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Review Article
Advances in immune checkpoint inhibitors for hepatocellular carcinoma
Ji Won Han1,2orcid, Su-Hyung Park3orcid
Journal of Liver Cancer 2021;21(2):139-145.
Published online: September 30, 2021

1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Seoul, Korea

2The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea

3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea

Corresponding author: Ji Won Han, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea,
Tel. +82-2-2258-2073, Fax. +82-2-3481-4025, E-mail:
Co-corresponding author: Su-Hyung Park, Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea,
Tel. +82-42-350-4248, Fax. +82-42-350-4240, E-mail:
• Received: September 14, 2021   • Revised: September 22, 2021   • Accepted: September 24, 2021

Copyright © 2021 by The Korean Liver Cancer Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 3 Citations
  • Hepatocellular carcinoma (HCC) is the fifth most common cancer, and the second leading cause of cancer-related death worldwide. Although recent advances in immune checkpoint inhibitor-based immunotherapy have initiated a new era for advanced HCC treatment, the majority of HCC patients receiving immune checkpoint blockades do not derive clinical benefit. Thus, there remains an urgent need for novel immunotherapeutic strategies with improved therapeutic efficacy. Here we review recent studies of immune checkpoint blockade in HCC, providing the necessary basis for the rational design of immunotherapy.
Liver cancer is among the most common cancers worldwide, and hepatocellular carcinoma (HCC) is the most common primary liver cancer.1 HCC frequently develops in a background of chronic liver disease caused by infection with hepatitis B virus or hepatitis C virus (HCV), or by cirrhosis induced by alcohol abuse, autoimmune hepatitis, or non-alcoholic fatty liver disease.2 HCC incidence is expected to continue increasing and HCC patients have a poor prognosis, such that the socioeconomic burden of HCC is among the most important global health issues.3 Patients with advanced HCC have limited therapeutic options. Sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib are the approved systemic treatments that prolong survival,46 but these agents show an unsatisfactory survival benefit and are frequently not tolerated. Therefore, novel HCC therapeutic strategies are urgently needed.
The HCC tumor microenvironment (TME) is a spatially structured mixture of various cells, including tumor cells, immune cells, tumor-associated fibroblasts, and hepatic non-parenchymal resident cells. These cellular components dynamically interact through cell-to-cell contacts, and this cellular interplay influences tumor immune evasion—for example, related to T-cell exhaustion. Although T-cell exhaustion was originally identified in chronic viral infections,7 similar dysfunctional features have been observed in cancers. T-cell exhaustion is defined as an impaired ability to secrete cytokines and proliferate, along with prolonged antigenic stimulation-induced overexpression of immune checkpoint receptors, such as programmed cell death-1 (PD-1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), cytotoxic T lymphocyte antigen-4 (CTLA-4), and lymphocyte-activation gene-3 (LAG-3).810 Immune checkpoint inhibitors (ICIs) targeting the PD-1/programmed cell death-ligand1( PD-L1) and CTLA-4 pathways are currently available for clinical use, and have revolutionized the treatment of various cancer types.11 Clinical trials of anti-PD-1 therapy in patients with advanced HCC show objective response rates (ORRs) of 16–20%,12,13 resulting in approval of the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab for use in HCC by in U.S. Food and Drug Administration (FDA). However, the majority of HCC patients receiving anti-PD-1 therapy do not have clinical benefit, highlighting that novel immunotherapeutic strategies with improved therapeutic efficacy such as ICI-based therapeutic strategies in combination with targeted agents, locoregional therapy, and other forms of immunotherapy are urgently needed.14
Here we review the advancements and clinical implications of immune checkpoint inhibitor use in HCC, focusing on results from clinical trials. In the first part of this paper, we review the usage of immune checkpoint inhibitors as monotherapies for HCC, and the clinical responses. In the second part, we summarize the current status of combined immunotherapy targeting immune checkpoint receptors and other molecules in HCC.
ICIs, such as anti-CTLA-4 and anti-PD-1 agents, have been tested as monotherapy in patients with unresectable HCC. A small pilot study evaluated the anti-CTLA-4 inhibitor tremelimumab in HCV-related HCC.15 This agent yielded an ORR of 17.6%, and exhibited good safety, with no patients requiring steroid treatment due to the immune-related adverse events.
However, the current mainstream of ICI treatment for HCC is based on targeting the PD-1/PD-L1 axis. The phase 1/2 trial CheckMate040 tested nivolumab in patients with advanced unresectable HCC including patients previously treated with sorafenib, and nivolumab yielded a promising ORR of 20%.12 Pembrolizumab has also shown an ORR of 17% in previously sorafenib-treated patients in a phase 2 trial. 13 Consequently, nivolumab and pembrolizumab were approved by the FDA in 2017 as post-sorafenib second-line systemic treatments for HCC.
In the randomized multi-center phase 3 trial Check-Mate-459 (NCT02576509), nivolumab was compared to sorafenib as first-line systemic treatment, among patients with advanced HCC who were ineligible for locoregional or surgical treatments.16 Unfortunately, the overall survival (OS) benefit of nivolumab compared to sorafenib did not reach statistical significance according to the pre-defined threshold in the trial design (HR, 0.84; P =0.042). The median OS was 16.4 months in the nivolumab group versus 14.7 months in the sorafenib group (P =0.075). However, several important findings of this study support the clinical benefit of nivolumab treatment. Firstly, ORR tended to be higher in the nivolumab group (15% versus 7%), including complete response (CR) in 14 patients (14/371, 4%) with nivolumab treatment, compared to only five patients (5/372, 1%) with sorafenib treatment. Secondly, grade 3 or 4 adverse events occurred in 81 patients (81/371, 22%) following nivolumab treatment, compared to in 179 patients (179/372, 49%) after sorafenib treatment, showing the safety and tolerability of nivolumab. A recent subgroup analysis further supports this safety of nivolumab, which also exhibited favorable safety and tolerability in patients with Child-Pugh B liver function.17
The randomized double-blind phase 3 trial KEYNOTE-224 evaluated pembrolizumab as a second-line systemic treatment compared with placebo for patients previously treated with sorafenib.18 The median OS was 13.9 months in the pembrolizumab group versus 10.6 months in the placebo group (P =0.024), but the statistical significance of this difference was insufficient according to the pre-defined criteria. Treatment-associated adverse events of grade 3 or higher occurred in 52 patients (52/278, 19%). These findings could justify the accelerated FDA approval of these two anti-PD-1 inhibitors as a second-line systemic treatment for HCC. However, the insufficient clinical benefit demonstrated in these phase 3 trials indicates the necessity of complementary combined strategies to improve ICI efficacy in HCC.
On the other hand, phase 3 randomized trials are examining anti-PD-1 agents as adjuvant treatments to reduce tumor recurrence following curative therapy, such as ablation or surgical resection. KEYNOTE-937 compares pembrolizumab versus placebo as adjuvant therapy, in terms of recurrence-free survival (RFS) and OS, in patients who achieved complete radiological response after curative treatments (NCT03867084). Furthermore, CheckMate-9DX compares nivolumab versus placebo as adjuvant therapy, in terms of OS, especially in high-risk patients. HCC has high recurrence rates following curative treatment, about 70% at 5 years after surgical resection,19 and about 50–70% after radiofrequency ablation.20 Thus, there is a need to further investigate the potential role of ICIs in improving clinical outcomes following curative treatments. In the phase 3 randomized STORM trial, adjuvant sorafenib following curative treatment failed to show clinical benefit in terms of RFS.21 Table 1 shows currently on-going phase 3 clinical trials of ICIs.
Table 1 presents the on-going trials investigating combined regimens based on ICIs. As introduced above, tumor-infiltrating lymphocytes (TILs) from HCC patients highly express multiple immune checkpoint molecules, including PD-1, TIM-3, LAG-3, and CTLA-4.22,23 Treatment with anti-PD-1 or anti-PD-L1 combined with anti-CTLA-4, anti-TIM-3, or anti-LAG-3 synergistically increases TIL proliferation and function.22,23 Beyond these experimental studies, the phase 1/2 clinical trial CheckMate-040 tested nivolumab plus ipilimumab as a second-line systemic treatment following sorafenib treatment.24 Administration of ipilimumab plus nivolumab, repeated four times, followed by nivolumab administration every 2 weeks, yielded a promising ORR rate of 32%. Most patients (94%) experienced treatment-related adverse events of any grade, but most adverse events were manageable. Based on these results, the FDA granted accelerated approval to this regimen on March 2020. Moreover, an ongoing phase 3 trial is comparing first-line treatment with the nivolumab-ipilimumab regimen versus sorafenib (Check-Mate-9DW, NCT04039607).
Targeting the vascular endothelial growth factor (VEGF)/VEGFR pathway is proposed to be a promising strategy for HCC chemotherapy, since this pathway is associated with high vascularization in the HCC microenvironment.25 Importantly, VEGF is immunosuppressive and affects various types of immune cells within the TME—impacting the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and the inhibition of dendritic cell maturation and T-cell function.26 A recent preclinical study in mice used orthotopic and induced HCC models to demonstrate that dual PD-1 and VEGFR blockade normalizes vascularity and restores anti-tumor immune responses.27 They reported CD8+ T-cell activation and Treg reduction, as well as reductions of M1 tumor-associated macrophages (TAMs) and chemokine receptor 2 monocytes. Therefore, the combination of ICI treatment and VEGFR blockade is expected to be a promising strategy to overcome resistance to ICI monotherapy.
Results from the phase 3 trial IMbrave-150 have opened a new horizon for systemic treatment of HCC. Compared to sorafenib, the anti-PD-L1 inhibitor atezolizumab in combination with the anti-VEGF inhibitor bevacizumab yielded a better OS and progression-free survival (PFS).28 At 12 months of treatment, the OS rate was 67% in the atezolizumab-bevacizumab group versus 55% in the sorafenib group (P <0.001; HR, 0.58). Moreover, the median PFS was 6.8 months in the atezolizumab-bevacizumab group versus 4.3 months in the sorafenib group (P <0.001). The atezolizumab-bevacizumab group was also superior to the sorafenib group in terms of the time to deterioration of quality of life. This finding has also been confirmed by a recent study that investigated patient-reported outcomes, including quality of life, functioning, and symptoms due to the disease, which were all superior in the atezolizumab-bevacizumab group compared to the sorafenib group.29 Adverse events of grade 3 or higher were comparable between the two groups, occurring in 201/329 (61.1%) of the atezolizumab-bevacizumab group and 95/156 (60.9%) of the sorafenib group. The risk of bleeding (any grade), including variceal bleeding, tended to be higher in the atezolizumab-bevacizumab group (25.2% versus 17.3%), indicating that endoscopic evaluation is required before treatment using this regimen. Overall, the atezolizumab-bevacizumab combination regimen could be a successful substitute for sorafenib, which has been the only option for systemic treatment of HCC for decades. In May 2020, the FDA approved this regimen as a first-line treatment for patients with unresectable or metastatic HCC.
Currently available multi-kinase inhibitors (MKIs) can target the VEGF/VEGFR pathway and angiogenesis, and also have immunomodulatory effects. For example, MKIs can regulate immunosuppressive populations (e.g., TAMs, MDSCs, and Tregs), as well as enhance T-cell responses.30 In particular, lenvatinib, an MKI that has been approved as a first-line systemic treatment, was recently investigated as part of a combinational regimen with anti-PD-1 in a murine model of HCC.31 The results demonstrated that lenvatinib downregulated PD-L1 expression on tumor cells, via FGF receptor 4 (FGFR4). Lenvatinib also acted through FGFR4 to hinder Treg differentiation by IL-2, and thereby synergistically improved anti-tumor immune responses in combination with anti-PD-1. These findings suggest that lenvatinib is a promising MKI in terms of combination immunotherapy with ICIs. A recent report from a phase 1b trial describes the safety and efficacy of lenvatinib plus pembrolizumab in patients with unresectable HCC.32 Although the study was small and did not have a comparative design, it demonstrated that pembrolizumab-lenvatinib treatment yielded an ORR of 36%, with a median OS of 22 months. Among the patients, 67% experienced adverse events of grade 3 or higher, but they were manageable. This regimen is presently being tested in a phase 3 randomized trial (LEAP-002, NCT03713593).
In addition to the role of combined regimens as systemic chemotherapy, they are also being investigated in phase 3 clinical trials for use as adjuvant treatments following curative treatments or transcatheter arterial chemoembolization (TACE). Specifically, phase 3 trials are examining the use of atezolizumab-bevacizumab (IMbrave-050, NCT04102098) and durvalumab-bevacizumab (EMERALD-2, NCT03847428) following resection or ablation, compared to radiofrequency ablation with placebo. Trials are also investigating durvalumab-bevacizumab (EMERALD-1, NCT03778957), nivolumabipilimumab (CheckMate-74W), and pembrolizumab-lenvatinib (LEAP-012, NCT04246177) following TACE. Combined immunotherapy may become a standard means of HCC treatment, not only as a first-or second-line systemic chemotherapy, but also as an adjuvant treatment following locoregional treatment for HCC.
In this review, we have discussed the recent advances in immunotherapy targeting immune checkpoint receptors for HCC treatment. While anti-PD-1 therapy shows great therapeutic success in some HCC patients, it exhibits limited efficacy in the majority of HCC patients. Various studies have investigated the factors that determine clinical responses to ICIs, and the mechanisms by which they modulate tumor-specific immunity in cancer patients. However, most have focused on tumor-intrinsic factors, rather than on the characteristics of exhausted tumor-infiltrating T cells. Overcoming the limitations of anti-PD-1 therapy for HCC will require a better understanding of T-cell exhaustion in TMEs. Recent studies have highlighted the heterogeneity of tumor-infiltrating CD8+ T cells (CD8+ TILs) in the context of T-cell exhaustion and T-cell activation in HCC patients,23,33 which was associated biomarkers indicating anti-PD-1 response.23,33 These findings support the importance of detailed characterizations of the heterogeneity within the exhausted CD8+ TIL population for cancer immunotherapy in HCC patients.
Our current knowledge of the mechanisms underlying ICI response lags behind the application of ICIs. Thus, there remains a need for more cross-disciplinary studies to better understand the biological and clinical implications of ICIs, by elucidating the cellular and molecular heterogeneity of tumor-infiltrating immune cells among HCC patients. The results of such investigations could enable the application of immunotherapies targeting various immune checkpoint receptors in combination with currently available ICIs. Considering that HCC patients exhibit variations in the expressions of checkpoint receptors other than PD-1,23 it will be important to find biomarkers to identify patients specifically eligible for each combinational checkpoint blockade regimen. Therefore, along with evaluations of the therapeutic efficacy of novel combined checkpoint blockade therapies, efforts to develop biomarkers clinically suitable for use as companion diagnostics may help advance personalized immunotherapy.
In conclusion, advances in immune checkpoint inhibitor-based immunotherapy have opened a new era for HCC treatment. Future clinical studies that evaluate the efficacy of combined immune checkpoint blockades in HCC patients, and further investigation of the immune biology of the TME in HCC, may provide the rationale for establishing optimal immunotherapy strategies in patients with HCC.

Conflicts of Interest

The authors have no conflicts of interest to disclose.

Ethics Statement

This article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, institutional review board approval or patient consent was not necessary.

Funding Statement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C2005176 to S.H.P).

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the study.

Author Contribution

Conception and study design: JWH and SHP

Supervision: SHP

Writing-original draft: JWH and SHP

Writing-review and editing: JWH and SHP

Funding: SHP

All authors reviewed and approved the final draft.

Table 1
Phase 3 clinical trials of immune checkpoint inhibitors for HCC
Clinical setting Regimen Trial name/number Estimated primary completion date
First-line systemic Pembrolizumab-envatinib LEAP-002/NCT03713593 May 2022
First-line systemic Nivolumab-ipilimumab CheckMate-9DW/NCT04039607 Mar 2023
First-line systemic Durvalumab-tremelimumab HIMALAYA/NCT03298451 Dec 2021
First-line systemic Atezolizumab-cabozantinib COSMIC-312/NCT03755791 Jun 2021
First-line systemic SHR-1210-apatinib NA/NCT03764293 Dec 2021
First-line systemic Sintilimab-IBI305 (anti-VEGF) ORIENT-32/NCT03794440 Dec 2022
First-line systemic Tislelizumab RATIONLALE-301/NCT03412773 May 2022
Adjuvant resection/ablation Pembrolizumab KEYNOTE-937/NCT03867084 Jun 2025
Adjuvant resection/ablation Nivolumab CheckMate-9DX/NCT03383458 Jan 2023
Adjuvant resection/ablation Atezolizumab-bevacizumab IMbrave-050/NCT04102098 Mar 2023
Adjuvant resection/ablation Durvalumab-bevacizumab EMERALD-2/NCT03847428 May 2023
Adjuvant TACE Durvalumab or Durvalumab-bevacizumab EMERALD-1/NCT03778957 Sep 2022
Adjuvant TACE Nivolumab or Nivolumab-ipilimumab CheckMate-74W/NCT04340193 Feb 2026
Adjuvant TACE Pembrolizumab-lenvatinib LEAP-012/NCT04246177 Apr 2025
Adjuvant TACE beads Nivolumab TACE-3/NCT04268888 Jun 2025

VEGF, vascular endothelial growth factor; TACE, transcatheter arterial chemoembolization.

  • 1. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18:525−543.ArticlePubMedPMC
  • 2. Lee HW, Cho KJ, Park JY. Current status and future direction of immunotherapy in hepatocellular carcinoma: what do the data suggest? Immune Netw 2020;20:e11. ArticlePubMedPMC
  • 3. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379:1245−1255.ArticlePubMed
  • 4. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases. Hepatology 2018;68:723−750.ArticlePubMed
  • 5. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56−66.ArticlePubMed
  • 6. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54−63.ArticlePubMedPMC
  • 7. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15:486−499.ArticlePubMedPMC
  • 8. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010;207:2175−2186.ArticlePubMedPMC
  • 9. Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest 2011;121:2350−2360.ArticlePubMedPMC
  • 10. Jeong S, Park SH. Co-stimulatory receptors in cancers and their implications for cancer immunotherapy. Immune Netw 2020;20:e3. ArticlePubMedPMC
  • 11. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8:1069−1086.ArticlePubMed
  • 12. 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;389:2492−2502.ArticlePubMedPMC
  • 13. 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;19:940−952.PubMed
  • 14. Greten TF, Lai CW, Li G, Staveley-O’Carroll KF. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology 2019;156:510−524.ArticlePubMed
  • 15. Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, 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.ArticlePubMed
  • 16. Yau T, Park J, Finn R, Cheng AL, Mathurin P, Edeline J, et al. 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 Oncol 2019;30:v874−v875.Article
  • 17. Kudo M, Matilla A, Santoro A, Melero I, Gracián AC, Acosta-Rivera M, et al. CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 2021;75:600−609.ArticlePubMed
  • 18. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020;38:193−202.ArticlePubMed
  • 19. Ishizawa T, Hasegawa K, Aoki T, Takahashi M, Inoue Y, Sano K, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908−1916.ArticlePubMed
  • 20. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009;49:453−459.ArticlePubMed
  • 21. Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16:1344−1354.ArticlePubMed
  • 22. Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology 2017;153:1107−1119e1110.ArticlePubMed
  • 23. Kim HD, Song GW, Park S, Jung MK, Kim MH, Kang HJ, et al. Association between expression level of PD1 by tumor-infiltrating CD8+ T cells and features of hepatocellular carcinoma. Gastroenterology 2018;155:1936−1950e1917.ArticlePubMed
  • 24. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020;6:e204564. ArticlePubMedPMC
  • 25. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol 2004;41:864−880.ArticlePubMed
  • 26. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 2018;9:978. ArticlePubMedPMC
  • 27. Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A, et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology 2020;71:1247−1261.ArticlePubMed
  • 28. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894−1905.ArticlePubMed
  • 29. Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, et al. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:991−1001.ArticlePubMed
  • 30. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 2018;15:310−324.ArticlePubMed
  • 31. Yi C, Chen L, Lin Z, Liu L, Shao W, Zhang R, et al. Lenvatinib targets FGF receptor 4 to enhance antitumor immune response of anti-programmed cell death-1 in HCC. Hepatology 2021;May 26 PMID: 10.1002/hep.31921. [Epub ahead of print].Article
  • 32. Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol 2020;38:2960−2970.ArticlePubMedPMC
  • 33. Kim HD, Park S, Jeong S, Lee YJ, Lee H, Kim CG, et al. 4-1BB delineates distinct activation status of exhausted tumor-infiltrating CD8+ T cells in hepatocellular carcinoma. Hepatology 2020;71:955−971.ArticlePubMed

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