Updates in immunotherapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) carries an unfavorable prognosis and novel therapeutic strategies are needed. Until now, only few systemic agents have improved survival in patients with advanced stage disease. Immunotherapy changed the landscape in several tumor types by producing unprecedented clinical outcomes with a favorable safety profile. Liver presents a particular immune-suppressive microenvironment and HCC develops in a background of chronic inflammation in the vast majority of cases. In this regard, immunotherapy may be a suitable strategy. Preliminary research focused on therapies involving immune cells and anti-tumor immune response for HCC has shown encouraging preliminary results. Immune checkpoint inhibitors, such the anti-PD-1/PD-L1 monoclonal antibodies, have provided durable responses in patients with advanced stage disease, although the pioneers phase III trials did not confirm survival superiority over the available agents. Cancer vaccines, adoptive cellular therapies and combinations of local modalities with immunotherapy are promising approaches under active research.

Keywords

Hepatocellular carcinoma / immunotherapy / immunosuppression / prognosis / immunology / antibody / vaccine

References

[1] IARC. Fact sheets by Population-Globocan-IARC. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf

[2] Ishizawa T,Aoki T,Inoue Y.Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma..Gastroenterology2008;134:1908-16

[3] Llovet JM,Mazzaferro V,Gane E.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[4] Cheng AL,Chen Z,Qin S.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial..Lancet Oncol2009;10:25-34

[5] Kudo M,Qin S,Ikeda K.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial..Lancet2018;391:1163-73

[6] Bruix J,Merle P,Huang YH.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet2017;389:56-66

[7] Abou-Alfa GK,Cheng AL,Rimassa L.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma..N Engl J Med2018;379:54-63

[8] Zhu AX,Yen CJ,Galle PR.Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet Oncol2019;20:282-96

[9] Finn RS,Granito A,Bodoky G.Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial..J Hepatol2018;69:353-8

[10] Coley WB.The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases..Am J Med Sci1893;105:487-510

[11] Dunn GP,Ikeda H,Schreiber RD.Cancer immunoediting: from immunosurveillance to tumor escape..Nat Immunol2002;3:991-8

[12] Morales A,Bruce AW.Intracavitary Bacillus Calmette-guerin in the treatment of superficial bladder tumors..J Urol1976;116:180-2

[13] Rudnicka D,Finch DK,Schofield DJ.Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity..Blood2013;121:4694-702

[14] Forner A,Bruix J.Hepatocellular carcinoma..Lancet2018;391:1301-14

[15] Pardee AD.Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities..Oncoimmunology2012;1:48-55 PMCID:PMC3376967

[16] Shetty S,Adams DH.Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity..Nat Rev Gastroenterol Hepatol2018;15:555-67

[17] Dixon LJ,Tang H,Nagy LE.Kupffer cells in the liver..Compr Physiol2013;3:785-97 PMCID:PMC4748178

[18] Fu J,Liu Z,Zhao P.Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients..Gastroenterology2007;132:2328-39

[19] Sprinzl MF.Immune control in hepatocellular carcinoma development and progression: role of stromal cells..Semin Liver Dis2014;34:376-88

[20] Mollinedo F.Neutrophil degranulation, plasticity, and cancer metastasis..Trends Immunol2019;40:228-42

[21] Zhou SL,Hu ZQ,Wang Z.Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to Sorafenib..Gastroenterology2016;150:1646-58.e17

[22] Draghiciu O,Nijman HW.Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy..Oncoimmunology2015;4:e954829 PMCID:PMC4368153

[23] Kumar V,Tcyganov E.The nature of myeloid-derived suppressor cells in the tumor microenvironment..Trends Immunol2016;37:208-20 PMCID:PMC4775398

[24] Mizukoshi E,Arai K,Kitahara M.Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma..Cancer Immunol Immunother2016;65:715-25

[25] Calderaro J,Amaddeo G,Charpy C.Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship With clinical and pathological features..Hepatology2016;64:2038-46

[26] Yan W,Ma H,Song X.Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages..Gut2015;64:1593-604

[27] Budhu A,Ye QH,He P.Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment..Cancer Cell2006;10:99-111

[28] Brown SD,Gibb EA,Spinelli JJ.Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival..Genome Res2014;24:743-50 PMCID:PMC4009604

[29] Schumacher TN.Neoantigens in cancer immunotherapy..Science2015;348:69-74

[30] Fujimoto A,Totoki Y,Kato M.Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer..Nat Genet2016;48:500-9

[31] Lee HJ,Cho D.Cellular immunotherapy as a beacon of hope for hematological malignancies..Blood Res2015;50:126-8 PMCID:PMC4595575

[32] Schmidt N,Thimme R.Cellular immune responses to hepatocellular carcinoma: lessons for immunotherapy..Dig Dis2012;30:483-91

[33] Palmer DH,Mirza N,Ahmed F.A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma..Hepatology2009;49:124-32

[34] El Ansary M,Elhamid SA,Aboelkasem F.Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC..J Cancer Res Clin Oncol2013;139:39-48 PMCID:PMC5223882

[35] Mizukoshi E,Arai K,Mukaida N.Enhancement of tumor-specific T-cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma..Int J cancer2010;126:2164-74

[36] Pexa-Vec/Nexavar combination fails phase III trial in liver cancer. Available from: https://www.genengnews.com/news/pexa-vec-nexavar-combination-fails-phase-iii-trial-in-liver-cancer/. [Last accessed on 9 Oct 2019]

[37] Liu D,Li G.Immune-based therapy clinical trials in hepatocellular carcinoma..J Clin Cell Immunol2015;6:376 PMCID:PMC4750497

[38] Onishi S,Fujikawa M,Matsuura Y.Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin 2 in patients with unresectable hepatocellular carcinoma..Hepatology1989;10:349-53

[39] Kawata A,Hosokawa M,Namieno T.Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone..Am J Clin Oncol1995;18:257-62

[40] Wang Y,Wu M,Cong W.Postoperative immunotherapy for patients with hepatocarcinoma using tumor-infiltrating lymphocytes..Chin Med J (Engl)1997;110:114-7

[41] Takayama T,Makuuchi M,Kosuge T.Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial..Lancet2000;356:802-7

[42] Lee JH,Lim YS,Song TJ.Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma..Gastroenterology2015;148:1383-91.e6

[43] Maus M V,Porter DL.Antibody-modified T cells: CARs take the front seat for hematologic malignancies..Blood2014;123:2625-35 PMCID:PMC3999751

[44] Qasim W,Gehring AJ,Schurich A.Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient..J Hepatol2015;62:486-91

[45] Reck M,Robinson AG,Csőszi T.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer..N Engl J Med2016;375:1823-33

[46] Robert C,Brady B,Maio M.Nivolumab in previously untreated melanoma without BRAF mutation..N Engl J Med2015;372:320-30

[47] Sangro B,de la Mata M,Garralda E.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C..J Hepatol2013;59:81-8

[48] Duffy AG,Makorova-Rusher O,Wedemeyer H.Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma..J Hepatol2017;66:545-51 PMCID:PMC5316490

[49] Wainberg ZA,Jaeger D,Marshall J.Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC)..J Clin Oncol2017;35:4071

[50] El-Khoueiry AB,Yau T,Kudo M.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502

[51] FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm577166.htm. [Last accessed on 10 Oct 2019]

[52] Bristol-Myers Squibb Announces Results from CheckMate -459 Study Evaluating Opdivo (nivolumab) as a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma. Available from: https://news.bms.com/press-release/bmy/bristol-myers-squibb-announces-results-checkmate-459-study-evaluating-opdivo-nivol. [Last accessed on 10 Oct 2019]

[53] Yau T,Finn RS,Mathurin P.CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)..Ann Oncol2019;30:mdz394.029

[54] Zhu AX,Edeline J,Ogasawara S.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial..Lancet Oncol2018;19:940-52

[55] FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625705.htm. [Last accessed on 10 Oct 2019]

[56] Finn RS,Merle P,Bouattour M.Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC)..J Clin Oncol2019;37:abstract4004

[57] Yau T,Kim TY,Santoro A.Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040..J Clin Oncol2019;37:4012

[58] Kelley RK,Bendell JC,Borad MJ.Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses..J Clin Oncol2017;35:4073

[59] Zhou Y,Ding J,Wang F.Dynamic changes of T-cell subsets and their relation with tumor recurrence after microwave ablation in patients with hepatocellular carcinoma..J Cancer Res Ther2018;14:40-5

[60] Pishvaian MJ, Lee MS, Ryoo B, Stein S, Lee K, et al. Updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Available from: https://oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/Updated-safety-and-clinical-activity-results-from-a-Phase-Ib-study-of-atezolizumab-bevacizumab-in-hepatocellular-carcinoma-HCC. [Last accessed on 10 Oct 2019]

[61] FDA grants Breakthrough Therapy Designation for Roche’s Tecentriq in combination with Avastin as first-line treatment for advanced or metastatic hepatocellular carcinoma (HCC). Available from: https://www.roche.com/media/releases/med-cor-2018-07-18.htm. [Last accessed on 10 Oct 2019]

[62] Ikeda M,Kudo M,Baron AD.A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC)..J Clin Oncol2018;36:abstract4076

[63] Kudo M,Wada Y,Kurosaki M.First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: results from a phase 1b trial (VEGF Liver 100)..J Clin Oncol2019;37:abstract4072

[64] Stein S,Lee MS,Hernandez S.Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC)..J Clin Oncol2018;36:4074

[65] El-Khoueiry AB,Yau TC,Kudo M.Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040..J Clin Oncol2018;36:475

[66] Gibney GT,Atkins MB.Predictive biomarkers for checkpoint inhibitor-based immunotherapy..Lancet Oncol2016;17:e542-51 PMCID:PMC5702534

[67] El-Khoueiry AB,Yau T,Kudo M.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial..Lancet2017;389:2492-502