Adult Glioblastoma (GBM) and paediatric brain High Grade Glioma (pHGG) are highly aggressive cancers with extremely poor long-term prognosis. GBM accounts for over 60% of CNS cancer diagnoses with a 5% 5-year survival rate, and similarly, pHGG overall has an extremely poor survival rate, with Diffuse Midline Glioma (DMG) subtype having just a 9-month median survival. Hence, there is a significant unmet clinical need to develop new innovative treatments.
Immunotherapies, such has immune check point blockade and Chimeric Antigen Receptor (CAR) T cell therapies, have recently provided clinicians with an exciting new pillar of therapies outside of brain cancer. However, the efficacy and impact of CAR T cell treatment in brain cancer, such as GBM and pHGG, is yet to be realised. Insights from GBM tumour samples obtained from CAR T cell clinical trials in GBM have demonstrated poor T cell infiltration with suboptimal clinical results being attributed to the presence of extracellular matrix (ECM) in the tumour microenvironment (TME). The ECM is a dense structural component of the TME composed of fibrous proteins and proteoglycans that act as a barrier, preventing T cell infiltration into tumour milieu. Supporting this, recent research has indicated that higher ECM signatures correlate with poorer overall survival in GBM.
Therefore, we hypothesise that we can improve T cell infiltration and therefore responses to immunotherapy by targeting the extensive ECM within the tumour microenvironment of solid tumours.
In the current landscape of brain tumours, the ECM remains poorly characterised and understood. We have gained access to crucial primary human GBM and rare paediatric pHGG samples and performed immunohistochemical staining on 45 of the primary adult GBM tumours and 9 primary pHGG tumours, to interrogate both the intra- and inter-tumoral variability and heterogeneity of the ECM. Matched serial sections were also explored for endogenous T cell infiltration to assess the correlation between ECM deposition and immune infiltration.
Our unique datasets are providing critical insights to elucidate and describe the previously poorly understood ECM of brain tumours. In addition, we are uncovering new ECM targets for the improvement of immunotherapy efficacy for approaches to treating brain cancer.