Immunomodulation and entry inhibition: Selgantolimod’s double punch against hepatitis B virus

Chronic hepatitis B virus (HBV) infection remains a significant global health burden, affecting over 250 million people worldwide who are at risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Currently available nucleos(t)ide analogues (NA) are effective in controlling viremia; however, functional cure, defined as loss of hepatitis B surface antigen (HBsAg), is rare and difficult to achieve and likely requires robust immune responses, reflecting the need for innovative therapeutic strategies [1]. Thus, the future of treating chronic HBV infections relies on combination therapies that include both direct-acting antiviral agents and immunomodulatory agents [2]. In this context, selgantolimod (SLGN), an agonist of Toll-like receptor 8 (TLR8), could be a promising candidate. Its efficacy in the treatment of chronic HBV infections has been investigated in preclinical models and clinical trials [3–5], but there remains limited understanding of its impact on immune effectors within the liver. The study by Roca Suarez published in Gut [6] aimed to bridge that knowledge gap by characterizing the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment and investigating its effect on HBV-host interactions.

The researchers of Fabien Zoulim’s laboratory identified TLR8-expressing cell types in the human liver using publicly available single-cell RNA sequencing (RNA-seq) data and developed a method to isolate Kupffer cells (KCs), the macrophages residing in the liver. They carefully analyzed the transcriptome and cytokine profiles of KCs after SLGN treatment and assessed the indirect effects through RNA-seq in hepatocytes treated with SLGN-conditioned media. The resulting data enabled a comprehensive understanding of the mechanisms of SLGN and provided several important insights that deepen our understanding of virus-host interactions in the liver. Importantly, Roca and colleagues found that SLGN not only exerts immunomodulatory effects but may also impair viral entry (Figure). A dual mechanism of a new agent could potentially be of value and was, for example, key to the success of another molecule currently in clinical development, bepirovirsen, an antisense oligonucleotide known to target HBV RNAs and elicit an immune response via TLR8 signaling [7]. The downregulation of the sodium taurocholate co-transporting polypeptide (NTCP) by SLGN-conditioned media, which is essential for HBV entry, underscores its versatile therapeutic potential. This could not only be relevant for the therapy of chronic HBV infection, but could be particularly relevant for chronic hepatitis D virus (HDV) infections, where entry inhibition by bulevirtide has brought a major breakthrough in therapy [8]. Notably, IL-6 emerged as the primary cytokine involved in SLGN's action on HBV entry. The involvement of IL-6 in mediating HBV entry inhibition opens up additional opportunities for exploring IL-6 as a therapeutic target. IL-6, however, plays a versatile and complex role in hepatocyte homeostasis and may be involved in both promoting and inhibiting HCC progression [9], and thus warrants careful consideration to avoid potential adverse effects in therapeutic interventions.

Figure. Multifaceted mechanisms of Selgantolimod against HBV.

The study also found an increase in programmed death-ligand 1 (PD-L1) expression in Kupffer cells after treatment with SLGN, consistent with previous observations that SLGN induced PD-L1 in monocytic myeloid-derived suppressor cells [5] and that a TLR7 agonist increases intrahepatic expression of PD-L1 in chimpanzees [10]. This effect could counteract an effective immune response and explain the rather modest effect of SLGN in combination with a NA on HBsAg levels shown so far [3,4]. This issue will now be addressed by the potential strategy of combining TLR agonists with immune checkpoint inhibitors (ICI), as investigated in a current clinical trial involving the sequential administration of NA plus siRNA (VIR-2218) followed by SLGN, and the ICI nivolumab to orchestrate inflammatory responses against HBV while preventing immune checkpoint activation (NCT04891770). The use of ICI together with other immunostimulatory agents is scientifically intriguing but carries the risk of potentially overstimulating the immune system with the risk of enhancing adverse effects. The upcoming clinical data that will provide further insights.

In addition, the study highlights the plasticity of Kupffer cells (KC), which can switch to antiviral transcriptional programs in response to SLGN, providing insights into broader inflammatory responses and liver disease. The ability to pharmacologically modulate KC plasticity could have additional implications for the treatment of various liver diseases, including fibrosis.

A strength of the study is the use of patient and nonhuman primate tissues and models for analyses which enhances the translatability of the mechanistic findings to patients. A limitation of the study is the pending clinical proof-of-concept to show that these mechanisms will contribute to HBV functional cure.

In summary, the results are important by unraveling a new mechanism to potentially improve outcomes of antiviral therapies and HBV cure. The study of Roca et al. not only advances our understanding of SLGN in hepatic immune responses, but also shows its potential as a promising candidate with multi-faceted mechanisms for future combination therapies against chronic HBV infections. To achieve a functional HBV cure, numerous viral and immunological barriers need to be overcome. Immunomodulatory agents such as SLGN, with their multiple effects, could play a crucial role in overcoming these challenges. However, additional combination partners are likely needed to enhance efficacy in clinical settings, as HBsAg level reductions with SLGN combined with NA treatment have so far been only modest [3,4].