9/19/2020 COVID19 as Immunology Boot Camp: Anti-Viral Defense, Cytokine Biology & Prospects for therapy Leonard H Calabrese Professor of Medicine Cleveland Clinic Lerner College of Medicine RJ Fasenmyer Chair of Clinical Immunology Department of Rheumatic and Immunologic Disease Cleveland Clinic @LCalabreseDO [email protected] COVID19 and Immunology 1 9/19/2020 Outline • Idealized clinical course of COVI19 • Immunology at 30,000 feet • Immunology of COVID-19 • Rheumatic therapies targeting cytokine storm • Unanswered questions 45000 40000 35000 30000 25000 Pubmed medRxiv 20000 bioRxiv Published articles Number Number of articles Peer reviewed 15000 No peer reviewed 10000 Curated 5000 AUGUST 10 2020 0 Feb-20 Mar-20 Apr-20 May-20 Jun-20 Jul-20 Aug-20 Sources: https://pubmed.ncbi.nlm.nih.gov, https://www.medrxiv.org, https://www.biorxiv.org 2 9/19/2020 ADAPTIVE ADVANCED CYTOKINE TYPE 1,2 3 IFN IMMUNITY FLOW DYSREGULATION INNATE IMMUNITY BIG PAMPS DATA DAMPS CD14+16+ Monocytes T Cell CYTOKINE STORM EXHAUSTION 3 9/19/2020 COVID-19 • Caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) • Single-stranded enveloped RNA virus • 7 human coronaviruses: - Severe disease: SARS-CoV, MERS-CoV, SARS-CoV-2 - Mild symptoms: HKU1, NL63, OC43 and 229E • Like SARS and MERS, SARS-CoV-2 believed to have moved from bats to an intermediate host – possibly Malayan Pangolin humans. Andersen KG, et al. Nat Med March 2020 Course of COVID-19 Infection – A Paradigm for Therapy ACT 1 ACT 2 ACT 3 asymptomatic non-severe symptomatic severe respiratory-inflammatory IMMUNE REPSONSE INNATE IMMUNE ADAPTIVE IMMUNE CYTOKINE OVER TIME ACTIVATION ACTIVATION MEDIATED RISK FOR STAGE 3 Self limiting in 80% SYNDROME Severe in 15-20% Viral engagement of Generation of specific Abs IL-6, IL-1, TNF, GM- Fatal 1-2% PAMPs and T cell response CSF, IFN, IFN AGE Low Type 1 IFN Release of DAMPS Immuno-Coagulopathy DM Quantitative viral load ASHD Renal disease HTN Viral response phase Hyperinflammatory phase Male sex Cytokine Storm Other Severity of Illness Severity IgM response day 5-10 IgG response day 7-14 Time Course ASHD = arteriosclerotic heart disease; HTN = hypertension; PAMP = pathogen-associated molecular pattern; DAMP = damage-associated molecular patterns; TNF = tumor necrosis factor; IL = Interleukin; GM-CSF = Granulocyte- macrophage colony-stimulating factor; IFN = interferon 4 9/19/2020 CCF Art Department Balance Calabrese LH, Marriot X Ann Rheum Dis Jan 2020 5 9/19/2020 Calabrese LH, Marriot X Ann Rheum Dis Jan 2020 CCOVID19 Calabrese LH, Marriot X Ann Rheum Dis Jan 2020 6 9/19/2020 Antiviral Immunity – 30,000 feet INNATE • Initiated at the cellular level following infections and replication • Viruses produce pathogenic RNA or DNA that are sensed by PRR (TLR RIG STING) • PRR engagement culminates in oligimerization of PRRs and activation of downstream transcription factors including interferon regulator factors(IRFs) and NFkB These launch 1. Cellular antiviral defenses IFN I & III and up regulation of IFN stimulated genes 2. Stimulation and coordination of innate and adaptive immune response via chemokines and cytokines McNab F et al Nat Reviews Immunology 15:87,2015 Evolution of the immune system and Viral Invasion Karim M. Yatim, and Fadi G. Lakkis CJASN 2015;10:1274- 1281 ©2015 by American Society of Nephrology 7 9/19/2020 PNAS first published July 9, 2020 https://doi.org/10.1073/pnas.2008410117 Flow of T-cell Memory Acute MILD viral infection COVID19 INFECTION Naïve T cell Functional memory CTL Central and peripheral 4 to 6 hours • 95% die • SELF-renewal IL-7, IL-15 x 10 days 106 week RECOVERY CTL effector cell 2 to 3 days inflammation 10-14 days 8 9/19/2020 Act 3 – Hyper-inflammation PAMP Driven DAMP DRIVEN Virus- Necroptosis Tissue tropism Local-regional Target organs damage Viremia Cells of innate immunity Bacteria Secondary HLH/MAS – lessons learned Cytokine Storm / Cytokine Release Syndrome loosely applies to wide variety of conditions also referred to as (SIRS) that can be triggered by a variety of factors such as infections and certain drugs Acute Primary Immunodeficiency States HLH inflammation Malignancy associated Castelmans End-organ Lymphoma / Rx CAR-T cell therapy damage Auto inflammatory diseases – JIA AOS Death Infections Influenza, EBV, COVID19 9 9/19/2020 Capable of predicting clinical outcomes more than 10 days in advance with 90% accuracy LDH >365 U/L = tissue damage CRP > 4.1mg% = inflammation Lymphocytes < 14.7% = immune activation VIRAL ESCAPE---------------PAMPS Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 PAMP DRIVEN Cell and animal models of SARS-CoV2 IFA and other viruses for in depth transcriptional responses Highlights • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response • Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models • Low innate antiviral defenses and high pro- inflammatory cues contribute to COVID-19 Blanco-Melo et al., 2020, Cell 181, 1–10 May 28, 2020 ª 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.04.026 10 9/19/2020 COVID19 and BIG DATA • Integrating large numbers of immune parameters( 200+) and clinical features • Multi-parameter flow • Transcriptomics • Proteomics • Phosphoproeomics • Single cell analysis • Immunologic Age Nature AUG 20 2020 11 9/19/2020 N=90 COVID19 n=71 controls T cell activation and non T B cell expansion ( myeloid compartment) Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. COVID19 immune responses are heterogeneous and some correlate with disease severity Science 15 Jul 2020:eabc8511DOI: 10.1126/science.abc8511 www.clinincaltrials.gov • August 28 +/- 3000 IFN Rx JAKi 1 GM-CSF Rx Anti-GM-CSF IL-7 ? Anti- pDC 12 9/19/2020 Immunotherapeutic Strategies for COVID-19 Cytokine Release and Beyond Kinase Inhibitors tofacitinib, baricitinib, Targeted ruxolitinib Therapy others Non specific Glucocorticoids, IL-1, IL-6, calcineurin- TNF, nhibitors, GMCSF M-tor-inhibitors Gamma IFN IMMUNOTHERAPY Tolerogenic therapies Passive Therapy IVIG, T regs immune plasma Low dose IL-2 Specific Abs CELLULAR THERAPIES NK cell therapies Anti-pDC others 30,000 foot view of COVID19 trial design 1. Diagnosis 2. Triage by severity 3. Comparator 1. Historical (non RCT) 2. SOC CHANGING!!! 3. Other 13 9/19/2020 Candidates • IL6 inhibitors • IL-1 inhibitors • Glucocorticoids • Kinase inhibitors –JAKi, PI3K,BTKi,TKIs others • GM-CSF inhibitors Cytokine Release Syndrome Course after tocilizumab Critical Care Med 2017 14 9/19/2020 IL-6 inhibitors • Advantage: approved agents for numerous autoimmune and auto-inflammatory syndromes including CAR-T cell cytokine storm • Administration: IV dosing, frequency undetermined, narrow therapeutic index (1-2x) • Disadvantage/caution: associated with SIEs in chronic use, increased liver enzymes, decreased platelets, WBC Anti-IL6 and COVID-19 Phase 1 Phase 2 Phase 3 Phase 4 Clazakinumab NCT04348500 NCT04359901 Sarilumab NCT04386239 NCT04315298 NCT04322773 NCT04333914 NCT04335071 NCT04315480 Tocilizumab NCT04445272 NCT04330638 NCT04377750 NCT04370834 NCT04331808 NCT04322773 15 9/19/2020 In these intubated patients, improvisent of survival: HR=0.55 (95% CI 0.33, 0.90) (red) and in spite an increasesarilumab of bacterial infections: (54% vs 26%) (orange) IL-1 Product of inflammasome activation DAMPS 16 9/19/2020 IL-1 • Advantages: Approved in various autoimmune/auto-inflammatory disorders (Cryopyrinopathies,JIA, AOS, RA) off label in many including sHLH/MAS and sepsis • Administration: Three agents in trial anakinra, canakinumab and rilonacept • Disadvantages/caution: Anakinra wide therapeutic index (100mgQD-3500mgQD) CALABRESE L, CALABRESE C. CYTOKINE RELEASE SYNDROME AND THE PROSPECTS FOR IMMUNOTHERAPY WITH COVID-19 PART 2: THE ROLE OF IL-1 CCJM JULY 2020 Anakinra – 3: 52 patients • No patient on mechanical ventilation • Anakinra: 200 mg SC /day 3 days and 100 mg SC /day 7 days • Historical controls Thelancet.com/rheumatology Published online May 29, 2020 17 9/19/2020 Glucocorticoids • GC known to modulate the immune system since 1924 with landmark by Dale et al. work in the 70s documenting immunosuppressive effects • More recently Human Immunome studies demonstrated suppression of NF-kB, apoptosis and cell death differentially effecting T and B cells and NK cells in humans (Olnes M et al Sci Reports 6:23002,16) • Previous work in SARS MERS& severe influenza mixed/underpowered and suffer from heterogeneity of agent/dose/duration • Currently over 40 trials using GC in COVID19 on clininctrial.gov Dexamethasone COVI9-19 : Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p NNT=8 for mortality 18 9/19/2020 Course of COVID-19 Infection – A Paradigm for Therapy ACT 1 ACT2 ACT 3 asymptomatic non-severe symptomatic severe respiratory-inflammatory IMMUNE REPSONSE INNATE IMMUNE ADAPTIVE IMMUNE CYTOKINE RELEASE OVER TIME ACTIVATIONAntivirals ACTIVATION SYNDROME RISK FOR STAGE 3 Self limiting in 80% Viral engagement of Generation of specific Abs IL-6, IL-1, TNF, GM- Severe in 15-20% PAMPsType 1 and 3 IFNsand T cell response CSF, IFN, IFN Fatal 1-2% Low TypeImmune 1 IFN plasmaRelease of DAMPS Coagulopathy AGE Complement DM Quantitative viral load ASHD Renal disease HTN Viral response phase Hyperinflammatory phase Male sex Cytokine Storm IgM response day 5-10 Other Severity of Illness Severity Immunomodulatory therapies targeting IgG response day 7-14 IL-1,TNF, IL-6,GMCSF Glucocorticoids, kinase inh Xrt-PD4 i Time Course others ASHD = arteriosclerotic heart disease; HTN = hypertension; PAMP = pathogen-associated molecular pattern; DAMP = damage-associated molecular patterns; TNF = tumor necrosis factor; IL = Interleukin; GM-CSF = Granulocyte- macrophage colony-stimulating factor; IFN = interferon • Timing is critical but its not about chronologic timing • Early in identifying Endotypes / Immunotypes • Lack of Biomarkers correlating correlating with Endotypes or Immunotypes of importance 2020 Jul; 19(7): 102567.