Skip to main content
SpringerLink
Log in

Novel Immunotherapy Using Liver-Derived Natural Killer Cells for Preventing Hepatocellular Carcinoma Recurrence in Liver Transplantation

  • Chapter
Gene Therapy and Cell Therapy Through the Liver

  • 1133 Accesses

Abstract

Tumor recurrence is the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be promoted by immunosuppressants. However, no prevention or treatment exists for HCC recurrence after liver transplantation. Here, we describe an adoptive immunotherapy approach that uses natural killer (NK) cells derived from both living and deceased donor liver graft perfusates. Liver NK cells exhibited the vigorous cytotoxicity against hepatoma cell line after IL-2 stimulation through the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-TRAIL receptor pathway. In an in vivo mouse model, adoptive transfer of TRAIL-expressing liver NK cells inhibited the growth of liver tumors. Taken together, these findings suggest that we have established a method of retrieving NK cells from donor liver graft perfusate under current good manufacturing practice conditions for the treatment of liver transplant recipients with HCC. Clinical trials of adoptive immunotherapy with liver NK cells have been conducted in both living and deceased donor liver transplantations.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 59.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 79.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. Horn M, Phebus C, Blatt J. Cancer chemotherapy after solid organ transplantation. Cancer. 1990;66(7):1468–71.

    Article  CAS  PubMed  Google Scholar 

  2. Saab S, Yeganeh M, Nguyen K, Durazo F, Han S, Yersiz H, et al. Recurrence of hepatocellular carcinoma and hepatitis B reinfection in hepatitis B surface antigen-positive patients after liver transplantation. Liver Transpl. 2009;15(11):1525–34.

    Article  PubMed  Google Scholar 

  3. Vivarelli M, Cucchetti A, La Barba G, Ravaioli M, Del Gaudio M, Lauro A, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg. 2008;248(5):857–62. doi:10.1097/SLA.0b013e3181896278.

    Article  PubMed  Google Scholar 

  4. Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer. 1991;68(10):2095–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Soderdahl G, Backman L, Isoniemi H, Cahlin C, Hockerstedt K, Broome U, et al. A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma. Transpl Int. 2006;19(4):288–94. doi:10.1111/j.1432-2277.2006.00279.x.

    Article  PubMed  Google Scholar 

  6. Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Hong J, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143(2):182–8. discussion 8.

    Article  PubMed  Google Scholar 

  7. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376.

    Article  CAS  PubMed  Google Scholar 

  8. Balch CM, Tilden AB, Dougherty PA, Cloud GA, Abo T. Heterogeneity of natural killer lymphocyte abnormalities in colon cancer patients. Surgery. 1984;95(1):63–70.

    CAS  PubMed  Google Scholar 

  9. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol. 2008;129(3):428–37. doi:10.1016/j.clim.2008.08.012.

    Article  CAS  PubMed  Google Scholar 

  10. Ishiyama K, Ohdan H, Ohira M, Mitsuta H, Arihiro K, Asahara T. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology. 2006;43(2):362–72. doi:10.1002/hep.21035.

    Article  CAS  PubMed  Google Scholar 

  11. Harada N, Shimada M, Okano S, Suehiro T, Soejima Y, Tomita Y, et al. IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice. J Immunol. 2004;173(11):6635–44.

    Article  CAS  PubMed  Google Scholar 

  12. Hirata M, Kita Y, Saito S, Nishimura M, Ito M, Mizuta K, et al. Increase in natural killer cell activity following living-related liver transplantation. Transpl Int. 1998;11 Suppl 1:S185–8.

    Article  PubMed  Google Scholar 

  13. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051–7.

    Article  CAS  PubMed  Google Scholar 

  14. Ohira M, Ohdan H, Mitsuta H, Ishiyama K, Tanaka Y, Igarashi Y, et al. Adoptive transfer of TRAIL-expressing natural killer cells prevents recurrence of hepatocellular carcinoma after partial hepatectomy. Transplantation. 2006;82(12):1712–9. doi:10.1097/01.tp.0000250935.41034.2d.

    Article  CAS  PubMed  Google Scholar 

  15. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005;42(4):501–10. doi:10.1016/j.molimm.2004.07.034.

    Article  CAS  PubMed  Google Scholar 

  16. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735–47. doi:10.1038/nri911.

    Article  CAS  PubMed  Google Scholar 

  17. Screpanti V, Wallin RP, Grandien A, Ljunggren HG. Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells. Mol Immunol. 2005;42(4):495–9.

    Article  CAS  PubMed  Google Scholar 

  18. Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, et al. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood. 2002;100(5):1728–33.

    CAS  PubMed  Google Scholar 

  19. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485–92. doi:10.1056/NEJM198512053132327.

    Article  CAS  PubMed  Google Scholar 

  20. Law TM, Motzer RJ, Mazumdar M, Sell KW, Walther PJ, O’Connell M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer. 1995;76(5):824–32.

    Article  CAS  PubMed  Google Scholar 

  21. Burns LJ, Weisdorf DJ, DeFor TE, Vesole DH, Repka TL, Blazar BR, et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transplant. 2003;32(2):177–86.

    Article  CAS  PubMed  Google Scholar 

  22. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.

    Article  CAS  PubMed  Google Scholar 

  23. Feng YX, Wang T, Deng YZ, Yang P, Li JJ, Guan DX, et al. Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model. Hepatology. 2011;53(2):483–92. doi:10.1002/hep.24075.

    Article  CAS  PubMed  Google Scholar 

  24. Xie F, Zhang X, Li H, Zheng T, Xu F, Shen R, et al. Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. PLoS One. 2012;7(8), e42879. doi:10.1371/journal.pone.0042879.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Shi FD, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol. 2011;11(10):658–71. doi:10.1038/nri3065.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ochi M, Ohdan H, Mitsuta H, Onoe T, Tokita D, Hara H, et al. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology. 2004;39(5):1321–31. doi:10.1002/hep.20204.

    Article  CAS  PubMed  Google Scholar 

  27. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med. 2001;7(1):94–100.

    Article  CAS  PubMed  Google Scholar 

  28. Park SK, Brody JI, Wallace HA, Blakemore WS. Immunosuppressive effect of surgery. Lancet. 1971;1(7689):53–5.

    Article  CAS  PubMed  Google Scholar 

  29. Morimoto H, Nio Y, Imai S, Shiraishi T, Tsubono M, Tseng CC, et al. Hepatectomy accelerates the growth of transplanted liver tumor in mice. Cancer Detect Prev. 1992;16(2):137–47.

    CAS  PubMed  Google Scholar 

  30. Minagawa M, Oya H, Yamamoto S, Shimizu T, Bannai M, Kawamura H, et al. Intensive expansion of natural killer T cells in the early phase of hepatocyte regeneration after partial hepatectomy in mice and its association with sympathetic nerve activation. Hepatology. 2000;31(4):907–15.

    Article  CAS  PubMed  Google Scholar 

  31. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5(2):157–63.

    Article  CAS  PubMed  Google Scholar 

  32. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3(6):673–82.

    Article  CAS  PubMed  Google Scholar 

  33. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276(5309):111–3.

    Article  CAS  PubMed  Google Scholar 

  34. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277(5327):818–21.

    Article  CAS  PubMed  Google Scholar 

  35. Ohira M, Nishida S, Tryphonopoulos P, Tekin A, Selvaggi G, Moon J, et al. Clinical-scale isolation of interleukin-2-stimulated liver natural killer cells for treatment of liver transplantation with hepatocellular carcinoma. Cell Transplant. 2012;21(7):1397–406. doi:10.3727/096368911X627589.

    Article  PubMed  Google Scholar 

  36. Wilson CH, Stansby G, Haswell M, Cunningham AC, Talbot D. Evaluation of eight preservation solutions for endothelial in situ preservation. Transplantation. 2004;78(7):1008–13. doi:00007890-200410150-00009 [pii].

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Masahiro Ohira & Hideki Ohdan M.D., Ph.D.

  2. Division of Liver and Gastrointestinal Transplantation, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

    Seigo Nishida

  3. Transplant Center, Cleveland Clinic Florida, Weston, FL, USA

    Andreas G. Tzakis

Authors
  1. Masahiro Ohira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seigo Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas G. Tzakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideki Ohdan M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideki Ohdan M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University , Niigata, Niigata, Japan

    Shuji Terai

  2. Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University, Niigata, Niigata, Japan

    Takeshi Suda

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Ohira, M., Nishida, S., Tzakis, A.G., Ohdan, H. (2016). Novel Immunotherapy Using Liver-Derived Natural Killer Cells for Preventing Hepatocellular Carcinoma Recurrence in Liver Transplantation. In: Terai, S., Suda, T. (eds) Gene Therapy and Cell Therapy Through the Liver. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55666-4_4

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-55666-4_4

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55665-7

  • Online ISBN: 978-4-431-55666-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation