Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis

Abstract

X M Large S (env) Core His6 Untreated viremic CHB patients Low Cytokine production High Treg population Treg cells HBV-specific CD8+ T cells Combined GS-4774 and TDF therapy Immune Restoration High Cytokine production Treg cells HBV-specific CD8+ T cells Low Treg population BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA !2000 IU/ mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n ¼ 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n ¼ 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood

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

“…Recently, the results of an open-label, multicenter, randomized study (http://clinicaltrials.gov no: NCT02174276) of CHB patients using tenofovir disoproxil fumarate (TDF) alone or combined with GS-4774 were published (128). Significantly increased IFN-γ, TNF, and IL2 production was evidenced in HBV-specific CD8 + T cells from individuals administered GS-4774 and TDF at weeks 24 and 48, but not in those under TDF monotherapy.…”

New Approaches to the Treatment of Chronic Hepatitis B

“…Nevertheless, although vaccination did not reduce levels of HBsAg, there was an increase production of IFN-α, TNF-α, and IL2 by CD8+ T cells exposed to antigenic peptides. This suggests that the strong immune stimulatory effect on CD8+ T cells recorded may be of benefit if the vaccine is used in combination with other antiviral agents in development to boost its antiviral potential [ 109 ].…”

Hepatitis B virus persistence and reactivation

“…Strategies include novel therapeutic vaccines, engineering HBV specific T cells,189190191 re-directing T cells or cytokines to infected hepatocytes via TCR-like antibodies,192193 and blocking checkpoint molecules on T cell surface 79105107108. New therapeutic vaccines alone or in combination with antivirals did not show statistically significant effects on HBsAg decline in phase II or III trials 194195196. Nivolumab, a programmed death receptor 1 (PD-1) inhibitor, showed potential to reverse defective T cell immune response and to induce HBsAg decline in a phase Ib study 197.…”