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GS-9688, a Toll-like Receptor 8 Agonist Induces
Innate and Adaptive Antiviral Immune
Response in Chronic Hepatitis B Patients
Arshi Khanam1, Ji Ae Yoon2, Bhawna Poonia3, Ethan Grant4,
Shyamasundaran Kottilil1 and Lydia Tang5, (1)Division of
Clinical Care and Research, Institute of Human Virology,
University of Maryland School of Medicine, Baltimore,
MD 21201, (2)University of Maryland School of Medicine,
Baltimore, MD 21201, (3)Division of Clinical Care and
Research, Institute of Human Virology, Institute of Human
Virology, University of Maryland School of Medicine, Baltimore,
MD 21201, (4)Biomarker, Gilead Sciences, (5)1. Division
of Clinical Care and Research, Institute of Human Virology,
University of Maryland School of Medicine, Baltimore, MD
21201
Background: As the leading cause of cirrhosis and
hepatocellular carcinoma, chronic hepatitis B virus (HBV)
infection presents a major global health concern. The outcome
of HBV infection is primarily dictated by the magnitude and
character of the innate and adaptive immune response.
Dysregulated antiviral response is critically associated
with persistent HBV infection. The main obstacle in the
development of effective therapeutics for HBV is the highly
restricted host range and tissue tropism of the virus. GS-9688
is a selective small molecule agonist of toll-like receptor 8
(TLR8) in phase 2 trials for the treatment of chronic hepatitis
B (CHB). In this study, we evaluated the ex-vivo effect of GS-
9688 in mediating antiviral immune responses using blood
samples from patients with CHB. Methods: Whole blood
samples were collected from patients with CHB with HBV viral
suppression on nucleos(t)ide analogue therapy in TruCulture
tubes preloaded with cell culture medium and GS-9688 at
a concentration of 1.11uM, with blood samples collected
in tubes with only 0.1% DMSO as controls. Samples were
incubated at 370 for 24 hours after which whole blood samples
were analyzed by flow cytometry for phenotypic and functional
alterations in dendritic cells, natural killer cells (NK), mucosal
associated invariant T (MAIT) cells, and CD4 and CD8 T cells.
For statistical analysis Wilcoxon matched pairs test was used.
Results: Samples from 22 patients have been analyzed.
Compared to the control, ex-vivo GS-9688 treatment was
associated with increased in myeloid dendritic cells frequency
(mDCs p=0.01), production of IL-1β (p=0.0004), IL-6
(p=0.006), IL-12 (p=0.0002), IL-15 (p=0.0002), and TNF-α
(p=0.0002), and IL-1R (p=0.04) expression by mDCs. IL-23
production was also amplified; however the differences were
not significant. The frequency of plasmacytoid dendritic cells,
NK, and MAIT CD4 and CD8 T cells remained comparable
post GS-9688 treatment. GS-9688 treatment also increased
CD69 expression on NK (p=0.0002), MAIT (p=0.0003),
CD4 (p=0.0005) and CD8 T cells (p=0.0003) and IFN-γ
production by these cells (NK-IFN-γ: p=0.0007, MAIT-IFN-γ:
p=0.0003, CD4-IFN-γ: p=0.007 and CD8-IFN-γ p=0.0007).
Conclusion: In this ex-vivo model, GS-9688 enhances the
functional activation of immune cells including mDCs, NK,
MAIT, CD4 and CD8 T cells and induces cytokine production
and antiviral effector functions crucial for viral clearance,
supporting GS-9688 as a potential therapeutic approach for
the treatment of CHB. Background: As the leading cause
of cirrhosis and hepatocellular carcinoma, chronic hepatitis B
virus (HBV) infection presents a major global health concern.
The outcome of HBV infection is primarily dictated by the
magnitude and character of the innate and adaptive immune
response. Dysregulated antiviral response is critically
associated with persistent HBV infection. The main obstacle
in the development of effective therapeutics for HBV is the
highly restricted host range and tissue tropism of the virus.
GS-9688 is a selective small molecule agonist of toll-like
receptor 8 (TLR8) in phase 2 trials for the treatment of chronic
hepatitis B (CHB). In this study, we evaluated the ex-vivo
effect of GS-9688 in mediating antiviral immune responses
using blood samples from patients with CHB. Methods:
Whole blood samples were collected from patients with CHB
with HBV viral suppression on nucleos(t)ide analogue therapy
in TruCulture tubes preloaded with cell culture medium and
GS-9688 at a concentration of 1.11uM, with blood samples
collected in tubes with only 0.1% DMSO as controls. Samples
were incubated at 370 for 24 hours after which whole blood
samples were analyzed by flow cytometry for phenotypic and
functional alterations in dendritic cells, natural killer cells (NK),
mucosal associated invariant T (MAIT) cells, and CD4 and
CD8 T cells. For statistical analysis Wilcoxon matched pairs
test was used.
Results: Samples from 22 patients have been
analyzed. Compared to the control, ex-vivo GS-9688 treatment
was associated with increased in myeloid dendritic cells
frequency (mDCs p=0.01), production of IL-1β (p=0.0004),
IL-6 (p=0.006), IL-12 (p=0.0002), IL-15 (p=0.0002) and TNF-α
(p=0.0002) and IL-1R (p=0.04) expression by mDCs. IL-23
production was also amplified; however the differences were
not significant. The frequency of plasmacytoid dendritic cells,
NK and MAIT CD4 and CD8 T cells remained comparable
post GS-9688 treatment. GS-9688 treatment also increased
CD69 expression on NK (p=0.0002), MAIT (p=0.0003), CD4
(p=0.0005) and CD8 T cells (p=0.0003) and IFN-γ production
by these cells (NK-IFN-γ: p=0.0007, MAIT-IFN-γ: p=0.0003,
CD4-IFN-γ: p=0.007 and CD8-IFN-γ p=0.0007). Conclusion:
In this ex-vivo model, GS-9688 enhances the functional
activation of immune cells including mDCs, NK, MAIT, CD4
and CD8 T cells and induces cytokine production and antiviral
effector functions crucial for viral clearance, supporting GS-
9688 as a potential therapeutic approach for the treatment
of CHB. |
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发表于 2018-10-25 16:06
