Targeted and Immune-Based Therapies for Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Greten TF
PROVIDER: S-EPMC6340758 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
| S-EPMC7190571 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.
| S-EPMC10493094 | biostudies-literature
Project description:Unlike most solid tumors, the incidence and mortality of hepatocellular carcinoma (HCC) have increased in the United States and Europe in the past decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has shown clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers have indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene addictions are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (eg, erlotinib) or compared with (eg, linifanib) sorafenib as a first-line therapy. For patients who do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (eg, ramucirumab) are being tested as second-line therapies. There are early stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate tumor progression, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost benefit.
| S-EPMC3682501 | biostudies-literature
Project description:Treatment of advanced hepatocellular carcinoma (HCC) still confronts great challenges due to high rate of therapeutic resistance. The emergence of systemic treatment with molecular targeted and immune checkpoint therapies has brought novel approaches towards patients with advanced HCC. However, sorafenib, as the first approved systemic treatment in 2007, only increased overall survival by three months in advanced HCC patients. Afterwards, little progress has been made for molecular targeted agents. Only four molecular drugs are empirically used in clinical practice. Lenvatinib acts as a first-line drug, whereas regorafenib, ramucirumab, and cabozantinib are defined as second-line drugs. Nevertheless, clinical findings reveal that overall survival remains unchanged. Albeit immunotherapy-based approaches are currently considered promising therapeutic strategies for advanced HCC, a minority of patients could benefit from them. These beneficiaries are to be accordingly identified. Combined immunotherapies with matched molecular targeted treatments would be a novel breakthrough. Herein, we summarize the current statuses of immunotherapies and molecular targeted drug therapies, and mainly identify clinically feasible chemoimmunotherapeutic strategies.
| S-EPMC7269783 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC.
| S-EPMC6780754 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common liver cancer and the third leading cause of cancer death. It has been a major worldwide health problem with more new cases being diagnosed each year. The current available therapies for patients with advanced HCC are extremely limited. Therefore, it is of great clinical interests to develop more effective therapies for systemic treatment of advanced HCC. Several promising target-based drugs have been tested in a number of clinical trials. One breakthrough of these efforts is the approved clinical use of sorafenib in patients with advanced HCC. Targeted therapies are becoming an attractive option for the treatment of advanced HCC. In this review, we summarize the most recent progress in clinical targeted treatments of advanced HCC.
| S-EPMC3667684 | biostudies-literature
Project description:Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.
| S-EPMC8150670 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is an aggressive neoplastic disease that has been rapidly increasing in incidence. It usually occurs in the background of liver disease, and cirrhosis. Definitive therapy requires surgical resection. However, in majority of cases surgical resection is not tolerated, especially in the presence of portal hypertension and cirrhosis. Orthotopic liver transplant (OLT) in well selected candidates has been accepted as a viable option. Due to a relative scarcity of donors compared to the number of listed recipients, long waiting times are anticipated. To prevent patients with HCC from dropping out from the transplant list due to progression of their disease, most centers utilize loco-regional therapies. These loco-regional therapies(LRT) include minimally invasive treatments like percutaneous thermal ablation, trans-arterial chemoembolization, trans-arterial radio-embolization or a combination thereof. The type of therapy or combination used is determined by the size and location of the HCC and Barcelona Clinic Liver Cancer (BCLC) classification. The data regarding the efficacy of LRT in reducing post-transplant recurrence or disease-free survival is limited. This article reviews the available therapies, their strengths, limitations, and current use in the management of patients with hepatocellular carcinoma awaiting transplant.
| S-EPMC5958916 | biostudies-other
Project description:BackgroundHepatocellular carcinoma (HCC) is an aggressive cancer with a high rate of death globally. The use of bioinformatics may help to identify immune cell-related genes both as targets for potential immunotherapies and for their value associated with predicting therapy responses.MethodsIn this study, mRNA expression profiles of HCC samples from The Cancer Genome Atlas (TCGA) database were subjected to gene enrichment, cell type abundance, immune cell infiltration, and pathway enrichment analyses to determine immune cell gene features, cell type abundance, and functional annotation characteristics. We also evaluated their prognostic values using Cox regression and Kaplan-Meier analyses and assessed potential responses to chemotherapy. Four subgroups (Groups 1-4) were identified. Group 4 was associated with advanced clinical characteristics, high immune cell enrichment scores, and the poorest outcomes.ResultsDifferentially expressed genes (DEGs) in the HCC samples were enriched in the following pathways: antigen binding, cell surface receptor signal transduction of the immune response, and cell surface activated receptor signal transduction of the immune response. Highly expressed genes in Group 4 were enriched in elements of the WNT signalling pathway. We identified five immune-related genes (SEMA3A, TNFRSF11B, GUCA2A, SAA1, and CALCR) that were significantly related to HCC prognosis. A prognostic model based on these five genes exhibited good predictive value, with 1-year and 5-year area under the curve (AUC) values of > 0.66. Group 4 was also potentially more sensitive to EHT 1864, FH535, and lapatinib chemotherapies than the other groups.ConclusionsWe identified and validated four HCC subgroups based on immune system-related genes and identified five genes that may be used for an immune-based prognostic model for HCC treatment.
| S-EPMC8422634 | biostudies-literature
Project description:PurposePrior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.Experimental designMatched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.ResultsWNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics.ConclusionsLinking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.See related commentary by Pinyol et al., p. 2021.
| S-EPMC6689131 | biostudies-literature