Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment

Safety of a new stent design during magnetic particle imaging

Aortic coarctation is a potentially life-threatening disease in newborns that requires early treatment. Recently, a new stent was developed for this purpose, which can be redilatated and thus adapted to the growth of the infant’s aorta. Due to the lack of ionizing radiation MPI is a very promising imaging technique for this clinically very important application in children. Therefore, the safety of this stent with regard to heating by oscillating magnetic fields must be investigated before the stent can be used

Safety Measurements for Heating of Instruments for Cardiovascular Interventions in Magnetic Particle Imaging (MPI) - First Experiences

Magnetic particle imaging (MPI) has emerged as a new imaging method with the potential of delivering images of high spatial and temporal resolutions and free of ionizing radiation. Recent studies demonstrated the feasibility of differentiation between signal-generating and non-signal-generating devices in Magnetic Particle Spectroscopy (MPS) and visualization of commercially available catheters and guide-wires in MPI itself. Thus, MPI seems to be a promising imaging tool for cardiovascular interventions. Several commercially available catheters and guide-wires were tested in this study regarding heating. Heating behavior was correlated to the spectra generated by the devices and measured by the MPI. The results indicate that each instrument should be tested separately due to the wide spectrum of measured temperature changes of signal-generating instruments, which is up to 85°C in contrast to non-signal-generating devices. Development of higher temperatures seems to be a limitation for the use of these devices in cardiovascular interventions

Stent Lumen Quantification of 21 Endovascular Stents with MPI

Restenoses are a common problem after stent implantations and may cause new ischemic events, e.g. heart attacks and strokes. Thus, early diagnosis and treatment of in stent stenoses has tremendous clinical impact. Visualization and quantification of the stent lumen with the established noninvasive imaging modalities MRI and CT is severely limited by stent induced artifacts. The aim of this study was to investigate whether MPI can quantify the stent lumen accurately.   Int. J. Mag. Part. Imag. 6(2), Suppl. 1, 2020, Article ID: 2009021, DOI: 10.18416/IJMPI.2020.200902

Heating of an Aortic Stent for Coarctation Treatment During Magnetic Particle Imaging and Magnetic Resonance Imaging—A Comparative In Vitro Study

Purpose!#!To evaluate heating of a redilatable stent for the treatment of aortic coarctation in neonates and small children in the new imaging modality magnetic particle imaging and established magnetic resonance imaging.!##!Materials and methods!#!The cobalt-chromium stent (BabyStent, OSYPKA AG, Rheinfelden, Germany) has a stent design which allows for redilatation and adjustment of the diameter from 6 to 16 mm for a use in aortic coarctation. The stent loses its radial integrity while opening at predetermined breaking points at a diameter of 14 mm or 16 mm, respectively. We measured the temperature increase in the stent at different diameters during 7-min magnetic particle imaging and magnetic resonance imaging scans with fiber optic thermometers under static conditions surrounded by air. In magnetic particle imaging, stents with diameters from 6 to 16 mm were tested while in magnetic resonance imaging only stents with diameters of 6 mm and 14 mm were investigated exemplarily.!##!Result!#!In magnetic particle imaging, the measured temperature differences increased up to 4.7 K with growing diameters, whereas the opened stents with discontinuous struts at 14 and 16 mm showed only minimal heating of max. 0.5 K. In contrast to magnetic particle imaging, our measurements showed no heating of the stents during magnetic resonance imaging under identical conditions.!##!Conclusion!#!The BabyStent did show only slight heating in magnetic particle imaging and no detectable temperature increase in magnetic resonance imaging

Extent determination of stent heating in MPI

MPI offers a huge potential for cardiovascular imaging and interventional guidance. Especially, stent lumen imaging is an advantageous feature of MPI. Due to the presence of oscillating magnetic fields some metallic objects show temperature increase during MPI scans. Regarding first available human size MPI scanners and thus, future clinical application, the extent of stent heating becomes an important safety issue which could limit the application of MPI for specific patient groups. In this work, the temperature increase of stents with large diameters was investigated to determine the extent of stent heating in MPI

Magnetic Particle Imaging (MPI): Experimental Quantification of Vascular Stenosis Using Stationary Stenosis Phantoms

<div><p>Magnetic Particle Imaging (MPI) is able to provide high temporal and good spatial resolution, high signal-to-noise ratio and sensitivity. Furthermore, it is a truly quantitative method as its signal strength is proportional to the concentration of its tracer, superparamagnetic iron oxide nanoparticles (SPIOs). Because of that, MPI is proposed to be a promising future method for cardiovascular imaging. Here, an interesting application may be the quantification of vascular pathologies like stenosis by utilizing the proportionality of the SPIO concentration and the MPI signal strength. In this study, the feasibility of MPI based stenosis quantification is evaluated based on this application scenario. Nine different stenosis phantoms with a normal diameter of 10 mm each and different stenoses of 1–9 mm and ten reference phantoms with a straight diameter of 1–10 mm were filled with a 1% Resovist dilution and measured in a preclinical MPI-demonstrator. The MPI signal intensities of the reference phantoms were compared to each other and the change of signal intensity within each stenosis phantom was used to calculate the degree of stenosis. These values were then compared to the known diameters of each phantom. As a second measurement, the 5 mm stenosis phantom was used for a serial dilution measurement down to a Resovist dilution of 1:3200 (0.031%), which is lower than a first pass blood concentration of a Resovist bolus in the peripheral arteries of an average adult human of at least about 1:1000. The correlation of the stenosis values based on MPI signal intensity measurements and based on the known diameters showed a very good agreement, proving the high precision of quantitative MPI in this regard.</p></div