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New Treatment Modalities
- Innate Immunity -
Adam J. Gehring, Ph.D.Biology Lead
Toronto Centre for Liver Disease
University Health Network (UHN)
Assistant Professor
Department of Immunology
University of Toronto
Disclosures: Gilead, Janssen, Novartis
Innate Immune Response to HBV
➢ Still have little understanding of its role in early viral response
➢ Studied mainly in context of immunopathogenesis of chronic HBV
➢ Arguably more complex than the T cell response
❖ Parenchymal cell responses • Hepatocytes, Endothelial Cells, Stellate cells
❖ Antigen presentation by professional antigen presenting cells (APCs)• Dendritic cells (DC), monocytes, macrophages
❖ Activation of innate effectors• NK cells, MAIT cells, γδ T cells
• Innate effectors can be negative regulators in chronic HBV patients
• Little data on their role in recognizing/eliminating infected hepatocytes
Pallett. Nat Med 21, 591–600 (2015).
Gehring J Clin Invest. 2013 Sep 3;123(9):3766-76 Boltjes PLoS ONE. 2014;9(5):e97006.
Myeloid cell function in chronic HBVDendritic cell • Ex vivo function largely intact
• In vitro studies: Inhibited, activated by HBV
Monocytes• Contain HBsAg in vivo
• No evidence of altered stimulatory capacity
• Intact cytokine production
TNF-α
Alterations in the Innate Immune Response to HBV
Caveats of myeloid cell analysis• Short-lived compared to T & B cells
• Spend few days in circulation
• Susceptible to environmental changes
Myeloid Derived Suppressor Cells (MDSC)• Produce Arginase and IL-10
• Suppress T cell expansion
Gehring Cell. Mol. Immunol. 2015 May;12(3):283–91
NK cell IFN-γ production suppressed• Related to IL-10
• Especially in hepatitis patients
Peppa, PLoS Pathog. 2010 Dec 16;6(12):e1001227.
Peppa J. Exp Med. 210, 99–114 (2013).
Alterations in the Innate Immune Response to HBV
NK cells kill HBV-specific T cells• TRAIL Mediated killing
Dunn, J. Exp Med. 2007 Feb 20;204(3):667–80.
NK cells kill hepatocytes via TRAIL• Induced by IFN-α
• Not HBV-specific (HepG2 cells)
A) Blocking NK TRAIL-mediated killing of HBV-specific T cells.
B) Inducing presentation of the HBV antigen depot in monocytes
C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18
D) TLR-7 mediated IFN-a production from plasmacytoid DC.
E) NKT cell recognition of CD1d on infected hepatocytes.
F) Blocking MDSC-mediated suppression
G) Direct triggering of RIG-I in infected hepatocytes
H) CpG induction of iMATEs
Opportunities for Innate-targeted
Immunotherapy
Maini & Gehring. J. Hepatol. 64, S60–S70 (2016).
Pattern Recognition receptors• TLR-7
• TLR-8
• Rig-I
• STING
• Inactivated viruses (PPOV)
Impact on antigen processing and T cell stimulation is unknown
Current Targets for Immunomodulatory Drug
Development
Indiscriminate
Targeting innate/antiviral cytokine production, • mainly from myeloid cells
• Cytokines: IL-1α, IL-1β, IL-6, IL-10, IL-12, IL-18, TNF-α,IFN-α, IFN-λ
• Chemokines: CXCL-8, -9, -10, Mip1a, Mip1B, MCP-1
Gehring, Best Pract Res Clin Gastroenterol. 2017 Jun;31(3):337-345
Mouse work clearly shows that innate activation can reduce HBV replication• infection with other viruses that stimulate innate immune response
• injection of TLR agonists
Mainly an IFN-α mediated response• Highly effective in mice
• IFN-α therapy in humans not so effective
Rationale for Targeting Pattern
Recognition Receptors
Isogawa J. Virol. 2005 May 12;79(11):7269–72.
Ebert, Gastroenterology. 2011 Aug;141(2):696–706.e3.
Luangsay J. Hepatol. 2015 Nov;63(5):1077–85.
RIG-I activation suppresses HBV replication in mice• Stimulates IFN-α, IFN-β and IFN-λ + other cytokines
Rationale for Targeting Pattern
Recognition Receptors
TNF-α
IFN
-γ
NK bright MAITLiver cells + TLR-8
TLR-8 activation of human liver monocytes
induces IL-12 and IL-18 production• Induces innate effector IFN-γ production
• NK cells, MAIT cells, γδ T cells
IL-12 restores HBV-specific T cell function in vitro• Increases IFN-γ production
• synergizes with anti-PD-L1
• Injected into chronic HBV patients = No success
Th1 promoting cytokines clear HBV from the mouse liver- IL-12/IL-18 injection in mice
- Induced IFN-γ production by NK/NKT cells
IL-12
IL-18
Rigopoulou Hepatology. 2005 Nov 1;42(5):1028–36.Schurich, PLoS Pathog. 2013 Mar 14;9(3):e1003208.
Jo et. al. PLoS Pathog. 2014 Jun;10(6):e1004210.
Kimura. J. Virol. 2002 Nov 1;76(21):10702–7.
Cavanaugh J. Virol. 1997 Apr;71(4):3236–43.
Pattern Recognition receptors• TLR-7
• TLR-8
• Rig-I
• STING
• Inactivated viruses (PPOV)
Current Targets for Immunomodulatory Drug
Development
Indiscriminate
Targeting innate/antiviral cytokine production, • mainly from myeloid cells
• Cytokines: IL-1α, IL-1β, IL-10, IL-6, IL-12, IL-18, TNF-α,IFN-α, IFN-λ
• Chemokines: CXCL-8, -9, -10, Mip1a, Mip1B, MCP-1
Gehring, Best Pract Res Clin Gastroenterol. 2017 Jun;31(3):337-345
TLR-7 IFN-α
TLR-7-mediated IFN-alpha Production and
Antiviral Efficacy
Janssen, H.L.A., AASLD Liver Meeting 2016; Poster ID: 1851
Gilead GS-9620 Phase II study• Data from 2016 AASLD
• 12w treatment with 12 w follow-up
• HBsAg decline < 0.5 Log10
Roche RG7795 (RO6864018)• Phase II, 12 w treatment
• No data available
• Removed from PhII Q3 2016?
Grippo, J., AASLD Liver Meeting 2016; Poster ID: 1869
Direct triggering of RIG-I in infected hepatocytes
Korolowicz. PLoS ONE 11, e0161313 (2016).
Chronic Woodchuck Hepatitis Virus Infection model
SpringBank SB-9200• Phase II
• 12 w daily administration then 12 w tenofovir
• Cohorts: 25, 50, 100, 200 mg
Yuen, presented at International HBV meeting, 2017
25 mg SB9200
TLR-8
IL-12/18
NK & MAIT
IFN-γ
TLR-8 activation of intrahepatic monocytes
stimulating IL-12 and IL-18
Daffis et. al. Presented at EASL 2017; ID: SAT-165
Gilead GS-9688• Phase I for chronic HBV
• WHV Data• 8w treatment window
• Significant reduction in WHV DNA
• Significant reduction in HBsAg
Pattern recognition receptor agonists (TLRs, RIG-I)• Real potential - justification from mice – realistic doses?
• IFN-α – limited efficacy
• IL-12 & IL-18 show good mouse/in vitro data but human data is lacking
• Liver is dominated by innate effectors
• Will they respond as predicted by tests in PBMC?
• Can antiviral immunity be targeted over inflammation?
• How can NK cells, γδ T cells, MAIT clear infected hepatocytes?
Negative Innate regulators of immunity• MDSC, NK-TRAIL
• Unclear if negative regulation can be effectively targeted
• Arginase inhibitors, IL-10 neutralization, TRAIL blocking
• Mechanisms may be cohort-specific
Will Innate Immunotherapy Strategies
Improve HBV Cure?