J Liver Cancer.  2019 Mar;19(1):1-11. 10.17998/jlc.19.1.1.

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma

• Cho Y
• Han J
• Kim W

• KMID: 2448271
• DOI: http://doi.org/10.17998/jlc.19.1.1

Abstract

Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumor-specific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.

Keyword

Hepatocellular carcinoma; Immunotherapy; Immune checkpoint inhibitor; Adoptive cell therapy; Oncolytic virus

MeSH Terms

Carcinoma, Hepatocellular*
Cell- and Tissue-Based Therapy
Cytokine-Induced Killer Cells
Homicide
Humans
Immune Tolerance
Immunotherapy
Neoplasm, Residual
Oncolytic Viruses
T-Lymphocytes
Tumor Microenvironment
Vaccination

Figure

• 

  Figure 1. The three main strategies of HCC immunotherapy. HCC, hepatocellular carcinoma; NK, natural killer; CIK, cytokine-induced killer; DC, dendritic cells.

• 

  Figure 2. The structure of CAR. scFv, single chain fragment variable; ITAM, immunoreceptor tyrosine-based activation motif; CM, costimulatory molecules; CAR, chimeric antigen receptor.

• 

  Figure 3. Interaction between major immune co-stimulatory and inhibitory molecules and their cognate receptors. Co-stimulatory and co-inhibitory molecules are indicated by closed and open boxes, respectively. Costimulatory and inhibitory signals are indicated by filled and hatched arrows, respectively. APC, antigen presenting cell; PD, programmed cell death; CTLA, cytotoxic T lymphocyte antigen; LAG, lymphocyte activation gene; TIM, T cell immunoglobulin and mucin domain; MHC, major histocompatibility complex; SIPR = sphingosine-1-phosphate receptor.

• 

  Figure 4. Immunotherapy-related adverse events in multi-organs.

Reference

1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018; 391:1301–1314.

2. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016; 2:16018.

3. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013; 31:4067–4075.

4. Johnson PJ, Qin S, Park JW, Poon R, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013; 31:3517–3524.

5. Zhu AX, Rosmorduc O, Evans T, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebocontrolled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2014; 33:559–566.

6. Abou-Alfa GK, Capanu M, O’Reilly EM, Ma J, Chou JF, Gansukh B, et al. A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol. 2014; 60:319–324.

7. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 noninferiority trial. Lancet. 2018; 391:1163–1173.

8. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet. 2017; 389:56–66.

9. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015; 47:505–511.

10. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2013; 2013:187204.

11. Greten TF, Manns MP, Korangy F. Immunotherapy of hepatocellular carcinoma. J Hepatol. 2006; 45:868–878.

12. Greten TF, Manns MP, Korangy F. Immunotherapy of HCC. Rev Recent Clin Trials. 2008; 3:31–39.

13. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, 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; 389:2492–2502.

14. Kassel R, Cruise MW, Iezzoni JC, Taylor NA, Pruett TL, Hahn YS. Chronically inflamed livers up‐regulate expression of inhibitory B7 family members. Hepatology. 2009; 50:1625–1637.

15. Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Büschenfelde KH, Gerken G. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol. 1995; 22:226–229.

16. Bissell D, Wang SS, Jarnagin W, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest. 1995; 96:447–455.

17. Moorman JP, Wang JM, Zhang Y, Ji XJ, Ma CJ, Wu XY, et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J Immunol. 2012; 189:755–766.

18. Schmidt N, Thimme R. Role of immunity in pathogenesis and treatment of hepatocellular carcinoma. Dig Dis. 2016; 34:429–437.

19. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–674.

20. Yeku O, Li X, Brentjens RJ. Adoptive T-cell therapy for solid tumors. Am Soc Clin Oncol Educ Book. 2017; 37:193–204.

21. Gao X, Mi Y, Guo N, Xu H, Xu L, Gou X, et al. Cytokine-induced killer cells as pharmacological tools for cancer immunotherapy. Frontiers in immunology. 2017; 8:774.

22. Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015; 148:1383–1391.e1386.

23. Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, et al. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother. 2019; 68:23–32.

24. Yu R, Yang B, Chi X, Cai L, Liu C, Yang L, et al. Efficacy of cytokineinduced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis. Drug Des Devel Ther. 2017; 11:851–864.

25. Badalamenti G, Fanale D, Incorvaia L, Barraco N, Listì A, Maragliano R, et al. Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone? Cell Immunol. 2018; Feb. 1. doi: 10.1016/j.cellimm.2018.01.013. [Epub ahead of print].

26. Jiang SS, Tang Y, Zhang YJ, Weng DS, Zhou ZG, Pan K, et al. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Oncotarget. 2015; 6:41339–41349.

27. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008; 9:503–510.

28. Chmielewski M, Hombach AA, Abken H. Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptorredirected T cells. Front Immunol. 2013; 4:371.

29. Priceman SJ, Forman SJ, Brown CE. Smart CARs engineered for cancer immunotherapy. Curr Opin Oncol. 2015; 27:466–474.

30. Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology. 2014; 60:1776–1782.

31. Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013; 59:81–88.

32. Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017; 66:545–551.

33. El-Khoueiry AB, Melero I, Crocenzi TS, Welling TH, Yau TC, Yeo W, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. ASCO. 2015; 33:18.

34. Zhong F, Cheng X, Sun S, Zhou J. Transcriptional activation of PD-L1 by Sox2 contributes to the proliferation of hepatocellular carcinoma cells. Oncol Rep. 2017; 37:3061–3067.

35. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15:971–979.

36. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372:320–330.

37. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014; 20:5064–5074.

38. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a nonrandomised, open-label phase 2 trial. Lancet Oncol. 2018; 19:940–952.

39. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114:1537–1544.

40. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017; 18:1182–1191.

41. Zerbini A, Pilli M, Penna A, Pelosi G, Schianchi C, Molinari A, et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer res. 2006; 66:1139–1146.

42. Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, et al. Enhancement of tumor‐associated antigen‐specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013; 57:1448–1457.

43. Sun T, Yan W, Yang C, Zhang L, Tang H, Chen Y, et al. Clinical research on dendritic cell vaccines to prevent postoperative recurrence and metastasis of liver cancer. Genet Mol Res. 2015; 14:16222–16232.

44. Butterfield LH, Ribas A, Meng WS, Dissette VB, Amarnani S, Vu HT, et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res. 2003; 9(16 Pt 1):5902–5908.

45. Sawada Y, Yoshikawa T, Ofuji K, Yoshimura M, Tsuchiya N, Takahashi M, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 2016; 5:e1129483.

46. Ormandy LA, Farber A, Cantz T, Petrykowska S, Wedemeyer H, Horning M, et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J Gastroenterol WJG. 2006; 12:3275–3282.

47. Shang N, Figini M, Shangguan J, Wang B, Sun C, Pan L, et al. Dendritic cells based immunotherapy. Am J Cancer Res. 2017; 7:2091–2102.

48. Lee JH, Lee Y, Lee M, Heo MK, Song JS, Kim KH, et al. A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Br J Cancer. 2015; 113:1666–1676.

49. Lee JH, Tak WY, Lee Y, Heo MK, Song JS, Kim HY, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology. 2017; 6:e1328335.

50. Bourke M, Salwa S, Harrington K, Kucharczyk M, Forde P, de Kruijf M, et al. The emerging role of viruses in the treatment of solid tumours. Cancer Treat Rev. 2011; 37:618–632.

51. Stanford MM, Bell JC, Vähä-Koskela MJ. Novel oncolytic viruses: riding high on the next wave? Cytokine Growth Factor Rev. 2010; 21:177–183.

52. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014; 2:295–300.

53. Zhang W, Ge K, Zhao Q, Zhuang X, Deng Z, Liu L, et al. A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4. Oncotarget. 2015; 6:20345–20355.

54. Breitbach CJ, Arulanandam R, De Silva N, Thorne SH, Patt R, Daneshmand M, et al. Oncolytic vaccinia virus disrupts tumorassociated vasculature in humans. Cancer Res. 2013; 73:1265–1275.

55. Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013; 19:329–336.

56. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017; 35:785–792.

57. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018; 378:158–168.

58. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016; 2:1346–1353.

59. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017; 28:368–376.