Therapeutic potential of TLR8 agonist GS‐9688 (selgantolimod) in chronic hepatitis B: re‐modelling of antiviral and regulatory mediators

Background & Aims: GS‐9688 (selgantolimod) is a toll‐like receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been evaluated in vitro in hepatitis B virus (HBV)‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators. Approach & Results: We characterised the effect of GS‐9688 on immune cell subsets in vitro in PBMC of healthy controls and CHB patients. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and CHB patients. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T‐cells (MAITs), CD4+ follicular helper T‐cells (TFH) and, in ~50% of patients, HBV‐specific CD8+T‐cells expressing interferon‐γ (IFNγ). Moreover, in vitro stimulation with GS‐9688 induced NK cell expression of IFNγ and TNFα and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4+ regulatory T‐cells and monocytic myeloid‐derived suppressor cells (MDSC). Residual MDSC expressed higher levels of negative immune regulators, galectin‐9 and PD‐L1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand+ (TRAIL) regulatory NK cells and degranulation of arginase‐I+ polymorphonuclear‐MDSC (PMN‐MDSC). Conclusions: GS‐9688 induces cytokines in human PBMC that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8+T‐cells, TFH, NK cells and MAITs). Whilst reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimise the antiviral efficacy of GS‐9688.