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Immunotherapy of Hepatocellular Carcinoma pp 51–68Cite as

Immune Checkpoint Inhibitors for the Treatment of Hepatocellular Carcinoma

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Abstract

Immune checkpoints are membrane-bound molecules that provide fine-tuning of the complex process of immune response against cancer. From a therapeutic perspective, interaction with checkpoint molecules has revolutionized the field of cancer therapy. Attention has focused in two players, CTLA-4 and PD-1. The former is essential for the activation of CD4+ T cells and the priming phase of the immune response while the latter inhibits CD4+ and CD8+ T cell activation. In patients with hepatocellular carcinoma, there is substantial evidence that supports a relevant role of immune checkpoints in the absence of an effective antitumor immune response. These negative signals can be blocked with the use of monoclonal antibodies. While CTLA-4 blockade first produced encouraging signals of antitumor activity, PD-1 blockade results in consistent tumor responses and prolonged stabilizations that lead to substantial prolongation of survival among patients with advanced tumors. This has fueled the interest in developing better therapeutic strategies through combinations of immune-oncology agents and combinations of such agents with targeted agents that may act synergistically.

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References

  1. Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, et al. Dendritic cells as pharmacological tools for cancer immunotherapy. Pharmacol Rev. 2015;67:731–53.

    Article  CAS  PubMed  Google Scholar 

  2. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10:99–111.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271–5.

    Article  CAS  PubMed  Google Scholar 

  7. Han Y, Chen Z, Yang Y, Jiang Z, Gu Y, Liu 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;59:567–79.

    Article  CAS  PubMed  Google Scholar 

  8. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  PubMed  Google Scholar 

  9. Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2:393–8.

    Article  CAS  PubMed  Google Scholar 

  10. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 – potential mechanisms of action. Nat Rev Immunol [Internet]. 2015;15:45–56.

    Article  CAS  Google Scholar 

  11. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.

    Article  CAS  PubMed  Google Scholar 

  12. Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol. 2005;6:90–8.

    Article  CAS  PubMed  Google Scholar 

  13. Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol. 2003;4:670–9.

    Article  CAS  PubMed  Google Scholar 

  14. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 2014;59:1415–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol. 2006;45:246–53.

    Article  CAS  PubMed  Google Scholar 

  16. Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 1998;27:407–14.

    Article  CAS  PubMed  Google Scholar 

  17. Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.

    Article  PubMed  Google Scholar 

  18. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, 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;62:1421–30.

    Article  CAS  PubMed  Google Scholar 

  19. Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J cancer. 2011;128:887–96.

    Article  CAS  PubMed  Google Scholar 

  20. 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;15:971–9.

    Article  CAS  PubMed  Google Scholar 

  21. Li FJ, Zhang Y, Jin GX, Yao L, Wu DQ. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8+ T cell in HCC patients. Immunol Lett. 2013;150:116–22.

    Article  CAS  PubMed  Google Scholar 

  22. Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012;56:1342–51.

    Article  CAS  PubMed  Google Scholar 

  23. Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, et al. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut. 2015;1–12.

    Google Scholar 

  24. Hokuto D, Sho M, Yamato I, Yasuda S, Obara S, Nomi T, et al. Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma. Eur J Cancer. 2015;51:157–65.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao Q, Huang Z-L, He M, Gao Z, Kuang D-M. BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma. Oncoimmunology. 2016;5

    Google Scholar 

  26. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  PubMed  Google Scholar 

  27. George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2:1179–86.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  PubMed  Google Scholar 

  29. Petrylak DP, Powles T, Bellmunt J, Braiteh FS, Loriot Y, Zambrano C, et al. A phase Ia study of MPDL3280A (anti-PDL1): updated response and survival data in urothelial bladder cancer (UBC). J Clin Oncol. 2015;Suppl 33: Abstr 4501.

    Google Scholar 

  30. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34:3838–45.

    Article  Google Scholar 

  32. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206:1717–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui 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;59:81–8.

    Article  CAS  PubMed  Google Scholar 

  34. Kavanagh B, O’Brien S, Lee D, Hou Y, Weinberg V, Rini B, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4 + T cells in a dose-dependent fashion. Blood. 2008;112:1175–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Duffy AG, Ulahannan SV, Makorova-Rusher O, Wedemeyer H, Pratt D, Davis JL, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545–51.

    Article  CAS  PubMed  Google Scholar 

  36. Sprinzl MF, Galle PR. Current progress in immunotherapy of hepatocellular carcinoma. J Hepatol [Internet]. 2017;66:482–4.

    Article  Google Scholar 

  37. Wang B-J, Bao J-J, Wang J-Z, Wang Y, Jiang M, Xing M-Y, et al. Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma. World J Gastroenterol. 2011;17:3322–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. El-Khoueiry A, Sangro B, Yau T, Crocenzi T, 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(10088):2492–502.

    Article  CAS  PubMed  Google Scholar 

  39. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

    Article  PubMed  Google Scholar 

  40. Segal HN, Scott A, Brahmer JR, Maio M, Blake-Haskins A, Li X, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol. 2014;32:5s abstr 3002.

    Google Scholar 

  41. Morales-Kastresana A, Sanmamed MF, Rodriguez I, Palazon A, Martinez-Forero I, Labiano S, et al. Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin Cancer Res. 2013;19:6151–62.

    Article  CAS  PubMed  Google Scholar 

  42. Hu-Lieskovan S, Robert L, Moreno BH, Ribas A. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges. J Clin Oncol. 2014;32:2248–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor vasculature as antitumor immune modulators: the role of vascular endothelial growth factor and endothelin. Curr Top Microbiol Immunol. 2011;344:129–48.

    CAS  PubMed  Google Scholar 

  44. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T, Huang Y, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61:1591–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016;150:1646–1658.e17.

    Article  CAS  PubMed  Google Scholar 

  47. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol. 1953;26:234–41.

    Article  CAS  PubMed  Google Scholar 

  48. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862–70.

    Article  PubMed  Google Scholar 

  49. Victor CT-S, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.

    Article  PubMed Central  Google Scholar 

  50. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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;19:329–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509–16.

    Article  CAS  PubMed  Google Scholar 

  53. Santoro A, Simonelli M, Rodriguez-Lope C, Zucali P, Camacho LH, Granito A, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55–63.

    Article  CAS  PubMed  Google Scholar 

  54. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57–67.

    Article  PubMed  Google Scholar 

  55. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. 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. 2015;16:859–70.

    Article  CAS  PubMed  Google Scholar 

  56. 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, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.

    Article  CAS  PubMed  Google Scholar 

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Conflicts of Interest

Bruno Sangro has received consulting and/or lecture fees from Adaptimmune, Astra Zeneca, Bayer Healthcare, Bristol-Myers-Squibb, and Medimmune.

Funding

Delia D’Avola is the recipient of the Grant for Study Expansion from the Spanish Association for the Study of the Liver (Asociación Espanola para el Estudio del Hígado AEEH) and Cancer Research Grant from Nuovo Soldati Foundation. This work was supported by EC FP7 Project Cancer Vaccine development for Hepatocellular Carcinoma – HEPAVAC (Grant Nr. 602,893), EC H2020 Project Immunology and Immunotherapy of cancer: strengthening the translational aspect – HepaMUT (Grant Nr. AC16/00165), and project PI16/01845, integrated in Plan Estatal de I + D + I 2013–2016 and co-financed by ISCIII-Subdirección General de Evaluación y Fomento de la investigación and Fondo Europeo de Desarrollo Regional (FEDER).

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Authors and Affiliations

  1. LiverUnit, Clínica Universidad de Navarra-IDISNA, Pamplona, Spain

    Mercedes Iñarrairaegui, Delia D’Avola & Bruno Sangro

  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, Spain

    Mercedes Iñarrairaegui, Delia D’Avola & Bruno Sangro

Authors
  1. Mercedes Iñarrairaegui
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  2. Delia D’Avola
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  3. Bruno Sangro
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Correspondence to Bruno Sangro .

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Editors and Affiliations

  1. National Cancer Institute, Center for Cancer Research National Cancer Institute, Bethesda, Maryland, USA

    Tim F. Greten

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Iñarrairaegui, M., D’Avola, D., Sangro, B. (2017). Immune Checkpoint Inhibitors for the Treatment of Hepatocellular Carcinoma. In: F. Greten, T. (eds) Immunotherapy of Hepatocellular Carcinoma. Springer, Cham. https://doi.org/10.1007/978-3-319-64958-0_4

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