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Year : 2019  |  Volume : 15  |  Issue : 2  |  Page : 267-268

Programmed cell death protein-1 inhibitor for the treatment of hepatocellular carcinoma: “A sharp sword”

1 Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
2 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China

Date of Web Publication1-Apr-2019

Correspondence Address:
Dr. Ping Liang
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Dr. Xin Ye
Department of Oncology, Shandong Provincial Hospital Affliated to Shandong University, 324 Jingwuweiqi Road, Jinan, Shandong Province 250021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_910_18

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How to cite this article:
Li X, Liang P, Ye X. Programmed cell death protein-1 inhibitor for the treatment of hepatocellular carcinoma: “A sharp sword”. J Can Res Ther 2019;15:267-8

How to cite this URL:
Li X, Liang P, Ye X. Programmed cell death protein-1 inhibitor for the treatment of hepatocellular carcinoma: “A sharp sword”. J Can Res Ther [serial online] 2019 [cited 2022 Jan 21];15:267-8. Available from: https://www.cancerjournal.net/text.asp?2019/15/2/267/255110

Hepatocellular carcinoma (HCC) is one of the most common cancers and leading causes of cancer deaths worldwide.[1] HCC is also one of the most common cancers and the main cause of cancer deaths in China.[2] Early immunotherapy approaches to treat HCC revolved around the infusion of cytokines and adoptive immunotherapy;[3] since the Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for the treatment of different cancer types, an era of immune-oncology has started.[4],[5] Liver is an immune-privileged organ and tolerogenic to immune response by various immunosuppressive mechanisms. Several reviews have analyzed in depth the already-published trials with immune checkpoint inhibitors in HCC.[4],[6] Among these immune checkpoint inhibitors, programmed cell death protein-1 (PD-1) gained more attention, which was first identified in 1992 by Professor Tasuku Honjo.[7] PD-1 is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligands PD-L1 and PD-L2, and blockage of this interaction unleashes the immune system to fight cancer. And in clinics, PD-1 is verified as an independent prognostic biomarker, monitoring prognosis after treatments and predicting response to immunotherapy. In 2017, Lancet firstly reported that nivolumab, a PD-1 inhibitor, induces durable objective responses in the treatment of advanced HCC.[8] The same result was recently verified by pembrolizumab, another PD-1 inhibitor in an open-label Phase 2 trial.[9] Thus, both nivolumab and pembrolizumab were approved as second-line treatment agents for HCC by the United States FDA. Based on the positive findings, a head-to-head trial testing sorafenib versus nivolumab was performed, and the results are urgently awaited by both oncology and hepatology communities.

A robust 10%–30% of HCC patients responded to anti-PD-1 therapy and only 70% of them benefited, while others did not respond at all.[10] For those unresponders, combination approaches with PD-1 inhibitors might produce a stronger antitumor response as evidenced by PD-1 inhibitors in conjunction with tyrosine kinase inhibitors such as sorafenib or lenvatinib. The clinical results demonstrate that combined nivolumab and sorafenib induced a stronger tumor growth inhibition compared to either monotherapy;[10] more impressively, pembrolizumab combined with lenvatinib yielded a response rate of 69.2% and disease control rate of 100%.[11] Another option is a combination of immune checkpoint inhibitors, such as anti-CTLA4 blockers with anti PD-1 inhibitors, which has already been started. This combination approach is extremely promising as combining the two drugs with different mechanisms of action produces not just an additive effect but rather a synergistic effect against the immunosuppressive tumor microenvironment.[12],[13]

Locoregional treatments play a significant role in treating HCC patients at all stages and have been demonstrated to induce antitumor immune response by releasing tumor-associated antigens and promoting the migration of cytotoxic T-lymphocytes. Thus, subsequent administration of anti-PD-1 antibody may produce a synergistic effect with locoregional treatments, contributing to the control of small intrahepatic metastatic loci. Therefore, combination approaches of locoregional treatments and anti-PD-1 antibody are expected to serve as an appropriate strategy for preventing the recurrence of HCC.[12],[13],[14] Anti-PD1 therapy with nivolumab combined with transarterial chemoembolization for advanced HCC showed a disease control rate of 81.8% and an objective response rate of 63.6%.

In summary, PD-1 inhibitor, as a sharp sword, and/or combination approaches may benefit a wide range of patients from the early, intermediate stage of HCC as adjuvant, to advanced stages. Therefore, further progress is ongoing and highly anticipated. The invention of PD-1 inhibitor may drastically change the landscape of HCC treatment.

 > References Top

Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA Oncol 2018;4:1553-68.  Back to cited text no. 1
Qiu WQ, Shi JF, Guo LW, Mao AY, Huang HY, Hu GY, et al. Medical expenditure for liver cancer in urban China: A 10-year multicenter retrospective survey (2002–2011). J Cancer Res Ther 2018;14:163-70.  Back to cited text no. 2
Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, et al. Ameta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Cancer Res Ther 2018;14:807-14.  Back to cited text no. 3
Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol 2017. pii: S0168-8278(17)32287-0.  Back to cited text no. 4
Koppolu V, Rekha Vasigala VK. Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma. J Cancer Res Ther 2018;14:1167-75.  Back to cited text no. 5
Greten TF, Wang XW, Korangy F. Current concepts of immune based treatments for patients with HCC: From basic science to novel treatment approaches. Gut 2015;64:842-8.  Back to cited text no. 6
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887-95.  Back to cited text no. 7
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-502.  Back to cited text no. 8
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19:940-52.  Back to cited text no. 9
Mocan T, Sparchez Z, Craciun R, Bora CN, Leucuta DC. Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: Prognostic and therapeutic perspectives. Clin Transl Oncol 2018. [Epub ahead of print].  Back to cited text no. 10
Kudo M. Systemic therapy for hepatocellular carcinoma: Latest advances. Cancers (Basel) 2018;10. pii: E412.  Back to cited text no. 11
Kudo M. Immuno-Oncology in Hepatocellular Carcinoma: 2017 Update. Oncology 2017; 93 Suppl 1:147-59.  Back to cited text no. 12
Kudo M. Combination cancer immunotherapy in hepatocellular carcinoma. Liver Cancer 2018;7:20-7.  Back to cited text no. 13
Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma. Hepatology 2018. doi: 10.1002/hep.30337. [Epub ahead of print].  Back to cited text no. 14


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