Combination therapies for advanced hepatocellular carcinoma: a beacon of light or a castle in the air.
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ABSTRACT:
SUBMITTER: Rai V
PROVIDER: S-EPMC9396096 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
Publications
Combination therapies for advanced hepatocellular carcinoma: a beacon of light or a castle in the air.
Rai Vikrant V Mukherjee Sandeep S
Hepatobiliary surgery and nutrition 20220801 4
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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.
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Project description:One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.
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Project description:BackgroundPrognosis is very poor for advanced HCC patients partially due to lack of effective systemic treatment. Sorafenib was the only approved agent for advanced HCC since 2007 until recent breakthroughs. In this article, we will review the newer approved and promising agents in the treatment of advanced HCC in the first line setting and beyond progression.Main bodyThe Food and Drug Administration approved sorafenib as it demonstrated 3 months overall survival benefit compared to placebo in the first line setting over 10 years ago. Multiple single agent and combination therapies have been studied but failed to show benefit. Chemotherapy has limited role in patients with advanced HCC given poor hepatic reserve due to underlying cirrhosis. A new era of treatment for advanced HCC arrived recently with exciting data presented for lenvatinib, regorafenib, cabozantinib, nivolumab, ramucirumab and several other promising clinical trials.ConclusionAdvanced HCC patients are difficult to treat with poor outcomes. After initial approval of sorafenib in 2007, we recently have multiple new agents that showed benefit and promising activity, and are set to change the landscape of HCC treatment.
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Project description:Hepatocellular carcinoma (HCC) is a significant cause of death worldwide. HCC is a highly vascular tumor, and proangiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor may play crucial roles in this disease. Sorafenib, a multikinase inhibitor that blocks VEGF and PDGF signaling, was the first systemic therapy to demonstrate improved survival in patients with advanced HCC. Several other drugs targeting VEGF are in development. Because of the anticipation of eventual resistance to anti-VEGF therapies, drugs that also target alternative proangiogenic pathways are being investigated. Recent clinical and preclinical data along with ongoing studies are reviewed.
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Project description:Hepatocellular carcinoma (HCC) is the most common liver cancer with high morbidity and mortality worldwide. Systemic treatments with several multi-targeted tyrosine kinase inhibitors (TKIs), including sorafenib, lenvatinib, regorafenib and cabozantinib, have been widely utilized int the treatment of HCC. However, with tolerable adverse events and relative low survival time, neo or optimized therapies for advanced HCC are still urgently needed. New developed immune checkpoint inhibitors therapy have been first demonstrated effective in metastatic melanoma through against CTLA-4 or PD-1/PD-L1 to renew T cell effector function. Preclinical data indicated that interference with immune checkpoint molecules results in HCC growth suppression, suggesting it may bring hope to the HCC treatment. Several clinical trials applying monoclonal antibodies to immune checkpoint molecules demonstrated that immune checkpoint inhibitors are safe and enable durable antitumor activity in advanced HCC patients. Several published immunotherapy trials in HCC using Anti-CTLA-4 agents (tremelimumab) or anit-PD-1 agents (Nivolumab) have showed promising results, in which have similar response rate (15%-30%) and disease control rate with TKIs therapies. This article will review the on-going clinical trials associated with immune checkpoint molecules monotherapy or co, and then discuss the optimal scheme of immune checkpoint therapy for advanced HCC.
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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.
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Project description:Purpose of reviewThis paper aims to summarize the data of recently completed and key ongoing clinical trials of systemic agents for advanced hepatocellular carcinoma (aHCC). In particular, the review focuses on ongoing checkpoint inhibitor combination trials and promising studies combining tyrosine kinase inhibitors with checkpoint inhibitors.Recent findingsThe recently approved combination of atezolizumab and bevacizumab based on the IMbrave150 trial has shown the most potential with the highest overall survival of any systemic agent in HCC to date, surpassing sorafenib. Despite COVID-19 delays, other promising trials that involve combining VEGF-directed therapy and checkpoint inhibition, cancer vaccines, phosphatidylserine, YIV-906, and oncolytic and immunotherapeutic vaccinia virus are actively recruiting patients.SummaryAfter almost a 10-year dormancy, the list of potential systemic treatment options for aHCC is growing rapidly. Given the promising data from the IMbrave150 trial, the combination of atezolizumab and bevacizumab is now the new first-line therapy. We discuss the change in landscape, the new second- and third-line systemic treatments in aHCC, and the ongoing clinical trials for newer agents including combination therapies.
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Project description: Not available
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Project description: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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Project description:ImportanceCombination therapies of anti-PD-1 and anti-angiogenesis regimens are emerging rapidly and exhibit more promising anti-tumor efficacy for advanced hepatocellular carcinoma (HCC), and consistently it is the hotspot in clinical studies.ObjectiveTo elaborate several issues which are warranted further consideration as more regimens are being investigated in combination therapies.Evidence reviewWe searched PubMed, MEDLINE, Cochrane Library and Google Scholar by 2021 February for publications on combination therapies for HCC.FindingsSeveral clinical issues are worth reconsidering, such as the evaluation on appropriate primary endpoints in phase III clinical trials as for different practical problems, the translation of surrogate endpoint objective response rate (ORR) benefits into overall survival (OS) benefits, and whether conversion surgery contributes to initial expectations of long-term survival or not. New concepts in novel immunotherapy and targeted therapy in combination with loco-regional therapies may improve overall survival for HCC.Conclusions and relevance for reviewsComprehensive understanding of the mechanism of immunotherapy and targeted therapy contributes to better prognosis of advanced HCC and more explorative combination therapies are needed.
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