Management and Treatment of Hepatocellular Carcinoma with Immunotherapy: A Review of Current and Future Options

Abstract

With mortality rates of liver cancer doubling in the last 20 years, this disease is on the rise and has become the fifth most common cancer in men and the seventh most common cancer in women. Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancers and is a major global health concern. Patients with HCC can be managed curatively with surgical resection or with liver transplantation, if they are diagnosed at an early stage. Unfortunately, most patients with HCC present with advanced stages of the disease and have underlying liver dysfunction, which allows only 15% of patients to be eligible for curative treatment. Several different treatment modalities are available, including locoregional therapy radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, transarterial radio-embolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, molecularly targeted therapies, and immunotherapy. Immunotherapy has recently become a promising method for inhibiting HCC tumor progression, recurrence, and metastasis. The term "Immunotherapy" is a catch-all, encompassing a wide range of applications and targets, including HCC vaccines, adoptive cell therapy, immune checkpoint inhibitors, and use of oncolytic viruses to treat HCC. Immunotherapy in HCC is a relatively safe option for treating patients with advanced disease in the USA who are either unable to receive or failed sorafenib/lenvatinib therapy and thus may offer an additional survival benefit for these patients. The purpose of this review is to elaborate on some of the most recent advancements in immunotherapy.

Keywords: Adoptive; Carcinoma; Hepatocellular; Immunotherapy; Nivolumab.

Fig. 1.. Hepatocellular carcinoma treatment in patients diagnosed with hepatocellular carcinoma.

Modified Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy: The BCLC system recommends pathways for treatment based on prognostic stages. The stage is determined by the number of lesions and their size, evidence of extrahepatic spread/portal invasion, performance status (ps), preserved liver function, and evidence of decompensated liver disease (usually determined by the Child-Pugh classification or the model for end-stage liver disease score). As noted, there are multiple treatment options, including resection, transplantation, chemoembolization, ablation, systemic therapy or best support care, which is essentially palliative care. Survival is predicted based on what initial therapy was chosen.

Fig. 2.. Mechanism of action of checkpoint inhibitors under investigation for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) tumor cells can up-regulate expression of programmed cell death-1, PD-1, which binds the programmed death-ligand 1, PD-L1, and stimulates peripheral T cell depletion. They can also activate cytotoxic T lymphocyte-associated protein-4 (CTLA-4), found on the surface of T cells and leading to down-regulation of T cells. Ipilimumab and tremelimumab bind to and inactivate CTLA-4, preventing its activation. PD-1-PD-L1 binding may be prevented by therapeutically blocking either PD-1 (nivolumab, pembrolizumab, tislelizumab, and camrelizumab) or PD-L1 (durvalumab and atezolizumab).