Letter to the Editor Open Access
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2022; 14(6): 1210-1212
Published online Jun 15, 2022. doi: 10.4251/wjgo.v14.i6.1210
Hepatocellular carcinoma and immunotherapy: Beyond immune checkpoint inhibitors
Hassan Mohammed Abushukair, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
Anwaar Saeed, Division of Medical Oncology, Department of Medicine, The University of Kansas Cancer Center, Kansas City, KS 66205, United States
ORCID number: Hassan Mohammed Abushukair (0000-0002-0068-5201); Anwaar Saeed (0000-0001-8024-9401).
Author contributions: Abushukair HA drafted the manuscript and conceptualized the concepts; Saeed A conceptualized the core concepts and critically revised the draft.
Conflict-of-interest statement: Anwaar Saeed reports research grants from AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, KAHR Medical, and Incyte, and advisory board fees from AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, and Pfizer. The other author has no conflicts of interest to declare.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Anwaar Saeed, MD, Division of Medical Oncology, Department of Medicine, The University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy, Kansas City, KS 66205, United States. asaeed@kumc.edu
Received: December 5, 2021
Peer-review started: December 5, 2021
First decision: December 27, 2021
Revised: December 29, 2021
Accepted: May 12, 2022
Article in press: May 12, 2022
Published online: June 15, 2022
Processing time: 187 Days and 2 Hours


Hepatocellular carcinoma (HCC) is one of the deadliest and most common malignancies of the liver. Considering the rich immune background of carcinogenesis in HCC, efforts have been focused on further understanding the role of the immune system in tumor suppression and promotion. The utilization of immunotherapy in HCC has led to encouraging results that has translated to longer survival and better quality of life among patients. The development of novel HCC-tailored regimens such as vaccine therapy and adoptive cellular therapy coupled with a deeper understanding of biomarkers predictive of the response to immunotherapy will lead to better treatment outcomes.

Key Words: Hepatocellular carcinoma, Immunotherapy, Biomarkers, Cancer vaccines, Adoptive cellular therapy

Core Tip: Immunotherapy has changed the treatment landscape for solid cancers. In advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors have become the standard of care due to their efficacy and safety outcomes. However, primary and acquired resistance is a major issue in the treatment paradigm, and more research is still needed to understand and identify potential predictors of the response in HCC. Other immunotherapy modalities, such as vaccine therapy and adoptive cellular therapy, could play a prominent role in certain HCC subcohorts and are currently being investigated in clinical trial settings.


We read with great interest the review by Mattos et al[1] on the immune landscape of hepatocellular carcinoma (HCC), which covered the immune aspects and markers of HCC as well as the immunotherapeutic modalities used in this malignancy. Considering the immunogenicity of HCC, it comes as no surprise that clinical and basic research has been directed to dive deeper into the immune-biological and therapeutic upside of HCC, especially with the rise of immunotherapy in oncology.

While the authors thoroughly discussed the therapeutic use of immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 and its ligand (nivolumab, pembrolizumab, and atezolizumab) and anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab), we would like to highlight the role of other promising immunotherapeutic modalities in HCC. The first being tumor-associated antigen vaccines, including the oncofetal antigen glypican-3 (GPC3) vaccine, which was investigated in adjuvant settings in HCC patients in a phase 2 trial and resulted in a median overall survival (mOS) of 20.1 mo[2]. Another potential vaccine antigen is the multidrug resistance-associated protein 3 (MRP3), a member of the adenosine triphosphate-binding cassette transporters highly expressed in HCC tissue[3]. MRP3-derived peptide vaccines resulted in a mOS of 19 mo in a phase 1 trial of 12 HCC patients. Oncolytic virotherapy is another immune modality that has been widely investigated in solid malignancies. Heo et al[4] conducted a phase 2 trial assessing the efficacy and safety of high- and low-dose JX-594, an oncolytic poxvirus, in HCC patients[4]. The investigators reported a significantly longer mOS with high-dose compared to low-dose JX-594 (14.1 mo vs 6.7 mo; P = 0.02). Lastly, adoptive cellular therapy, which is a promising option that is being used more in hematological and solid cancers, has been investigated in HCC, specifically through genetically modified T cells expressing chimeric antigen receptors for GPC3 in a phase 1 trial on 13 patients, which resulted in a mOS of 278 d[5]. Table 1 includes the characteristics of the clinical trials on non-ICI immunotherapeutic options for HCC patients.

Table 1 Clinical trials characteristics on vaccine therapy, oncolytic virotherapy, and adoptive cellular therapy in hepatocellular carcinoma patients.
Study design
Sample size
Survival outcomes
Sawada et al[2], 2016GPC3Phase 2 trial41mOS: 20.1 mo (95%CI: 14.7-25.5)
Mizukoshi et al[9], 2015MRP3Phase 1 trial12mOS: 14 mo (95%CI: 9.6-18.5)
Palmer et al[10], 2009DCsPhase 2 trial35mOS: 168 d
Butterfield et al[11], 2014AFPPhase 1 trial2RFS: 9 and 18 mo
Heo et al[4], 2013JX-594Phase 2 trial30mOS in high- vs low-dose: 14.1 mo vs 6.7 mo
Shi et al[5], 2020CAR-GPC3 T-cellPhase 1 trial13mOS: 278 d (95%CI: 48-615)

We would also like to emphasize the importance of identifying biomarkers predictive of the immunotherapy response in HCC. To date, limited evidence exists on this topic, yet some preclinical and clinical data point to potential targets. For instance, emerging evidence suggests that activated Wnt/beta-catenin signaling can predict primary immunotherapy resistance in HCC[6]. There is also growing interest in the microbiome’s predictive value to ICI response in other cancers. For HCC, this is especially relevant since chronic liver disease alters the microbiome components[7]. Established ICI predictive biomarkers in other malignancies, such as microsatellite instability and high tumor mutational burden, are of limited use in HCC due to their rarity[6,8].


Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Oncology

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): D

Grade E (Poor): E

P-Reviewer: Elshimi E, Egypt; Limaiem F, Tunisia; Song B, China A-Editor: Ma LS S-Editor: Fan JR L-Editor: Filipodia P-Editor: Fan JR

1.  Mattos ÂZ, Debes JD, Boonstra A, Vogel A, Mattos AA. Immune aspects of hepatocellular carcinoma: From immune markers for early detection to immunotherapy. World J Gastrointest Oncol. 2021;13:1132-1143.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
2.  Sawada Y, Yoshikawa T, Ofuji K, Yoshimura M, Tsuchiya N, Takahashi M, Nobuoka D, Gotohda N, Takahashi S, Kato Y, Konishi M, Kinoshita T, Ikeda M, Nakachi K, Yamazaki N, Mizuno S, Takayama T, Yamao K, Uesaka K, Furuse J, Endo I, Nakatsura T. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 2016;5:e1129483.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 115]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
3.  Mizukoshi E, Honda M, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma. J Hepatol. 2008;49:946-954.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 24]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
4.  Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19:329-336.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 490]  [Cited by in F6Publishing: 571]  [Article Influence: 51.9]  [Reference Citation Analysis (0)]
5.  Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, Lu Q, Gao H, Jiang H, Wang H, Yuan D, Ma H, Li Z, Zhai B. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Clin Cancer Res. 2020;26:3979-3989.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 185]  [Article Influence: 46.3]  [Reference Citation Analysis (0)]
6.  Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut. 2021;70:204-214.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 145]  [Article Influence: 48.3]  [Reference Citation Analysis (0)]
7.  Keenan BP, Fong L, Kelley RK. Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response. J Immunother Cancer. 2019;7:267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 129]  [Article Influence: 25.8]  [Reference Citation Analysis (0)]
8.  Kole C, Charalampakis N, Tsakatikas S, Vailas M, Moris D, Gkotsis E, Kykalos S, Karamouzis MV, Schizas D. Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers (Basel). 2020;12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 79]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
9.  Mizukoshi E, Nakagawa H, Kitahara M, Yamashita T, Arai K, Sunagozaka H, Iida N, Fushimi K, Kaneko S. Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett. 2015;369:242-249.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 31]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
10.  Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Kerr DJ, Young LS, Adams DH. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49:124-132.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 201]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
11.  Butterfield LH, Economou JS, Gamblin TC, Geller DA. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients. J Transl Med. 2014;12:86.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 39]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]