Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13(6): 448-472 [PMID: 35949435 DOI: 10.5306/wjco.v13.i6.448]
Corresponding Author of This Article
Georgios Tsoulfas, FACS, FICS, MD, PhD, Professor, Department of Transplantation Surgery, Aristotle University School of Medicine, 66 Tsimiski Street, Thessaloniki 54622, Greece. tsoulfasg@gmail.com
Research Domain of This Article
Oncology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Clin Oncol. Jun 24, 2022; 13(6): 448-472 Published online Jun 24, 2022. doi: 10.5306/wjco.v13.i6.448
Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances
Kathrine S Rallis, Dimitrios Makrakis, Ioannis A Ziogas, Georgios Tsoulfas
Kathrine S Rallis, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
Kathrine S Rallis, Dimitrios Makrakis, Ioannis A Ziogas, Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
Dimitrios Makrakis, Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
Ioannis A Ziogas, Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
Georgios Tsoulfas, Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
Author contributions: Rallis KS and Makrakis D contributed equally to the writing, reviewing, and designing of the manuscript and are equal joint first authors; Ziogas IA and Tsoulfas G lead the initial conceptualization, designing, reviewing, and supervision of the work in this manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors declare that they have no conflict of interest.
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: Georgios Tsoulfas, FACS, FICS, MD, PhD, Professor, Department of Transplantation Surgery, Aristotle University School of Medicine, 66 Tsimiski Street, Thessaloniki 54622, Greece. tsoulfasg@gmail.com
Received: January 31, 2022 Peer-review started: January 31, 2022 First decision: April 13, 2022 Revised: April 27, 2022 Accepted: May 28, 2022 Article in press: May 28, 2022 Published online: June 24, 2022
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
Core Tip: In the last five years, immune checkpoint inhibitors (ICIs) have entered the treatment landscape of hepatocellular carcinoma (HCC) in the 1st and 2nd line setting. However, due to restrictions in clinical trial inclusion and exclusion criteria, there remains a need for further real-world data on the efficacy, toxicity, and cost-effectiveness of ICIs in a broader cohort of HCC patients. New trials are underway investigating further ICI regimens, including combination therapy strategies, while novel immunotherapies are also being brought to the fore. This review discusses key clinical trials, real-world data, and future advances of immunotherapy for HCC, with a focus on ICIs.
