Top

Published in:

01-04-2019 | Hepatocellular Carcinoma | Review

Immunotherapy: Current Status and Future Perspectives

Authors: Charalampos S. Floudas, Gagandeep Brar, Tim F. Greten

Published in: Digestive Diseases and Sciences | Issue 4/2019

Abstract

Hepatocellular carcinoma (HCC) has an increasing incidence and dismal prognosis, with few systemic treatments approved, including several small molecule tyrosine kinase inhibitors. The application of immune checkpoint inhibitors (ICIs) to HCC has resulted in durable activity, and further evaluation is ongoing. In this review, we discuss the immunologic principles and the mechanism of action of the ICIs and present the relevant clinical data. Furthermore, we provide an overview of the current and emerging immunotherapeutic approaches for HCC, such as combination treatments, vaccines, and cellular therapies.

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.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.CrossRefPubMed

Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed

Karin M. Nuclear factor-κB in cancer development and progression. Nature. 2006;441:431–436.CrossRefPubMed

Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2016;2:16018.CrossRefPubMed

Makarova-Rusher OV, Altekruse SF, McNeel TS, et al. Population attributable fractions of risk factors for hepatocellular carcinoma in the United States: US HCC-attributable risk factors. Cancer. 2016;122:1757–1765.CrossRefPubMed

Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci. 2013;1281:106–122.CrossRefPubMedPubMedCentral

Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.CrossRefPubMed

Benson AB, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw. 2017;15:563–573.CrossRefPubMedPubMedCentral

10.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.CrossRefPubMed

11.

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;391:1163–1173.CrossRefPubMed

12.

Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36:207.CrossRef

13.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–1813.CrossRefPubMedPubMedCentral

14.

Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–461.CrossRefPubMedPubMedCentral

15.

Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–384.CrossRefPubMed

16.

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;389:2492–2502.CrossRefPubMedPubMedCentral

17.

Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology. 2014;146:1193–1207.CrossRefPubMed

18.

Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, et al. The yin and yang of evasion and immune activation in HCC. J Hepatol. 2015;62:1420–1429.CrossRefPubMed

19.

Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12:681–700.CrossRefPubMed

20.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.CrossRefPubMedPubMedCentral

21.

Gao Q, Wang X-Y, Qiu S-J, 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.CrossRefPubMed

22.

Calderaro J, Rousseau B, Amaddeo G, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016;64:2038–2046.CrossRefPubMed

23.

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

24.

Ormandy LA, Hillemann T, Wedemeyer H, et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Can Res. 2005;65:2457–2464.CrossRef

25.

Arihara F, Mizukoshi E, Kitahara M, et al. Increase in CD14 + HLA-DR −/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother. 2013;62:1421–1430.CrossRefPubMed

26.

Greten TF, Wang XW, Korangy F. Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches. Gut. 2015;64:842–848.CrossRefPubMed

27.

Hoechst B, Ormandy LA, Ballmaier M, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4 + CD25 + Foxp3 + T cells. Gastroenterology. 2008;135:234–243.CrossRefPubMed

28.

Llovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000;31:54–58.CrossRefPubMed

29.

Sangro B, Mazzolini G, Ruiz J, et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol. 2004;22:1389–1397.CrossRefPubMed

30.

Mazzolini G, Alfaro C, Sangro B, et al. Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas. J Clin Oncol. 2005;23:999–1010.CrossRefPubMed

31.

Faivre SJ, Santoro A, Kelley RK, et al. A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2014;32:LBA173.CrossRef

32.

Faivre SJ, Santoro A, Gane E, et al. A phase 2 study of galunisertib, a novel transforming growth factor-beta (TGF-β) receptor I kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC) and low serum alpha fetoprotein (AFP). J Clin Oncol. 2016;34:4070.CrossRef

33.

Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3 + regulatory T cell function. Science. 2008;322:271–275.CrossRefPubMed

34.

Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–687.CrossRefPubMed

35.

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;59:81–88.CrossRefPubMed

36.

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

37.

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. Lancet Oncol. 2018;. https://doi.org/10.1016/s1470-2045(18)30351-6.CrossRefPubMed

38.

Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2017;35:4071.CrossRef

39.

Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339:1546–1558.CrossRefPubMedPubMedCentral

40.

Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–2199.CrossRefPubMedPubMedCentral

41.

Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2017;359:97–103.CrossRefPubMedPubMedCentral

42.

Routy B, Chatelier EL, Derosa L, et al. Gut microbiome influences efficacy of PD-1—based immunotherapy against epithelial tumors. Science. 2018;359:91–97.CrossRefPubMed

43.

Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.CrossRefPubMedPubMedCentral

44.

Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy. Science. 2018;359:1355–1360.CrossRefPubMed

45.

Butterfield LH, Ribas A, Meng WS, et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res. 2003;9:5902–5908.PubMed

46.

Butterfield LH, Economou JS, Gamblin T, et al. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients. J Transl Med. 2014;12:86.CrossRefPubMedPubMedCentral

47.

Nakagawa H, Mizukoshi E, Kobayashi E, et al. Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology. 2017;152:e10.CrossRef

48.

Feng M, Gao W, Wang R, et al. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci. 2013;110:E1083–E1091.CrossRefPubMedPubMedCentral

49.

Gao H, Li K, Tu H, et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res. 2014;20:6418–6428.CrossRefPubMed

50.

Acloque H, Adams MS, Fishwick K, et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Investig. 2009;119:1438–1449.CrossRefPubMedPubMedCentral

51.

Sun CK, Chua M-S, He J, et al. Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-β2. Neoplasia. 2011;13:735–747.CrossRefPubMedPubMedCentral

52.

Wu Y, Liu H, Weng H, et al. Glypican-3 promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through ERK signaling pathway. Int J Oncol. 2015;46:1275–1285.CrossRefPubMed

53.

Sawada Y, Yoshikawa T, Nobuoka D, et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 2012;18:3686–3696.CrossRefPubMed

54.

Sawada Y, Yoshikawa T, Shimomura M, et al. Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2015;46:28–36.CrossRefPubMed

55.

Sawada Y, Yoshikawa T, Ofuji K, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. OncoImmunology. 2016;5:e1129483.CrossRefPubMedPubMedCentral

56.

Nakano K, Ishiguro T, Konishi H, et al. Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. Anticancer Drugs. 2010;21:907.CrossRefPubMed

57.

Zhu AX, Gold PJ, El-Khoueiry AB, et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against Glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2013;19:920–928.CrossRefPubMed

58.

Greten TF, Forner A, Korangy F, et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer. 2010;10:209.CrossRefPubMedPubMedCentral

59.

Park B-H, Hwang T, Liu T-C, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008;9:533–542.CrossRefPubMed

60.

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

61.

Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017.CrossRefPubMedPubMedCentral

62.

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;35:4073.CrossRef

63.

Harding JJ, Dika IE, Abou-Alfa GK. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer. 2016;122:367–377.CrossRefPubMed

64.

Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.CrossRefPubMedPubMedCentral

65.

Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4074.CrossRef

66.

Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol. 2018;68:157–166.CrossRef

67.

Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–68.CrossRefPubMedPubMedCentral

68.

Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–4557.CrossRefPubMedPubMedCentral

69.

Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4 + T cells in a patient with epithelial cancer. Science. 2014;344:641–645.CrossRefPubMedPubMedCentral

70.

Haruta I, Yamauchi K, Aruga A, et al. Analytical study of the clinical response to two distinct adoptive immunotherapies for advanced hepatocellular carcinoma: comparison between LAK cell and CTL therapy. J Immunother Emphas Tumor Immunol. 1996;19:218–223.CrossRef

71.

Huang Z-M, Li W, Li S, et al. Cytokine-induced killer cells in combination with transcatheter arterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma patients. J Immunother. 2013;36:287–293.CrossRefPubMed

72.

Yu X, Zhao H, Liu L, et al. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocelluar carcinoma. J Clin Immunol. 2014;34:194–203.CrossRefPubMed

73.

Lee JH, Lee J-H, Lim Y-S, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015;148:e6.CrossRef

74.

Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013;13:525–541.CrossRefPubMed

75.

Clay TM, Custer MC, Sachs J, et al. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol. 1999;163:507–513.PubMed

76.

Morgan RA, Dudley ME, Yu YYL, et al. High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol. 2003;171:3287–3295.CrossRefPubMed

77.

Gehring AJ, Xue S-A, Ho ZZ, et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol. 2011;55:103–110.CrossRefPubMed

78.

Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2014;257:56–71.CrossRefPubMedPubMedCentral

79.

Zhai B, Shi D, Gao H, et al. A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3 + hepatocellular carcinoma (r/r GPC3 + HCC). J Clin Oncol. 2017;35:3049.CrossRef

80.

Liu B, Song Y, Liu D. Clinical trials of CAR-T cells in China. J Hematol Oncol. 2017;10:166.CrossRefPubMedPubMedCentral

Title: Immunotherapy: Current Status and Future Perspectives
Authors: Charalampos S. Floudas
Gagandeep Brar
Tim F. Greten
Publication date: 01-04-2019
Publisher: Springer US
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Sorafenib
Checkpoint Inhibitors
Published in: Digestive Diseases and Sciences / Issue 4/2019
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-019-05516-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2019

Living Donor Liver Transplantation for Hepatocellular Carcinoma: An Asian Perspective

Design and Endpoints of Clinical Trials, Current and Future

Current State of Tumor Ablation Therapies

Changing Epidemiology of HCC: How to Screen and Identify Patients at Risk?

Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies

Biomarkers: What Role Do They Play (If Any) for Diagnosis, Prognosis and Tumor Response Prediction for Hepatocellular Carcinoma?

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage