Therapeutic Potential of TLR8 Agonist GS‐9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators

Abstract

BaCKgRoUND aND aIMS: GS-9688 (selgantolimod) is a toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS-9688 has previously been evaluated in vitro in HBVinfected 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 aND ReSUltS: We characterized the effect of GS-9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. 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 patients with CHB. GS-9688 increased the frequency of activated natural killer (NK) cells, mucosalassociated invariant T cells, CD4 + follicular helper T cells, and, in about 50% of patients, HBV-specific CD8 + T cells expressing interferonγ. Moreover, in vitro stimulation with GS-9688 induced NK-cell expression of interferonγ 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 (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin-9 and programmed death-ligand 1. Conversely, GS-9688 induced an expansion of immunoregulatory TNFrelated apoptosis-inducing ligand + NK cells and degranulation of arginase-I + polymorphonuclear MDSCs.CoNClUSIoNS: GS-9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBVspecific CD8 + T cells, CD4 + follicular helper T cells, NK cells, and mucosal-associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS-9688. (Hepatology 2021;0:1-17). C hronic hepatitis B (CHB) remains a global health concern with an estimated 260 million people infected worldwide. CHB

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

“…Reports have shown both functional ( 10 ) and defective TLR8 response ( 37 ) in CHB. However, in vitro testing of Selgantolimod showed comparable levels of cytokines in PBMC from healthy and CHB subjects ( 31 ). In clinical trial of this agonist in healthy subjects, we previously showed IL-12p40, IL-12p70, IL-1RA and IL-18 induction in serum ( 14 ), here we show T FH polarizing cytokines, IL-12 is induced with the agonist in monocytes from CHB patients which led to naïve CD4 + T cells to differentiated into CXCR5 + BCL-6 + ICOS + IL-21 + T FH .…”

Increased Circulating T Follicular Helper Cells Induced via IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure

“…Therefore, the frequency of Tfh cells might be used as a novel predictor for the prognosis of HBV-ACLF. In fact, a recent study showed that TLR8 agonist GS-9688 (selgantolimod) promoted Tfh differentiation and function by increasing the expression of ICOS, which may be able to activate antiviral effector function (22). Thus, we suppose Tfh cells may be a therapeutic target in those treatment-resistant HBV-ACLF patients through regulating the function of Tfh cells in the future.…”

Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview

“…In another study, GS-9688 was reported to exert anti-HBV effect in the woodchuck model of CHB [ 118 ], where it reduced viral loads over 5 logs and suppressed woodchuck hepatitis surface antigen (WHsAg) in 50% of the treated chronically infected woodchucks [ 118 ]. Another recent study also showed the therapeutic potential of GS-9688 in CHB, where GS-9688 induced cytokines in human PBMCs that could activate antiviral effector function by different immune mediators, including NK cells, HBV-specific CD8+ T cells, CD4+ follicular helper T cells, and mucosal-associated invariant T cells [ 119 ]. The anti-HBV activity of TLR9-ligand has been reported previously [ 120 , 121 ].…”