DOI: 10.1097/hc9.0000000000000337 ISSN: 2471-254X

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

Conan Chua, Loghman Salimzadeh, Ann T. Ma, Oyedele A. Adeyi, Hobin Seo, Giselle M. Boukhaled, Aman Mehrotra, Anjali Patel, Sara Ferrando-Martinez, Scott H. Robbins, Danie La, David Wong, Harry L.A. Janssen, David G. Brooks, Jordan J. Feld, Adam J. Gehring
  • Hepatology
Show PDF Cite

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.

More from our Archive