晚期原发性肝细胞癌免疫治疗现状及研究进展
Current Status and Research Progress of Immunotherapy for Advanced Primary Hepatocellular Carcinoma
DOI: 10.12677/ACM.2023.1361342, PDF,   
作者: 张海容:青海大学研究生院,青海 西宁;马金华:青海大学附属医院肿瘤内科,青海 西宁
关键词: 原发性肝细胞癌免疫治疗免疫检查点抑制剂肠道菌群Primary Hepatocellular Carcinoma Immunotherapy Immune Checkpoint Inhibitor Intestinal Flora
摘要: 原发性肝细胞性肝癌(HCC)的治疗是以手术为主,辅以介入、放化疗及局部治疗的综合疗法,但因其早期诊断率较低,恶性度较高,病情进展迅速,并且化疗及分子靶向药物疗效欠佳,导致我国肝癌总体仍处于高发病、低生存的状态。免疫疗法是目前肝癌治疗领域的一个研究热点,其中以免疫检查点抑制剂为主要的免疫治疗为中、晚期肝癌患者带来了新的生存获益。另有研究发现,肠道菌群失调可能会导致肝癌的发生发展,同时通过调节肠道菌群的组成也可以发挥免疫抗肿瘤作用。本文就免疫检查点抑制剂及肠道菌群在肝细胞癌免疫治疗中的现状及研究进展作一综述。
Abstract: The treatment of primary hepatocellular carcinoma (HCC) is mainly surgery, supplemented by comprehensive therapies such as intervention, radiotherapy and chemotherapy, and local treat-ment. However, due to its low early diagnosis rate, high malignancy, rapid progression of the dis-ease, and poor efficacy of chemotherapy and molecular targeted drugs, overall liver cancer in China is still in a state of high incidence and low survival. Immunotherapy is currently a research hotspot in the field of liver cancer treatment, with immune checkpoint inhibitors as the main immunother-apy providing new survival benefits for patients with mid to late stage liver cancer. Other studies have found that dysregulation of gut microbiota may lead to the occurrence and development of liver cancer, and regulating the composition of gut microbiota can also exert immune anti-tumor effects. This article reviews the current status and research progress of immune checkpoint inhibi-tors and gut microbiota in immunotherapy for hepatocellular carcinoma.
文章引用:张海容, 马金华. 晚期原发性肝细胞癌免疫治疗现状及研究进展[J]. 临床医学进展, 2023, 13(6): 9592-9598. https://doi.org/10.12677/ACM.2023.1361342

参考文献

[1] 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版) [J]. 中华消化病与影像杂志(电子版), 2020, 10(1): 22-48.
[2] Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. [Google Scholar] [CrossRef] [PubMed]
[3] ARC (2021) Latest Global Cancer Data: Cancer Burden Rises to 19.3 Mil-lion New Cases and 10.0 Million Cancer Deaths in 2020.
https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets
[4] Allemani, C., Weir, H.K., Carreira, H., et al. (2015) Global Surveillance of Cancer Survival 1995-2009: Analysis of Individual Data for 25676887 Patients from 279 Population-Based Registries in 67 Countries (CONCORD-2). The Lancet, 385, 977-1010. [Google Scholar] [CrossRef
[5] Gerbes, A., Zoulim, F., Tilg, H., et al. (2018) Gut Roundtable Meeting Paper: Selected Recent Advances in Hepatocellular Carcinoma. Gut, 67, 380-388. [Google Scholar] [CrossRef] [PubMed]
[6] Eso, Y. and Marusawa, H. (2018) Novel Approaches for Molec-ular Targeted Therapy against Hepatocellular Carcinoma. Hepatology Research, 48, 597-607. [Google Scholar] [CrossRef] [PubMed]
[7] Prasad, V., Kaestner, V. and Mailankody, S. (2018) Cancer Drugs Ap-proved Based on Biomarkers and Not Tumor Type-FDA Approval of Pembrolizumab for Mismatch Repair-Deficient Solid Cancers. JAMA Oncology, 4, 157-158. [Google Scholar] [CrossRef] [PubMed]
[8] Qin, S., Ren, Z., Meng, Z., et al. (2020) Camrelizumab in Pa-tients with Previously Treated Advanced Hepatocellular Carcinoma: A Multicentre, Open-Label, Parallel-Group, Ran-domised, Phase 2 Trial. The Lancet Oncology, 21, 571-580. [Google Scholar] [CrossRef
[9] Xing, P., Zhang, F., Wang, G., et al. (2019) Incidence Rates of Immune-Related Adverse Events and Their Correlation with Response in Advanced Solid Tumours Treated with NIVO or NIVO+IPI: A Systematic Review and Meta-Analysis. The Journal for ImmunoTherapy of Cancer, 7, Article No. 341. [Google Scholar] [CrossRef] [PubMed]
[10] Duffy, A.G., Ulahannan, S.V., Makorova-Rusher, O., et al. (2017) Tremelimumab in Combination with Ablation in Patients with Advanced Hepatocellular Carcinoma. Journal of Hepatology, 66, 545-551. [Google Scholar] [CrossRef] [PubMed]
[11] Finn, R.S., Qin, S., Ikeda, M., et al. (2020) Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. The New England Journal of Medicine, 382, 1894-1905. [Google Scholar] [CrossRef
[12] Ren, Z., Xu, J., Bai, Y., et al. (2021) Sintilimab plus a Bevacizumab Biosimilar (IBI305) versus Sorafenib in Unresectable Hepatocellular Carcinoma (ORIENT-32): A Randomised, Open-Label, Phase 2-3 Study. The Lancet Oncology, 22, 977-990. [Google Scholar] [CrossRef
[13] Shigeta, K., Datta, M., Hato, T., et al. (2020) Dual Pro-grammed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normali-zation and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma. Hepatology, 71, 1247-1261. [Google Scholar] [CrossRef] [PubMed]
[14] Finn, R.S., Ikeda, M., Zhu, A.X., et al. (2020) Phase Ib Study of Len-vatinib plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma. Journal of Clinical Oncology, 38, 2960-2970. [Google Scholar] [CrossRef
[15] Xu, J., Shen, J., Gu, S., et al. (2021) Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-Label, Phase II Trial. Clinical Cancer Research, 27, 1003-1011. [Google Scholar] [CrossRef
[16] Kudo, M., Finn, R.S., Qin, S., et al. (2018) Lenvatinib ver-sus Sorafenib in Firstline Treatment of Patients with Unresectable Hepatocellular Carcinoma: A Randomised Phase 3 Non-Inferiority Trial. The Lancet, 391, 1163-1173. [Google Scholar] [CrossRef
[17] Kelley, R.K., Sangro, B., Harris, W.P., et al. (2020) Efficacy, Tolerability, and Biologic Activity of a Novel Regimen of Tremelimumab (T) in Combination with Durvalumab (D) for Patients (pts) with Advanced Hepatocellular Carcinoma (aHCC). Journal of Clinical Oncology, 38, 4508-4508. [Google Scholar] [CrossRef
[18] Qin, S., Bai, Y., Lim, H.Y., et al. (2013) Randomized, Multicenter, Open-Label Study of Oxaliplatin plus Fluorouracil/Leucovorin versus Doxorubicin as Palliative Chemo-therapy in Patients with Advanced Hepatocellular Carcinoma from Asia. Journal of Clinical Oncology, 31, 3501-3508. [Google Scholar] [CrossRef
[19] Qin, S., Cheng, Y., Liang, J., et al. (2014) Efficacy and Safety of the FOLFOX4 Regimen versus Doxorubicin in Chinese Patients with Advanced Hepatocellular Carcinoma: A Subgroup Analysis of the EACH Study. Oncologist, 19, 1169-1178. [Google Scholar] [CrossRef] [PubMed]
[20] Qin, S., Chen, Z., Liu, Y., et al. (2019) A Phase II Study of Anti-PD-1 Antibody Camrelizumab plus FOLFOX4 or GEMOX Systemic Chemotherapy as First-Line Therapy for Advanced Hepatocellular Carcinoma or Biliary Tract Cancer. Journal of Clinical Oncology, 37, 4074. [Google Scholar] [CrossRef
[21] Yu, L.X. and Schwabe, R.F. (2017) The Gut Microbi-ome and Liver Cancer: Mechanisms and Clinical Translation. Nature Reviews Gastroenterology & Hepatology, 14, 527-539. [Google Scholar] [CrossRef] [PubMed]
[22] Zhu, L., Baker, S.S., Gill, C., Liu, W., Alkhouri, R., Baker, R.D. and Gill, S.R. (2013) Characterization of Gut Microbiomes in Nonalcoholic Steatohepatitis (NASH) Patients: A Connection between Endogenous Alcohol and NASH. Hepatology, 57, 601-609. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, Y., Yang, F., Lu, H., Wang, B., Chen, Y., Lei, D., Wang, Y., Zhu, B. and Li, L. (2011) Characterization of Fecal Microbial Communities in Patients with Liver Cirrhosis. Hepatology, 54, 562-572. [Google Scholar] [CrossRef] [PubMed]
[24] 辛海荣, 李喜, 孙瑞芳, 等. 原发性肝癌患者内毒素与肠道菌群变化的相关性研究[J]. 中华普通外科杂志, 2019, 34(8): 686-688.
[25] 高艳颖, 向慧玲, 梁静, 韩涛, 张旭. 肠道菌群失衡在肝癌发生发展中的影响机制及益生菌对肝癌的预防作用[J]. 临床肝胆病杂志, 2022, 38(3): 699-702.
[26] Zheng, Y., Wang, T., Tu, X., et al. (2019) Gut Microbiome Affects the Response to Anti-PD-1 Immuno-therapy in Patients with Hepatocellular Carcinoma. The Journal for ImmunoTherapy of Cancer, 7, Article No. 193. [Google Scholar] [CrossRef] [PubMed]
[27] Routy, B., Le Chatelier, E., Derosa, L., et al. (2018) Gut Micro-biome Influences Efficacy of PD-1-Based Immunotherapy against Epithelial Tumors. Science, 359, 91-97. [Google Scholar] [CrossRef] [PubMed]
[28] Delaune, V., Orci, L.A., Lacotte, S., et al. (2018) Fecal Microbiota Transplantation: A Promising Strategy in Preventing the Progression of Non-Alcoholic Steatohepatitis and Improving the Anti-Cancer Immune Response. Expert Opinion on Biological Therapy, 18, 1061-1071. [Google Scholar] [CrossRef] [PubMed]
[29] Smits, L.P., Bouter, K.E.C., De Vos, W.M., et al. (2013) Therapeutic Potential of Fecal Microbiota Transplantation. Gastroenterology, 145, 946-953. [Google Scholar] [CrossRef] [PubMed]
[30] Spakowicz, D., Hoyd, R., Muniak, M., Husain, M., Bassett, J.S., Wang, L., et al. (2020) Inferring the Role of the Microbiome on Survival in Patients Treated with Immune Checkpoint Inhibitors: Causal Modeling, Timing, and Classes of Concomitant Medications. BMC Cancer, 20, Article No. 383. [Google Scholar] [CrossRef] [PubMed]
[31] Fessas, P., Naeem, M., Pinter, M., et al. (2021) Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma. Liver Cancer, 10, 583-592. [Google Scholar] [CrossRef] [PubMed]
[32] Han, J.J., Zhang, S.Y., Xu, Y., et al. (2020) Beneficial Effect of Antibiotics and Microbial Metabolites on Expanded Vδ2Vγ9 T Cells in Hepatocellular Carcinoma Immunotherapy. Fron-tiers in Immunology, 11, Article No. 1380. [Google Scholar] [CrossRef] [PubMed]