Seroclearance of HBsAg in Chronic Hepatitis B Patients After a Tolerance Breaking Immuno-Therapy: GM-CSF, followed by A Recombinant HBV Vaccine
ABSTRACT Background Chronic hepatitis B (CHB) remains incurable due to the immune system’s tolerance towards the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy.Methods CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (cohort 1) or ADV combined with interferon-alpha (IFN-alpha) (cohort 2). Additionally, a third cohort received the THRIL-GM-Vac regimen: three low-dose GM-CSF injections followed by one dose of the HBV vaccine, alongside standard treatment.Results THRIL-GM-Vac treatment (cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants compared to 0% and 4.17% in cohorts 1 and 2, respectively. Furthermore, THRIL-GM-Vac significantly reduced HBV-specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti-HBV T cell responses confirmed THRIL-GM-Vac’s ability to disrupt HBV tolerance and enhance HBsAg-specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels.Conclusion THRIL-GM-Vac treatment in cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti-viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.Significance of This Study What Is Already Known <jats:list list-type="simple">- Persistent viral replication in chronic HBV infection increases the risk of disease progression. Achieving virological suppression is crucial, yet patients with HBsAg still face adverse outcomes, like hepatocellular carcinoma (HCC).- The ideal treatment goal is a functional cure, or HBsAg loss, which significantly improves clinical outcomes.- Current treatments include Nucleos(t)ide analogs (NAs) and Interferon (IFNs), with NAs being potent in viral replication inhibition but less effective in HBsAg clearance. IFNs offer a modestly better HBsAg loss rate.- Combining NAs with IFNs or switching to IFNs has shown some improvement in HBsAg seroclearance in clinical trials.New Findings <jats:list list-type="simple">- Previous studies highlighted GM-CSF as potential vaccine adjuvants that boost antitumor and antiviral immunity. Our study demonstrates that a combination of GM-CSF therapy and HBV vaccination (THRIL-GM-Vac), along with ADV and IFN-α as standard treatment, significantly reduces HBsAg levels and enhances anti-HBsAg cell-mediated immunity compared to the standard treatments.- Specifics include a considerable decrease of HBsAg in 43.5% of patients, with 21.7% exhibiting a major reduction, including HBsAg seroclearance in 8.7% of participants. This response coincided with an increase in cellular immunity markers.Clinical Implications <jats:list list-type="simple">- The THRIL-GM-Vac strategy, when combined with conventional antiviral treatments, opens avenues for achieving a functional HBV cure in a more significant proportion of patients.- Our findings suggest that targeting Treg-dependent immunotolerance correlates with HBsAg reduction, providing a potential immune-surrogate endpoint to predict treatment efficacy.- This approach offers a promising direction for future research and treatment strategies to meet unmet medical needs in chronic HBV treatment..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 13. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Geng, Shuang [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.04.18.22273874 |
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| PPN (Katalog-ID): |
XBI035807776 |
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| 245 | 1 | 0 | |a Seroclearance of HBsAg in Chronic Hepatitis B Patients After a Tolerance Breaking Immuno-Therapy: GM-CSF, followed by A Recombinant HBV Vaccine |
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| 520 | |a ABSTRACT Background Chronic hepatitis B (CHB) remains incurable due to the immune system’s tolerance towards the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy.Methods CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (cohort 1) or ADV combined with interferon-alpha (IFN-alpha) (cohort 2). Additionally, a third cohort received the THRIL-GM-Vac regimen: three low-dose GM-CSF injections followed by one dose of the HBV vaccine, alongside standard treatment.Results THRIL-GM-Vac treatment (cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants compared to 0% and 4.17% in cohorts 1 and 2, respectively. Furthermore, THRIL-GM-Vac significantly reduced HBV-specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti-HBV T cell responses confirmed THRIL-GM-Vac’s ability to disrupt HBV tolerance and enhance HBsAg-specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels.Conclusion THRIL-GM-Vac treatment in cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti-viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.Significance of This Study What Is Already Known <jats:list list-type="simple">- Persistent viral replication in chronic HBV infection increases the risk of disease progression. Achieving virological suppression is crucial, yet patients with HBsAg still face adverse outcomes, like hepatocellular carcinoma (HCC).- The ideal treatment goal is a functional cure, or HBsAg loss, which significantly improves clinical outcomes.- Current treatments include Nucleos(t)ide analogs (NAs) and Interferon (IFNs), with NAs being potent in viral replication inhibition but less effective in HBsAg clearance. IFNs offer a modestly better HBsAg loss rate.- Combining NAs with IFNs or switching to IFNs has shown some improvement in HBsAg seroclearance in clinical trials.New Findings <jats:list list-type="simple">- Previous studies highlighted GM-CSF as potential vaccine adjuvants that boost antitumor and antiviral immunity. Our study demonstrates that a combination of GM-CSF therapy and HBV vaccination (THRIL-GM-Vac), along with ADV and IFN-α as standard treatment, significantly reduces HBsAg levels and enhances anti-HBsAg cell-mediated immunity compared to the standard treatments.- Specifics include a considerable decrease of HBsAg in 43.5% of patients, with 21.7% exhibiting a major reduction, including HBsAg seroclearance in 8.7% of participants. This response coincided with an increase in cellular immunity markers.Clinical Implications <jats:list list-type="simple">- The THRIL-GM-Vac strategy, when combined with conventional antiviral treatments, opens avenues for achieving a functional HBV cure in a more significant proportion of patients.- Our findings suggest that targeting Treg-dependent immunotolerance correlates with HBsAg reduction, providing a potential immune-surrogate endpoint to predict treatment efficacy.- This approach offers a promising direction for future research and treatment strategies to meet unmet medical needs in chronic HBV treatment. | ||
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| 700 | 1 | |a Yang, Feifei |4 aut | |
| 700 | 1 | |a Jia, Hongyu |4 aut | |
| 700 | 1 | |a Zhao, Gan |4 aut | |
| 700 | 1 | |a Zhao, Weidong |4 aut | |
| 700 | 1 | |a Yu, Jie |4 aut | |
| 700 | 1 | |a Zhu, Haoxiang |4 aut | |
| 700 | 1 | |a Cai, Huan |4 aut | |
| 700 | 1 | |a Yang, Lishan |4 aut | |
| 700 | 1 | |a Zhang, Shuren |4 aut | |
| 700 | 1 | |a Zhou, Xian |4 aut | |
| 700 | 1 | |a Li, Chaofan |4 aut | |
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| 700 | 1 | |a Zhang, Shijie |4 aut | |
| 700 | 1 | |a Wang, Xianzheng |4 aut | |
| 700 | 1 | |a Yang, Yida |4 aut | |
| 700 | 1 | |a Zhang, Jimin |4 aut | |
| 700 | 1 | |a Wang, Bin |4 aut | |
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