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Cancers
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Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular...
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Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 24245

Special Issue Editors

Dr. Bruno Daniele

E-Mail Website
Guest Editor
Medical Oncology Unit, Ospedale del Mare, Napoli, Italy
Interests: hepatocellular carcinoma; gastrointestinal tumors
Dr. Angelica Petrillo

E-Mail Website
Guest Editor
1. Medical Oncology Unit, Ospedale del Mare, Naples, Italy
2. Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy
Interests: gastric cancer; esophageal diseases; pancreatic cancer; cancer biomarkers; oncology; prognosis; treatment; tumors; chemotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Piera Federico

E-Mail Website
Guest Editor
Medical Oncology Unit, Ospedale del Mare, 80147 Napoli, Italy
Interests: hepatocellular carcinoma; immune checkpoint inhibitors

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is the first primary liver cancer in incidence and the third cause of cancer-related death worldwide. Despite therapeutic advances, the prognosis of HCC is severe, especially in patients with advanced disease. For this reason, every HCC patient requires a careful and comprehensive evaluation in dedicated and high-volume centers by a multidisciplinary team. This team should include oncologists, radiologists, radiotherapists, surgeons, nutritionists, and hepatologists due to the complexity of the management of HCC patients, who often show variable degrees of liver function impairment due to cirrhosis, malnutrition due to alcohol abuse or metabolic alterations in case of NASH patients. In this context, there is an unmet need for a better understanding of genetic alterations and prognostic and predictive factors in order to choose the best tailored therapy for each patients.

The aim of this Special Issue is to present novel perspectives in the management of HCC, with a special focus on immunotherapy, the search of prognostic and predictive factors, and the evaluation of novel strategies for individualized treatment. We are inviting relevant original research, systematic reviews, meta-analyses, and short communications covering the abovementioned topics.

Dr. Bruno Daniele
Dr. Angelica Petrillo
Dr. Piera Federico
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • target therapy
  • locoregional treatment
  • immunotherapy
  • predictive factors
  • biomarkers
  • surgical treatment
  • nutrition and cancer
  • multimodality therapy

Published Papers (7 papers)

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Review

22 pages, 1234 KiB  
Review
Unraveling the Synergy between Atezolizumab and Bevacizumab for the Treatment of Hepatocellular Carcinoma
by Cedric Brackenier, Lisa Kinget, Sarah Cappuyns, Chris Verslype, Benoit Beuselinck and Jeroen Dekervel
Cancers 2023, 15(2), 348; https://doi.org/10.3390/cancers15020348 - 05 Jan 2023
Cited by 4 | Viewed by 3115
Abstract
Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials [...] Read more.
Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
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20 pages, 2653 KiB  
Review
Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact
by Piera Federico, Emilio Francesco Giunta, Andrea Tufo, Francesco Tovoli, Angelica Petrillo and Bruno Daniele
Cancers 2022, 14(24), 6245; https://doi.org/10.3390/cancers14246245 - 18 Dec 2022
Viewed by 2011
Abstract
Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the [...] Read more.
Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
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Figure 1

16 pages, 343 KiB  
Review
Immunotherapy and Hepatocellular Cancer: Where Are We Now?
by Marine Valery, Baptiste Cervantes, Ramy Samaha, Maximiliano Gelli, Cristina Smolenschi, Alina Fuerea, Lambros Tselikas, Caroline Klotz-Prieux, Antoine Hollebecque, Valérie Boige and Michel Ducreux
Cancers 2022, 14(18), 4523; https://doi.org/10.3390/cancers14184523 - 19 Sep 2022
Cited by 7 | Viewed by 3198
Abstract
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies [...] Read more.
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
12 pages, 256 KiB  
Review
Impact and Novel Perspective of Immune Checkpoint Inhibitors in Patients with Early and Intermediate Stage HCC
by Luca Marzi, Andrea Mega, Stefano Gitto, Filippo Pelizzaro, Andreas Seeber and Gilbert Spizzo
Cancers 2022, 14(14), 3332; https://doi.org/10.3390/cancers14143332 - 08 Jul 2022
Cited by 10 | Viewed by 2797
Abstract
Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) [...] Read more.
Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
17 pages, 1384 KiB  
Review
Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation
by Nitin N. Katariya, Blanca C. Lizaola-Mayo, David M. Chascsa, Emmanouil Giorgakis, Bashar A. Aqel, Adyr A. Moss, Pedro Luiz Serrano Uson Junior, Mitesh J. Borad and Amit K. Mathur
Cancers 2022, 14(9), 2056; https://doi.org/10.3390/cancers14092056 - 19 Apr 2022
Cited by 24 | Viewed by 4012
Abstract
Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied [...] Read more.
Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25–35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
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Figure 1

15 pages, 303 KiB  
Review
Current Landscape of Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma
by Nikolaos Machairas, Diamantis I. Tsilimigras and Timothy M. Pawlik
Cancers 2022, 14(8), 2018; https://doi.org/10.3390/cancers14082018 - 16 Apr 2022
Cited by 15 | Viewed by 5344
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting [...] Read more.
Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
17 pages, 1419 KiB  
Review
Novel Perspectives in Immune Checkpoint Inhibitors and the Management of Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma
by Landon L. Chan and Stephen L. Chan
Cancers 2022, 14(6), 1526; https://doi.org/10.3390/cancers14061526 - 16 Mar 2022
Cited by 6 | Viewed by 2876
Abstract
Immune checkpoint inhibitors have revolutionised the systemic treatment of advanced hepatocellular carcinoma. Although phase III trials, testing single agent nivolumab and pembrolizumab, failed to meet their primary endpoints, the combination of atezolizumab and bevacizumab has demonstrated a remarkable objective response and unprecedented survival [...] Read more.
Immune checkpoint inhibitors have revolutionised the systemic treatment of advanced hepatocellular carcinoma. Although phase III trials, testing single agent nivolumab and pembrolizumab, failed to meet their primary endpoints, the combination of atezolizumab and bevacizumab has demonstrated a remarkable objective response and unprecedented survival benefits, replacing sorafenib as the standard first-line treatment for advanced hepatocellular carcinoma. Despite these successes observed in immune checkpoint inhibitors in the management of advanced hepatocellular carcinoma, not all patients responded to treatment, which has led to the search of risk factors and biomarkers that could predict the response to immune checkpoint inhibitors. Recent translational studies have begun to shed light on the impact of an underlying liver disease, namely NASH, which might affect the response to immune checkpoint inhibitors. In addition, antidrug-antibody and gene expression assays have demonstrated promises in predicting the response to immune checkpoint inhibitors. In this article, we will provide an overview of the use of ICI in the management of advanced HCC, review the evidence that surrounds the recent controversy regarding NASH-HCC, and discuss potential biomarkers that predict the response to immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
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