Background: Tumor necrosis factor alpha (TNFα) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFα has been undermined by the induced-NF-κB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFα though the regulation of NF-κB activation. Results: In this study, we demonstrate that MA significantly enhanced TNFα-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFα-induced cell apoptosis by suppressing TNFα-induced NF-κB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFα-induced IκBα degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-κB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-κB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl. Conclusions: Our data demonstrate that MA can potentiate the anti-tumor activities of TNFα and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and its downstream gene expression. Therefore, MA together with TNFα could be new promising agents in the treatment of pancreatic cancer.

Purpose: This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti–programmed death ligand 1 (PD-L1) mAb socazolimab in patients diagnosed with recurrent or metastatic cervical cancer. Patients and Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5 mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: 104 patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1–positive tumor expression (combined positive score ≥1). ORR was 15.4% [95% confidence interval (CI), 8.7%–24.5%]. Median PFS was 4.44 months (95% CI, 2.37–5.75 months), and the median OS was 14.72 months (95% CI, 9.59–NE months). ORR of PD-L1–positive patients was 16.7%, and the ORR of PD-L1–negative patients was 17.9%. No treatment-related deaths occurred. Conclusions: Our study demonstrates that socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 mAbs.