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Annual Review of Medicine

Volume 73, 2022

Hepatocellular Carcinoma Immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in early-phase trials, a finding that was not confirmed in phase III studies. The combination of atezolizumab (an anti-PD-L1 ICI) with bevacizumab (an anti-VEGF antibody) was approved as first-line therapy in 2020, however, with significant improvement in response rate, progression-free survival, and overall survival in comparison with the previous standard of care, sorafenib. Numerous ongoing clinical trials are assessing ICIs in combination with each other or with targeted agents, and also in earlier stages with local therapies. This review summarizes the latest concepts in the use of ICIs for the management of HCC.

Keyword(s): carcinoma therapy, hepatocellular carcinoma, immune checkpoint inhibitors, liver cancer
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2022-01-27
2025-04-30
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Literature Cited

  1. 1. 
    Sung H, Ferlay J, Siegel RL, et al. 2021.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. . CA: Cancer J. Clin. 71:(3):209–49
     [Google Scholar]
  2. 2. 
    Singal AG, El-Serag HB. 2015.. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. . Clin. Gastroenterol. Hepatol. 13:(12):2140–51
     [Google Scholar]
  3. 3. 
    Bruix J, Sherman M. 2011.. Management of hepatocellular carcinoma: an update. . Hepatology 53:(3):1020–22
     [Google Scholar]
  4. 4. 
    Llovet JM, Bustamante J, Castells A, et al. 1999.. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. . Hepatology 29:(1):62–67
     [Google Scholar]
  5. 5. 
    Kumada T, Nakano S, Takeda I, et al. 1997.. Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. . Hepatology 25:(1):87–92
     [Google Scholar]
  6. 6. 
    Lohitesh K, Chowdhury R, Mukherjee S. 2018.. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. . Cancer Cell Int. 18::44
     [Google Scholar]
  7. 7. 
    Miyahara K, Nouso K, Yamamoto K. 2014.. Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age. . World J. Gastroenterol. 20:(15):4151–59
     [Google Scholar]
  8. 8. 
    Morse MA, Sun W, Kim R, et al. 2019.. The role of angiogenesis in hepatocellular carcinoma. . Clin. Cancer Res. 25:(3):912–20
     [Google Scholar]
  9. 9. 
    Llovet JM, Ricci S, Mazzaferro V, et al. 2008.. Sorafenib in advanced hepatocellular carcinoma. . N. Engl. J. Med. 359:(4):378–90
     [Google Scholar]
  10. 10. 
    Kudo M, Finn RS, Qin S, et al. 2018.. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. . Lancet 391:(10126):1163–73
     [Google Scholar]
  11. 11. 
    Bruix J, Qin S, Merle P, et al. 2017.. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. . Lancet 389:(10064):56–66
     [Google Scholar]
  12. 12. 
    Zhu AX, Park JO, Ryoo BY, et al. 2015.. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. . Lancet Oncol. 16:(7):859–70
     [Google Scholar]
  13. 13. 
    Abou-Alfa GK, Meyer T, Cheng A-L, et al. 2018.. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. . N. Engl. J. Med. 379:(1):54–63
     [Google Scholar]
  14. 14. 
    Llovet JM, Sala M, Castells L, et al. 2000.. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. . Hepatology 31:(1):54–58
     [Google Scholar]
  15. 15. 
    Sangro B, Mazzolini G, Ruiz J, et al. 2004.. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. . J. Clin. Oncol. 22:(8):1389–97
     [Google Scholar]
  16. 16. 
    Thallinger C, Füreder T, Preusser M, et al. 2018.. Review of cancer treatment with immune checkpoint inhibitors: current concepts, expectations, limitations and pitfalls. . Wien. Klin. Wochenschr. 130:(3–4):85–91
     [Google Scholar]
  17. 17. 
    Chang CY, Park H, Malone DC, et al. 2020.. Immune checkpoint inhibitors and immune-related adverse events in patients with advanced melanoma: a systematic review and network meta-analysis. . JAMA Netw. Open 3:(3):e201611
     [Google Scholar]
  18. 18. 
    Wang J, Li X, Wu X, et al. 2019.. Role of immune checkpoint inhibitor-based therapies for metastatic renal cell carcinoma in the first-line setting: a Bayesian network analysis. . EBioMedicine 47::78–88
     [Google Scholar]
  19. 19. 
    Dafni U, Tsourti Z, Vervita K, Peters S. 2019.. Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. . Lung Cancer 134::127–40
     [Google Scholar]
  20. 20. 
    Borcoman E, Kanjanapan Y, Champiat S, et al. 2019.. Novel patterns of response under immunotherapy. . Ann. Oncol. 30:(3):385–96
     [Google Scholar]
  21. 21. 
    Pennock GK, Chow LQM. 2015.. The evolving role of immune checkpoint inhibitors in cancer treatment. . Oncologist 20:(7):812–22
     [Google Scholar]
  22. 22. 
    Garcia KC, Adams EJ. 2005.. How the T cell receptor sees antigen—a structural view. . Cell 122:(3):333–36
     [Google Scholar]
  23. 23. 
    Wherry EJ. 2011.. T cell exhaustion. . Nat. Immunol. 12:(6):492–99
     [Google Scholar]
  24. 24. 
    Schadendorf D, Hodi FS, Robert C, et al. 2015.. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. . J. Clin. Oncol. 33:(17):1889–94
     [Google Scholar]
  25. 25. 
    Walker LSK, Sansom DM. 2011.. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. . Nat. Rev. Immunol. 11:(12):852–63
     [Google Scholar]
  26. 26. 
    Berkson JD, Slichter CK, DeBerg HA, et al. 2020.. Inflammatory cytokines induce sustained CTLA-4 cell surface expression on human MAIT cells. . ImmunoHorizons 4:(1):14–22
     [Google Scholar]
  27. 27. 
    Buchbinder EI, Desai A. 2016.. CTLA-4 and PD-1 pathways similarities, differences, and implications of their inhibition. . Am. J. Clin. Oncol. Cancer Clin. Trials 39:(1):98–106
     [Google Scholar]
  28. 28. 
    Spranger S, Spaapen RM, Zha Y, et al. 2013.. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. . Sci. Transl. Med. 5:(200):200ra116
     [Google Scholar]
  29. 29. 
    Kinter AL, Godbout EJ, McNally JP, et al. 2008.. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. . J. Immunol. 181:(10):6738–46
     [Google Scholar]
  30. 30. 
    Chalmers ZR, Connelly CF, Fabrizio D, et al. 2017.. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. . Genome Med. 9:(1):34
     [Google Scholar]
  31. 31. 
    Kassel R, Cruise MW, Iezzoni JC, et al. 2009.. Chronically inflamed livers up-regulate expression of inhibitory B7 family members. . Hepatology 50:(5):1625–37
     [Google Scholar]
  32. 32. 
    Sia D, Jiao Y, Martinez-Quetglas I, et al. 2017.. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. . Gastroenterology 153:(3):812–26
     [Google Scholar]
  33. 33. 
    El-Khoueiry AB, Sangro B, Yau T, et al. 2017.. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. . Lancet 389:(10088):2492–502
     [Google Scholar]
  34. 34. 
    Colombo M, Lleo A. 2019.. Is liver injury an affordable risk of immune checkpoint inhibitor therapy for cancer?. Gastroenterology 155:(6):2021–23
     [Google Scholar]
  35. 35. 
    Zhu AX, Finn RS, Edeline J, et al. 2018.. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. . Lancet Oncol. 19:(7):940–52
     [Google Scholar]
  36. 36. 
    Finn RS, Ryoo BY, Merle P, et al. 2020.. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. . J. Clin. Oncol. 38:(3):193–202
     [Google Scholar]
  37. 37. 
    Yau T, Park JW, Finn RS, et al. 2019.. CheckMate 459: A randomized, multi-center phase 3 study of nivolumab (NIVO) versus sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). . Ann. Oncol. 30:(Suppl. 5):v851–934
     [Google Scholar]
  38. 38. 
    Karlovitch S. 2021.. ODAC opposes ongoing FDA approval of nivolumab for HCC in patients pretreated with sorafenib. . Apr. 29, Targeted Oncology. Accessed May 12. https://www.targetedonc.com/view/odac-opposes-ongoing-fda-approval-of-nivolumab-for-hcc-in-patients-pretreated-with-sorafenib
  39. 39. 
    FDA. 2020.. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. June 1, US Food Drug Adm. Accessed May 24, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma
    [Google Scholar]
  40. 40. 
    Finn RS, Qin S, Ikeda M, et al. 2020.. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. . N. Engl. J. Med. 382:(20):1894–905
     [Google Scholar]
  41. 41. 
    Helwick C. 2020.. Patient-reported outcomes from IMbrave150: better quality of life with doublet. . Feb. 25, ASCO Post. Accessed May 10, 2021. https://ascopost.com/issues/february-25-2020/patient-reported-outcomes-from-imbrave150/
  42. 42. 
    Finn RS, Ikeda M, Zhu AX, et al. 2020.. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. . J. Clin. Oncol. 38:(26):2960–70
     [Google Scholar]
  43. 43. 
    Puri S, Shafique M. 2020.. Combination checkpoint inhibitors for treatment of non-small-cell lung cancer: an update on dual anti-CTLA-4 and anti-PD-1/PD-L1 therapies. . Drugs Context 9::2019-9-2
     [Google Scholar]
  44. 44. 
    Rotte A. 2019.. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. . J. Exp. Clin. Cancer Res. 38:(1):255
     [Google Scholar]
  45. 45. 
    Huyghe N, Baldin P, van den Eynde M. 2020.. Immunotherapy with immune checkpoint inhibitors in colorectal cancer: What is the future beyond deficient mismatch-repair tumours?. Gastroenterol. Rep. 8:(1):11–24
     [Google Scholar]
  46. 46. 
    FDA. 2020.. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. Mar. 11, US Food Drug Adm. Accessed May 10, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma
    [Google Scholar]
  47. 47. 
    Yau T, Kang Y-K, Kim T-Y, et al. 2019.. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. . J. Clin. Oncol. 37:(15 Suppl.):4012–12
     [Google Scholar]
  48. 48. 
    2021.. Diretrizes de Tratamentos Oncológicos Recomendados Pela Sociedade Brasileira de Oncologia Clínica. https://www.sboc.org.br/images/1.-Diretrizes-SBOC-2021---CHC-v11-FINAL-COM-CONTRIBUIES.pdf
    [Google Scholar]
  49. 49. 
    Troiani T, de Falco V, Napolitano S, et al. 2021.. How we treat locoregional melanoma. . ESMO Open 6:(3):100136
     [Google Scholar]
  50. 50. 
    Vivaldi C, Catanese S, Massa V, et al. 2020.. Immune checkpoint inhibitors in esophageal cancers: Are we finally finding the right path in the mist?. Int. J. Mol. Sci. 21:(5):1658
     [Google Scholar]
  51. 51. 
    Vansteenkiste J, Wauters E, Reymen B, et al. 2019.. Current status of immune checkpoint inhibition in early-stage NSCLC. . Ann. Oncol. 30:(8):1244–53
     [Google Scholar]
  52. 52. 
    Liu J, Blake SJ, Yong MCR, et al. 2016.. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. . Cancer Discov. 6:(12):1382–99
     [Google Scholar]
  53. 53. 
    Menzies AM, Amaria RN, Rozeman EA, et al. 2021.. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). . Nat. Med. 27::301–9
     [Google Scholar]
  54. 54. 
    Chalabi M, Fanchi LF, Dijkstra KK, et al. 2020.. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. . Nat. Med. 26::566–76
     [Google Scholar]
  55. 55. 
    Kaseb AO, Vence L, Blando J, et al. 2019.. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. . Cancer Immunol. Res. 7:(9):1390–95
     [Google Scholar]
  56. 56. 
    Paavola KJ, Roda JM, Lin VY, et al. 2021.. The fibronectin–ILT3 interaction functions as a stromal checkpoint that suppresses myeloid cells. . Cancer Immunol. Res. 9:(11):128397
     [Google Scholar]
  57. 57. 
    Zhu AX, Finn RS, Edeline J, et al. 2018.. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. . Lancet Oncol. 19:(7):940–52
     [Google Scholar]
  58. 58. 
    Finn RS, Ryoo BY, Merle P, et al. 2020.. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. . J. Clin. Oncol. 38:(3):193–202
     [Google Scholar]
  59. 59. 
    El-Khoueiry AB, Sangro B, Yau T, et al. 2017.. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. . Lancet 389:(10088):2492–502
     [Google Scholar]
  60. 60. 
    Finn RS, Qin S, Ikeda M, et al. 2020.. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. . N. Engl. J. Med. 382:(20):1894–905
     [Google Scholar]
  61. 61. 
    Yau T, Kang Y-K, Kim T-Y, et al. 2019.. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. . J. Clin. Oncol. 37:(15 Suppl.):4012
     [Google Scholar]
  62. 62. 
    Kelley RK, W Oliver J, Hazra S, et al. 2020.. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 phase III study design. . Future Oncol. 16:(21):1525–36
     [Google Scholar]
  63. 63. 
    Qin S, Finn RS, Kudo M, et al. 2019.. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. . Future Oncol. 15:(16):1811–22
     [Google Scholar]
/content/journals/10.1146/annurev-med-042220-021121
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Hepatocellular Carcinoma Immunotherapy
Annual Review of Medicine 73, 267 (2022); https://doi.org/10.1146/annurev-med-042220-021121
/content/journals/10.1146/annurev-med-042220-021121
/content/journals/10.1146/annurev-med-042220-021121
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