Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study

Gane, Edward; Verdon, Daniel J; Brooks, Anna; Gaggar, Anuj; Nguyen, Anh H.; Subramanian, G. Mani; Schwabe, Christian; Dunbar, P. Rod

doi:10.1016/j.jhep.2019.06.028

Cited by 252 publications

(218 citation statements)

References 25 publications

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“…Interestingly, 2/10 patients in the GS-4774 + nivolumab group and 1/12 of the nivolumab monotherapy group had serum HBsAg reductions ≥ 0.5 log10 IU/ml at 24 weeks. A single individual with significantly decreased HBsAg levels in the nivolumab arm showed HBsAg loss at week 16, and anti-HBsAg responses at 10 weeks upon trial completion with anti-HB titers surpassing 500 IU/L 12 months after treatment (138).…”

Section: The Anti-pd-1 Antibody Nivolumabmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Section: The Anti-pd-1 Antibody Nivolumabmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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“…Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases period, after WHsAg loss and detection of WHsAb. This delay between WHsAg loss and the increase in peripheral immune response may reflect localization of virus-specific T cells in the liver until clearance of infected hepatocytes is complete (19). Future studies will therefore focus on characterizing the intrahepatic immune response during GS-9688 treatment.…”

Section: Accepted Articlementioning

confidence: 99%

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (T FH) and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusion: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. Approximately 260 million individuals are chronically infected with hepatitis B virus (HBV), and over half a million people are estimated to die each year due to liver diseases associated with chronic hepatitis B (CHB), such as cirrhosis and hepatocellular carcinoma (HCC). Immunological control of CHB ("functional cure") is defined as sustained loss of HBV surface antigen (HBsAg) off treatment, with or without seroconversion to anti-HBs antibody. Several nucleos(t)ide analogs, as well as interferon-alpha (IFN-α), are approved for the treatment of CHB. These therapies reduce viremia and

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“…cant decline in qHBsAg in patients receiving nivolumab was also observed, with no added benefit using also GS-4774 [42]. Recently, another trial showed qHBsAg reduction and in one patient becoming undetectable at week 20 even if an hepatitis flare was observed accompanied by a significant increase in peripheral HBsAg-specific T cells [43].…”

Section: Key Points Y Mortality For Complication or Sequelae Of Viralmentioning

confidence: 97%

Novel Therapies in HBV Infection

Scaglione

Torti

2019

CMI

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Current treatments for chronic hepatitis B are able to provide a sustained suppression of the viral replication (i.e., persistent undetectability of HBV DNA). This leads to improvement of liver fibrosis and reduction of clinical complications. However, hepatitis B surface antigen (HBsAg) persists in most patients, probably justifying a still increased risk of hepatocellular carcinoma. Indeed, obtaining a complete and sterilizing cure with elimination of the covalently closed circular DNA (cccDNA) or silencing its activity is still a holy grail. New molecules are under evaluation to suppress viral replication acting on multiple phases of the HBV cycle or improve specific immune response against HBV. Molecules acting on HBV cycle have already showed encouraging results, such as entry inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators (CAMs), nucleic acid polymers (NAPs). Also, promising results have been observed with immune-modulators, therapeutic vaccines, and other immune-based approaches. Among these, toll-like (TLR) or anti-programmed receptor agonists antibody 1 of the cell death protein (PD1) (e.g., nivolumab) are most promising. This paper describes newer drugs appearing on the horizon, including antiviral drugs targeting different steps of the HBV life cycle and therapeutic approaches based on immune-modulation.

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Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study

Cited by 252 publications

References 25 publications

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Novel Therapies in HBV Infection

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