局部介入联合免疫检查点抑制剂治疗中晚期肝癌研究进展

doi:10.3760/cma.j.cn371439-20230428-00121

摘要/Abstract

摘要：

据世界卫生组织国际癌症研究机构预测，到2025年，原发性肝癌患病人数每年将超过100万，是人类生命健康的重要威胁。根据国家卫生健康委员会发布的《原发性肝癌诊疗指南（2022年版）》，以消融术和经导管肝动脉化疗栓塞（TACE）术为代表的局部介入治疗已成为不可切除中晚期肝细胞癌的主要治疗手段，其中TACE术适应证包括Ⅰb~Ⅲb期肝细胞癌患者。局部介入治疗已被证明有明确的免疫激活效应，随着免疫检查点抑制剂在国内外临床试验和应用的逐步推广，局部介入与免疫检查点抑制剂的联合疗法展现出更有效的肿瘤反应率、更缓慢的进展时间及更长的生存期，为无法手术的中晚期肝癌患者带来新的希望。

关键词: 癌，肝细胞, 射频消融术, 化学栓塞，治疗性, 免疫疗法, 综合疗法

Abstract:

According to the International Agency for Research on Cancer （IARC） of the World Health Organization， the number of people with primary liver cancer is predicted to exceed 1 million per year by 2025， making it a major threat to human life and health. According to "Standardization for Diagnosis and Treatment of Hepatocellular Carcinoma （2022 edition）" issued by the National Health Commission of China， locoregional interventional therapy represented by ablation and transcatheter arterial chemoembolization （TACE） has become the main treatment for unresectable intermediate-advanced hepatocellular carcinoma （HCC）， in which the indications for TACE include patients with stage Ⅰb to Ⅲb HCC. Locoregional interventional therapy has been proved to have a clear immune activation effect， and with the gradual promotion of immune checkpoint inhibitors in clinical trials and applications at home and abroad， the combination therapy of locoregional intervention and immune checkpoint inhibitors has shown a more effective objective response rate， slower progression time and longer survival， bringing new hope to patients with inoperable intermediate-advanced HCC.

Key words: Carcinoma， hepatocellular, Radiofrequency ablation, Chemoembolization， therapeutic, Immunotherapy, Combined modality therapy

田津铭, 杨继金. 局部介入联合免疫检查点抑制剂治疗中晚期肝癌研究进展[J]. 国际肿瘤学杂志, 2023, 50(10): 636-640.

Tian Jinming, Yang Jijin. Research progress of locoregional interventional therapies combined with immune checkpoint inhibitors for intermediate-advanced hepatocellular carcinoma[J]. Journal of International Oncology, 2023, 50(10): 636-640.

参考文献 28

[1]	Anwanwan D, Singh SK, Singh S, et al. Challenges in liver cancer and possible treatment approaches[J]. Biochim Biophys Acta Rev Cancer, 2020, 1873(1): 188314. DOI: 10.1016/j.bbcan.2019.188314.
[2]	Singal AG, Llovet JM, Yarchoan M, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma[J/OL]. Hepatology, (2023-05-22).https://pubmed.ncbi.nlm.nih.gov/37199193/. DOI: 10.1097/HEP.0000000000000466.
[3]	El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2. pmid: 28434648
[4]	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade[J]. N Engl J Med, 2018, 378(2): 158-168. DOI: 10.1056/NEJMra1703481.
[5]	Erinjeri JP, Fine GC, Adema GJ, et al. Immunotherapy and the interventional oncologist: challenges and opportunities — a society of interventional oncology white paper[J]. Radiology, 2019, 292(1): 25-34. DOI: 10.1148/radiol.2019182326. pmid: 31012818
[6]	Xu L, Zou C, Zhang S, et al. Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors[J]. J Hematol Oncol, 2022, 15(1): 87. DOI: 10.1186/s13045-022-01307-2.
[7]	Khanam A, Kottilil S. New therapeutics for HCC: does tumor immune microenvironment matter?[J]. Int J Mol Sci, 2022, 24(1): 437. DOI: 10.3390/ijms24010437.
[8]	Pinato DJ, Murray SM, Forner A, et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy[J]. J Immunother Cancer, 2021, 9(9): e003311. DOI: 10.1136/jitc-2021-003311.
[9]	Ren Z, Yue Y, Zhang Y, et al. Changes in the peripheral blood Treg cell proportion in hepatocellular carcinoma patients after transarterial chemoembolization with microparticles[J]. Front Immunol, 2021, 12: 624789. DOI: 10.3389/fimmu.2021.624789.
[10]	Tischfield DJ, Gurevich A, Johnson O, et al. Transarterial embolization modulates the immune response within target and nontarget hepatocellular carcinomas in a rat model[J]. Radiology, 2022, 303(1): 215-225. DOI: 10.1148/radiol.211028. pmid: 35014906
[11]	Montasser A, Beaufrère A, Cauchy F, et al. Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma[J]. Histopathology, 2021, 79(1): 36-46. DOI: 10.1111/his.14317.
[12]	Leuchte K, Staib E, Thelen M, et al. Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma[J]. Cancer Immunol Immunother, 2021, 70(4): 893-907. DOI: 10.1007/s00262-020-02734-1.
[13]	Duan X, Wang M, Han X, et al. Combined use of microwave ablation and cell immunotherapy induces nonspecific immunity of hepatocellular carcinoma model mice[J]. Cell Cycle, 2020, 19(24): 3595-3607. DOI: 10.1080/15384101.2020.1853942. pmid: 33283623
[14]	Chen Z, Meng L, Zhang J, et al. Progress in the cryoablation and cryoimmunotherapy for tumor[J]. Front Immunol, 2023, 14: 1094009. DOI: 10.3389/fimmu.2023.1094009.
[15]	Tan J, Liu T, Fan W, et al. Anti-PD-L1 antibody enhances curative effect of cryoablation via antibody-dependent cell-mediated cytoto-xicity mediating PD-L1^highCD11b⁺ cells elimination in hepatocellular carcinoma[J]. Acta Pharm Sin B, 2023, 13(2): 632-647. DOI: 10.1016/j.apsb.2022.08.006.
[16]	Zhang N, Li Z, Han X, et al. Irreversible electroporation: an emerging immunomodulatory therapy on solid tumors[J]. Front Immunol, 2022, 12: 811726. DOI: 10.3389/fimmu.2021.811726.
[17]	Dai Z, Wang Z, Lei K, et al. Irreversible electroporation induces CD8⁺ T cell immune response against post-ablation hepatocellular carcinoma growth[J]. Cancer Lett, 2021, 503: 1-10. DOI: 10.1016/j.canlet.2021.01.001.
[18]	Keisari Y. Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation[J]. Front Biosci (Landmark Ed), 2017, 22(2): 310-347. DOI: 10.2741/4487. pmid: 27814617
[19]	Marinelli B, Kim E, D'Alessio A, et al. Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study[J]. J Immunother Cancer, 2022, 10(6): e004205. DOI: 10.1136/jitc-2021-004205.
[20]	You R, Xu Q, Wang Q, et al. Efficacy and safety of camrelizumab plus transarterial chemoembolization in intermediate to advanced hepatocellular carcinoma patients: a prospective, multi-center, real-world study[J]. Front Oncol, 2022, 12: 816198. DOI: 10.3389/fonc.2022.816198.
[21]	Zhu C, Dai B, Zhan H, et al. Neoadjuvant transarterial chemoembolization (TACE) plus PD-1 inhibitor bridging to tumor resection in intermediate-stage hepatocellular carcinoma patients[J]. Ir J Med Sci, 2023, 192(3): 1065-1071. DOI: 10.1007/s11845-022-03131-6.
[22]	Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremeli-mumab in combination with ablation in patients with advanced hepatocellular carcinoma[J]. J Hepatol, 2017, 66(3): 545-551. DOI: 10.1016/j.jhep.2016.10.029.
[23]	Xie C, Duffy AG, Mabry-Hrones D, et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer[J]. Hepatology, 2019, 69(5): 2048-2060. DOI: 10.1002/hep.30482.
[24]	黄斯琪, 崔新江, 宁厚法, 等. 靶向治疗加免疫治疗联合多介入手段治疗晚期肝癌一例[J]. 国际肿瘤学杂志, 2020, 47(7): 444-445. DOI: 10.3760/cma.j.cn371439-20191114-00054.
[25]	Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173. DOI: 10.1016/S0140-6736(18)30207-1. pmid: 29433850
[26]	Cai M, Huang W, Huang J, et al. Transarterial chemoembolization combined with lenvatinib plus PD-1 inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study[J]. Front Immunol, 2022, 13: 848387. DOI: 10.3389/fimmu.2022.848387.
[27]	Qu S, Zhang X, Wu Y, et al. Efficacy and safety of TACE combined with lenvatinib plus PD-1 inhibitors compared with TACE alone for unresectable hepatocellular carcinoma patients: a prospective cohort study[J]. Front Oncol, 2022, 12: 874473. DOI: 10.3389/fonc.2022.874473.
[28]	Zhu HD, Li HL, Huang MS, et al. Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001)[J]. Signal Transduct Target Ther, 2023, 8(1): 58. DOI: 10.1038/s41392-022-01235-0.