IL-2 produced by HBV-specific T cells as a biomarker of viral control and predictor of response to PD-1 therapy across clinical phases of chronic hepatitis B

Author:

Chua Conan12ORCID,Salimzadeh Loghman2ORCID,Ma Ann T.23ORCID,Adeyi Oyedele A.4,Seo Hobin5ORCID,Boukhaled Giselle M.5ORCID,Mehrotra Aman2,Patel Anjali2,Ferrando-Martinez Sara6,Robbins Scott H.7,La Danie2,Wong David2ORCID,Janssen Harry L.A.12,Brooks David G.58ORCID,Feld Jordan J.12ORCID,Gehring Adam J.128ORCID

Affiliation:

1. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

2. Toronto Centre for Liver Disease, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

3. Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain

4. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

5. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

6. Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA

7. Late Stage Oncology Development, Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA

8. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

Abstract

Background: There are no immunological biomarkers that predict control of chronic hepatitis B (CHB). The lack of immune biomarkers raises concerns for therapies targeting PD-1/PD-L1 because they have the potential for immune-related adverse events. Defining specific immune functions associated with control of HBV replication could identify patients likely to respond to anti-PD-1/PD-L1 therapies and achieve a durable functional cure. Methods: We enrolled immunotolerant, HBeAg+ immune-active (IA+), HBeAg− immune-active (IA−), inactive carriers, and functionally cured patients to test ex vivo PD-1 blockade on HBV-specific T cell functionality. Peripheral blood mononuclear cells were stimulated with overlapping peptides covering HBV proteins +/−α-PD-1 blockade. Functional T cells were measured using a 2-color FluoroSpot assay for interferon-γ and IL-2. Ex vivo functional restoration was compared to the interferon response capacity assay, which predicts overall survival in cancer patients receiving checkpoint inhibitors. Results: Ex vivo interferon-γ+ responses did not differ across clinical phases. IL-2+ responses were significantly higher in patients with better viral control and preferentially restored with PD-1 blockade. Inactive carrier patients displayed the greatest increase in IL-2 production, which was dominated by CD4 T cell and response to the HBcAg. The interferon response capacity assay significantly correlated with the degree of HBV-specific T cell restoration. Conclusions: IL-2 production was associated with better HBV control and superior to interferon-γ as a marker of T cell restoration following ex vivo PD-1 blockade. Our study suggests that responsiveness to ex vivo PD-1 blockade, or the interferon response capacity assay, may support stratification for α-PD-1 therapies.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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