Mala MainiDivision of Infection and Immunity
UCL, London
Toronto HBV Cure 2016
Checkpoint inhibitors for HBV cure
Effective T cells control virus Exhausted T cells loose control of virus
CD8 T cells
Infected hepatocytes Infected hepatocytes
INF-γTNF-αIL-2
GranzymePerforin
?Checkpoint blockade
Reversal of T cell exhaustion: the goal of checkpoint inhibitors
T cell activation requires 3 signals
Signal 1
Signal 2
Signal 3
Excessive co-inhibitory signals drive T cell exhaustion
Iwai Y et al, 2003, J.Exp. Med, Dong Immunity 2004, Yu et al, 2004, Hepatol, Mulbauer J Hep 2006Boni et al, J.Virol, 2007, Zhang Gastro 2008, Diehl et al, 2008; Hepatol Kassel Hepatol 2009, Fisicaro et al 2010.Gastroenterology, Schurich et al,2011, Shi et al, IJC, 2011, Hepatology, Tzeng et al, 2012. Plos Pathogens,Maier et al, 2013, JI, Chen J et al, 2013, Inflam Res.
PD-L1
Relevance of PD-1 pathway to HBV-infected patients:a dominant immune checkpoint driving T cell exhaustion in the liver
PD-L1:• expressed by liver parenchymal & non-parenchymal cells• Upregulated during viral hepatitis
PD-1:• Upregulated on HBV-specific T cells
Fisicaro et al, Gastro 2010
Relevance of PD-1 pathway to HBV-infected patients
First clues of in vivo effects will come from trials in HBV-related HCC
PD-1 highly expressed on HBV-specific & intrahepatic T cells
In vitro rescue upon PD-L1 blockade
Lessons from woodchuck hepadnaviral infection:Combining PD-1 blockade with therapeutic vaccination
• Boosting of T and B cell immunity• Sustained viral suppression and sAg seroconversion
Complex layers of co-inhibition drive T cell exhaustion
Blocking CTLA-4 can restore HBV-specific T cell responses
Anna Schurich
Pooja Khanna
Gaia Nebbia
Complementary roles for CTLA-4 and PD-1 in CHB
Schurich, Khanna et al, Hepatology 2011
The co-inhibitory receptor TIM-3 is upregulatedon HBV-specific CD8 T cells
Nebbia et al, PLoSOne 2012
The TIM-3 / Galectin-9 pathway is induced in CHB
Non-redundant role with PD-1
Checkpoint modulation to boost antiviral T cells-need for personalised combinations?
Revived
Co-inhibitory signalsPD-1CTLA-4Tim-3Lag-3
CD8 T cell
Co-stimulatory signalsBoni J Virol 2007Fisicaro Gastro 2010Schurich Hepatol 2011Nebbia PLoS One 2012
Response to HBV-specific T cell blockade• dominated by PD-1 • predicted by intermediate T cell differentiation
Bengsh et al, J Hep 2014
?
Enhancing co-stimulation as an alternative to checkpoint blockade
Revived
Co-inhibitory signalsPD-1CTLA-4Tim-3Lag-3
CD8 T cell
Co-stimulatory signals41BBOX-40ICOSIL-12
,,,,
Fisicaro Gastro 2012Isogawa PLoS Path 2013Schurich PLoS Path 2013
Boni J Virol 2007Fisicaro Gastro 2010Schurich Hepatol 2011Nebbia PLoS One 2012
IL-12 increases IFN-g production by HBV-specific but not CMV-specific CD8 T cells
Schurich et al PLoS Path 2013
PD-L blockade in combination with IL-12 optimisesHBV-specific CD8 T cell recovery in vitro
HBV DNA (IU/ml)
Going deeper than Checkpoint inhibitors
Irreversible epigenetic T cell defects Pauken et al Science 2016
Metabolic and mitochondrial T cell defects Schurich et al Cell Reports 2016
Schurich et al Cell Rep 2016
IL-12 re-programmes defective mitochondrial metabolism
The trade-off between immunity and immunopathology
• Minimize antigen load
• Develop adjunctive approaches to limit collateral damage
• Focus T cell boosting on HBV-specific component
Hepatic flares an inevitable result of effective immune boosting
Potential immunomodulatory approaches for CHB
Checkpoint blockade
• PD-1 is the dominant exhaustion marker in chronic HBV• Nearly 100% of HBV-specfiic T cells in liver are PD-1+
• PD-1, CTLA-4 and Tim-3 play potentially non-redundant roles
• May require personalized approach to optimally restore T cells
Enhancing co-stimulation• Cytokines – Signal 3
• IL-12 enhances T cell expansion and functionality
• Additive/synergistic effect in combination with PD-1
• Restore effective T cell metabolism
AcknowledgementsDivision of Infection and Immunity, UCL
Dimitra PeppaRoss Lopes
Abhishek DasClaire Dunn
Pooja KhannaLorenzo Micco
Gaia NebbiaAntony ChenSimran Singh
Anna SchurichLaura Palletttziar Otano
Kerstin StegmannWei-Chen HuangNicholas Easom
Kasha SinghAlice Burton
Emily Colbeck
All healthy donors, patients and clinic staff
University of DundeeDoreen Cantrell
UCL Clinical CollaboratorsWilliam Rosenberg
Guiseppe FusaiEleni NastouliRichard GilsonBrian Davidson
Francis RobertsonA*Star, Singapore
Muzlifa HaniffaAntonio Bertoletti
UCL collaboratorsNiclas ThomasNathan Davies
Barts and the London HospitalUpkar GillJyoti Hansi
Patrick KennedyKings Liver InstituteAlberto Quaglia