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

Background & Aims: TQ-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). Methods: In 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. Results: Triple 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. Conclusions: The 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.