Application of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma_West China Medical Journal

Authors：

ZENG Zhu ,  LIAO Zhengyin

Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIAO Zhengyin, Email: liaozhengyin@163.com

Keywords：

Hepatocellular carcinoma; Immune checkpoint inhibitors; Programmed death-1 inhibitors; Programmed death ligand-1 inhibitors; Cytotoxic T-lymphocyte antigen-4 inhibitors

DOI：

10.7507/1002-0179.201909205

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

In recent years, the incidence of primary liver cancer has been increasing, among which hepatocellular carcinoma (HCC) being the most common subtype. The treatment of early HCC is mainly surgery, but most patients are not diagnosed until the late stage of the disease. The treatment methods and effects are very limited and the prognosis is very poor. Although targeted therapy has prolonged the overall survival of patients with HCC, the overall efficacy is unsatisfactory. The emergence of immunotherapy has brought new therapeutic prospects for HCC. Immune checkpoint inhibitors, among which programmed death-1/programmed death ligand-1 and cytotoxic T-lymphocyte associated antigen-4 are the representative immunological checkpoints, have attracted more attention. This article will introduce the application of immune checkpoint inhibitors in the treatment of advanced HCC, in order to provide a theoretical basis for the use of immune checkpoint inhibitors in the treatment of advanced HCC.

Citation： ZENG Zhu, LIAO Zhengyin. Application of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma. West China Medical Journal, 2020, 35(2): 230-235. doi: 10.7507/1002-0179.201909205 Copy

1.	McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis, 2015, 19(2): 223-238.
2.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3.	Zeng H, Chen W, Zheng R, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health, 2018, 6(5): e555-e567.
4.	Kanwal F, Kramer J, Asch SM, et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology, 2017, 153(4): 996-1005.e1.
5.	Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology, 2016, 150(4): 835-853.
6.	Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064): 56-66.
7.	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. Lancet, 2018, 391(10126): 1163-1173.
8.	Greten TF, Lai CW, Li G, et al. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology, 2019, 156(2): 510-524.
9.	Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N EnglJ Med, 2018, 379(1): 54-63.
10.	Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
11.	Sprinzl MF, Galle PR. Current progress in immunotherapy of hepatocellular carcinoma. J Hepatol, 2017, 66(3): 482-484.
12.	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. Lancet, 2017, 389(10088): 2492-2502.
13.	Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase2 trial. Lancet Oncol, 2018, 19(7): 940-952.
14.	Eggert T, Greten TF. Tumor regulation of the tissue environment in the liver. Pharmacol Ther, 2017, 173: 47-57.
15.	Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology, 2017, 92(Suppl 1): 40-49.
16.	Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun, 2010, 34(1): 1-6.
17.	Jiang Y, Han QJ, Zhang J. Hepatocellular carcinoma: mechanisms of progression and immunotherapy. World J Gastroenterol, 2019, 25(25): 3151-3167.
18.	Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad SciU S A, 2013, 110(27): E2480-E2489.
19.	EI Dika I, Khalil DN, Abou-Alfa GK. Immune checkpoint inhibitors for hepatocellular carcinoma. Cancer, 2019, 125(19): 3312-3319.
20.	Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology, 2017, 93(Suppl 1): 147-159.
21.	Mizukoshi E, Kaneko S. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol, 2019, 12(1): 52.
22.	Benson AB 3rd, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, Version 1.2017. J Natl Compr Canc Netw, 2017, 15(5): 563-573.
23.	Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2019, 30(5): 871-873.
24.	Chow P, Li L, Li J, et al. Differences in presentation and management patterns in patients with hepatocellular carcinoma (HCC): data from HCC registry in Asia. J Clin Oncol, 2019, 37(4_suppl): 229.
25.	Yau T, Hsu C, Kim TY, et al. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol, 2019, 71(3): 543-552.
26.	Sangro B, Park JW, Cruz C, et al. A randomized, multicenter, phase 3 study of nivolumab vs sorafenib as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): CheckMate-459. J Clin Oncol, 2016, 34(15_suppl): TPS4147.
27.	Finn RS, Chan SI, Zhu AX, et al. Phase 3, randomized study of pembrolizumab (pembro) vs best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC): KEYNOTE-240. J Clin Oncol, 2017, 35(15_suppl): TPS4143.
28.	Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase Ⅲ trial. J Clin Oncol, 2019, 2: JCO1901307.
29.	Qin SK, Ren ZG, Meng ZQ, et al. LBA27A randomized multicentered phase II study to evaluate SHR-1210(PD-1 antibody) in subjects with advanced hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol, 2018, 29(suppl 8): viii719-viii720.
30.	中国医学论坛报. 卡瑞利珠单抗多领域表现亮眼, 开启中国免疫治疗新篇章. (2019-09-20)[2019-12-26]. http://www.sohu.com/a/342308499_333130.
31.	Xu JM, Zhang Y, Jia R, et al. Anti-programmed death-1 antibody SHR-1210(S) combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric cancer (GC) or esophagogastric junction (EGJ) cancer refractory to standard therapy: a phase 1 trial. J Clin Oncol, 2018, 36(15_suppl): 4075.
32.	Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res, 2019, 25(2): 515-523.
33.	生物_医药_科研. 卡瑞利珠单抗(PD-1)获批两大适应症Ⅲ临床, 适应症拓展提升产品潜力!!. (2019-07-20)[2019-12-26]. http://www.360doc.com/content/19/0720/17/52645714_849986591.shtml.
34.	医脉通. 秦叔逵教授解读肝癌最新进展的“得与失”. (2019-06-10)[2019-12-26]. http://news.medlive.cn/cancer/info-progress/show-158323_53.html.
35.	Pishvaian MJ, Lee MS, Ryoo BY, et al. LBA26Updated safety and clinical activity results from a phase Ib study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol, 2019(suppl 8): viii718-viii719.
36.	Ikeda M, Sung MW, Kudo M, et al. A phase Ⅰb trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol, 2018, 36(15): 4076.
37.	Agdashian D, ElGindi M, Xie C, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother, 2019, 68(4): 599-608.
38.	Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol, 2013, 59(1): 81-88.
39.	Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol, 2019, 37(15_suppl): 4012.
40.	Abou-Alfa GK, Chan SI, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol, 2018, 36(15): Suppl S.
41.	Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase Ⅰ safety and efficacy analyses. J Clin Oncol, 2017, 35(suppl 15): 4073.

1. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis, 2015, 19(2): 223-238.
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3. Zeng H, Chen W, Zheng R, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health, 2018, 6(5): e555-e567.
4. Kanwal F, Kramer J, Asch SM, et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology, 2017, 153(4): 996-1005.e1.
5. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology, 2016, 150(4): 835-853.
6. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064): 56-66.
7. 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. Lancet, 2018, 391(10126): 1163-1173.
8. Greten TF, Lai CW, Li G, et al. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology, 2019, 156(2): 510-524.
9. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N EnglJ Med, 2018, 379(1): 54-63.
10. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, 2015, 12(12): 681-700.
11. Sprinzl MF, Galle PR. Current progress in immunotherapy of hepatocellular carcinoma. J Hepatol, 2017, 66(3): 482-484.
12. 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. Lancet, 2017, 389(10088): 2492-2502.
13. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase2 trial. Lancet Oncol, 2018, 19(7): 940-952.
14. Eggert T, Greten TF. Tumor regulation of the tissue environment in the liver. Pharmacol Ther, 2017, 173: 47-57.
15. Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology, 2017, 92(Suppl 1): 40-49.
16. Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun, 2010, 34(1): 1-6.
17. Jiang Y, Han QJ, Zhang J. Hepatocellular carcinoma: mechanisms of progression and immunotherapy. World J Gastroenterol, 2019, 25(25): 3151-3167.
18. Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad SciU S A, 2013, 110(27): E2480-E2489.
19. EI Dika I, Khalil DN, Abou-Alfa GK. Immune checkpoint inhibitors for hepatocellular carcinoma. Cancer, 2019, 125(19): 3312-3319.
20. Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology, 2017, 93(Suppl 1): 147-159.
21. Mizukoshi E, Kaneko S. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol, 2019, 12(1): 52.
22. Benson AB 3rd, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, Version 1.2017. J Natl Compr Canc Netw, 2017, 15(5): 563-573.
23. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2019, 30(5): 871-873.
24. Chow P, Li L, Li J, et al. Differences in presentation and management patterns in patients with hepatocellular carcinoma (HCC): data from HCC registry in Asia. J Clin Oncol, 2019, 37(4_suppl): 229.
25. Yau T, Hsu C, Kim TY, et al. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol, 2019, 71(3): 543-552.
26. Sangro B, Park JW, Cruz C, et al. A randomized, multicenter, phase 3 study of nivolumab vs sorafenib as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): CheckMate-459. J Clin Oncol, 2016, 34(15_suppl): TPS4147.
27. Finn RS, Chan SI, Zhu AX, et al. Phase 3, randomized study of pembrolizumab (pembro) vs best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC): KEYNOTE-240. J Clin Oncol, 2017, 35(15_suppl): TPS4143.
28. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase Ⅲ trial. J Clin Oncol, 2019, 2: JCO1901307.
29. Qin SK, Ren ZG, Meng ZQ, et al. LBA27A randomized multicentered phase II study to evaluate SHR-1210(PD-1 antibody) in subjects with advanced hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol, 2018, 29(suppl 8): viii719-viii720.
30. 中国医学论坛报. 卡瑞利珠单抗多领域表现亮眼, 开启中国免疫治疗新篇章. (2019-09-20)[2019-12-26]. http://www.sohu.com/a/342308499_333130.
31. Xu JM, Zhang Y, Jia R, et al. Anti-programmed death-1 antibody SHR-1210(S) combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric cancer (GC) or esophagogastric junction (EGJ) cancer refractory to standard therapy: a phase 1 trial. J Clin Oncol, 2018, 36(15_suppl): 4075.
32. Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res, 2019, 25(2): 515-523.
33. 生物_医药_科研. 卡瑞利珠单抗(PD-1)获批两大适应症Ⅲ临床, 适应症拓展提升产品潜力!!. (2019-07-20)[2019-12-26]. http://www.360doc.com/content/19/0720/17/52645714_849986591.shtml.
34. 医脉通. 秦叔逵教授解读肝癌最新进展的“得与失”. (2019-06-10)[2019-12-26]. http://news.medlive.cn/cancer/info-progress/show-158323_53.html.
35. Pishvaian MJ, Lee MS, Ryoo BY, et al. LBA26Updated safety and clinical activity results from a phase Ib study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol, 2019(suppl 8): viii718-viii719.
36. Ikeda M, Sung MW, Kudo M, et al. A phase Ⅰb trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol, 2018, 36(15): 4076.
37. Agdashian D, ElGindi M, Xie C, et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother, 2019, 68(4): 599-608.
38. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol, 2013, 59(1): 81-88.
39. Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol, 2019, 37(15_suppl): 4012.
40. Abou-Alfa GK, Chan SI, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol, 2018, 36(15): Suppl S.
41. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase Ⅰ safety and efficacy analyses. J Clin Oncol, 2017, 35(suppl 15): 4073.

Previous Article
Review of FLASH Radiotherapy
Next Article
Research progress of assessment of outpatients safety culture

West China Medical Journal

Application of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content