Abstract IA13: Treatment of COVID-19 pulmonary failure by targeting BTK

Abstract

Abstract Pulmonary failure is the main cause of mortality related to COVID-19 infection. Up to 80% of patients hospitalized for 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. ATII cells 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) and can trigger inflammatory cytokines and chemoattractants in response to pathogens that recruit and activate other immune cells, including macrophages and neutrophils. We and others previously showed that BTK, and its upstream activator HCK, were involved in TLR-mediated signaling. Both BTK and HCK are triggered by MYD88, a TLR-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 inflammatory responses with ATII cells. As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokine production through ERK1/2. The potential for BTK inhibitors to abrogate lung injury and death was demonstrated in an experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse-adapted strain of H1N1 influenza virus were protected against lung injury. Control mice developed respiratory failure, along with histologic and CT findings consistent with lung injury in sharp contrast to the mice that received ibrutinib. Control mice also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss and all survived. Mice treated with ibrutinib also showed decreased inflammatory cell infiltration as well as proinflammatory cytokines 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’s macroglobulinemia (WM) patients who were on full-dose ibrutinib (420 mg/day) and contracted COVID-19, none experienced dyspnea. In this series, one WM patient who contracted COVID-19 on reduced-dose ibrutinib (140 mg/day) experienced dyspnea and became hypoxic when ibrutinib was stopped and required mechanical ventilation. He was started on full-dose ibrutinib and showed rapid improvement, was extubated the next day, and did not require any oxygen supplementation two days later. Consistent with his rapid course of improvement on ibrutinib, 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 oxygenation and 8 on mechanical ventilation. Eight of 11 (73%) and 2/8 (25%) on supplemental oxygenation and mechanical ventilation were discharged on room air, respectively. Ex vivo analysis of peripheral blood samples showed attenuation of activated monocyte BTK expression and IL-6 production following acalabrutinib. Serially collected blood 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 chemoattractant cytokines that greatly overlapped with those reported elevated in the plasma of SARS-Cov-1 and SARS-COV-2 patients, and in ACE2+ cells from lung tissue of SARS-CoV-1 patients. In the iLLUMINATE randomized study, CLL subjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed significantly decreased levels of inflammatory cytokines associated with infusion related reactions (a cytokine release syndrome). These findings are consistent with a shift from an M1 to M2 polarized macrophage response following ibrutinib and are supported by preclinical and clinical studies showing dependence of macrophage lineage commitment on BTK function. BTK-inhibitors may therefore provide protection against lung injury and even improve pulmonary function in hypoxic patients with COVID-19. Randomized clinical trials to examine the benefit of BTK-inhibitors in COVID-19 patients in pulmonary distress and/or accompanying corollary studies to identify response biomarkers have been initiated: NCT04439006, NCT04382586, NCT04346199, NCT04380688. Selected