Atezolizumab-bevacizumab 加 Y-90 TARE 用於治療肝細胞癌：臨床前原

StephenW

Atezolizumab-bevacizumab 加 Y-90 TARE 用於治療肝細胞癌：臨床前原理和正在進行的臨床試驗
亞歷山德羅·迪·費德里科
ORCID 圖標，亞歷山德羅·里佐
, 里卡爾多·卡洛尼
, 安德里亞·德·吉格里奧
, 里卡多·布魯諾
, 達莉亞·利瑪竇
＆ 顯示所有
2021 年 9 月 28 日收稿，2021 年 11 月 18 日接受，接受的作者版本在線發布：2021 年 11 月 19 日，在線發布：2021 年 12 月 1 日

    下載引文 https://doi.org/10.1080/13543784.2022.2009455 CrossMark 標誌 CrossMark

抽象的
介紹

自免疫療法引入以來，晚期肝細胞癌 (HCC) 的治療算法不斷發展。 IMbrave150 試驗將 atezolizumab-bevacizumab 設置為不可切除的 HCC 患者的新標準一線治療。然而，對於有門靜脈血栓形成但沒有遠處轉移的中晚期患者，90 釔經動脈放射栓塞 (90Y-TARE) 被認為是首選治療方法。
覆蓋區域

我們討論了有關在 HCC 中使用 90Y-TARE 的主要證據、該腫瘤免疫療法的最新進展，以及將 VEGF 阻斷劑與其他兩種治療策略相結合的臨床前基本原理。
專家意見

HCC 具有極其異質的腫瘤免疫微環境。這可以解釋免疫檢查點抑製劑獲得的不一致結果。確定最能從免疫療法中受益的患者至關重要；然而，缺乏可靠的反應標誌。放射治療和 VEGF 抑制與免疫治療具有確定的協同作用，主要與增強抗原呈遞和減少免疫抑制性免疫浸潤有關。因此，將免疫檢查點抑製劑與 VEGF 阻斷劑和 90Y-TARE 相結合可能會克服單獨施用這些治療中的每一種時觀察到的原發性耐藥性。

關鍵詞：肝細胞癌免疫療法VEGFatezolizumab貝伐單抗放射療法TARE

文章亮點

    90Y-TARE 仍然是不適合其他局部治療的 BCLC B 患者或伴有門靜脈血栓形成且無轉移的 BCLC C 患者的關鍵治療方法。

    VEGF促進腫瘤血管化並具有免疫抑製作用。高水平的 VEGF 會在腫瘤浸潤的 CD8+ T 細胞上誘導 PD-1 和其他抑制性分子（如 Tim-3、CTLA-4 和 Lag-3）的表達。

    許多臨床前研究證明，聯合放療和抗 VEGF 藥物可增強腫瘤反應。

    SIRT 可以增加釋放的腫瘤抗原的數量，並與免疫療法具有協同作用。

    由於缺乏 HCC 患者 ICI 的預測性生物標誌物，並且考慮到少數患者對單藥 ICI 有反應，聯合策略代表了克服原發性耐藥的有希望的方法。

StephenW

Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials
Alessandro Di Federico
ORCID Icon, Alessandro Rizzo
, Riccardo Carloni
, Andrea De Giglio
, Riccardo Bruno
, Dalia Ricci
& show all
Received 28 Sep 2021, Accepted 18 Nov 2021, Accepted author version posted online: 19 Nov 2021, Published online: 01 Dec 2021

    Download citation https://doi.org/10.1080/13543784.2022.2009455 CrossMark Logo CrossMark

ABSTRACT
Introduction

The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, 90Yttrium transarterial radioembolization (90Y-TARE) is considered the treatment of choice.
Areas Covered

We discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies.
Expert opinion

HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and 90Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.

KEYWORDS: Hepatocellular carcinomaimmunotherapyVEGFatezolizumabbevacizumabradiation therapyTARE

Article highlights

    90Y-TARE remains the pivotal treatment for BCLC B patients not suitable for other locoregional treatments or BCLC C with portal vein thrombosis and without metastasis.

    VEGF promotes tumor vascularization and has immunosuppressive effects. High levels of VEGF induce the expression of PD-1 and other inhibitory molecules, such as Tim-3, CTLA-4, and Lag-3, on tumor-infiltrating CD8+ T cells.

    Many preclinical studies documented enhanced tumor responses with the combination of RT and anti-VEGF agents.

    SIRT can enhance the number of released tumor antigens and has a proven synergism with immunotherapy.

    In the absence of predictive biomarkers to ICI for HCC patients and given the minority of patients who respond to single agent ICIs, combination strategies represent a promising approach to overcome primary resistance.