Preclinical and clinical therapeutic strategies affecting tumor-associated macrophages in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted

NOX1 inhibition attenuates the development of a pro‐tumorigenic environment in experimental hepatocellular carcinoma

BackgroundThe poor prognosis of advanced HCC and limited efficacy of current systemic treatments emphasize the need for new or combined targeted therapies. The development of HCC is a multistage process in which liver injury appears in a complex microenvironment associated with oxidative stress. NOX enzymes are the main source of ROS during hepatocarcinogenesis and NOX1 in particular has shown correlation with poor prognosis of HCC patients. This study evaluates the effect of pharmacological NOX1 inhibition on the development and progression of HCC and its effect on the tumor microenvironment.MethodsThe in vitro cytotoxic effects of the NOX1 inhibitor GKT771 (Genkyotex) on human Huh7 and Hep3B and murine Hepa1-6 HCC cell lines, the human THP1 monocyte cell line and mouse macrophages were evaluated via MTT, LDH activity and CaspGlo (R) assays. In order to induce in vivo HCC, male SV129 wild-type mice received weekly IP injections of diethylnitrosamine (DEN) (35 mg/kg) for 20-25 weeks. Mice were treated with vehicle or GKT771 (30 mg/kg) via oral gavage, daily or twice daily, in preventive and therapeutic studies. The liver damage was evaluated for inflammation, angiogenesis, fibrosis and HCC development via histology, RT-qPCR, multiplex analyses and ROS levels.ResultsA concentration-dependent reduction in cellular activity of the human HCC cell lines without cytotoxicity was observed. GKT771 treatment reduced LPS-induced pro-inflammatory bone-marrow derived macrophage polarization. DEN injections resulted in 100% tumor formation and the induction of HCC markers which could be reduced by twice daily dosing of GKT771 at early onset of advanced HCC. DEN-induced HCC resulted in an upregulation of pro-inflammatory, angiogenic and fibrotic markers which was less pronounced in GKT771 treated mice in all treatment regimens. In line, liver fibrosis was induced in HCC mice and this to a lesser extend upon GKT771 treatment.ConclusionsNOX1 inhibition showed to be safe and well tolerated and was able to attenuate the induction of a pro-inflammatory, angiogenic and pro-fibrotic microenvironment suggesting that this might be a promising adjuvant therapeutic strategy in the treatment of advanced HCC

Local control of hepatocellular carcinoma and colorectal liver metastases after surgical microwave ablation without concomitant hepatectomy

Purpose Microwave ablation (MWA) is an accepted technique in the multimodal treatment of hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). Study endpoints were to evaluate the local efficacy of surgical MWA in selected patients with oligonodular disease without the combination of liver resection to allow a clear interpretation of the follow-up imaging and compare it to the results on percutaneous MWA available in the literature. Methods Consecutive MWA-only procedures performed between May 2013 and May 2018 for HCC and CRLM with free-hand ultrasound guidance were identified. MWA systems with 2450 MHz were used. Incomplete ablation (IA) was defined as residual disease within 1 cm of the ablation site at the first post-ablation imaging and local recurrence (LR) as the presence of disease after at least one tumor-free imaging. Results A total of 70 tumors in 47 patients were treated with 46 laparoscopic and 1 open procedures. Each patient had no more than 3 tumors, and median size of the lesions was 15 mm (IQR: 10-22). After a median follow-up of 26 months (IQR: 12-40), IA rate was 8.6% and LR rate was 29.4%. Multivariable analysis showed that vascular proximity (OR = 3.4; 95% CI = 1.26-9.22; p=0.016) was the only significant predictor of the combined outcome IA or LR. Discussion In the present study, after mostly laparoscopic MWA, LR was higher than the rates available in the literature for percutaneous MWA of HCC but lower than in the limited studies analyzing isolated percutaneous MWA of liver metastases. Future developments may help establish the role of each therapeutic modality per tumor, in order to improve the outcomes

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

Different Models to Predict the Risk of Recurrent Hepatocellular Carcinoma in the Setting of Liver Transplantation

Liver transplantation is the preferred therapeutic option for non-resectable hepatocellular carcinoma in early-stage disease. Taking into account the limited number of donor organs, liver transplantation is restricted to candidates with long-term outcomes comparable to benign indications on the waiting list. Introducing the morphometric Milan criteria as the gold standard for transplant eligibility reduced the recurrence rate. Even with strict patient selection, there is a risk of recurrence of between 8 and 20% in the transplanted liver, and this is of even greater importance when using more expanded criteria and downstaging protocols. Currently, it remains challenging to predict the risk of recurrence and the related prognosis for individual patients. In this review, the recurrence-risk-assessment scores proposed in the literature are discussed. Currently there is no consensus on the optimal model or the implications of risk stratification in clinical practice. The most recent scorings include additional biological markers for tumour behavior, such as alfa-foetoprotein, and the response to locoregional therapies, in addition to the number and diameter of tumoral nodules. The refinement of the prediction of recurrence is important to better inform patients, guide decisions about prioritization and listing and implement individualized surveillance strategies. In the future, this might also provide indications for tailored immunosuppressive therapy or inclusion in trials for adjuvant treatment

Reduction of Lams-Related Adverse Events with Accumulating Experience in a Large-Volume Tertiary Referral Center

Background and aims: Lumen-apposing metal stents (LAMSs) are increasingly used both for on- and off-label indications. We continuously adapt our step-by-step protocol to optimize the safe deployment of LAMSs for the different indications. The aim of this study was to evaluate the impact of this approach over time. Methods: We conducted a single-center study on consecutive patients who underwent LAMS placement for on- and off-label indications between June 2020 and June 2022. Endpoints included technical success, clinical success and adverse event rates. We compared the results with our previously published early experience with LAMSs (N = 61), between March 2018 and May 2020. Results: This cohort consisted of 168 LAMSs in 153 patients. Almost half of them (47.6%) were placed for off-label indications (gastro-enterostomy, temporary access to the excluded stomach in patients with previous gastric bypass, drainage of postsurgical collections, stenting of short refractory gastrointestinal strictures). While the technical and clinical success rates were similar to those in our previously published cohort (97% and 93.5% versus 93.4% and 88.5%, respectively), the adverse event rate dropped from 21.3% to 8.9%. Conclusions: Our results demonstrate the impact of a learning curve in LAMS placement, with a clinically relevant drop in LAMS-related adverse events over time