Year 2022 / Volume 114 / Number 11
Review
Immunotherapy in hepatocellular carcinoma

663-670

DOI: 10.17235/reed.2022.8876/2022

Manuel de la Torre, Paloma Sangro, Delia D´Avola, Bruno Sangro,

Abstract
Hepatocellular carcinoma is a highly prevalent tumor worldwide and when it reaches an advanced stage, few systemic treatments are available to improve the survival of these patients. However, greater knowledge about the tumor microenvironment and the role of the immune system in the control of tumor progression has allowed the development of treatments targeting immune checkpoints, which result in encouraging tumor response rates and prolonged survival. Although most of these treatments are well tolerated, up to 20 % of patients may experience side effects derived from non-specific stimulation of the immune system. In the cirrhotic patient, the early diagnosis and treatment of such adverse events is particularly challenging. Therefore, the ongoing investigation on the use of these new therapies will allow us to better understand the profile of the patients who will benefit most.
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References
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians. 2015 Mar;65(2):87–108.
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018 Nov;68(6):394–424.
3. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015 Mar 1;136(5):E359–86.
4. Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2016 Dec 22;2(1):16018.
5. Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology. 2019 Jan;156(2):477-491.e1.
6. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. Journal of Hepatology. 2022 Mar;76(3):681–93.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of Medicine. 2008 Jul 24;359(4):378–90.
8. 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. The Lancet. 2018 Mar;391(10126):1163–73.
9. 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. The Lancet. 2017 Jan;389(10064):56–66.
10. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. New England Journal of Medicine. 2018 Jul 5;379(1):54–63.
11. Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2019 Feb;20(2):282–96.
12. Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology. 2021 Aug 13;18(8):525–43.
13. Cai L, Michelakos T, Yamada T, et al. Defective HLA class I antigen processing machinery in cancer. Cancer Immunology, Immunotherapy. 2018 Jun 27;67(6):999–1009.
14. Yarchoan M, Johnson BA, Lutz ER, et al. Targeting neoantigens to augment antitumour immunity. Nature Reviews Cancer. 2017 Apr 24;17(4):209–22.
15. Greten TF, Sangro B. Targets for immunotherapy of liver cancer. Journal of Hepatology. 2018 Jan;68(1):157–66.
16. Han Y, Chen Z, Yang Y, et al. Human CD14 + CTLA-4 + regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. Hepatology. 2014 Feb;59(2):567–79.
17. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006 Feb 28;439(7077):682–7.
18. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 — potential mechanisms of action. Nature Reviews Immunology. 2015 Jan 23;15(1):45–56.
19. D’Avola D, Granito A, Torre-Aláez M de la, et al. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma. Journal of Hepatology. 2021 Nov.
20. 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. Journal of Hepatology. 2013 Jul;59(1):81–8.
21. 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. The Lancet. 2017 Jun;389(10088):2492–502.
22. Finn RS, Ryoo B-Y, 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. Journal of Clinical Oncology. 2020 Jan 20;38(3):193–202.
23. Yau T, Park J-W, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. The Lancet Oncology. 2022 Jan;23(1):77–90.
24. Qin S, Chen Z, Fang W, et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study. Journal of Clinical Oncology. 2022 Feb 1;40(4_suppl):383–383.
25. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Journal of Clinical Oncology. 2022 Feb 1;40(4_suppl):379–379.
26. Li Z, Li N, Li F, et al. Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma. Medicine. 2016 Dec;95(52):e5749.
27. Andrews LP, Marciscano AE, Drake CG, et al. LAG3 (CD223) as a cancer immunotherapy target. Immunological Reviews. 2017 Mar;276(1):80–96.
28. Zhou G, Sprengers D, Boor PPC, et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology. 2017 Oct;153(4):1107-1119.e10.
29. Cheng A-L, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. Journal of Hepatology. 2022 Apr;76(4):862–73.
30. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. New England Journal of Medicine. 2020 May 14;382(20):1894–905.
31. Bruix J, Chan SL, Galle PR, et al. Systemic treatment of hepatocellular carcinoma: An EASL position paper. Journal of Hepatology. 2021 Oct;75(4):960–74.
32. Yau T, Kang Y-K, Kim T-Y, El- et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib. JAMA Oncology. 2020 Nov 12;6(11):e204564.
33. Kelley RK, Sangro B, Harris W, et al. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Journal of Clinical Oncology. 2021 Sep 20;39(27):2991–3001.
34. Kelley RK, Yau T, Cheng A-L, et al. VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): Results from the randomized phase III COSMIC-312 trial. Annals of Oncology. 2022 Jan 1;33(1):114–6.
35. Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. Journal of clinical Oncology. 2020 Feb 4;38(4 supo.):478–478.
36. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. Journal of Clinical Oncology. 2020 Sep 10;38(26):2960–70.
37. Sangro B, Chan SL, Meyer T, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. Journal of Hepatology. 2020 Feb;72(2):320–41.
38. De Martin E, Michot J-M, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. Journal of Hepatology. 2018 Jun;68(6):1181–90.
39. Yoshikawa S, Asano T, Morino M, et al. Pruritus is common in patients with chronic liver disease and is improved by nalfurafine hydrochloride. Scientific Reports. 2021 Dec 4;11(1):3015.
40. Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Alimentary Pharmacology & Therapeutics. 2009 Jun;29(12):1273–81.
41. Piantanida E, Ippolito S, Gallo D, et al. The interplay between thyroid and liver: implications for clinical practice. Journal of Endocrinological Investigation. 2020 Jul 12;43(7):885–99.
42. Moini M, Yazdani Sarvestani M, et al. Evaluation of Adrenal Function in Nonhospitalized Patients with Cirrhosis. Canadian Journal of Gastroenterology and Hepatology. 2017;2017:1–6.
43. Bolondi L, Burroughs A, Dufour J-F, et al. Heterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment Decisions. Seminars in Liver Disease. 2013 Feb 8;32(04):348–59.
44. de la Torre MA, Buades-Mateu J, de la Rosa PA, et al. A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib. Liver International. 2016 Aug;36(8):1206–12.
45. Duffy AG, Ulahannan S V, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. Journal of Hepatology. 2017 Mar;66(3):545–51.
46. de la Torre-Aláez M, Matilla A, Varela M, et al. A Preliminary Analysis Of Early Liver Adverse Events (LAE) In Patients With Hepatocellular Carcinoma Treated With Selective Internal Radiation Therapy (SIRT) And Nivolumab. Presented at: International Liver Cancer Association 2019 Conference. September 20-22, 2019.
47. De La Torre M, Matilla A, Varela M et al. Nivolumab after selective internal radiation therapy using sir spheres resin microspheres in patients with hepatocellular carcinoma: the NASIR HCC trial. Presented at: International Liver Cancer Association 2020 Virtual Conference. September 11-13, 2020.
48. Tai D, Loke K, Gogna A, et al. Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial. The Lancet Gastroenterology & Hepatology. 2021 Dec 6;6(12):1025–35.
49. 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 phase 2 trial. The Lancet Oncology. 2018 Jul;19(7):940–52.
50. Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. The Lancet Oncology. 2020 Apr;21(4):571–80.
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de la Torre M, Sangro P, D´Avola D, Sangro B. Immunotherapy in hepatocellular carcinoma. 8876/2022


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Publication history

Received: 20/04/2022

Accepted: 25/04/2022

Online First: 15/06/2022

Published: 07/11/2022

Article Online First time: 56 days

Article editing time: 201 days


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