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Development of Immunotherapy for Hepatocellular Carcinoma

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Inflammation and Immunity in Cancer

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Abstract

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer globally. Although many different kinds of treatment are performed for HCC according to the practical guidelines, the prognosis of patients is not still satisfactory because the effects of treatments are limited for advanced tumors and the recurrence rate of HCC, even in early stages, is very high. Therefore, immunotherapy is highly anticipated as a new treatment method for HCC. For the development of a new HCC therapy, we attempted to establish immunotherapy using dendritic cells (DCs) and peptide vaccine. In several clinical trials that we performed, we confirmed that the immunotherapy was safe and well-tolerated by HCC patients. We observed that DC therapy prolonged the recurrence-free survival of patients compared with that of patients without DC infusion, as well as observing the radiological anti-tumor effect in HCC patients with peptide vaccine. In this chapter, we summarize the results of previous studies using DC and peptide vaccine, including our own data, and describe the prospects of immunotherapy for HCC.

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References

  • Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Butterfield LH, Meng WS, Koh A, Vollmer CM, Ribas A, Dissette VB, Faull K, Glaspy JA, McBride WH, Economou JS (2001) T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein. J Immunol 166(8):5300–5308

    Article  CAS  PubMed  Google Scholar 

  • Butterfield LH, Ribas A, Meng WS, Dissette VB, Amarnani S, Vu HT, Seja E, Todd K, Glaspy JA, McBride WH, Economou JS (2003) T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res 9(16 Pt 1):5902–5908

    CAS  PubMed  Google Scholar 

  • Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, Duran SD, Hernandez J, Seja E, Potter DM, McBride WH, Finn R, Glaspy JA, Economou JS (2006) A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12(9):2817–2825

    Article  CAS  PubMed  Google Scholar 

  • Chi KH, Liu SJ, Li CP, Kuo HP, Wang YS, Chao Y, Hsieh SL (2005) Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother 28(2):129–135

    Article  PubMed  Google Scholar 

  • El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576

    Article  CAS  PubMed  Google Scholar 

  • El-Serag HB, Marrero JA, Rudolph L, Reddy KR (2008) Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134(6):1752–1763

    Article  PubMed  Google Scholar 

  • Greten TF, Forner A, Korangy F, N’Kontchou G, Barget N, Ayuso C, Ormandy LA, Manns MP, Beaugrand M, Bruix J (2010a) A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10:209

    Article  PubMed Central  PubMed  Google Scholar 

  • Greten TF, Ormandy LA, Fikuart A, Hochst B, Henschen S, Horning M, Manns MP, Korangy F (2010b) Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother 33(2):211–218

    Article  CAS  PubMed  Google Scholar 

  • Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135(1):234–243

    Article  CAS  PubMed  Google Scholar 

  • Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M, Chen CL, Kawano K, Kitano S (2003) A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 52(3):155–161

    CAS  PubMed  Google Scholar 

  • Komori H, Nakatsura T, Senju S, Yoshitake Y, Motomura Y, Ikuta Y, Fukuma D, Yokomine K, Harao M, Beppu T, Matsui M, Torigoe T, Sato N, Baba H, Nishimura Y (2006) Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 12(9):2689–2697

    Article  CAS  PubMed  Google Scholar 

  • Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, Greten TF (2004) Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 10(13):4332–4341

    Article  CAS  PubMed  Google Scholar 

  • Ladhams A, Schmidt C, Sing G, Butterworth L, Fielding G, Tesar P, Strong R, Leggett B, Powell L, Maddern G, Ellem K, Cooksley G (2002) Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. J Gastroenterol Hepatol 17(8):889–896

    Article  PubMed  Google Scholar 

  • Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF (2005) Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 28(5):496–504

    Article  PubMed  Google Scholar 

  • Mizukoshi E, Nakamoto Y, Marukawa Y, Arai K, Yamashita T, Tsuji H, Kuzushima K, Takiguchi M, Kaneko S (2006a) Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology 43(6):1284–1294

    Article  CAS  PubMed  Google Scholar 

  • Mizukoshi E, Nakamoto Y, Tsuji H, Yamashita T, Kaneko S (2006b) Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24+ patients with hepatocellular carcinoma. Int J Cancer 118(5):1194–1204

    Article  CAS  PubMed  Google Scholar 

  • Mizukoshi E, Honda M, Arai K, Yamashita T, Nakamoto Y, Kaneko S (2008) Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma. J Hepatol 49(6):946–954

    Article  CAS  PubMed  Google Scholar 

  • Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Sakai A, Sakai Y, Kagaya T, Honda M, Kaneko S (2011) Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology 53(4):1206–1216

    Article  CAS  PubMed  Google Scholar 

  • Mizukoshi E, Fushimi K, Arai K, Yamashita T, Honda M, Kaneko S (2012) Expression of chondroitin-glucuronate C5-epimerase and cellular immune responses in patients with hepatocellular carcinoma. Liver Int 32(10):1516–1526

    Google Scholar 

  • Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, Kagaya T, Fushimi K, Kaneko S (2013) Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 57(4):1448–1457

    Article  CAS  PubMed  Google Scholar 

  • Nakamoto Y, Mizukoshi E, Tsuji H, Sakai Y, Kitahara M, Arai K, Yamashita T, Yokoyama K, Mukaida N, Matsushima K, Matsui O, Kaneko S (2007) Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety. Clin Exp Immunol 147(2):296–305

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nakamoto Y, Mizukoshi E, Kitahara M, Arihara F, Sakai Y, Kakinoki K, Fujita Y, Marukawa Y, Arai K, Yamashita T, Mukaida N, Matsushima K, Matsui O, Kaneko S (2011) Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization. Clin Exp Immunol 163(2):165–177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Kerr DJ, Young LS, Adams DH (2009) A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49(1):124–132

    Article  PubMed  Google Scholar 

  • Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2(9):533–543

    Article  CAS  PubMed  Google Scholar 

  • Qiu Y, Xu MB, Yun MM, Wang YZ, Zhang RM, Meng XK, Ou-Yang XH, Yun S (2011) Hepatocellular carcinoma-specific immunotherapy with synthesized alpha1, 3-galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells. World J Gastroenterol 17(48):5260–5266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ribas A (2010) Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol 37(5):450–454

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Thomas L, Bondarenko I, O’Day S, M DJ, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    Article  CAS  PubMed  Google Scholar 

  • Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y, Mizuno S, Ishii H, Nakachi K, Konishi M, Nakagohri T, Takahashi S, Gotohda N, Takayama T, Yamao K, Uesaka K, Furuse J, Kinoshita T, Nakatsura T (2012) 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 18(13):3686–3696

    Article  CAS  PubMed  Google Scholar 

  • Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Schueller G, Zontsich T, Benkoe T, Radelbauer K, Brostjan C, Jakesz R, Gnant M (2003) Dendritic cell-based vaccination in solid cancer. J Clin Oncol 21(1):135–142

    Article  CAS  PubMed  Google Scholar 

  • Tada F, Abe M, Hirooka M, Ikeda Y, Hiasa Y, Lee Y, Jung NC, Lee WB, Lee HS, Bae YS, Onji M (2012) Phase I/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Int J Oncol 41(5):1601–1609

    PubMed Central  CAS  PubMed  Google Scholar 

  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, Coleman N, Alexander GJ (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41(4):722–730

    Article  CAS  PubMed  Google Scholar 

  • Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M (1998) Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27(2):407–414

    Article  CAS  PubMed  Google Scholar 

  • Zerbini A, Pilli M, Soliani P, Ziegler S, Pelosi G, Orlandini A, Cavallo C, Uggeri J, Scandroglio R, Crafa P, Spagnoli GC, Ferrari C, Missale G (2004) Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8 + cells in patients with hepatocellular carcinoma. J Hepatol 40(1):102–109

    Article  CAS  PubMed  Google Scholar 

  • Zhou P, Liang P, Dong B, Yu X, Han Z, Xu Y (2011) Phase clinical study of combination therapy with microwave ablation and cellular immunotherapy in hepatocellular carcinoma. Cancer Biol Ther 11(5):450–456

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

The authors disclose no conflicts of interest.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, 920-8641, Japan

    Eishiro Mizukoshi & Shuichi Kaneko M.D.

Authors
  1. Eishiro Mizukoshi
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  2. Shuichi Kaneko M.D.
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Corresponding author

Correspondence to Shuichi Kaneko M.D. .

Editor information

Editors and Affiliations

  1. Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

    Tsukasa Seya

  2. Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

    Misako Matsumoto

  3. Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

    Keiko Udaka

  4. School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan

    Noriyuki Sato

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Mizukoshi, E., Kaneko, S. (2015). Development of Immunotherapy for Hepatocellular Carcinoma. In: Seya, T., Matsumoto, M., Udaka, K., Sato, N. (eds) Inflammation and Immunity in Cancer. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55327-4_10

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