OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection

Qin

et al. 2020

Preprint

24Programmed death ligand 1 (PD-L1) has been recently shown to be a major 25 obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) 26 on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely 27 used to treat hepatitis B virus(HBV)infection, but its antiviral effect vary greatly 28 and the mechanism is not totally clear. We found that IFN-α/γ induced a marked 29 increase of PD-L1 expression in hepatocytes. Signal and activators of transcription 30 ( Stat1) was then identified as a major transcription factor involved in 31 IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the 32 PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell 33 activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in 34 HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an 35 important role in mediating T cell hyporesponsiveness and inactivating 36 liver-infiltrating T cells in the hepatic microenvironment. These data raise further 37 potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic 38 vaccines. 39 40 42 hepatitis B virus (HBV). Ultimate HBV clearance requires the coordination of the 43 potent T cell immune response and effective humoral immunity. However, -3 -44 HBV-specific T cell response, which plays a vital role in HBV clearance, is severely 45 impaired in chronic hepatitis B (CHB) patients, leading to long-term immune 46 tolerance [1, 2]. Several mechanisms may contribute to HBV-specific T cell tolerance 47 and exhaustion, including upregulation of co-inhibitory molecules such as 48 programmed death 1 (PD-1), T-cell immunoglobulin and mucin domain-49 containing molecule 3 (TIM-3), T-cell immunoglobulin and ITIM domain 50 (TIGIT), lymphocyte-activation gene 3 (LAG3), immunosuppressive prostaglandin 51 E2 (PGE2) receptors, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and proapoptotic 52 protein Bcl2-interacting mediator (Bim) on HBV-specific CD8 + T cells, as well as on 53 CD4+ T cells and NK cells. [3-5]. Additionally, regulatory T cells and suppressive 54 cytokines also contribute to virus-specific T cell failure [6]. 55 Among the co-expressed inhibitory receptors on T cells, programmed death 56 ligand 1 (PD-L1) plays a critical role in impaired T cell immune responses. Of note, 57 its ligand PD-L1, a 40 kDa transmembrane protein, is constitutively expressed on 58 liver DCs, Kupffer cells, stellate cells, liver sinusoidal endothelial cells, and 59 hepatocytes. Binding of PD-L1 to PD-1 leads to T cell dysfunction by inhibiting T 60 cell activation, causing T cell exhaustion, anergy, and T cell apoptosis, as well as by 61 inducing Treg differentiation [7-11]. In addition, elevated PD-L1 levels in liver were 62 observed in chronic necroinflammatory liver diseases and autoimmune hepatitis [12, 63 13]. These indicate the immune regulatory function of the liver microenvironment that 64 may lead to T cell tolerance. 65 As an first-line treatment option, ...

Section: Discussionmentioning

confidence: 99%

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

Qin

et al. 2020

Preprint

“…A recent ex vivo study showed that HBV-specific CD4 + T cells isolated from individuals with HBeAg-negative HBV infection could be activated by OX40 stimulation combined with PD-L1 blockade, with remarkably increased IFN-γ and IL-21 production in vitro. Functional boost of HBV-specific CD4 + T cells via both treatment with OX40 and PD-1 pathway blockade might be useful in curing CHB (111).…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

“…ex vivo (93,94) and in animal studies. (95) This approach is being evaluated in human studies in combination with therapeutic vaccination.…”

mentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.