Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection

Balsitis, Scott; Gali, Volodymyr; Mason, Pamela; Chaniewski, Susan; Levine, Steven M.; Wichroski, Michael J.; Feulner, Michael; Song, Yunling; Granaldi, Karen; Loy, James; Thompson, Chris; Lesniak, Jacob; Brockus, Catherine; Kishnani, Narendra S.; Menne, Stephan; Cockett, Mark I.; Iyer, Renuka; Mason, Stephen W.; Tenney, Daniel J.

doi:10.1371/journal.pone.0190058

Cited by 40 publications

(33 citation statements)

References 55 publications

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“…These findings suggest that T-cell exhaustion is maintained by various immune checkpoints [68,143,155]. In isolated HBV-specific T-cells from a woodchuck model of HBV infection, blocking these immune checkpoints restored exhausted T-cells such that they to responded appropriately to stimulation by HBV antigens [63,156].…”

Section: Hepatitis Virus Infection Upregulates Immune Checkpoint Protmentioning

confidence: 90%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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Section: Hepatitis Virus Infection Upregulates Immune Checkpoint Protmentioning

confidence: 90%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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“…Meanwhile, we believe that it is very intelligent to conduct early clinical try of checkpoint inhibitors in virally suppressed HBeAg-negative patients [15].…”

Section: Discussionmentioning

confidence: 99%

“…HBV also promotes the expression of PD-L1 on hepatocytes in cell model and transgenic mice, which correlates with the levels of HBsAg, hepatitis B e antigen (HBeAg) and HBV DNA in mouse sera [14]. The blockage of the PD-1/PD-L1 axis using anti-PD-1 antibody can enhance virus-specific immunity in the woodchuck model of HBV infection [15], and nivolumab therapy is well-tolerated and leads to HBsAg decline in most virally suppressed HBeAg-negative patients (a phase Ib study) [16]. Therefore, the blockage of the PD-1/PD-L1 axis may be a feasible way to restore the antiviral immune responses in chronic HBV infection.…”

mentioning

confidence: 98%

Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

Rm¹,

Wx²,

Lj³

et al. 2020

Preprint

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Background The restoration of immune responses is thought as a complementary approach to the nucleos(t)ide analogue (NUC) therapy of chronic HBV infection. The antiviral immunity is negatively regulated by the programmed cell death-1/programmed death ligand-1 (PD-1/PD-L1) axis. Here, the soluble form of PD-L1 (sPD-L1) that represents the amount of PD-L1 expression cells was used as an indicator to investigate the involvement of this axis in chronic HBV infection, especially in the setting of NUC therapy. Methods A total of 273 adult patients with chronic HBV infection, regardless of the treatment, and 86 healthy controls were consecutively enrolled. Serum sPD-L1 was measured using an ELISA assay. Its correlations with clinical/virological characteristics were analyzed. Results Serum sPD-L1 levels in patients with chronic HBV infection (median 425.2 IQR 245.8-558.6 pg/mL) were significantly higher than those in healthy controls (median 81.69 IQR 54.62-121.1 pg/mL). Among patients at various disease phases, those with immune-tolerant CHB had the lowest sPD-L1 levels (median 205.3 IQR 92.27-340.7 pg/mL). These results indicated that serum sPD-L1 was significantly increased in a manner of two steps from health to infection and from immunotolerance to immunoactivation in chronic HBV infection. Furthermore, the serum sPD-L1 in immune-active CHB was correlated with HBsAg positively, HBV DNA negatively and liver damage marginally. Interestingly, the increased serum sPD-L1 levels were strongly associated with the treatment of NUCs, especially in HBeAg-positive immune-active CHB. Conclusions Serum sPD-L1 might be a meaningful indicator to monitor the immune status and disease progression in chronic HBV infection. The correlations of the increased sPD-L1 with HBsAg and NUC treatment suggest that the activated PD-1/PD-L1 axis may explain the rarity of HBsAg seroconversion of NUC therapy and the clinically available checkpoint inhibitors may serve as partners for NUCs to improve their anti-HBV efficacy in the future

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“…18,25 Similarly, in vivo PD-L1 blockade in the woodchuck model of chronic hepatitis showed sustained antiviral effects without liver damage. 26 As preclinical evidence supports targeting of the PD-1:PD-L1 axis as a therapeutic strategy to treat patients with chronic HBV infection, our aim was to determine how the clinical and treatment status of patients affects HBV-specific T cell reactivity in the absence or presence of blockade of the PD-1:PD-L1 axis with the anti-PD-L1 monoclonal antibody MEDI2790.…”

Section: Hbeag Seroconversion Is Associated With a More Effective Pd-mentioning

confidence: 99%

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

et al. 2019

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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.

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Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection

Cited by 40 publications

References 55 publications

Immune Checkpoints in Viral Infections

Immune Checkpoints in Viral Infections

Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

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

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