Perspectives of immunotherapy in hepatocellular carcinoma (HCC)

Abstract

Immunotherapy is considered a new treatment option for many tumor entities, as decades of research into cancer immunotherapy have recently yielded promising results. Indeed, impressive clinical results of checkpoint blockade inhibitors in malignant melanoma and non-small cell lung cancer indicate the therapeutic potential of tumor-specific immune restoration. Over the years, different immunotherapeutic approaches have been evaluated for the treatment of hepatocellular carcinoma (HCC) with some respectable results. In this review article, we will summarize the key studies of the past 30 years and will elucidate in which direction the dynamic field of HCC immunotherapy is currently moving.

Zusammenfassung

Viele Jahrzehnte der Forschung im Bereich der Immuntherapie haben letztendlich vielversprechende Ergebnisse erzielt und diese Form der Tumortherapie wird als neue Behandlungsoption angesehen. Beeindruckende klinische Ansprechraten für das maligne Melanom und nicht-kleinzellige Lungenkarzinom mit Checkpoint Blockade Hemmern zeigen das immense therapeutische Potential der Wiederherstellung einer tumorspezifischen Immunantwort. Auch für das hepatozelluläre Karzinom wurden zahlreiche verschiedene immun-therapeutische Ansätze, mit zum Teil beachtlichen Ergebnissen, getestet. In dieser Übersicht werden wir die wichtigsten Studien der letzten Jahre zusammenfassen und herausarbeiten in welche Richtung sich das dynamische Feld der Immuntherapie bewegen wird.

Schlüsselwörter

Hepatozelluläres Karzinom (HCC) - Tumorantigen - Immuntherapie

Key words

hepatocellular carcinoma (HCC) - tumor antigen - immunotherapy

• References

• 1 International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012 Accessed at http://globocan.iarc.fr
• 2 Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities. Oncoimmunology 2012; 1: 48-55
• 3 Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015; 12: 681-700
• 4 Rinaldi M, Iurescia S, Fioretti D et al. Strategies for successful vaccination against hepatocellular carcinoma. Int J Immunopathol Pharmacol 2009; 22: 269-277
• 5 Llovet JM, Villanueva A, Lachenmayer A et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 2015; 12: 408-424
• 6 Bruix J, Merle P, Granito A et al. LBA-03: Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Ann Oncol 2016; 27: ii140-ii141
• 7 Unitt E, Marshall A, Gelson W et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 2006; 45: 246-253
• 8 Wada Y, Nakashima O, Kutami R et al. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 1998; 27: 407-414
• 9 Gao Q, Qiu SJ, Fan J et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25: 2586-2593
• 10 Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB (Oxford) 2012; 14: 500-505
• 11 Korangy F, Höchst B, Manns MP et al. Immunotherapy of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2010; 4: 345-353
• 12 Castro FA, Liu X, Forsti A et al. Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease. Clin Gastroenterol Hepatol 2014; 12: 1038-1045
• 13 Iwanaga T. Studies on cases of spontaneous regression of cancer in Japan in 2011, and of hepatic carcinoma, lung cancer and pulmonary metastases in the world between 2006 and 2011. Gan To Kagaku Ryoho 2013; 40: 1475-1487
• 14 Kumar A, Le DT. Hepatocellular Carcinoma Regression After Cessation of Immunosuppressive Therapy. J Clin Oncol 2016; 34: e90-e92
• 15 Epstein RJ, Leung TW. Reversing hepatocellular carcinoma progression by using networked biological therapies. Clin Cancer Res 2007; 13: 11-17
• 16 Peck-Radosavljevic M, Greten TF, Lammer J et al. Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2010; 22: 391-398
• 17 Zhou L, Wang CP, Lu YY et al. Decrease in size of non-treated lesions after cryoablation for hepatocellular carcinoma. Hepatogastroenterology 2012; 59: 252-254
• 18 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018-2028
• 19 Brunner SM, Rubner C, Kesselring R et al. Tumor-infiltrating, interleukin-33-producing effector-memory CD8(+) T cells in resected hepatocellular carcinoma prolong patient survival. Hepatology 2015; 61: 1957-1967
• 20 Endig J, Buitrago-Molina LE, Marhenke S et al. Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. Cancer Cell 2016; 30: 308-323
• 21 Greten TF, Manns MP, Korangy F. Immunotherapy of hepatocellular carcinoma. J Hepatol 2006; 45: 868-878
• 22 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
• 23 Flecken T, Schmidt N, Hild S et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014; 59: 1415-1426
• 24 Morgan RA, Chinnasamy N, Abate-Daga D et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36: 133-151
• 25 Nagao M, Nakajima Y, Hisanaga M et al. The alteration of Fas receptor and ligand system in hepatocellular carcinomas: how do hepatoma cells escape from the host immune surveillance in vivo?. Hepatology 1999; 30: 413-421
• 26 Nagao M, Nakajima Y, Kanehiro H et al. The impact of interferon gamma receptor expression on the mechanism of escape from host immune surveillance in hepatocellular carcinoma. Hepatology 2000; 32: 491-500
• 27 Buonaguro L, Petrizzo A, Tagliamonte M et al. Challenges in cancer vaccine development for hepatocellular carcinoma. J Hepatol 2013; 59: 897-903
• 28 Floros T, Tarhini AA. Anticancer Cytokines: Biology and Clinical Effects of Interferon-alpha2, Interleukin (IL)-2, IL-15, IL-21, and IL-12. Semin Oncol 2015; 42: 539-548
• 29 Llovet JM, Sala M, Castells L et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000; 31: 54-58
• 30 Lai CL, Lau JY, Wu PC et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology 1993; 17: 389-394
• 31 Lee D, Chung YH, Kim JA et al. Safety and efficacy of adjuvant pegylated interferon therapy for metastatic tumor antigen 1-positive hepatocellular carcinoma. Cancer 2013; 119: 2239-2246
• 32 Li M, Lu C, Cheng J et al. Combination therapy with transarterial chemoembolization and interferon-alpha compared with transarterial chemoembolization alone for hepatitis B virus related unresectable hepatocellular carcinoma. J Gastroenterol Hepatol 2009; 24: 1437-1444
• 33 Sachs E, Di Bisceglie AM, Dusheiko GM et al. Treatment of hepatocellular carcinoma with recombinant leucocyte interferon: a pilot study. Br J Cancer 1985; 52: 105-109
• 34 Nair PV, Tong MJ, Kempf R et al. Clinical, serologic, and immunologic effects of human leukocyte interferon in HBsAg-positive primary hepatocellular carcinoma. Cancer 1985; 56: 1018-1022
• 35 Lai CL, Wu PC, Lok AS et al. Recombinant alpha 2 interferon is superior to doxorubicin for inoperable hepatocellular carcinoma: a prospective randomised trial. Br J Cancer 1989; 60: 928-933
• 36 Breitenstein S, Dimitroulis D, Petrowsky H et al. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009; 96: 975-981
• 37 Shen YC, Hsu C, Chen LT et al. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010; 52: 889-894
• 38 Wang J, He XD, Yao N et al. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol 2013; 27: 351-363
• 39 Chen LT, Chen MF, Li LA et al. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012; 255: 8-17
• 40 Kumamoto T, Tanaka K, Matsuo K et al. Adjuvant hepatic arterial infusion chemotherapy with 5-Fluorouracil and interferon after curative resection of hepatocellular carcinoma: a preliminary report. Anticancer Res 2013; 33: 5585-5590
• 41 Kaseb AO, Shindoh J, Patt YZ et al. Modified cisplatin/interferon alpha-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma. Cancer 2013; 119: 3334-3342
• 42 Leung TW, Tang AM, Zee B et al. Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Cancer 2002; 94: 421-427
• 43 Yeo W, Mok TS, Zee B et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005; 97: 1532-1538
• 44 National Cancer Institute Milan, Associazione Italiana per la Ricerca sul Cancro. Treatment With IFN After Curative Resection of HCC in HCV-Related Cirrhosis. In. NCT00273247
• 45 The University of Hong Kong. Postoperative Adjuvant Therapy With Recombinant Interferon-Alpha Following Curative Resection of HCC. In. NCT00234182
• 46 Fudan University. The Efficiency of Postoperative Interferon-alpha Treatment in p48 Positive Patients With Hepatocellular Carcinoma. In. NCT00838968 2012
• 47 Kyoto University. Low-dose Peg-interferon Plus Ribavirin (IFN/RBV) for Prevention of Hepatocellular Carcinoma (HCC) Recurrence in Patients Who Had Surgery to Remove Primary HCC. In. NCT00375661 2012
• 48 Fudan University. The Effect of Postoperative Interferon- Alpha Treatment in Low miR-26 Expression Patients With HCC. In. NCT01681446 2016
• 49 Kansai Hepatobiliary Oncology Group. P2 Study of Postoperative Interferon/Fluorouracil vs Cisplatin/Fluorouracil for Hepatocellular Carcinoma. In. NCT01834963
• 50 Albert Einstein College of Medicine of Yeshiva University, National Cancer Institute. Combination Chemotherapy Plus Interferon Alfa Followed by Filgrastim in Treating Patients With Gastrointestinal Tract Cancer. In. NCT00019474
• 51 National Cancer Centre Singapore, National Cancer Institute. Combination Chemotherapy and Interferon Alfa-2b in Treating Patients With Nonmetastatic Liver Cancer That Cannot Be Removed by Surgery. In. NCT00471484
• 52 Hoffmann-La Roche. A Study of Capecitabine (Xeloda) and Peginterferon Alfa-2a (Pegasys) in Treatment-Naive Participants With Advanced Liver Cancer. In. NCT02576964 2008
• 53 National Cancer Institute. Thalidomide Plus Interferon Alfa in Treating Patients With Progressive Liver Cancer That Cannot be Surgically Removed. In. NCT00006006 2005
• 54 University of New Mexico. Trial of Thalidomide, a- Interferon +/- Octreotide in Patients With Unresectable Hepatocellular Carcinoma. In. NCT00250796 2006
• 55 Hospital Authority Hong Kong, Schering-Plough. A Comparative Study of the Efficacy of Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Pegylated Interferon Embolization (TAIE) for Liver Cancer. In. NCT00563095
• 56 Rosenberg SA, Mule JJ, Spiess PJ et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985; 161: 1169-1188
• 57 Shirai M, Watanabe S, Nishioka M. Antitumour effect of intratumoral injection of human recombinant interleukin-2 in patients with hepatocellular carcinoma: a preliminary report. Eur J Cancer 1990; 26: 1045-1048
• 58 Palmieri G, Montella L, Milo M et al. Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma. Am J Clin Oncol 2002; 25: 224-226
• 59 Yamamoto M, Iizuka H, Fujii H et al. Hepatic arterial infusion of interleukin-2 in advanced hepatocellular carcinoma. Acta Oncol 1993; 32: 43-51
• 60 Chien CH, Hsieh KH, Yang PM. Immunochemotherapy with recombinant interleukin-2 and adriamycin in primary hepatocellular carcinoma. Asian Pac J Allergy Immunol 1991; 9: 75-81
• 61 Roswell Park Cancer Institute. Doxorubicin and Interleukin-2 in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery. In. NCT00004248 2000
• 62 Sun Yat-sen University. A Study of Adoptive Immunotherapy With Autologous Tumor Infiltrating Lymphocytes in Solid Tumors. In. NCT01462903 2014
• 63 Mizukoshi E, Nakamoto Y, Arai K et al. Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology 2011; 53: 1206-1216
• 64 Meng WS, Butterfield LH, Ribas A et al. alpha-Fetoprotein-specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination. Cancer Res 2001; 61: 8782-8786
• 65 Cany J, Barteau B, Tran L et al. AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. J Hepatol 2010; 54: 115-121
• 66 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
• 67 Butterfield LH, Ribas A, Potter DM et al. Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother 2007; 56: 1931-1943
• 68 Evdokimova VN, Liu Y, Potter DM et al. AFP-specific CD4+ helper T-cell responses in healthy donors and HCC patients. J Immunother 2007; 30: 425-437
• 69 Greten TF, Ormandy LA, Fikuart A 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: 211-218
• 70 Thimme R, Neagu M, Boettler T et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 2008; 48: 1821-1833
• 71 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
• 72 Mizukoshi E, Nakagawa H, Kitahara M et al. Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett 2015; 369: 242-249
• 73 Mizukoshi E, Nakagawa H, Kitahara M et al. Immunological features of T cells induced by human telomerase reverse transcriptase-derived peptides in patients with hepatocellular carcinoma. Cancer Lett 2015; 364: 98-105
• 74 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
• 75 GlaxoSmithKline. A Phase III Study to Test the Benefit of a New Kind of Anti-cancer Treatment in Patients With Melanoma, After Surgical Removal of Their Tumor. In. NCT00796445 2015
• 76 Vansteenkiste JF, Cho BC, Vanakesa T et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; [Epub ahead of print]
• 77 Tada F, Abe M, Hirooka M et al. Phase I/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Int J Oncol 2012; 41: 1601-1609
• 78 Lee WC, Wang HC, Hung CF et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 2005; 28: 496-504
• 79 Palmer DH, Midgley RS, Mirza N et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009; 49: 124-132
• 80 NHS. NIHR Evaluation, Trials and Studies | 09/160/24 – A Phase II randomised clinical trial of conditioning cyclophosphamide and chemoembolisation with or without vaccination with dendritic cells pulsed with HepG2 lysate ex vivo in patients with Hepatocellular Carcinoma: IMMUNOTACE. In: Nhs ed. NHS web page: NHS 2013
• 81 Milhem M, Lee RHIA, Howard LK et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015; 33: 2780-2788
• 82 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
• 83 Abou-Alfa GK, Galle PR, Chao Y et al. PHOCUS: A phase 3 randomized, open-label study comparing the oncolytic immunotherapy Pexa-Vec followed by sorafenib (SOR) vs SOR in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. J Clin Oncol 2016 34. (suppl; abstr TPS4146)
• 84 Eberlein TJ, Rosenstein M, Rosenberg SA. Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. J Exp Med 1982; 156: 385-397
• 85 Cheever MA, Kempf RA, Fefer A. Tumor neutralization, immunotherapy, and chemoimmmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro. J Immunol 1977; 119: 714-718
• 86 Kawata A, Une Y, Hosokawa M et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18: 257-262
• 87 Une Y, Kawata A, Uchino J. Adopted immunochemotherapy using IL-2 and spleen LAK cell--randomized study. Nihon Geka Gakkai Zasshi 1991; 92: 1330-1333
• 88 Bertelli R, Neri F, Tsivian M et al. Endolymphatic immunotherapy in inoperable hepatocellular carcinoma. Transplant Proc 2008; 40: 1913-1915
• 89 Takeda T, Watanabe M, Umeshita K et al. Long-term prognosis of hepatocellular carcinoma patients treated with adoptive immunotherapy. Gan To Kagaku Ryoho 2004; 31: 1646-1648
• 90 Komatsu T, Yamauchi K, Furukawa T et al. Transcatheter arterial injection of autologous lymphokine-activated killer (LAK) cells into patients with liver cancers. J Clin Immunol 1990; 10: 167-174
• 91 Okuno K, Takagi H, Nakamura T et al. Treatment for unresectable hepatoma via selective hepatic arterial infusion of lymphokine-activated killer cells generated from autologous spleen cells. Cancer 1986; 58: 1001-1006
• 92 Ishikawa T, Imawari M, Moriyama T et al. Immunotherapy of hepatocellular carcinoma with autologous lymphokine-activated killer cells and/or recombinant interleukin-2. J Cancer Res Clin Oncol 1988; 114: 283-290
• 93 Onishi S, Saibara T, Fujikawa M et al. Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin 2 in patients with unresectable hepatocellular carcinoma. Hepatology 1989; 10: 349-353
• 94 Ferlazzo G, Scisca C, Iemmo R et al. Intralesional sonographically guided injections of lymphokine-activated killer cells and recombinant interleukin-2 for the treatment of liver tumors: a pilot study. J Immunother 1997; 20: 158-163
• 95 Lee JH, Lim YS, Yeon JE et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015; 148: 1383-1391
• 96 Yu X, Zhao H, Liu L et al. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 2013; 34: 194-203
• 97 Cui J, Wang N, Zhao H et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer 2013; 134: 342-351
• 98 Zhao M, Wu PH, Zeng YX et al. Cytokine-induced killer cell fusion to lower recurrence of hepatocellular carcinoma after transcatheter arterial chemoembolization sequentially combined with radiofrequency ablation: a randomized trial. Zhonghua Yi Xue Za Zhi 2006; 86: 1823-1828
• 99 Weng DS, Zhou J, Zhou QM et al. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2007; 31: 63-71
• 100 Hui D, Qiang L, Jian W et al. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2008; 41: 36-41
• 101 Hao MZ, Lin HL, Chen Q et al. Efficacy of transcatheter arterial chemoembolization combined with cytokine-induced killer cell therapy on hepatocellular carcinoma: a comparative study. Chin J Cancer 2010; 29: 172-177
• 102 Pan CC, Huang ZL, Li W et al. Serum alpha-fetoprotein measurement in predicting clinical outcome related to autologous cytokine-induced killer cells in patients with hepatocellular carcinoma undergone minimally invasive therapy. Chin J Cancer 2010; 29: 596-602
• 103 Forman D, Franceschi S, Sankaranarayanan R et al. Do cervical cancer data justify human papillomavirus vaccination in India? Epidemiological data sources and comprehensiveness. J R Soc Med 2012; 105: 365-366
• 104 Li X, Dai D, Song X et al. A meta-analysis of cytokine-induced killer cells therapy in combination with minimally invasive treatment for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2014; 38: 583-591
• 105 Takayama T, Sekine T, Makuuchi M et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356: 802-807
• 106 Alliancells-PuRui Biocience Co., Ltd., Zhongyuan Union Stem Cell Bio-engineering Corporation. Safety Study of Cord Blood-derived Cytokine-induced Killer Cells in Patients With Solid Tumor After Radical Resection. In. NCT01914263 2016
• 107 Guangxi Medical University. A Study of DC-CIK to Treat Hepatocellular Carcinoma. In. NCT01821482
• 108 Sherief A-E, Tanta University. Evaluation of Cytokine-induced Killer (CIK) Cells as Therapy or Adjuvant Treatment for Advanced HCC. In. NCT02568748 2017
• 109 Sun Yat-sen University. CIK Treatment for HCC Patient Underwent Radical Resection. In. NCT01749865 2014
• 110 Sun Yat-sen University. Study of Cytokine-induced Killer Cell (CIK) Treatment in Patients After Resection of Liver Cancer. In. NCT00769106 2014
• 111 Tianjin Medical University Cancer Institute and Hospital. A Clinical Trail of Iodine 131I Metuximab Injection With CIK Cells for Preventing Hepatocellular Carcinoma. In. NCT01758679; 2016
• 112 Dudley ME, Wunderlich JR, Shelton TE et al. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother 2003; 26: 332-342
• 113 Jiang SS, Tang Y, Zhang YJ et al. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Oncotarget 2015; 6: 41339-41349
• 114 Wang Y, Chen H, Wu M et al. Postoperative immunotherapy for patients with hepatocarcinoma using tumor-infiltrating lymphocytes. Chin Med J (Engl) 1997; 110: 114-117
• 115 National Cancer Institute, National Institutes of Health Clinical Center. Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer. In. NCT01174121
• 116 Maus MV, Grupp SA, Porter DL et al. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014; 123: 2625-2635
• 117 Fuda Cancer Hospital Guangzhou. CAR-T Cell Immunotherapy for HCC Targeting GPC3. In. NCT02723942 2016
• 118 RenJi Hospital. Anti-GPC3 CAR T for Treating Patients With Advanced HCC. In. NCT02395250 2016
• 119 Shanghai GeneChem Co., Ltd. A Study of GPC3 Redirected Autologous T Cells for Advanced HCC. In. NCT02715362
• 120 Sinobioway Cell Therapy Co., Ltd. Study Evaluating the Efficacy and Safety With CAR-T for Liver Cancer. In. NCT02729493 2016
• 121 Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd. A Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab and the Combination Nivolumab Plus Ipilimumab in Patients With Advanced Liver Cancer. In. NCT01658878 2016
• 122 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
• 123 National Cancer Institute, National Institutes of Health Clinical Center. Tremelimumab With Chemoembolization or Ablation for Liver Cancer. In. NCT01853618 2016
• 124 MedImmune LLC. A Study of MEDI4736 With Tremelimumab, MEDI4736 or Tremelimumab Monotherapy in Unresectable Hepatocellular Carcinoma. In. NCT02519348 2017
• 125 Duffy AG, Makarova-Rusher OV, Pratt D et al. Tremelimumab: A monoclonal antibody against CTLA-4 In combination with subtotal ablation (trans catheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) or cryoablation) in patients with hepatocellular carcinoma (HCC) and biliary tract carcinoma (BTC). J Clin Oncol 2016 34. (suppl 4S; abstr 270)
• 126 Brahmer JR, Tykodi SS, Chow LQ et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455-2465
• 127 El-Khoueiry AB, Melero I, Crocenzi TS et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015 33. (suppl; abstr LBA101)
• 128 Sangro B, Crocenzi TS, Welling TH et al. Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis. J Clin Oncol 2013 31. (suppl; abstr TPS3111)
• 129 Bristol-Myers Squibb, Ono Pharmaceutical Co. Ltd. A Study of Nivolumab Compared to Sorafenib as a Primary Treatment in Patients With Advanced Hepatocellular Carcinoma. In. NCT02576509 2017
• 130 Sangro B, Park J, Dela Cruz CM et al. A randomized, multicenter, phase 3 study of nivolumab vs sorafenib as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): CheckMate-459. J Clin Oncol 2016 34. (suppl; abstr TPS4147)
• 131 Eli Lilly and Company, Bristol-Myers Squibb. A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, Hepatocellular Carcinoma, or Glioblastoma. In. NCT02423343
• 132 Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) as Monotherapy in Adults With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224). In. NCT02702414 2017
• 133 Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) vs. Best Supportive Care in Participants With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-240/KEYNOTE-240). In. NCT02702401
• 134 Bristol-Myers Squibb. Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors. In. NCT01968109