeni
ORCID 图标 & 显示全部
2021 年 12 月 21 日收到，2022 年 2 月 10 日接受，接受的作者版本在线发布：2022 年 2 月 14 日，在线发布：2022 年 2 月 22 日

    下载引文 https://doi.org/10.1080/13543784.2022.2042253 CrossMark Logo CrossMark

抽象的
介绍

为了防止对源自肠道的自身抗原和毒素的免疫反应造成损害，肝脏促进了免疫耐受环境，为癌细胞的免疫逃逸提供了肥沃的土壤。因此，在肝细胞癌 (HCC) 中使用和评估免疫检查点抑制剂 (ICI) 是一种治疗原理。
覆盖面积

在本文中，我们讨论了双重 ICI 阻断在晚期 HCC 中的作用，涵盖了它们组合的生物学基础、它们的作用机制，以及测试 nivolumab + ipilimumab 和 durvalumab + tremelimumab 的早期研究结果。此外，我们提供了 III 期 HIMALAYA 试验的结果，并概述了正在进行的研究不同疾病阶段的双重 ICI 的试验。
专家意见

晚期 HCC 双重 ICI 阻断策略的潜在批准将确定无抗血管生成选择的进入，扩大符合一线治疗条件的患者比例。然而，它将带来一系列临床挑战，相当大比例的患者，即 Child-Pugh B、老年人和免疫功能低下的患者，仍然被边缘化。此外，鉴于疾病进展的速度，确定可靠的预测性生物标志物对于告知治疗选择和顺序至关重要。最后，这种组合令人信服的响应率正在为它们在早期阶段的评估铺平道路。

关键词：CTLA-4durvalumabHCC免疫检查点抑制剂免疫疗法ipilimumabnivolumabPD-1PD-L1tremelimumab

文章重点

    由于肝脏特殊的免疫耐受微环境，肝细胞癌 (HCC) 可以通过各种机制逃避免疫监视，包括抗原呈递受损、T 细胞反应失调和免疫抑制性骨髓细胞的上调。因此，生物学原理支持在这种情况下评估免疫检查点抑制剂 (ICI)。

    抗 PD-(L)1 和抗 CTLA-4 的组合产生协同效应，同时降低了原发性耐药率。

    Nivolumab 加 ipilimumab 和 durvalumab 加 tremelimumab 在大多数接受过索拉非尼治疗且无法切除的 HCC 人群中显示出有希望的临床活性和可控的安全性。

    与 durvalumab（STRIDE 方案）相关的单次启动剂量的曲美木单抗被证明是早期研究 22 中最活跃的策略，在生物学水平上具有令人着迷的相关性结果。

    在 III 期 HIMALAYA 试验中，发现 STRIDE 方案和 durvalumab 作为单药是有效的一线治疗选择，与索拉非尼相比，分别被证明优于和非劣效。

    这些化合物的潜在批准将扩大符合一线治疗条件的患者比例，为那些有抗血管生成药物主要禁忌症的患者提供服务，但对于某些患者亚群来说，治疗仍然具有挑战性。

    迫切需要可靠的反应生物标志物和更合适的放射反应标准以及指导治疗顺序的高质量证据。

    由于晚期 HCC 具有令人信服的反应率，许多研究正在研究早期疾病阶段的双重免疫检查点抑制，并提供初步有希望的数据。

此框总结了文章中包含的要点。

StephenW

The dual checkpoint blockade in unresectable hepatocellular carcinoma: opportunities emerging in clinical trials
Antonella Cammarota
ORCID Icon, Valentina Zanuso
ORCID Icon, Antonio D’Alessio
ORCID Icon, Tiziana Pressiani
ORCID Icon, Silvia Bozzarelli
ORCID Icon, Nicola Personeni
ORCID Icon & show all
Received 21 Dec 2021, Accepted 10 Feb 2022, Accepted author version posted online: 14 Feb 2022, Published online: 22 Feb 2022

    Download citation https://doi.org/10.1080/13543784.2022.2042253 CrossMark Logo CrossMark

ABSTRACT
Introduction

To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale.
Area covered

In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early-phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages.
Expert Opinion

The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.

KEYWORDS: CTLA-4durvalumabHCCimmune checkpoint inhibitorsimmunotherapyipilimumabnivolumabPD-1PD-L1tremelimumab

Article highlights

    As a result of the peculiar immune-tolerant microenvironment of the liver, hepatocellular carcinoma (HCC) can elude the immune surveillance via various mechanisms, including impaired antigen presentation, dysregulation of T-cell response, and upregulation of immunosuppressive myeloid cells. Thus, a biological rationale supports the evaluation of immune checkpoint inhibitors (ICIs) in this setting.

    The combination of anti PD-(L)1 and anti-CTLA-4 resulted in a synergistic effect while reducing the rate of primary resistance.

    Nivolumab plus ipilimumab and durvalumab plus tremelimumab demonstrated promising clinical activity with a manageable safety in a mostly sorafenib-experienced population with unresectable HCC.

    A single priming dose of tremelimumab associated with durvalumab (STRIDE regimen) was proven as the most active strategy in the early-phase Study 22, with fascinating correlative results at the biological level.

    In the phase III HIMALAYA trial, the STRIDE regimen and durvalumab as single-agent were found to be effective first-line treatment options, proving to be superior and non-inferior compared to sorafenib, respectively.

    The potential approval of these compounds will expand the proportion of patients eligible for a first-line treatment, serving those with major contraindications to antiangiogenics, but treatment will remain challenging for certain subsets of patients.

    Reliable biomarkers of response and more appropriate radiological response criteria as well as high-quality evidence to guide treatment sequencing are urgently needed.

    Due to the compelling response rate in advanced HCC, numerous studies are investigating the dual immune checkpoint inhibition in earlier disease stages with preliminary promising data.

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