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836
CLONAL AMPLIFICATION OF PERIPHERAL B AND T CELLS IS
ASSOCIATED WITH CLINICAL RESPONSE TO CHECKPOINT
BLOCKADE IN CHRONIC HEPATITIS B
Jeffrey Wallin1, Diana Chen1, Circe McDonald2, Sam Kim1,
Calvin Chang1, Julie Lin1, Xiaoyun Yang1, Ondrej Podlaha1,
Scott Patterson3, Edward J. Gane4, Rod Dunbar5 and Anuj
Gaggar1, (1)Gilead Sciences, Inc., (2)Gilead Sciences, Inc,
Foster City, California, USA, (3)Gilead Sciences, Inc., Foster
City, CA, USA, (4)Auckland Clinical Studies, Auckland, New
Zealand, (5)School of Biological Sciences, University of
Auckland
Background: Therapeutic strategies for HBV aim to achieve
functional cure of infection, defined by sustained off-treatment
loss of HBV surface antigen (HBsAg) Emerging treatment
modalities are designed to enhance HBV-specific immune
responses To investigate potential mechanisms of action
underlying the activity of checkpoint blockade in chronic
hepatitis B (CHB), we used flow cytometry and single cell
sequencing to characterize peripheral blood mononuclear
cells (PBMCs) from subjects that responded or did not respond
to treatment Methods: CHB subjects were treated with a
single dose of the PD-1 inhibitor nivolumab with or without
the vaccine GS-4774 To compare immune populations in
response groups, we analyzed baseline, week 4 and week
24/28 PBMCs by flow cytometry. Single cell sequencing was
performed at the same time points from two responders (R1
and R2; characterized by an HBsAg decline of ≥0.5 log10 IU/
ml) and two non-responders (NR1 and NR2) Subject R1
achieved HBsAg negative status during treatment Results:
Responding subjects had elevated baseline levels of naïve
CD8+ T cells (Tn) and stem cell-like memory CD8+ T cells
(Tscm) with marked expression of transcription factors Lef1
and Tcf7 At on-treatment time points, frequencies of CD8+ Tn
and Tscm were reduced in responding subjects and increases
in CD8+ effector T cells (Teff) were detected Tn, Tscm or
Teff CD8+ populations were not significantly changed in nonresponding
subjects Total B cells increased with treatment
for evaluated subjects while elevations of memory B cells
were identified only for responding subjects. On-treatment
increases of individual T and B cell clones were also found
to be associated with response. T cell clones emerged (>30
clones with frequencies ≥10) at week 24 for subject R1 and
were mapped to a Teff phenotype There was no T cell clonal
expansion in other subjects. An on-treatment amplification of
B cell clones was observed for responding subjects, but not
non-responding subjects At week 24/28, four and seven B
cell clones with frequencies ≥10 were detected for R1 and
R2, respectively. The identified emerging B cell clones were
not detected at earlier timepoints Conclusion: These results
suggest a pronounced peripheral baseline Tn and Tscm
signal may be associated with clinical response to checkpoint
blockade in CHB On-treatment expansion of peripheral B
and T cell clones may also inform treatment outcome. |
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发表于 2020-10-31 17:28
