Improving the Efficacy of Liver Cancer Immunotherapy: The Power of Combined Preclinical and Clinical Studies

Abstract

Hepatocellular carcinoma (HCC) is a most deadly malignant disease worldwide, with no effective mechanism‐based therapy available. Therefore, following the “miracle” outcomes seen in a few patients at the advanced stages of melanoma or lung cancer, the immune checkpoint inhibitors (ICIs) immediately entered clinical trials for advanced HCC patients without pre‐clinical studies. Emerging data of clinical studies showed manageable toxicity and safety but limited therapeutic benefit to HCC patients, suggesting low response rate. Thus, one urgent issue is how to convert the liver tumors from cold to hot and responsive, which may rely on in‐depth mechanistic studies in animal models and large scale data analysis in human patients. One ongoing approach is to design combinatorial treatment of different ICIs with other reagents and modalities. Indeed, a phase 3 clinical trial showed that combination of atezolizumab and bevacizumab achieved better overall and progression‐free survival rates than sorafenib in unresectable HCC. This review highlights the value of animal models and the power of combining pre‐clinical and clinical studies in efforts to improve HCC immunotherapy.

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

“…In a recent study, it was reported that in contrast to lung cancer and melanoma, HCC presented a low response rate to immune checkpoint inhibitors (Feng et al, 2020), indicating the complexity in the application of HCC immunotherapy. Because HCC occurs almost exclusively in the context of chronic inflammation (Ringelhan et al, 2018), further understanding of the associations of immune response would provide new clues for HCC diagnosis and therapy.…”

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

“…Although this is in line with results found in many other cancers, it is surprising for HCC since the liver plays a central role in human immune regulation via the complex interaction of sinusoidal endothelial cells and resident macrophages (Kupffer cells) with NK cells and different CD4+/CD8+ T cell subsets and many HCCs develop on the basis of an underlying chronic inflammatory process [62,63]. As recently discussed elsewhere, the main issue to overcome the limitations of immunotherapy (alone or in combination) is to include the specific immunogenicity of tumor cells in relation to immune escape mechanisms in HCC [60].…”

“…Under these circumstances, the clinical efficacy of immune modulation via checkpoint inhibitors is essentially influenced by the baseline immune response and by triggering pre-existing immunity, leading to the concept of “hot” and “cold” tumors on the basis of level and spatial distribution of CD3+ and CD8+ T cell infiltration into the tumor [ 58 , 59 ]. The already mentioned response rate of e.g., atezolizumab and bevacizumab in HCC is mostly comparable to a rate of “hot” HCC of about 20–30% [ 60 , 61 ]. Although this is in line with results found in many other cancers, it is surprising for HCC since the liver plays a central role in human immune regulation via the complex interaction of sinusoidal endothelial cells and resident macrophages (Kupffer cells) with NK cells and different CD4+/CD8+ T cell subsets and many HCCs develop on the basis of an underlying chronic inflammatory process [ 62 , 63 ].…”

“…Although this is in line with results found in many other cancers, it is surprising for HCC since the liver plays a central role in human immune regulation via the complex interaction of sinusoidal endothelial cells and resident macrophages (Kupffer cells) with NK cells and different CD4+/CD8+ T cell subsets and many HCCs develop on the basis of an underlying chronic inflammatory process [ 62 , 63 ]. As recently discussed elsewhere, the main issue to overcome the limitations of immunotherapy (alone or in combination) is to include the specific immunogenicity of tumor cells in relation to immune escape mechanisms in HCC [ 60 ]. Possible new treatment strategies for “cold” HCC could be based on intensive immune priming (e.g., vaccines, adoptive cell therapy or oncolytic approaches) and modulation (e.g., classical radiotherapy, chemotherapy and targeted therapy) to essentially enhance response to checkpoint inhibitors [ 58 ] as also addressed in the following sections.…”

Identifying Potential Prognostic Biomarkers Associated With Clinicopathologic Characteristics of Hepatocellular Carcinoma by Bioinformatics Analysis

“…Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the clinical setting, which represents the second highest cause of cancer-related deaths worldwide [1,2]. Nowadays HCC was still associated with enormous mortality and morbidity that cause large burden to the society [3,4].…”