5A. Crossing the blood-brain barrier for local immune modulation of the tumour micro-environment by innovative drug delivery methods

H3K27M-altered diffuse midline glioma (DMG) is a deadly brain cancer that mostly occurs in children and young adults. Despite decades of clinical trials, survival has remained largely unchanged. These tumours display a tumour immune micro-environment (TIME), with an abundance of bone marrow-derived macrophages and resident microglia, that is immune suppressive and tumour-promoting. Furthermore, an intact blood-brain barrier prevents more than 90% of drugs from entering the tumour to therapeutic concentrations.

Focused ultrasound-mediated BBB opening (FUS-BBBO) is a technology with which the BBB can be temporarily and locally opened using microbubbles injected into the bloodstream. These microbubbles are subsequently induced to oscillate in the blood vessels of the brain with ultrasound delivered non-invasively outside the skull. This causes temporary and local disruption of the tight junctions of the endothelial cells in the BBB, as well as stimulation of transcytosis. Convection-enhanced delivery is another drug delivery technique that allows for delivery of therapeutics to the brain using a constant pressure flow over mini-catheters placed into the tumour and its (immune) micro-environment.

This project will focus on the reversal of the immunosuppressive state of the micro-environment by bringing drugs into the TIME that render the macrophages and microglia in the tumour more immunogenic, aiming for a better anti-tumour response by the adaptive immune system. The novel drug delivery technologies mentioned above will be employed for delivery of immunomodulatory drugs over the BBB.

Both in vitro assays and immune proficient DMG models in vivo will be used in this context. By using clinically available drugs in these models, this project has a high translational value, with the potential of being translated into early phase clinical trials in these detrimental cancers.