Treatment of COVID-19 pulmonary failure by targeting BTK
Authors: Steven Peter Treon
Journal: Clinical Cancer Research (2020)

Pulmonary failure is the main cause of mortality related to COVID-19 infection  Up to 80% of patients hospitalizedfor COVID-19 infection require supplemental oxygenation, of whom 30-40% may require mechanical ventilation SARS-CoV-2 binds via the ACE2-receptor that is highly expressed on alveolar type II (ATII) cells in the lung  ATIIcells constitute 5-15% of the lung epithelium  While alveolar type I cells are highly adapted for gas exchange, alveolar type II cells have a specialized role in innate immune response  ATII cells express Toll receptors (TLRs) andcan trigger inflammatory cytokines and chemoattractants in response to pathogens that recruit and activate otherimmune cells, including macrophages and neutrophils  We and others previously showed that BTK, and itsupstream activator HCK, were involved in TLR-mediated signaling  Both BTK and HCK are triggered by MYD88, aTLR-adaptor protein that signals for all Toll receptors except TLR3 in response to viral and bacterial pathogens, including coronaviruses  ATII cells express TLRs, as do alveolar macrophages that coordinate inflammatoryresponses with ATII cells  As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokineproduction through ERK1/2  The potential for BTK inhibitors to abrogate lung injury and death was demonstrated inan experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse-adapted strain ofH1N1 influenza virus were protected against lung injury  Control mice developed respiratory failure, along withhistologic and CT findings consistent with lung injury in sharp contrast to the mice that received ibrutinib  Controlmice also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss and allsurvived  Mice treated with ibrutinib also showed decreased inflammatory cell infiltration as well as proinflammatorycytokines in lung tissues that included proinflammatory and chemoattractant cytokines such as IL-1β, IL-6, KC/CXCL1, TNFα, and MCP-1 observed in SARS-Cov-1 and SARS-CoV-2 patients  In a series of Waldenstrom'smacroglobulinemia (WM) patients who were on full-dose ibrutinib (420 mg/day) and contracted COVID-19, noneexperienced dyspnea  In this series, one WM patient who contracted COVID-19 on reduced-dose ibrutinib (140mg/day) experienced dyspnea and became hypoxic when ibrutinib was stopped and required mechanicalventilation  He was started on full-dose ibrutinib and showed rapid improvement, was extubated the next day, anddid not require any oxygen supplementation two days later  Consistent with his rapid course of improvement onibrutinib, his C-reactive protein level showed a marked decrease  In a subsequent and larger experience, Roschewski and colleagues administered acalabrutinib to 19 COVID-19 patients, 11 on supplemental oxygenationand 8 on mechanical ventilation  Eight of 11 (73%) and 2/8 (25%) on supplemental oxygenation and mechanicalventilation were discharged on room air, respectively  Ex vivo analysis of peripheral blood samples showedattenuation of activated monocyte BTK expression and IL-6 production following acalabrutinib  Serially collectedblood samples from patients with chronic lymphocytic leukemia (CLL), WM, and chronic graft-versus-host disease(cGVHD) on ibrutinib monotherapy also showed marked reductions in proinflammatory and chemoattractantcytokines that greatly overlapped with those reported elevated in the plasma of SARS-Cov-1 and SARS-COV-2patients, and in ACE2+ cells from lung tissue of SARS-CoV-1 patients  In the iLLUMINATE randomized study, CLLsubjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed significantly decreasedlevels of inflammatory cytokines associated with infusion related reactions (a cytokine release syndrome)  Thesefindings are consistent with a shift from an M1 to M2 polarized macrophage response following ibrutinib and aresupported by preclinical and clinical studies showing dependence of macrophage lineage commitment on BTKfunction  BTK-inhibitors may therefore provide rotection against lung injury and even improve pulmonary function inhypoxic patients with COVID-19  Randomized clinical trials to examine the benefit of BTK-inhibitors in COVID-19patients in pulmonary distress and/or accompanying corollary studies to identify response biomarkers have beeninitiated: