Research ArticleAnti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study
Graphical abstract
Introduction
More than 240 million people worldwide are chronically infected with the hepatitis B virus (HBV)[1], [2]. In the Asia-Pacific region, where it is most prevalent, chronic HBV infection is the leading cause of cirrhosis, liver failure, and hepatocellular carcinoma.[2], [3], [4], [5], [6] While currently approved oral nucleos(t)ide analogs effectively suppress viral replication, providing important clinical benefits, there are several disadvantages of this therapeutic approach. First, since antiviral therapy is rarely curative, most patients must receive life-long treatment with the attendant cost, cumulative toxicity, and risk of breakthrough through either non-adherence or the emergence of antiviral resistance. Moreover, viral suppression with nucleos(t)ide analogs does not eliminate the risk of hepatocellular carcinoma.7 A finite course of treatment that can provide sustained off-treatment HBV suppression and clinical response is a clear unmet medical need. Current guidelines recognize clearance of the hepatitis B surface antigen (HBsAg) from the patient’s serum as a so-called “functional cure” and can be distinguished from a “sterilizing cure” which requires the elimination of the covalently closed circular DNA (cccDNA) nuclear reservoir of the virus.[5], [8], [9] Functional cure has been associated with improved outcomes, however, and is a current goal of curative approaches for HBV.10
A major barrier to achieving a cure of chronic HBV infection is the presence of a dysfunctional immune response to the virus.11 Whereas in acute self-limited infection, the CD8 T cell response is diverse and vigorous, the T cell response in patients with chronic infection is characterized by a depleted population of antigen-specific T cells and an inability to control or eliminate the virus. During the course of chronic HBV infection, inhibitory receptors on T cells are overexpressed, limiting T cell effector function.12 Of the many inhibitory receptors present on exhausted T cells in patients with HBV, programmed death receptor 1 (PD-1) is the most highly expressed, especially on HBV-specific T cells within the liver.[13], [14] One of the ligands for PD-1, programmed cell death ligand 1 (PD-L1), is normally found on cells within the liver, but its expression is increased in the setting of chronic infection.15 Together, this increased expression of PD-L1 in HBV-infected hepatocytes and increased PD-1 on HBV-specific T cells likely contribute to T cell effector dysfunction. Reversal of “T cell exhaustion” through blockade of the PD-1:PD-L1 axis, has improved specific anti-HBV T cell responses in human intrahepatic T cells and in models of HBV, including mouse and woodchuck models.[16], [17], [18] In woodchucks with chronic woodchuck hepatitis virus infection, blockade of PD-L1 combined with DNA vaccination effectively controlled viremia, while antiviral treatment alone or antiviral treatment plus vaccination had no effect.19
To date, checkpoint blockade inhibitors have been tested mainly in the treatment of cancer and have shown efficacy in relieving in situ T cell dysfunction in patients with advanced malignancy. PD-1 and PD-L1 inhibitors disrupt PD-1 immune checkpoint signaling and restore antitumor activity of otherwise suppressed effector T cells. In clinical studies, nivolumab (Bristol-Myers Squibb, Princeton, NJ, United States), a fully human immunoglobulin G4, increased time to progression and improved survival in patients with advanced melanoma, non-small cell lung cancer, and non-Hodgkin’s lymphoma. Nivolumab is now approved treatment for these and other cancers.20 In the first clinical study of nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040 Study), 3 of 51 patients (6%) with chronic HBV infection who received 3.0 mg/kg every 2 weeks demonstrated a 1 log decline in HBsAg during nivolumab therapy.21 These studies suggest that the new PD-1 and PD-L1 inhibitors have potential in the treatment of patients with chronic HBV infection.
Doses of nivolumab selected for this pilot study (0.1 mg/kg and 0.3 mg/kg) were based on receptor occupancy (a surrogate marker of efficacy) and safety data reported from phase I dose-finding studies of nivolumab in patients with malignancies.[22], [23] In these studies, peripheral receptor occupancy was similar across doses ranging from 0.1 mg/kg to 10 mg/kg. Importantly, doses below 1 mg/kg were safe with no serious adverse events (SAEs) and fewer treatment-related grade 3–4 adverse events (AEs) and no autoimmune disorders have been reported in patients who received single or multiple doses below 1 mg/kg.
One cohort of patients received GS-4774, a yeast-based therapeutic HBV vaccine along with nivolumab. At the time of study initiation, GS-4774 was being evaluated in phase II studies for the treatment of chronic HBV infection. GS-4774, which contains a fusion antigen including major antigenic regions of the HBx, HBc, and HBs antigens, had been shown to stimulate modest T cell responses in preclinical and phase I studies. However, in phase II evaluations, GS-4774 did not demonstrate antiviral efficacy against HBV.[24], [25], [26]
Section snippets
Patient inclusion criteria
Eligible patients were 18 to 65 years of age (inclusive), with documented evidence of chronic HBV infection (i.e., positive for HBsAg for more than 6 months), and negative for HBV e antigen (HBeAg) at screening. Pregnant or lactating women were excluded. Patients were also required to have been receiving approved HBV oral antiviral treatment for ≥1 year prior to screening, with HBV DNA <69 IU/ml (measured at least once) for ≥6 months prior to screening, and HBV DNA <20 IU/ml at screening.
Results
Patients were enrolled and treated at 1 site in New Zealand from November 29, 2015 through November 28, 2016. Of the 27 patients with HBeAg-negative chronic hepatitis B on oral antiviral therapy who were screened for this study 24 were enrolled (Fig. S1). Three patients withdrew consent before the initiation of dosing. All 24 participants completed the study and are included in the final analysis.
Overall, patients were 75% male, 38% Asian, 50% Polynesian, with median baseline HBsAg levels
Discussion
In this first clinical study of checkpoint inhibition in chronic HBV infection, a single dose of nivolumab with or without GS-4774 was safe and well-tolerated. No symptoms or signs of autoimmune disorders were observed, and the single grade 3 ALT flare occurred in the patient who underwent HBsAg seroconversion. Nivolumab treatment was associated with a decrease in HBsAg titers in 20/22 (91%) patients receiving 0.3 mg/kg. HBsAg titers decreased by 0.5 log reduction in 3 patients at week 24 post
Financial support
This study was funded by Gilead Sciences, Inc.
Conflicts of interest
Edward Gane has served on advisory boards for Gilead Sciences, Janssen, Roche, and AbbVie, and as a speaker for Gilead Sciences and AbbVie. Daniel Verdon, Anna Brooks, and Rod Dunbar have served as consultants and have conducted contract research for Gilead Sciences. Anuj Gaggar, Anh Hoa Nguyen, and G. Mani Subramanian, are employees of and hold stock interest in Gilead Sciences. Christian Schwabe declares no conflicts of interest.
Please refer to the accompanying ICMJE disclosure forms for
Role of study sponsor
The sponsor (Gilead Sciences, Inc.) was involved with the study design, statistical analysis, interpretation of data, and drafting of this manuscript.
Authors’ contributions
Edward Gane, Anuj Gaggar, G. Mani Subramanian, and P. Rod Dunbar designed the study. Edward Gane and Christian Schwabe collected study data. Daniel J. Verdon, Anna E. Brooks, and P. Rod Dunbar analyzed the data. Anh Hoa Nguyen provided statistical analysis. All authors analyzed the study data, and reviewed the manuscript prior to submission.
Acknowledgement
Writing and editorial assistance was provided by David McNeel and Sandra Chen, both of Gilead Sciences.
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