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Response Prediction in Immune Checkpoint Inhibitor Immunotherapy for Advanced Hepatocellular Carcinoma.

ABSTRACT: Immune checkpoint inhibitors (ICI) have been applied to treat advanced stage hepatocellular carcinoma (HCC) and obtain promising effects. However, tumor response to treatment was unpredictable. A predicting biomarker of objective response or disease-control is an unmet need for patient selection. In this study, 45 advanced HCC patients who failed to sorafenib treatment and received nivolumab, 3 mg/kg bi-weekly, were included. Tumor responses to nivolumab treatment were assessed by the modified response evaluation criteria in solid tumors (mRECIST) criteria. Tumor responses were correlated to clinical characteristics to find out response predictors. In this small series, the prevalence of extrahepatic nodal metastasis, distant metastasis, and portal vein thrombus among the patients were 22.2% (n = 10), 48.9% (n = 22), and 42.2% (n = 19), respectively. The pre-treatment tumor size was 7.2 ± 4.2 cm in maximal diameter, and the calculated total tumor volume was 619.0 ± 831.1 cm³. Among 45 patients, 3 patients had partial response (PR), 11 had stable disease (SD), and the other 31 had progression of disease. By correlating clinical data to the patients with PR and SD, serum neutrophil-to-lymphocyte ratio (NLR) (hazard ratio (HR) = 2.04) and patient-generated subjective global assessment (PG-SGA) score (HR = 2.30) were the independent factors in multivariate analysis. By receiver operating characteristic curve analysis, pre-treatment NLR ≤ 2.5 and PG-SGA score < 4 were the cutoff points to predict tumor response to ICI treatment. In conclusion, biomarkers to predict tumor response for HCC are still lacking in this costly ICI therapy. In this study, NLR ≤ 2.5 and PG-SGA score < 4 indicated disease-control, and can be applied as biomarkers to select the right patients to receive this costly therapy.

SUBMITTER: Hung HC

PROVIDER: S-EPMC8036568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.

Project description:Immune checkpoint genes (ICGs), the foundation of immunotherapy, are involved in the incidence and progression of hepatocellular carcinoma (HCC). Cuproptosis is characterized by copper-induced cell death, and this novel cell death pathway has piqued the interest of researchers in recent years. It is worth noting that there is little information available in the literature to determine the relationship between cuproptosis and anti-tumor immunity. We identified 39 cuproptosis-related ICGs using ICGs co-expressed with cuproptosis-related genes. A prognostic risk signature was constructed using the Cox regression and the least absolute shrinkage and selection operator analysis methods. The signature was built using the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma database. The TCGA and International Cancer Genome Consortium cohorts were classified into two groups; the low- and high-risk groups were determined using a prognostic signature comprised of five genes. The multivariate Cox regression analysis revealed that the signature could independently predict overall survival. Furthermore, the level of immune infiltration analysis revealed the robustness of the prognostic signature-immune cell infiltration relationship observed for Tregs, macrophages, helper T cells, and naive B cells. Both groups showed significant differences in immune checkpoint expression levels. The gene enrichment analysis was used for characterization, and the results revealed that enriching various pathways such as PI3K-AKT-mTOR signaling, glycolysis, Wnt/beta-catenin signaling, and unfolded protein response could potentially influence the prognosis of patients with HCC and the level of immune infiltration. The sensitivity of the two groups of patients to various drug-targeted therapy methods and immunotherapy was analyzed. In conclusion, the findings presented here lay the foundation for developing individualized treatment methods for HCC patients. The findings also revealed that studying the cuproptosis-based pathway can aid in the prognosis of HCC patients. It is also possible that cuproptosis contributes to developing anti-tumor immunity in patients.

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Response Prediction in Immune Checkpoint Inhibitor Immunotherapy for Advanced Hepatocellular Carcinoma.

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