ABSTRACT
OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Subject(s)
Mice , Animals , Receptors, Tumor Necrosis Factor/physiology , Receptors, OX40 , Membrane Glycoproteins , Ligands , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacologyABSTRACT
Objective:To investigate the clinical impact factors of liver regeneration after hemihepatectomy in patients with hepatocellular carcinoma (HCC).Methods:Patients who underwent hemihepatectomy due to HCC from Sep 2013 to Sep 2018 were included in the study. Liver volumes were calculated by perioperative simulations to analyze the influencing factors of postoperative liver regeneration, and to compare the albumin bilirubin (ABLI) score and the end-stage liver disease (MELD) score at weeks 1, 5, 9, and 13 after operation.Results:A total of 163 patients were included, of which 13 developed postoperative liver failure. The median liver regeneration rates at 1, 5, 9 and 13 weeks after operation were 22.0%, 32.2%, 33.7% and 35.4%, respectively. Multivariate analysis showed that remnant liver volume (RLV) <611.1 cm 3, %RLV and liver cirrhosis were the influencing factors of liver regeneration. ALBI score and MELD score were lower in the low regeneration group compared to the high regeneration group in the first 5 weeks after operation. Conclusion:RLV and cirrhosis are influential factors in postoperative liver regeneration. Liver regeneration proceeded rapidly within 1 week and slowed down until week 5.
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Objective: To explore the correlation between standard remnant liver volume(SRLV) and post-hepatectomy liver failure (PHLF)in patients with hepatocellular carcinoma(HCC)and cirrhotic livers.Methods:In total,181 patients who underwent hemihepa-tectomy in Affiliated Tumor Hospital of Guangxi Medical University from September 2013 to August 2016 were enrolled in the study. Total liver,tumor,remnant liver,and resected liver volumes were measured using the Myrian liver surgical planning system before sur-gery. Intraoperative resected liver volume (including resected normal liver and tumor volumes) were collected using the drainage method.The patients were divided into the PHLF(22 cases)and non-PHLF groups(159 cases)according to whether PHLF occurred based on the"50/50"criteria.The risk factors of PHLF were then explored.The cut-off of SRLV and efficiency of predicting PHLF were analyzed in the subgroup of patients with cirrhotic livers.The grade of liver cirrhosis was retrospectively analyzed using helical comput-ed tomography(CT).Results:Twenty-two of the 181 patients developed PHLF and one died of it.Preoperative total bilirubin levels and SRLV were identified as independent factors for predicting PHLF using a Logistic regression model.In total,102 patients with cirrhotic livers were selected in subgroup analysis based on postoperative cirrhotic pathology.Eighteen patients developed PHLF and one died of PHLF in the subgroup.Using receiver-operating characteristic(ROC)curve analysis,340 mL/m2was the cut-off of SRLV for patients with HCC and cirrhotic livers(area under the curve:0.861,P<0.01;sensitivity and specialty rates were 94.4% and 74.7%,respectively). Eighty-four cases were of grade Ⅰ or Ⅱ cirrhosis,18 cases were of grade Ⅲ cirrhosis,and there were no cases of grade Ⅳ cirrhosis based on retrospective analysis using helical CT.Conclusions:Patients with cirrhotic livers with an anticipated SRLV of≤340 Ml/m2after he-patic resection are at increased risk for PHLF after emihepatectomy.
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Objective:To evaluate the effect of antiviral therapy on HBV reactivation and liver function after liver resection in patients with hepatocellular carcinoma (HCC). Methods:A total of 174 HBV-DNA(?) HCC patients were recruited into two groups:antiviral ther-apy group (66 cases) and control group (108 cases). In the antiviral group, patients were given entecavir dispersible tablet, whereas no antiviral therapies were given in the control group. The HBV reactivation and liver function index rates were statistically analyzed. Re-sults:Rates of HBV reactivation after hepatectomy were 3.0%and 27.8%in the antiviral therapy group and control group, respectively. Multivariate analysis revealed that minor hepatectomy (HR, 4.695;95%CI, 1.257-17.537, P=0.021) and no antiviral therapy (HR, 8.164;95%CI, 1.831-36.397, P=0.006) were independent risk factors for HBV reactivation. The levels of ALT, TBil, ALB, and PT within 7 days af-ter liver resection were similar between the antiviral therapy group and the control group and between the reactivation group and no-reactivation group. However, the ALT and ALB levels were significantly better in the antiviral group compared with that in the control group after 30 days. Conclusion:HBV reactivation can occur after liver resection for HBV-DNA(?) HCC patients. Preoperative antiviral therapy can reduce the risk of HBV reactivation, thus protecting liver function in patients undergoing liver resection.