Skip to main content

Cytokine-Induced Killer Cells for the Adjuvant Treatment of Patients with HCC

  • Chapter
  • First Online:
Immunotherapy of Hepatocellular Carcinoma
  • 719 Accesses

Abstract

The prognosis is still poor in patients with hepatocellular carcinoma (HCC). One of the reasons for poor prognosis is a frequent tumor recurrence from diseased remnant liver even after potentially curative treatment following early detection of tumor during regular surveillance for HCC. Until now, however, the benefit of any form of adjuvant therapy remains unclear, and current international practice guidelines do not recommend any adjuvant therapy after curative treatment. Meanwhile, a recent randomized controlled trial showed that adjuvant cellular immunotherapy using cytokine-induced killer (CIK) cells is safe and prolongs both recurrence-free survival and overall survival in patients treated with curative treatment. CIK cells are a mixture of T lymphocytes, which are expanded ex vivo with cytokines, comprising CD3+/CD56+ cells, CD3/CD56+ natural killer cells, and CD3+/CD56 cytotoxic T cells. Among them CD3+/CD56+ natural killer-like T cells have high proliferation rate and are the main effector cells killing tumor without major histocompatibility complex restriction. Several potential methods should be considered to improve the efficacy of CIK cell therapy. Now combination therapy with other cellular immunotherapy such as dendritic cell vaccines or immune checkpoint inhibitors is being investigated to enhance the efficacy of CIK cell immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015;35:2155–66.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.

    Article  PubMed  Google Scholar 

  3. Cho EJ, Lee JH, Yoo JJ, Choi WM, Lee MJ, Cho Y, et al. Serum insulin-like growth factor-I level is an independent predictor of recurrence and survival in early hepatocellular carcinoma: a prospective cohort study. Clin Cancer Res. 2013;19:4218–27.

    Article  CAS  PubMed  Google Scholar 

  4. Youn HG, An JY, Choi MG, Noh JH, Sohn TS, Kim S. Recurrence after curative resection of early gastric cancer. Ann Surg Oncol. 2010;17:448–54.

    Article  PubMed  Google Scholar 

  5. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL, Wong J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg. 1995;221:291–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  7. European Association for The Study of The Liver, European Organisation for Research Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Article  Google Scholar 

  8. Yee C, Greenberg P. Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses. Nat Rev Cancer. 2002;2:409–19.

    Article  CAS  PubMed  Google Scholar 

  9. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest. 2004;114:701–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10:753–66.

    Article  CAS  PubMed  Google Scholar 

  11. Kuniyasu Y, Marfani SM, Inayat IB, Sheikh SZ, Mehal WZ. Kupffer cells required for high affinity peptide-induced deletion, not retention, of activated CD8+ T cells by mouse liver. Hepatology. 2004;39:1017–27.

    Article  PubMed  Google Scholar 

  12. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. Interaction of tumor cells with the microenvironment. Cell Commun Signal. 2011;9:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7:651–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Korangy F, Hochst B, Manns MP, Greten TF. Immune responses in hepatocellular carcinoma. Dig Dis. 2010;28:150–4.

    Article  PubMed  Google Scholar 

  16. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    Article  CAS  PubMed  Google Scholar 

  17. Flecken T, Spangenberg HC, Thimme R. Immunobiology of hepatocellular carcinoma. Langenbeck’s Arch Surg. 2012;397:673–80.

    Article  Google Scholar 

  18. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2010;52:370–9.

    Article  CAS  PubMed  Google Scholar 

  19. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–42.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233:1318–21.

    Article  CAS  PubMed  Google Scholar 

  21. Steinman DA, Rutt BK. On the nature and reduction of plaque-mimicking flow artifacts in black blood MRI of the carotid bifurcation. Magn Reson Med. 1998;39:635–41.

    Article  CAS  PubMed  Google Scholar 

  22. Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49:124–32.

    Article  PubMed  Google Scholar 

  23. Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res. 2006;12:2817–25.

    Article  CAS  PubMed  Google Scholar 

  24. 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;113:1666–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  26. Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol. 2006;6:520–31.

    Article  CAS  PubMed  Google Scholar 

  27. Yang Y, Lim O, Kim TM, Ahn YO, Choi H, Chung H, et al. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Cancer Immunol Res. 2016;4:215–24.

    Article  CAS  PubMed  Google Scholar 

  28. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107:2409–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ochoa AC, Gromo G, Alter BJ, Sondel PM, Bach FH. Long-term growth of lymphokine-activated killer (LAK) cells: role of anti-CD3, beta-IL 1, interferon-gamma and -beta. J Immunol. 1987;138:2728–33.

    CAS  PubMed  Google Scholar 

  30. Thanendrarajan S, Nowak M, Abken H, Schmidt-Wolf IG. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res. 2011;35:1136–42.

    Article  CAS  PubMed  Google Scholar 

  31. Kim HM, Lim J, Yoon YD, Ahn JM, Kang JS, Lee K, et al. Anti-tumor activity of ex vivo expanded cytokine-induced killer cells against human hepatocellular carcinoma. Int Immunopharmacol. 2007;7:1793–801.

    Article  CAS  PubMed  Google Scholar 

  32. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802–7.

    Article  CAS  PubMed  Google Scholar 

  33. Weng DS, Zhou J, Zhou QM, Zhao M, Wang QJ, Huang LX, et al. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother. 2008;31:63–71.

    Article  PubMed  Google Scholar 

  34. Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis. 2009;41:36–41.

    Article  PubMed  Google Scholar 

  35. 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;148:1383–91. e6

    Article  CAS  PubMed  Google Scholar 

  36. Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006;108:804–11.

    Article  CAS  PubMed  Google Scholar 

  37. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59.

    Article  CAS  PubMed  Google Scholar 

  38. Poh SL, Linn YC. Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother. 2016;65:525–36.

    Article  CAS  PubMed  Google Scholar 

  39. Greten TF, Ormandy LA, Fikuart A, Hochst B, Henschen S, Horning M, et al. Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother. 2010;33:211–8.

    Article  CAS  PubMed  Google Scholar 

  40. Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J, et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. 2013;123:1580–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Greten TF, Duffy AG, Korangy F. Hepatocellular carcinoma from an immunologic perspective. Clin Cancer Res. 2013;19:6678–85.

    Article  CAS  PubMed  Google Scholar 

  42. Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood. 2008;111:5610–20.

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y, Huang Y, Reiberger T, Duyverman AM, Huang P, Samuel R, et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology. 2014;59:1435–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krusch M, Salih J, Schlicke M, Baessler T, Kampa KM, Mayer F, et al. The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro. J Immunol. 2009;183:8286–94.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jung-Hwan Yoon .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Lee, JH., Yoon, JH. (2017). Cytokine-Induced Killer Cells for the Adjuvant Treatment of Patients with HCC. In: F. Greten, T. (eds) Immunotherapy of Hepatocellular Carcinoma. Springer, Cham. https://doi.org/10.1007/978-3-319-64958-0_5

Download citation

Publish with us

Policies and ethics