Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers

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.

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Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies

Genes & Diseases ◽

10.1016/j.gendis.2019.06.006 ◽

2019 ◽

Vol 6 (3) ◽

pp. 232-246 ◽

Cited By ~ 6

Author(s):

Hongxing Shen ◽

Eddy Shih-Hsin Yang ◽

Marty Conry ◽

John Fiveash ◽

Carlo Contreras ◽

...

Keyword(s):

Immune Checkpoint ◽

Predictive Biomarkers ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Combination Therapies

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Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

Hepatic Oncology ◽

10.2217/hep-2020-0004 ◽

2020 ◽

Vol 7 (2) ◽

pp. HEP20

Author(s):

Christoph Roderburg ◽

Burcin Özdirik ◽

Alexander Wree ◽

Münevver Demir ◽

Frank Tacke

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Systemic Treatment ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Predictive Biomarkers ◽

Current Data ◽

Advanced Hepatocellular Carcinoma ◽

Combination Therapies ◽

Current Standard

For almost a decade, systemic therapy of advanced hepatocellular carcinoma (HCC) was limited to the tyrosine kinase inhibitor (TKI) sorafenib. Different agents including checkpoint inhibitors, TKIs and anti-VEGFR antibodies demonstrated efficacy in treatment. For the first time, the combination of atezolizumab and bevacizumab, a first-line treatment that is superior to the current standard was identified, potentially changing the way we treat HCC. In this review, we summarize current data on systemic treatment of patients with advanced HCC, focusing on combination therapies comprising immune checkpoint inhibitors, TKIs and locoregional therapies. We elucidate findings from recent trials and discuss such challenges as the lack of predictive biomarkers for identification of subgroups that will benefit from novel treatment strategies.

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CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02777-4 ◽

2020 ◽

Author(s):

Simon Fietz ◽

Romina Zarbl ◽

Dennis Niebel ◽

Christian Posch ◽

Peter Brossart ◽

...

Keyword(s):

Protein Expression ◽

Promoter Methylation ◽

Single Agent ◽

Stage Iv ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Response To Treatment ◽

Free Survival ◽

Stage Iv Melanoma

AbstractAnti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.

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Immunotherapy in Advanced Biliary Tract Cancers

Cancers ◽

10.3390/cancers13071569 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1569

Author(s):

Alice Boilève ◽

Marc Hilmi ◽

Cristina Smolenschi ◽

Michel Ducreux ◽

Antoine Hollebecque ◽

...

Keyword(s):

Biliary Tract ◽

Immune Checkpoint ◽

Single Agent ◽

Predictive Biomarkers ◽

Immune Checkpoint Blockade ◽

Clinical Activity ◽

Liver Malignancies ◽

Biliary Tract Cancers ◽

Advanced Stages ◽

Molecular Therapies

Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

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Can Combined Therapy Benefit Immune Checkpoint Blockade Response in Hepatocellular Carcinoma?

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666181114112431 ◽

2019 ◽

Vol 19 (2) ◽

pp. 222-228 ◽

Cited By ~ 1

Author(s):

Fan Zhongqi ◽

Sun Xiaodong ◽

Chen Yuguo ◽

Lv Guoyue

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Immune Checkpoint ◽

Combined Therapy ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cancer Resistance ◽

Combination Therapies ◽

Factors Influencing ◽

Early Phase Clinical Trials

Background: Hepatocellular Carcinoma (HCC) is one of the most common cancers with high mortality rate. The effects of most therapies are limited. The Immune Checkpoint Blockade (ICB) improves the prognosis in multiple malignancies. The application of immune checkpoint blockade to hepatocellular carcinoma patients has recently started. Early phase clinical trials have shown some benefits to cancer patients. Methods/Results: This review focuses on the immune system of liver and clinical trials of ICB. In particular, we analyze the mechanisms by which immune checkpoint blockade therapies can be used for the treatment of hepatocellular carcinoma patients, then examine the factors in cancer resistance to the therapies and finally suggest possible combination therapies for the treatment of hepatocellular carcinoma patients. Conclusion: ICB is a promising therapy for advanced HCC patients. Combined therapy exhibits a great potential to enhance ICB response in these patients. The better understanding of the factors influencing the sensitivity of ICB and more clinical trials will consolidate the efficiency and minimize the adverse effects of ICB.

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Combination strategies to maximize the benefits of cancer immunotherapy

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01164-5 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Shaoming Zhu ◽

Tian Zhang ◽

Lei Zheng ◽

Hongtao Liu ◽

Wenru Song ◽

...

Keyword(s):

Adoptive Cell Therapy ◽

Clinical Status ◽

Single Agent ◽

Immune Checkpoint Blockade ◽

Medical Product ◽

Combination Therapies ◽

Secondary Resistance ◽

Therapeutic Modalities ◽

National Medical ◽

Combination Strategies

AbstractImmunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.

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Understanding the Effects of Radiotherapy on the Tumour Immune Microenvironment to Identify Potential Prognostic and Predictive Biomarkers of Radiotherapy Response

Cancers ◽

10.3390/cancers12102835 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2835

Author(s):

Shuhui Cheng ◽

Eleanor J. Cheadle ◽

Timothy M. Illidge

Keyword(s):

Clinical Decision Making ◽

Single Agent ◽

Predictive Biomarkers ◽

Clinical Decision ◽

Tumour Microenvironment ◽

Immune Checkpoint Blockade ◽

Rational Approach ◽

Immunomodulatory Effects ◽

Combination Treatments ◽

Immunological Effects

Radiotherapy (RT) is a highly effective anti-cancer treatment. Immunotherapy using immune checkpoint blockade (ICI) has emerged as a new and robust pillar in cancer therapy; however, the response rate to single agent ICI is low whilst toxicity remains. Radiotherapy has been shown to have local and systemic immunomodulatory effects. Therefore, combining RT and immunotherapy is a rational approach to enhance anti-tumour immune responses. However, the immunomodulatory effects of RT can be both immunostimulatory or immunosuppressive and may be different across different tumour types and patients. Therefore, there is an urgent medical need to establish biomarkers to guide clinical decision making in predicting responses or in patient selection for RT-based combination treatments. In this review, we summarize the immunological effects of RT on the tumour microenvironment and emerging biomarkers to help better understand the implications of these immunological changes, and we provide new insights into the potential for combination therapies with RT and immunotherapy.

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Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2017-315068 ◽

2017 ◽

Vol 67 (2) ◽

pp. 380-388 ◽

Cited By ~ 71

Author(s):

Alexander Gerbes ◽

Fabien Zoulim ◽

Herbert Tilg ◽

Jean-François Dufour ◽

Jordi Bruix ◽

...

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Causes Of Death ◽

Critical Evaluation ◽

Predictive Biomarkers ◽

Phase Iii ◽

Combination Therapies ◽

Novel Drugs ◽

Phase Iii Trials

Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC.

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Impact of Viral Etiologies on the Development of Novel Immunotherapy for Hepatocellular Carcinoma

Seminars in Liver Disease ◽

10.1055/s-0039-3399534 ◽

2019 ◽

Vol 40 (02) ◽

pp. 131-142

Author(s):

Chun Jye Lim ◽

Valerie Chew

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Chronic Hepatitis ◽

Response Rate ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Common Type ◽

Liver Inflammation ◽

Molecular Features ◽

Viral Etiologies

AbstractHepatocellular carcinoma (HCC), is the most common type of liver cancer which is derived mostly from the background of chronic inflammation. Chronic hepatitis viral infection remains one of the most common etiologies implicated in chronic liver inflammation, cirrhosis, and HCC. With such background inflammation, immunotherapy—particularly the checkpoint inhibitors—have been tested in HCC patients with unprecedented success. However, despite the initial enthusiasm, the response rate to immunotherapy remains modest in most clinical trials (approximately 20%), with mixed reports on response rates in hepatitis viral-related HCC as compared with nonviral HCC. Given such complexity in response to immunotherapy, it is increasingly appreciated that deeper understanding of the tumor molecular features and tumor microenvironment of hepatitis viral-related HCC is crucial for the design of more effective immunotherapeutics. We discuss herein the current knowledge in tumor genomic mutational and immune landscapes as well as the ongoing immunotherapy trials in HCC with the unique focus on their viral etiologies. Based on this understanding, we also outline perspectives and rationale on the design of potential immunotherapeutic strategies in HCC patients according to their viral etiologies.

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Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000987 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000987 ◽

Cited By ~ 3

Author(s):

Harry Ho Man Ng ◽

Ren Yuan Lee ◽

Siting Goh ◽

Isabel Shu Ying Tay ◽

Xinru Lim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Response Rates ◽

Immune Checkpoint Blockade ◽

Advanced Hcc ◽

Cytokine Analysis ◽

Macrophage Density ◽

Cell Proportion

IntroductionHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC.MethodsClinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis.ResultsIHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB.ConclusionsA high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.

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