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