Cancer immuotherapy for hepatocellular carcinoma

Abstract

Most hepatocellular carcinomas (HCCs) arise on a background of chronically inflamed liver, and thus are considered typical immunogenic cancers. Although there have been advances in treatment options for HCC, many patients still struggle with a limited chance of survival requiring further innovative approach. Especially for the advanced HCC, many other molecular targeted therapies had been evaluated without success. Based on the immunological mechanisms thought to be acting during HCC development, the effects of diverse immunomodulatory regimens such as therapeutic vaccination, immune checkpoint inhibitors, and adoptive cellular immunotherapy have been investigated. Notably, many strategies have been developed in adoptive cellular immunotherapy, including dendritic cells, cytotoxic T cells, natural killer cells, cytokine-induced killer (CIK) cells, and genetically engineered T cells. In recent clinical trials, adjuvant CIK cell immunotherapy increased progression free survival after curative treatment of HCC. Most recently, new immunomodulatory agents were introduced for oncological treatment, eventually leading to the clinical breakthrough of checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). To date, very promising published evidence with checkpoint inhibitors in HCC has been reported in the clinical trials with anti-CTLA-4 agent tremelimumab and a large phase II trial with anti-PD-1 agent nivolumab. Further investigations of immuno-oncology potentially popularized the applications of immunotherapy in the various stages of HCCs, and thus immune-based therapies are the promising innovative approach for patients with HCC. Hopefully, the immuno-oncology will bring about a paradigm shift of anti-cancer treatment for HCC.

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

“…Finally, a decrease of ADAM9 mRNA may indicate a candidate who can expect synergistic effects by adding adoptive cell therapy. Adoptive cell therapy composed of NK or CD8+ T cells have shown efficacy in treatment of HCC [3,17,22,[59][60][61]. However, the patient population who had survival benefits was mostly restricted to those with minimal tumor burden after treatments with curative modality [17,22,62].…”

“…Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer associated mortality worldwide [1,2]. Advanced stage HCC accompanied with portal vein invasion, distant metastasis, or lymph node metastasis is hard to treat due to the underlying liver cirrhosis, frequent recurrence, or multiple occurrence [3,4]. Currently, the tyrosine kinase inhibitors (TKI) sorafenib and lenvatinib are the first-line treatments in advanced HCC [5][6][7][8].…”

“…As a leading therapeutic in immunotherapy targeting programmed cell death 1 protein (PD-1), nivolumab demonstrated a 20% objective response rate and a 64% disease control rate in HCC patients who progressed on sorafenib [16]. Adoptive cellular immunotherapy using natural killer (NK) cells, cytokine induced killer (CIK) cells, or dendritic cells have also been studied [3]. Some adoptive cellular immunotherapy treatment modalities exhibited survival benefit in HCC patients [17].…”