Clinical trials

Background

In 2008 Overbeek et al. reported a patient who demonstrated very fast recovery of pulmonary edema upon initiation of imatinib therapy. This patient was admitted for pulmonary hypertension (based on pulmonary veno-occlusive disease), but had severe respiratory impairment, among others due to concomitant pulmonary edema. Upon initiation of imatinib for the pulmonary hypertension (Schermuly 2005, Hoeper 2013), rapid recovery of respiratory status and reversal of edema was observed. Due to the very fast effect, a direct effect of imatinib on pulmonary endothelial barrier function was hypothesized (Overbeek 2008). This hypothesis was evaluated in subsequent preclinical in vitro and in vivo studies.

Imatinib is a small molecule inhibitor that is well known for its ability to block the ATPase activity of various kinase enzymes, including c-Abl, Abl-related gene (ARG), PDGFR, DDR-1 and c-KIT. c-Abl is a proto-oncogene, on fusion of which with bcr results in a chimeric Bcr-Abl protein with activated Abl tyrosine kinase activity (Lugo 1990), the underlying cause of CML (Schiffer 2007; Druker 2001).

Figure 1. Cartoon illustrating the process of vascular leak and edema formation due to damage to the alveolar-capillary barrier. Primed/activated neutrophils and circulating cytokines lead to activation of endothelial cells, and subsequent gap formation between adjacent endothelial cells. Disruption of the alveolar-capillary barrier finally results in flooding of the alveoli. Figure from Matthay et al. J Clin Invest 2012

Using in vitro measures of endothelial permeability, Aman et al (2012) demonstrated that imatinib preserves endothelial barrier integrity during stimulation with inflammatory stimuli. The effect was demonstrated in primary human endothelial cells from various origins (umbilical vein, pulmonary microvasculature, and skin microvasculature) and with various inflammatory stimuli (thrombin, histamine, vascular endothelial growth factor (VEGF)). These effects were observed with imatinib concentrations that parallel plasma concentrations measured in CML patients receiving imatinib. A range of preclinical evidence indicates that imatinib protects endothelial barrier function via the inhibition of Abl-related gene (ARG) (Aman et al, patent WO2012150857 A1). Knockdown of ARG using ARG siRNA in this in vitro model significantly reduced thrombin-induced hyper-permeability, with a similar profile of effects on electrical resistance and permeability, compared to imatinib treatment.

The protective effect of imatinib on the endothelial barrier has been confirmed using in vivo models of vascular leak. Pretreatment of mice with imatinib reduced VEGF-induced vascular leak in skin. Similarly, imatinib attenuated vascular leak in an ex vivo model of pulmonary vascular permeability. The relevance of imatinib treatment to disease states was demonstrated in a sepsis model, in which it reduced inflammatory vascular leak in both the kidneys and lungs. Of note, imatinib in these mice was initiated 6 hours after induction of sepsis (Aman 2012).

Together, this preclinical work indicates that imatinib effectively protects the pulmonary endothelial barrier during inflammation, both in human microvascular lung endothelial cells, and in murine models of pulmonary vascular leak and systemic inflammation. As inflammatory disruption of the endothelial barrier is a key pathophysiological mechanism in the development of ARDS, these data strongly support application of imatinib in ARDS. The protective effect of imatinib was confirmed in several other preclinical studies, which also demonstrated that imatinib reduced pulmonary vascular leak, improved oxygenation and reduced mortality in various mouse models of acute lung injury (Stephens et al, 2014; Letsiou, 2015).

In vitro studies 

Model 

Effect of imatinib 

Reference 

Rat aortic endothelial cells  

Protects endothelial barrier 

Kurimoto et al, Am J Physiol Heart Circ Physiol 2004 Link

Human umbilical vein endothelial cells 

Protects endothelial barrier, improves cell-matrix adhesion 

Aman et al, Circ 2012 Link

Human lung microvascular endothelial cells 

Protects endothelial barrier 

Aman et al, Circ 2012 Link

Immortalized endothelial cells 

Protects endothelial barrier 

Chislock et al, PLoS One 2013 Link

Human umbilical vein endothelial cells 

Protects endothelial barrier 

Kim et al, ATVB 2014 Link

Mouse lung microvascular endothelial cells 

Protects endothelial barrier 

Stephens et al, Am J Physiol 2014 Link

 

In vivo studies 

Model 

Effect of imatinib 

Reference 

Bleomycin-induced lung injury

Anti-inflammatory; anti-fibrotic

Rhee et al, Respiration 2011 Link

Isolated perfused lung model (mouse) 

Inhibits lung vascular leak 

Aman et al, Circ 2012 Link

Miles assay (mouse) 

Attenuates vascular leak in skin 

Aman et al, Circ 2012 Link

Cecal Ligation & Puncture (Sepsis) (mouse) 

Attenuates vascular leak in lungs, kidneys 

Aman et al, Circ 2012 Link

Intratracheal LPS (mouse) 

Attenuates pulmonary edema 

Kim et al, Crit Care 2013 Link

Ischemia-reperfusion in reperfusion lung

Reduces endothelial cytotoxicity

Stephens et al, Am J Physiol 2014 Link

Miles assay (mouse) 

Attenuates vascular leak in skin 

Kim et al, ATVB 2014 Link

Intratracheal LPS (mouse) 

Attenuates vascular leak and inflammation, reduces mortality

Letsiou et al, Am J Physiol 2015 Link; Rizzo et al, Am J Physiol 2015 Link

Cardiac bypass surgery

Attenuates vascular leak, improves perfusion, improves oxygenation

Koning, BJA 2016 Link

Case-reports (human) 

Condition/disease 

Effect of imatinib 

Reference 

Pulmonary veno-occlusive disease

Resolution of pulmonary edema, improvement of oxygenation (<24h) 

Overbeek et al, Eur Respir J 2008 Link

Bleomycin-induced pneumonitis / lung injury  

Resolution of pulmonary edema 

Carnevale-Schianca et al, J Clin Oncol 2011 Link

Idiopathic pulmonary vascular leak 

Resolution of pulmonary edema, reduction of pulmonary vascular leak  

Aman et al, Am J Respir Crit Care 2013  Link

Severe systemic capillary leak syndrome

Loss of fluid and normalization of hematocrit (0.8 before treatment) 

Unpublished 

Pulmonary GvHD with ground glass opacities and severe hypoxemia 

Within 5 days, improvement of SaO2, weaning from Optiflow (FiO2 90%) 

Unpublished 

Drug-induced pneumonitis 

Resolution of pneumonitis, case series 

Langberg, Acta Oncol 2018 Link

COVID-19 

Resolution of disease and pulmonary opacities 

Morales-Ortega, Acta Oncol 2018 Link