HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic hepatitis B infection

Abstract

Background & Aims: Current therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1:PD-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade. Methods: Expression patterns of the PD-1:PD-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790). Results: Chronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients' clinical or treatment status. Conclusion: Patients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B

“…Conversely, in a preclinical study of woodchucks, αPD-L1 monotherapy showed no efficacy; however, αPD-L1 plus ETV treatment reduced WHV DNA and WHsAg levels compared to ETV treatment alone, while both therapies were tolerable [ 139 ]. A recent study has shown that the inhibitory PD-1/PD-L1 axis is upregulated during CHB infection but not restored after successful antiretroviral therapy using NAs (undetectable viremia) [ 140 ]. In HBeAg-patients, treatment with monoclonal anti-PD-L1 antibodies (MEDI2790) increased HBV-specific T cell responses [ 140 ], while a phase Ib study found that the PD-1 inhibitor nivolumab (single dose, 0.1 or 0.3 mg/kg) was safe and well-tolerated with or without a therapeutic vaccine (GS-4774) [ 84 ] and decreased HBsAg titers by 0.5 log at 24 week, achieving sustained HBsAg loss and seroconversion in one patient [ 84 ].…”

Role of Immunomodulators in Functional Cure Strategies for HBV

“…This effect was linked to intermediate T cell differentiation [50]. The effect of PD-1 blockade on HBV-specific CD8+ T cells from blood and liver of chronically infected patients could in some cases be boosted by the addition of CD137L [51,52] and was shown to be more efficient in HBeAg+ patients [53]. But not only CD8+ T cells are affected by checkpoint inhibitors.…”

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers

“… 19 , 29 , 30 , 31 Although TLR7 agonists would not directly lower HBsAg, it has been suggested that TLR7 agonists could be used effectively in combination with direct‐acting antivirals or drugs that have complementary immunomodulatory activity. 19 , 32 , 33 , 34 This concept remains to be determined in the phase II setting and clinical trials are currently ongoing in patients with CHB to test this hypothesis.…”

“…Promising antiviral activity has been observed with TLR7 agonists in preclinical models of HBV, 18,27,28 but significant HBsAg decline has yet to be demonstrated with TLR7 agonists administered alone or in combination with NUCs in the clinical CHB setting 19,29–31 . Although TLR7 agonists would not directly lower HBsAg, it has been suggested that TLR7 agonists could be used effectively in combination with direct‐acting antivirals or drugs that have complementary immunomodulatory activity 19,32–34 . This concept remains to be determined in the phase II setting and clinical trials are currently ongoing in patients with CHB to test this hypothesis.…”