Monneret AER SEPSIS 2017 V2

ImmunomodulaOon et sepsis : Actualités 2017 Guillaume Monneret Hôp. E. Herriot / Hospices Civils de Lyon EA 7426 -‐ Pathophysiology of Injury-‐Induced Immunosuppression -‐ U. Lyon 1 ISPB (School of Pharmacy) – U. Lyon 1 Flow Division Immunology Department Sepsis-‐3 definiOon Uncontrolled Inflammatory response Decreased arterial pressure Shock MulOple organ failure Singer et al., JAMA 2016 ImmunomodulaOon: first aZempts Uncontrolled inflammatory response Adjunc2ve therapy in addi2on to symptoma2c treatments : an2-‐inflammatory drugs Failure of clinical trials tesOng anO-‐inflammatory therapies Number of Number of Mortality (%) Drug studies paOents Placebo Drug AnO-‐endotoxine 4 2010 3 5 3 5 AnO-‐bradykinine 2 755 3 6 3 9 AnO-‐PAF 2 870 5 0 4 5 AnO-‐TNF 8 4132 4 1 4 0 R solubles TNF 2 688 3 8 4 0 AINS 3 514 4 0 3 7 Steroids 9 1267 3 5 3 9 (high doses) … … … … … Total 3 3 12034 3 8 3 8 Zeni et al, Crit Care Med, 1997 Opal et al. 2013 SOll a room for blocking inflammaOon ? Eichacker, P.Q. et al. Risk and the efficacy of anOinflammatory agents: retrospecOve and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002. Panacek, E.A. et al. Afelimomab in paOents with severe sepsis and elevated interleukin-‐6 levels. Crit Care Med 2004 From IL1-‐RA trials (JAMA 1994, CCM ): 1997 MAS IL1-RA measurments Shakoory B et al., CCM 2016 Meyer NL et al., CCM 2017 SOll a room for blocking inflammaOon ? Eichacker, P.Q. et al. Risk and the efficacy of anOinflammatory agents: retrospecOve and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002. Panacek, E.A. et al. Afelimomab in paOents with severe sepsis and elevated interleukin-‐6 levels. Crit Care Med 2004 From IL1-‐RA trials (JAMA 1994, CCM ): 1997 MAS IL1-RA measurments Shakoory B et al., CCM 2016 Meyer NL et al., CCM 2017 SOll a room for blocking inflammaOon ? Eichacker, P.Q. et al. Risk and the efficacy of anOinflammatory agents: retrospecOve and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002. Panacek, E.A. et al. Afelimomab in paOents with severe sepsis and elevated interleukin-‐6 levels. Crit Care Med 2004 From IL1-‐RA trials (JAMA 1994, CCM ): 1997 MAS Early interven2on IL1-RA measurments + Stra2fica2on mandatory Shakoory B et al., CCM 2016 Meyer NL et al., CCM 2017 Medzhitov et al., Science 2012 The sepsis-‐induced immunosuppression hypothesis Do sepOc paOents present immune alteraOons ? Myeloid cells (summary) Venet & Monneret, 2018 Lymphoid cells (summary) Venet & Monneret, 2018 What about (lymphoid) organs ? Boomer et al. Blood Macrophages (lung, spleen) Lymphoid organs are also affected (post-‐mortem biopsy) : spleen, lungs (+ circulaOng blood) Controls Non-‐ICU paOents ICU paOents SepOc sepsis shock Faivre et al., 2016 Thymus SEPSIS Adapted from Chaudhry HS, J Immunol 2017 Summary Summary Consequences of sepsis-‐induced immunosuppression Severe fungal Infec2ons (Leroy, CCM 2009 ; Hatermink ICM 2003) Decreased clearance of iniQal infecQon (Torgersen 2009) Increased nosocomial infec2ons Viral reac2va2on : CMV, HSV (Landelle, ICM 2010, Grimaldi ICM 2011) (Luyt, AJRCCM 2007 ; Limaye, JAMA 2008 ) Consequences of sepsis-‐induced immunosuppression Severe fungal Infec2ons (Leroy, CCM 2009 ; Hatermink ICM 2003) Decreased clearance of iniQal infecQon (Torgersen 2009) ↗ mortality Increased nosocomial infec2ons Viral reac2va2on : CMV, HSV (Landelle, ICM 2010, Grimaldi ICM 2011) (Luyt, AJRCCM 2007 ; Limaye, JAMA 2008 ) Median discharge = 11 days ImmunosOmulaOon in sepsis Slide courtsey : P. Pickkers Principles of immunotherapy AnObioOcs Principles of immunotherapy AnObioOcs Rejuvenate / s2mulate immune cells Principles of immunotherapy Compelling preclinical results in sepsis: -‐ Improves bacterial clearance and mortality in mice -‐ Restores immune funcOons ex-‐vivo in human cells Restoring innate response 2013 1. INTERFERON -‐ γ (IMUKIN) Docke WD et al. Nat Med. 1997;3:678-‐81 Monocyte deac2va2on in sep2c pa2ents: restora2on by IFN-‐gamma treatment 9 patients severe sepsis 26 patients severe sepsis HLA-DR < 30 % HLA-DR < 30 % (2 consecutive days) Non randomized (2 consecutive days) Interferon-gamma Mortality 33 % Mortality 58 % Case reports (successful) -‐ Nakos et al., CCM 2002 (nosocomial infecOons in trauma) -‐ Luckasewicz et al., CCM 2009 (nosocomial) -‐ Delsing et al, BMC InfecOous Diseases 2014 (fungal infecOons) -‐ Nalos et al., AJRCCM 2012 (staph sepsis) -‐ Mezidi et al., Minerva Anesth 2014 (fungal infecOon) -‐ Grimaldi et al., Lancet infect Dis 2017 (mucormycosis) Current trial in fungal infecOons (Netea, Nijmingen) – non randomized 2. GM-‐CSF (Leukine) -‐ No adverse effects -‐ Significantly shorter Ome of venOlaOon (148 vs 208 h, p=0.04) -‐ shorter length of intra-‐hospital stay (59 vs 69 days) -‐ shorter length of ICU stay (41 vs 52) -‐ 28-‐day mortality not different (trial not powered for mortality) Absence of nosocomial InfecOons on GM-‐CSF The GRID study GM-CSF to Decrease ICU Acquired Infections (GRID trial – French multicenter – NCT02361528 ) N = 488 D – 3 1 year ICU release D1 follow-‐up D3 D5 D7 D28 72-‐96 hr TRAITEMENT HLA DR HLA DR HLA DR HLA DR Sepsis diag. Randomisation End of treatment Survival Trial ended by promoter at 100 paOents Results to be published in 2018 Restoring adapOve response 2013 3. AnO-‐PD1 / AnO-‐PD-‐L1 Early ICU course: -‐ Acute Lung Injury -‐ OsteomyeliOs -‐ Deep wound infecOon -‐ MDR enterobacteria -‐ Mucormycosis Low levels of mHLA-‐DR High levels of PD1 on Tcells Immunkin (IFNg) Nivolumab (anO PD-‐1) Current trials ANTI PD-‐1 / ANTI-‐PD-‐L1 Two Phase 1b/2a, randomized, double-‐blinded, placebo-‐controlled, mulOcenter study to evaluate the safety, tolerability, pharmacokineOcs and pharmacodynamics: -‐ Nivolumab (anO-‐PD1, NCT02960854) -‐ BMS-‐936559 (anO-‐PD-‐L1, NCT02576457) Next trial in preparaOon : PD-‐1 (internaOonal mulOcenter, randomized trial) 4. IL-‐7 Restores ability of T cells to make IFN-‐ γ. IL-‐7 acts at mulOple levels Increases cell to improve funcOonality adhesion Decreases molecules of CD4 and CD8 T cells T cell and secondarily exhausOon. adapOve immunity. IL-‐7 offers a new approach to infecOous disease. Increases proliferaOon Decreases apoptosis Increases T cell receptor diversity. => Day 4 total lymphocyte count absence (>1200) Severe (< 600) Ly increase between baseline and day 3 The IRIS trial (to be submiZed) §. Richard Hotchkiss §. Andrew Walton §. Edward Sherwood §. Bruno Francois §. Thomas Daix §. Emilie Lereclus §. Michelle Nouaille §. Ludmila Baudrillart §. Michel Morre §. Guillaume Monneret §. Thomas Rimmelé ImmunosOmulaOon (summary) -‐ Preclinical results in sepsis : +++ -‐ Several clinical cases : +++ -‐ First trials promising (no adverse “cytokine storm”) -‐ GRID (GM-‐CSF) & IRIS (IL-‐7) : to be published in 2018 -‐ AnO-‐PD-‐1 : to be started in 2018 => AwaiOng good news from mulOcenter RCT 2016 The future? => The « sepsis immunogram » sepsis mHLA-‐DR Lymphocyte count mRNA panel Cytokines MDSC count Inhibitory FuncOonal tesOng checkpoints monocyte (meningococcemia ≠ immunosenescence ≠ diabetes) + impact of biotherapies LYON, F EA 7426 « Pathophysiology of Injury-induced Immunosuppression » Crédit photo : Julie Mouillaux .

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