TLR7 agonist plus anti-PD-L1 enhances HBsAg decline and reinvigorates HBV-specific CD8+ T cells: OCEANcure05 RCT study.

Background & aimsTQ-A3334, a selective Toll-like receptor 7 (TLR7) agonist, activates innate immunity against hepatitis B virus (HBV). TQ-B2450, a humanized programmed death ligand 1 (PD-L1) antibody, could restore T cell function. This study assessed the safety, efficacy, and immunological profile of nucleos(t)ide analogues (NAs) plus TQ-A3334 with or without TQ-B2450 in virally suppressed patients with chronic hepatitis B (CHB).MethodsIn the OCEANcure05 study (NCT04202653), 24 NAs-experienced patients with hepatitis B surface antigen (HBsAg) 250-5000 IU/mL were randomized to NAs monotherapy, dual therapy (NAs + TQ-A3334), or triple therapy (NAs + TQ-A3334 + TQ-B2450) for 24 weeks. The primary endpoint was HBsAg reduction at end of treatment (EOT). Single-cell RNA-seq and flow cytometry were conducted to characterize HBV-specific CD8+ T cell responses.ResultsTriple therapy demonstrated numerically greater HBsAg reduction at EOT than dual therapy or monotherapy. Parallel trends were observed for HBV RNA and hepatitis B e antigen levels. In the triple therapy arm, baseline PD-L1 expression declined more markedly in patients with HBsAg decline ≥0.5 log10 IU/mL. Triple therapy increased IFN-γ, TNF-α, and CD107a expression in HBV-specific CD8+ T cells and broadened HBV peptide recognition. Reversible thyroid abnormalities were the predominant adverse event during triple therapy. No serious adverse events or deaths occurred.ConclusionsThe combination therapy showed acceptable tolerability. In virally suppressed patients, the addition of PD-L1 antibody to NAs plus TLR7 agonist induced moderate HBsAg decline and elicited HBV-specific CD8+ T cell responses, supporting multi-target immunotherapy as a potential treatment strategy for CHB.