Checkpoint inhibitors for HBV cure

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1 Checkpoint inhibitors for HBV cure Mala Maini Division of Infection and Immunity UCL, London Toronto HBV Cure 2016

2 Reversal of T cell exhaustion: the goal of checkpoint inhibitors CD8 T cells Granzyme Perforin INF-γ TNF-α IL-2 Infected hepatocytes Effective T cells control virus Infected hepatocytes Exhausted T cells loose control of virus? Checkpoint blockade

3 T cell activation requires 3 signals Signal 1 Signal 2 Signal 3

4 Excessive co-inhibitory signals drive T cell exhaustion

5 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 PD-L1 Iwai Y et al, 2003, J.Exp. Med, Dong Immunity 2004, Yu et al, 2004, Hepatol, Mulbauer J Hep 2006 Boni 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, Plos Pathogens, Maier et al, 2013, JI, Chen J et al, 2013, Inflam Res.

6 Relevance of PD-1 pathway to HBV-infected patients PD-1 highly expressed on HBV-specific & intrahepatic T cells In vitro rescue upon PD-L1 blockade Fisicaro et al, Gastro 2010 First clues of in vivo effects will come from trials in HBV-related HCC

7 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

8 Complex layers of co-inhibition drive T cell exhaustion

9 Blocking CTLA-4 can restore HBV-specific T cell responses Anna Schurich Pooja Khanna Gaia Nebbia

10 Complementary roles for CTLA-4 and PD-1 in CHB Schurich, Khanna et al, Hepatology 2011

11 The TIM-3 / Galectin-9 pathway is induced in CHB The coinhibitory receptor TIM-3 is upregulated on HBV-specific CD8 T cells Non-redundant role with PD-1 Nebbia et al, PLoSOne 2012

12 Checkpoint modulation to boost antiviral T cells -need for personalised combinations?? Co-inhibitory signals PD-1 CTLA-4 Tim-3 Lag-3 Boni J Virol 2007 Fisicaro Gastro 2010 Schurich Hepatol 2011 Nebbia PLoS One 2012 Co-stimulatory signals CD8 T cell Revived Response to HBV-specific T cell blockade dominated by PD-1 predicted by intermediate T cell differentiation Bengsh et al, J Hep 2014

13 Enhancing co-stimulation as an alternative to checkpoint blockade Boni J Virol 2007 Fisicaro Gastro 2010 Schurich Hepatol 2011 Nebbia PLoS One 2012,,,, Co-inhibitory signals PD-1 CTLA-4 Tim-3 Lag-3 CD8 T cell Co-stimulatory signals 41BB OX-40 ICOS IL-12 Fisicaro Gastro 2012 Isogawa PLoS Path 2013 Schurich PLoS Path 2013 Revived

14 IL-12 increases IFN-g production by HBV-specific but not CMV-specific CD8 T cells Schurich et al PLoS Path 2013

15 PD-L blockade in combination with IL-12 optimises HBV-specific CD8 T cell recovery in vitro HBV DNA (IU/ml)

16 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

17 IL-12 re-programmes defective mitochondrial metabolism Schurich et al Cell Rep 2016

18 The trade-off between immunity and immunopathology Hepatic flares an inevitable result of effective immune boosting Minimize antigen load Develop adjunctive approaches to limit collateral damage Focus T cell boosting on HBV-specific component

19 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

20 Acknowledgements Division of Infection and Immunity, UCL Dimitra Peppa Ross Lopes Abhishek Das Claire Dunn Pooja Khanna Lorenzo Micco Gaia Nebbia Antony Chen Simran Singh Anna Schurich Laura Pallett tziar Otano Kerstin Stegmann Wei-Chen Huang Nicholas Easom Kasha Singh Alice Burton Emily Colbeck UCL collaborators Niclas Thomas Nathan Davies Kings Liver Institute Alberto Quaglia University of Dundee Doreen Cantrell UCL Clinical Collaborators William Rosenberg Guiseppe Fusai Eleni Nastouli Richard Gilson Brian Davidson Francis Robertson All healthy donors, patients and clinic staff Barts and the London Hospital Upkar Gill Jyoti Hansi Patrick Kennedy A*Star, Singapore Muzlifa Haniffa Antonio Bertoletti

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