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PS-050
Combined GS-4774 and tenofovir therapy can improve HBVspecific
T cell responses in patients with chronic active hepatitis B
C. Boni1, M. Rossi1, A. Vecchi1, D. Laccabue1, T. Giuberti1, A. Alfieri1,
P. Andreone2, C. Cursaro2, M. Margotti2, A. Mangia3, R. Santoro3,
V. Piazzolla3, M.R. Brunetto4, B. Coco4, D. Cavallone4, A. Lau5,
A. Gaggar5, C. Ferrari1. 1Unit of Infectious Diseases and Hepatology,
Azienda-Ospedaliero-Universitaria of Parma, Parma; 2Dipartimento di
Scienze Mediche e Chirurgiche, University of Bologna, Bologna; 3Liver
Unit, IRCCS, ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo,
Foggia; 4Hepatology Unit and Liver Physiopathology Laboratory,
University Hospital of Pisa, Pisa, Italy; 5Gilead Sciences, Foster City, CA,
United States
E-mail: [email protected]
Background and Aims: HBV-specific T cells are essential for HBV
control but they are functionally defective in chronic HBV infection.
Thus, correction of their dysfunction may represent a rational
strategy to treat chronic hepatitis B (CHB). GS-4774 is a yeast-based
T-cell vaccine containing HBV core, surface and X proteins which has
been shown to be immunogenic in mouse models and healthy
volunteers. Aim of the study was to characterize the modulatory
effect of GS-4774 on HBV-specific T cell responses in naïve HBeAg
negative CHB patients.
Methods: 12 HBeAg negative, naïve, viremic, genotype D infected
CHB patients received 6 consecutive monthly doses of vaccine in
combination with Tenofovir Disoproxil Fumarate (TDF), as part of the
larger GS-US-330-1401 study. 26 chronic HBeAg negative genotype D
infected patients treated with NUC alone served as controls.
HBVspecific T cell responses were studied before, during (weeks 12 and
24) and after vaccine therapy (week 48) both ex vivo (IFN-γ Elispot)
and after 10 days in vitro expansion (intracellular cytokine staining
for IFN-γ, TNF-a, IL-2 and CD107 degranulation) in the presence
of peptides covering the overall HBV proteome or control HBV
unrelated peptides. Immunological data were assessed in relation to
HBsAg/HBV-DNA/ALT declines.
Results: No patients had a significant HBsAg decline while all
normalized ALT and suppressed HBV-DNA. Ex vivo IFN-g Elispot
responses were significantly improved upon HBV core peptide
stimulation at week 48 compared to baseline. Following in vitro
expansion, a significant increase in the percentage of HBV-specific
IFN-g and IL2 producing CD3+ T cells was detected at week 24
and 48. This functional improvement was predominantly sustained
by CD8+ T cells which showed also an increased production of
TNF-a. IFN-g was more improved than IL2 and TNF-a. Maximal
stimulatory activity was expressed by polymerase at all time
points, while a progressive increase of IFN-g production was
induced by core and envelope during combined GS-4774 and NUC
administration. A simultaneous improvement of more than one T cell
function was detected in 11 of 12 patients; this was associated with
an increased percentage of double and triple positive HBV-specific
T cells.
Conclusions: GS-4774 combined with TDF can improve the T cell
function with a prevalent effect on CD8 cells. This seems to be
however insufficient to induce a substantial decline of HBsAg which
was similar in patients treated with NUC alone or combined with
GS-4774.
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发表于 2017-4-9 10:12
