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Background and Aim: Serum interleukin‐6 (IL‐6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil‐to‐lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL‐6 for the efficacy of Atez + Bev in patients with HCC. Methods: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL‐6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL‐6 levels with treatment efficacy was evaluated. Results: IL‐6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non‐progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression‐free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first‐line therapy. In the multivariate analyses, IL‐6 levels at the initiation of the second course were independent predictive factors for progression‐free and overall survival. Conclusions: Serum levels of IL‐6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)‐targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. Methods: Twenty‐two patients were randomized 1:1 to receive VEGFR‐targeted peptides or placebo. The primary end‐point was the safety assessment of the immunization. The secondary end‐points were evaluation of immunological responses and clinical outcomes. Results: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1‐specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2‐specific CTL response was induced in 10 (83.3%). The median progression‐free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. Conclusions: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide‐specific CTLs in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high‐throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule‐1 (VCAM1), and α‐fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression‐free survival. In addition, "NR‐index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN‐resistant HepG2 cells (HepG2‐SR) and found that sCLU significantly increased in HepG2‐SR cells compared with normal HepG2 cells, and confirmed that HepG2‐SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient‐related transcription factor, sterol regulatory element binding protein 1c (SREBP‐1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2‐SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU‐related NR‐index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU‐overexpressing HCC might be susceptible to mTOR inhibition. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the optimal management of first or later‐line lenvatinib therapy (LEN) for patients with unresectable hepatocellular carcinoma (uHCC), by clarifying the difference of degree between relative dose intensity (RDI) to achieve objective response (OR) and disease control (DC) by aiming at stable disease (SD), taking dose modifications into consideration. Methods: One hundred uHCC patients who received LEN in first‐ or later‐line settings, between April 2018 and December 2020 in our hospital were analyzed retrospectively. The factors associated with overall survival (OS), time to progression (TTP), OR and DC were assessed. The optimal cut‐off values of RDI 4 weeks after initiation of LEN (RDI during cycle 1) and total RDI (RDI during all cycles) to predict achievement of OR and DC by aiming at SD were determined by receiver operator curve analysis. Results: Achievement of OR and SD were favorable factors for OS (HR, 0.080 and 0.20) and TTP (HR, 0.052 and 0.073), with progressive disease defined as the reference. RDI ≥ 0.8 during cycle 1 and RDI ≥ 0.4 during cycle 1 contributed to achievement of OR (odds ratio, 3.28) and DC (odds ratio, 4.85), respectively. Experience of dose interruption was associated with a favorable TTP (HR, 0.58). The therapeutic line of LEN did not contribute to OS, TTP or best response. Conclusions: To achieve OR and SD for a favorable outcome of first‐ or later‐line LEN, high and moderate early‐phase RDI are required, respectively. The degree of RDI during LEN and tolerance need compatible by dose modifications. [ABSTRACT FROM AUTHOR]

Aim: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population., Methods: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders., Results: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis., Conclusions: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome., Clinical Trial Registration: UMIN Clinical Trials Registry with the number UMIN000043798., (© 2024 Japan Society of Hepatology.)

Background & Aims: Relationships of serum C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) levels with hot immune features have been reported in patients with hepatocellular carcinoma (HCC). Therefore, we examined the utility of their levels for predicting the efficacy of atezolizumab plus bevacizumab (Atez/Bev) in patients with HCC., Design: In total, 98 patients with HCC treated with Atez/Bev were enrolled, and their initial responses were evaluated at least once via dynamic computed tomography or magnetic resonance imaging. Serum CCL5 and CXCL10 levels were assessed by enzyme-linked immunosorbent assay before treatment and at the start of the second course of Atez/Bev therapy, and their relationships with treatment efficacy were determined., Results: No analyzed factor was associated with the initial therapeutic response. Among the 56 patients with Barcelona Clinic Liver Cancer (BCLC) stage C, serum CXCL10 levels at the beginning of course two (CXCL10-2c) tended to be higher in responders than in non-responders in the initial evaluation, and its optimal cutoff level of 690 pg/mL could be used to stratify patients regarding overall survival (OS; high vs. low: not reached vs. 17.6 months, p = 0.034) and progression-free survival (high vs. low: 13.6 vs. 5.1 months, p = 0.014). In multivariate analysis, high CXCL10 levels and neutrophil-to-lymphocyte ratios at the start of course two and Child-Pugh stage A at baseline were independent predictive factors of improved OS., Conclusions: Serum CXCL10-2c levels were predictive of Atez/Bev efficacy in patients with BCLC stage C HCC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)