We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. In the discovery cohort, clinical benefit 6 months (CB_6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB_6m than in those with CB_6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8⁺ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8⁺ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Park BS, et al. J Clin Neurol. 2020 Jul;16(3):390-400. https://doi.org/10.3988/jcn.2020.16.3.390

Liposomal irinotecan (nal-IRI) combined with fluorouracil (5-FU)/leucovorin (LV) as a second-line treatment for biliary tract cancer (BTC) following progression on gemcitabine-based therapy in the Korean NIFTY and German NALIRICC trials yielded conflicting outcomes. This necessitated a comprehensive pooled analysis to evaluate its efficacy and safety. Individual patient data were pooled from the intention-to-treat populations of the NIFTY and NALIRICC trials. The primary endpoint was progression-free survival (PFS). A total of 278 patients were included: 137 in the nal-IRI plus 5-FU/LV group and 141 in the 5-FU/LV group. The nal-IRI plus 5-FU/LV group showed significantly longer median PFS (3.6 months [95% confidence interval [CI], 2.7-4.4] vs 1.8 months (95% CI, 1.5-2.6), hazard ratio [HR) 0.65, p<0.001). Median overall survival was 8.1 months (95% CI, 6.0-8.9) and 6.1 months (95% CI, 5.3-7.5), respectively (HR 0.77, p=0.051). Overall response rates (ORR) was also higher in the nal-IRI plus 5-FU/LV group (17.5% vs 2.8%; p<0.001) than in the 5-FU/LV group. Post-study irinotecan-containing therapy was administered in 4 (2.9%) and 21 (15.3%) patients in the nal-IRI plus 5-FU/LV group and 5-FU/LV group, respectively. Adverse events varied by ethnicity, with gastrointestinal toxicities more common in Germans and neutropenia more prevalent in Koreans; treatment discontinuation without disease progression was 31.3% vs 8.0%, respectively. The addition of nal-IRI to 5-FU/LV significantly improved PFS and ORR, supporting its potential as subsequent-line therapy. Differences in safety profiles underscore the relevance of ethnicity for nal-IRI in patients with BTC. Current standard of care for second-line therapy in patients with advanced biliary tract cancer (BTC) is FOLFOX. This study provides robust evidence supporting the potential role of additional liposomal irinotecan (nal-IRI) to fluorouracil and leucovorin (5-FU/LV) as a subsequent therapy for patients with BTC who have progressed on gemcitabine-based regimens. The findings demonstrate significant improvements in progression-free survival and overall response rates, emphasizing its potential to address the limited treatment options in this patient population. Furthermore, the study underscores the necessity of considering ethnic differences in adverse event profiles to optimize treatment administration and patient outcomes. NCT03524508 and NCT03043547.

Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110α isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti-neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4⁺, CD8⁺, and IFN-γ⁺CD8⁺ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-γ levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu−) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110α-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer.

Acute exacerbation of interstitial lung disease (AE-ILD) causes clinically significant deterioration and has an extremely poor prognosis with high mortality. Recently, several studies reported the effectiveness of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) in patients with AE-ILD as a potential therapy. This study describes the clinical effectiveness and safety of PMX-DHP in patients with AE-ILD. We retrospectively reviewed the medical records of 10 patients (11 episodes) with AE-ILD treated with PMX-DHP from January 2018 to June 2019. We compared laboratory and physiologic data of the ratio of partial pressure arterial oxygen to fraction of inspired oxygen (P/F ratio) and level of inflammatory markers before and after implementation of PMX-DHP. Ten patients were included according to the 2016 revised definition of acute exacerbation of idiopathic pulmonary fibrosis (IPF). Nine patients had IPF and one patient had fibrotic nonspecific interstitial pneumonia. Most patients (90.9%) were treated with a steroid pulse, and four patients (36.4%) were treated with an immunosuppressant. The median number of PMX-DHP cycles was 2, and the median duration of each cycle was 6 hours. After PMX-DHP, the mean P/F ratio improved (86 [range, 63–106] vs. 145 [86–260], P=0.030) and interleukin-6 and c-reactive protein decreased (79 [35–640] vs. 10 [5–25], P=0.018 and 14 [4–21] vs. 5 [2–6], P=0.019, respectively). The 30-day mortality rate was 27.3% and the 90-day mortality rate was 72.7%. PMX-DHP treatment improved P/F ratio and reduced inflammatory markers in AE-ILD patients.