Next generation vascular targeting for brain tumors

Glioblastomas are aggressive gliomas characterised by an extreme invasiveness and dysfunctional vessels.

The abnormal vessels promote tumor progression (1) by providing a route of invasion into the brain and (2) by limiting T cell recruitment.CD93 is highly expressed in glioblastoma vessels and associated with poor prognosis. We have unpublished data showing that CD93 is necessary for perivascular spread of glioma cells.

Our first aim is to explore mechanisms necessary for perivascular invasion of glioma cells by analysis of preclinical glioma models and human glioma tissue, and to test a CD93-targeting antibody that we have developed to block glioma invasion.The efficacy of cancer immunotherapy is hampered by the immunosuppression in glioblastoma.

Tumor vessels respond poorly to inflammatory signals and express low levels of adhesion molecules and chemokines needed for T cell recruitment.

We have recently demonstrated an exciting new approach to increasing T cell recruitment in glioma, by using a brain endothelial targeted AAV to induce LIGHT expression in tumor vessels, changing their phenotype to that of high endothelial venules (HEV).

Our second aim is to use preclinical glioma models and human glioma tissue to investigate  mechanisms involved in anti-tumor immunity induced by tumor associated HEVs.

We will also develop new AAV-targeting vectors that specifically infect tumor endothelial cells in human glioblastoma to enable clinical translation of the AAV-LIGHT therapy.