Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance

Abstract

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies.

Monoclonal Antibody Development for Cancer Treatment Using the Phage Display Library Platform

“…For instance, the triple therapy combining the PD-L1 inhibitor atezolizumab with the BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib has gained approval as a first-line treatment for advanced melanoma patients with BRAFV600 mutations [65]. Building on the success of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) has become the standard frontline treatment for patients with advanced-stage hepatocellular carcinoma (HCC) [66]. In the IMpassion031 trial, the combination of atezolizumab and nab-paclitaxel exhibited increased overall survival compared to placebo plus nab-paclitaxel in early triple-negative breast cancer (TNBC) patients, irrespective of the PD-L1 status [67].…”

Advances in Immunotherapy for Hepatocellular Carcinoma (HCC)

“…Most recently, a preclinical study of CCX559, a PD-L1 small-molecule inhibitor, was shown to achieve reversible PD-L1 internalization, activation of T cells, and anti-tumor activity in murine models [85,86]. An ongoing phase I study with single-agent CCX559 in solid tumors reported on-target pharmacokinetic effects suggesting PD-L1 inhibition [87].…”

Neutrophil-to-Lymphocyte Ratio and Early Tumor Shrinkage as Predictive Biomarkers in Unresectable Hepatocellular Carcinoma Patients Treated With Lenvatinib, PD-1 Inhibitors, in Combination With TACE

“…Immunotherapy-based combination therapy has greatly improved the therapeutic approaches for hepatocellular carcinoma (HCC) and demonstrating promising antitumor efficacy in recent years. 1 – 3 Combination of atezolizumab and bevacizumab showed a higher objective response rate (ORR) and better survival compared to sorafenib in patients with unresectable HCC (uHCC), 4 and the encouraging outcomes also was obtained in the KEYNOTE 524 study. 5 Transcatheter arterial chemoembolization (TACE) into systemic combination therapy may improve antitumor activity even further.…”