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Cancers
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Immunotherapy in Hepatocellular Carcinoma
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Immunotherapy in Hepatocellular Carcinoma

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 71599

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Naoshi Nishida

E-Mail Website
Guest Editor
Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan
Interests: hepatocellular carcinoma; molecular classification; tumor microenvironment; genome; epigenome; transcriptome; diagnosis; treatment; molecular targeted agent; multikinase inhibitor; immune checkpoint inhibitor; artificial intelligence
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Masatoshi Kudo

grade E-Mail Website
Guest Editor
Department of Gastroenterology and Hepatology, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan
Interests: nodule-in-nodule HCC; Coded phase inversion harmonic; Pure arterial phase imaging; dysplastic nodule; nodule-in-nodule; Sonazoid

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with a high recurrence rate and mortality, especially for patients with advanced stages of the disease. Recent advancements of molecular targeted therapy—such as targeting VEGFR, FGFR, PDGFR, RAF, and MET—have led to improvements in the survival of such patients. However, a variety of genetic and epigenetic changes emerging in HCC cells should result in the acquisition of resistance to molecular targeted therapies.

On the other hand, restoring acquired immunity to HCC should suppress the progression of this type of tumor even in patients who progress on molecular targeted therapies. For example, recent clinical trials showed that immune checkpoint inhibitors are effective regardless of the response to prior therapies, including tyrosine kinase inhibitors, and a durable response was also observed. More importantly, a combination of immune checkpoint inhibitors with molecular targeted therapy, reportedly cause a strong anti-tumor response in HCC. The U.S. Food and Drug Administration granted a breakthrough therapy designation to the atezolizumab (anti-PD-L1 antibody)/bevacizumab (anti-VEGF-A antibody) combination as the first-line treatment for patients with advanced HCC. Although many HCC patients still remain refractory to the monotherapy of immune checkpoint inhibitors, several other trials that target immune suppressive cells and molecules—including stromal cells, humoral mediators, and suppressive checkpoint molecules—are ongoing, suggesting the rapid advancement of immunotherapy in the field of HCC treatment in the near future.

Based on this evidence, a deep understanding of the immunological status and biological targets modulating immunological microenvironments should be quite informative for the development of future immunotherapy in HCC. From this point of view, this Special Issue will highlight the current state of the art in the immunotherapy of HCC from both the basic and clinical perspectives, and outline future perspectives for improving therapies.

Dr. Naoshi Nishida
Prof. Dr. Masatoshi Kudo
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

  • hepatocellular carcinoma
  • immunotherapy
  • immuno-oncology
  • immune checkpoint inhibitors
  • clinical trial

Published Papers (15 papers)

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Research

Jump to: Review

11 pages, 2685 KiB  
Article
Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy
by Ying-Chun Shen, Ching-Ping Yeh, Yung-Ming Jeng, Chiun Hsu, Chih-Hung Hsu, Zhong-Zhe Lin, Yu-Yun Shao, Li-Chun Lu, Tsung-Hao Liu, Chien-Hung Chen and Ann-Lii Cheng
Cancers 2021, 13(20), 5142; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205142 - 14 Oct 2021
Cited by 2 | Viewed by 1969
Abstract
Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with [...] Read more.
Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). Results: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0–92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). Conclusions: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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14 pages, 1915 KiB  
Article
Programmed Death 1 Ligand Expression in the Monocytes of Patients with Hepatocellular Carcinoma Depends on Tumor Progression
by Akira Asai, Hidetaka Yasuoka, Masahiro Matsui, Yusuke Tsuchimoto, Shinya Fukunishi and Kazuhide Higuchi
Cancers 2020, 12(8), 2286; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082286 - 14 Aug 2020
Cited by 5 | Viewed by 1981
Abstract
Monocytes (CD14+ cells) from advanced-stage hepatocellular carcinoma (HCC) patients express programmed death 1 ligand (PD-L)/PD-1 and suppress the host antitumor immune response. However, it is unclear whether cancer progression is associated with CD14+ cells. We compared CD14+ cell properties before [...] Read more.
Monocytes (CD14+ cells) from advanced-stage hepatocellular carcinoma (HCC) patients express programmed death 1 ligand (PD-L)/PD-1 and suppress the host antitumor immune response. However, it is unclear whether cancer progression is associated with CD14+ cells. We compared CD14+ cell properties before and after cancer progression in the same HCC patients and examined their role in antitumor immunity. CD14+ cells were isolated from 15 naïve early-stage HCC patients before treatment initiation and after cancer progression to advanced stages. Although CD14+ cells from patients at early HCC stages exhibited antitumor activity in humanized murine chimera, CD14+ cells from the same patients after progression to advanced stages lacked this activity. Moreover, CD14+ cells from early HCC stages scantly expressed PD-L1 and PD-L2 and produced few cytokines, while CD14+ cells from advanced stages showed increased PD-L expression and produced IL-10 and CCL1. CD14+ cells were also isolated from five naïve advanced-stage HCC patients before treatment as well as after treatment-induced tumor regression. The CD14+ cells from patients with advanced-stage HCC expressed PD-L expressions, produced IL-10 and CCL1, and exhibited minimal tumoricidal activity. After treatment-induced tumor regression, CD14+ cells from the same patients did not express PD-Ls, failed to produce cytokines, and recovered tumoricidal activity. These results indicate that PD-L expression as well as CD14+ cell phenotype depend on the tumor stage in HCC patients. PD-L expressions of monocytes may be used as a new marker in the classification of cancer progression in HCC. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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16 pages, 9163 KiB  
Article
Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization
by Naoshi Odagiri, Hoang Hai, Le Thi Thanh Thuy, Minh Phuong Dong, Maito Suoh, Kohei Kotani, Atsushi Hagihara, Sawako Uchida-Kobayashi, Akihiro Tamori, Masaru Enomoto and Norifumi Kawada
Cancers 2020, 12(8), 2045; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082045 - 24 Jul 2020
Cited by 10 | Viewed by 3459
Abstract
Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC [...] Read more.
Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p < 0.001) were increased at Week 1, while levels of sCD27 (p < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain–3) (p < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain–1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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14 pages, 1054 KiB  
Article
Effectiveness and Safety of Nivolumab in Child–Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study
by Won-Mook Choi, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Changhoon Yoo, Sook Ryun Park, Min-Hee Ryu, Baek-Yeol Ryoo and Jonggi Choi
Cancers 2020, 12(7), 1968; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071968 - 20 Jul 2020
Cited by 39 | Viewed by 3815
Abstract
Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world [...] Read more.
Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; p = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio [AHR], 2.10; p < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; p < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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16 pages, 1779 KiB  
Article
A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy
by Sooyeon Oh, YoungJoon Park, Hyun-Jung Lee, Jooho Lee, Soo-Hyeon Lee, Young-Seok Baek, Su-Kyung Chun, Seung-Min Lee, Mina Kim, Young-Eun Chon, Yeonjung Ha, Yuri Cho, Gi Jin Kim, Seong-Gyu Hwang and KyuBum Kwack
Cancers 2020, 12(3), 745; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030745 - 21 Mar 2020
Cited by 21 | Viewed by 3790
Abstract
The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed [...] Read more.
The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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14 pages, 1777 KiB  
Article
Predictors of Response and Survival in Immune Checkpoint Inhibitor-Treated Unresectable Hepatocellular Carcinoma
by Pei-Chang Lee, Yee Chao, Ming-Huang Chen, Keng-Hsin Lan, Chieh-Ju Lee, I-Cheng Lee, San-Chi Chen, Ming-Chih Hou and Yi-Hsiang Huang
Cancers 2020, 12(1), 182; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010182 - 11 Jan 2020
Cited by 79 | Viewed by 6128
Abstract
Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC [...] Read more.
Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child–Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259, p = 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%, p < 0.001) and disease control rate (81.8% vs. 14.3%, p < 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child–Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child–Pugh class determines survival by ICI treatment. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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21 pages, 7683 KiB  
Article
Etiology-Specific Analysis of Hepatocellular Carcinoma Transcriptome Reveals Genetic Dysregulation in Pathways Implicated in Immunotherapy Efficacy
by Wei Tse Li, Angela E. Zou, Christine O. Honda, Hao Zheng, Xiao Qi Wang, Tatiana Kisseleva, Eric Y. Chang and Weg M. Ongkeko
Cancers 2019, 11(9), 1273; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091273 - 30 Aug 2019
Cited by 9 | Viewed by 3000
Abstract
Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced hepatocellular carcinoma (HCC), but the failure of a large percentage of patients to respond to immunotherapy remains as the ultimate obstacle to successful treatment. Etiology-associated dysregulation of immune-associated (IA) [...] Read more.
Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced hepatocellular carcinoma (HCC), but the failure of a large percentage of patients to respond to immunotherapy remains as the ultimate obstacle to successful treatment. Etiology-associated dysregulation of immune-associated (IA) genes may be central to the development of this differential clinical response. We identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC and validated alcohol-induced dysregulations in vitro while using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA). Thirty-four clinically relevant dysregulated IA genes were identified. We profiled the correlation of all genomic alterations in HCC patients to IA gene expression while using the information theory-based algorithm REVEALER to investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification. We also studied gene expression regulators and identified multiple microRNAs that were implicated in HCC pathogenesis that can potentially regulate these IA genes’ expression. Our study identified potential key pathways, including the IL-7 signaling pathway and TNFRSF4 (OX40)- NF-κB pathway, to target in immunotherapy treatments and presents microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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Review

Jump to: Research

20 pages, 1973 KiB  
Review
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives
by Piera Federico, Angelica Petrillo, Pasqualina Giordano, Davide Bosso, Antonietta Fabbrocini, Margaret Ottaviano, Mario Rosanova, Antonia Silvestri, Andrea Tufo, Antonio Cozzolino and Bruno Daniele
Cancers 2020, 12(10), 3025; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103025 - 18 Oct 2020
Cited by 53 | Viewed by 4519
Abstract
Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 [...] Read more.
Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an “ill-defined” small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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29 pages, 3648 KiB  
Review
Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma
by Sophia Heinrich, Darko Castven, Peter R. Galle and Jens U. Marquardt
Cancers 2020, 12(9), 2495; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092495 - 03 Sep 2020
Cited by 12 | Viewed by 2952
Abstract
Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and [...] Read more.
Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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17 pages, 1452 KiB  
Review
Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma
by Naoshi Nishida and Masatoshi Kudo
Cancers 2020, 12(5), 1274; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051274 - 18 May 2020
Cited by 24 | Viewed by 4422
Abstract
Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers [...] Read more.
Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers to predict outcome and develop novel combination therapies that enhance the efficacy of ICIs. Recently, several attempts have been made to classify HCC based on genome, epigenome, and transcriptome analyses. These molecular classifications are characterized by unique clinical and histological features of HCC, as well immune phenotype. For example, HCCs exhibiting gene expression patterns with proliferation signals and stem cell markers are associated with the enrichment of immune infiltrates in tumors, suggesting immune-proficient characteristics for this type of HCC. However, the presence of activating mutations in β-catenin represents a lack of immune infiltrates and refractoriness to ICIs. Although the precise mechanism that links the immunological phenotype with molecular features remains controversial, it is conceivable that alterations of oncogenic cellular signaling in cancer may lead to the expression of immune-regulatory molecules and result in the acquisition of specific immunological microenvironments for each case of HCC. Therefore, these molecular and immune characteristics should be considered for the management of HCC using immunotherapy. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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12 pages, 2906 KiB  
Review
Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma
by Masatoshi Kudo
Cancers 2020, 12(5), 1089; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051089 - 27 Apr 2020
Cited by 119 | Viewed by 10125
Abstract
A successful phase III trial for the combination of atezolizumab and bevacizumab (the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been reported. This is groundbreaking because nivolumab and pembrolizumab, both programmed cell death-1 (PD-1) antibodies, have failed to show efficacy as first- [...] Read more.
A successful phase III trial for the combination of atezolizumab and bevacizumab (the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been reported. This is groundbreaking because nivolumab and pembrolizumab, both programmed cell death-1 (PD-1) antibodies, have failed to show efficacy as first- and second-line therapeutics, respectively, in phase III clinical trials. Immunotherapy with a combination of atezolizumab and bevacizumab resulted in better survival than treatment with sorafenib for the first time since sorafenib was approved in 2007. The high efficacy of the combination of PD-1/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) antibodies is not only due to their additive effects on tumor growth, but also to their reprogramming of the immunosuppressive microenvironment into an immunostimulatory microenvironment. These results were confirmed in a phase Ib trial that showed significantly longer progression-free survival in the atezolizumab plus bevacizumab group than in patients that received atezolizumab alone. These results demonstrate that immunotherapy with a combination of PD-1/PD-L1 and VEGF inhibitors is effective and may result in a reprogramming of the tumor microenvironment. The results of an ongoing phase III trial of a PD-1 antibody in combination with the VEGF receptor tyrosine kinase inhibitor (TKI) are highly anticipated. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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15 pages, 293 KiB  
Review
Recent Advances in Immunotherapy for Hepatocellular Carcinoma
by Shigeharu Nakano, Yuji Eso, Hirokazu Okada, Atsushi Takai, Ken Takahashi and Hiroshi Seno
Cancers 2020, 12(4), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040775 - 25 Mar 2020
Cited by 60 | Viewed by 6258
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
27 pages, 1049 KiB  
Review
Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers
by David Tai, Su Pin Choo and Valerie Chew
Cancers 2019, 11(12), 1926; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121926 - 03 Dec 2019
Cited by 27 | Viewed by 6360
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly with immune checkpoint blockade (ICB). Despite the initial enthusiasm, treatment [...] Read more.
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is derived mostly from a background of chronic inflammation. Multiple immunotherapeutic strategies have been evaluated in HCC, with some degree of success, particularly with immune checkpoint blockade (ICB). Despite the initial enthusiasm, treatment benefit is only appreciated in a modest proportion of patients (response rate to single agent ~20%). Therapy-induced immune-related adverse events (irAEs) and economic impact are pertinent considerations with ICB. It is imperative that a deeper understanding of its mechanisms of action either as monotherapy or in combination with other therapeutic agents is needed. We herein discuss the latest developments in the immunotherapeutic approaches for HCC, the potential predictive biomarkers and the rationale for combination therapies. We also outline promising future immunotherapeutic strategies for HCC patients. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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22 pages, 2551 KiB  
Review
Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice
by Edoardo G. Giannini, Andrea Aglitti, Mauro Borzio, Martina Gambato, Maria Guarino, Massimo Iavarone, Quirino Lai, Giovanni Battista Levi Sandri, Fabio Melandro, Filomena Morisco, Francesca Romana Ponziani, Maria Rendina, Francesco Paolo Russo, Rodolfo Sacco, Mauro Viganò, Alessandro Vitale, Franco Trevisani and on behalf of the Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest Group
Cancers 2019, 11(11), 1689; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111689 - 30 Oct 2019
Cited by 40 | Viewed by 5033
Abstract
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of [...] Read more.
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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14 pages, 664 KiB  
Review
Predictive Factors for Response to PD-1/PD-L1 Checkpoint Inhibition in the Field of Hepatocellular Carcinoma: Current Status and Challenges
by Zuzana Macek Jilkova, Caroline Aspord and Thomas Decaens
Cancers 2019, 11(10), 1554; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101554 - 14 Oct 2019
Cited by 76 | Viewed by 6610
Abstract
Immunotherapies targeting immune checkpoints are fast-developing therapeutic approaches adopted for several tumor types that trigger unprecedented rates of durable clinical responses. Immune checkpoint programmed cell death protein 1 (PD-1), expressed primarily by T cells, and programmed cell death ligand 1 (PD-L1), expressed mainly [...] Read more.
Immunotherapies targeting immune checkpoints are fast-developing therapeutic approaches adopted for several tumor types that trigger unprecedented rates of durable clinical responses. Immune checkpoint programmed cell death protein 1 (PD-1), expressed primarily by T cells, and programmed cell death ligand 1 (PD-L1), expressed mainly by tumor cells, macrophages, and dendritic cells, are molecules that impede immune function, thereby allowing tumor cells to proliferate, grow and spread. PD-1/PD-L1 checkpoint inhibitors have emerged as a promising treatment strategy of hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from this therapy. To find a niche for immune checkpoint inhibition in HCC patients, future strategies might require predictive factor-based patient selection, to identify patients who are likely to respond to the said therapy and combination strategies in order to enhance anti-tumor efficacy and clinical success. This review provides an overview of the most recent data pertaining to predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of HCC. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
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