Mats Hellström – Translational research on immunotherapy for glioblastoma

My research programme has two overall aims. The first is to develop, characterize and use novel mouse models that recapitulate key aspects of human glioblastoma. The goal is to identify drugs that can be translated into clinical trials and supported by rigorous pre-clinical data. The second main aim is to identify novel combinations of protein biomarkers that can be used to follow disease status in glioblastoma patients.

Gliomas are the most common primary malignant brain tumours and have an incidence of approximately 5 per 100,000 people. The most malignant form of glioma – glioblastoma multiforme (GBM) – is also the most common type and has a peak incidence at 64 years of age in the adult population. Despite recent advances in understanding the genetics and biology of GBM, the treatment options are few and prognosis is dismal. The median survival after diagnosis is around 15 months.

Difficult to find new drugs for gliobastoma

In the last decade, the oncogenic signalling pathways in GBM have been characterized. Receptor tyrosine kinases (RTKs), and in particular epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRa), have been suggested to have prominent roles. Despite the increasing knowledge of RTK signalling, this has not translated to any success in clinical trials for GBM.

One reason for this could be the significant amount of heterogeneity within in each tumour, with clones of glioma cells expressing distinct sets of mutated or amplified RTKs. In addition, drugs aimed to block RTK signalling face the blood brain barrier, a significant hurdle that prevents free access of blood borne drugs to the central nervous system (CNS).

Immunotherapy for glioblastoma

Immunotherapy has recently established itself as a potent and safe treatment in cancer. In particular, immune checkpoint inhibitors, targeting the negative signalling mediated by PD1 and CTLA-4 on T-cells in the tumour microenvironment (TME), have shown great success in the treatment of for example malignant melanoma, lung- and kidney cancer. The complex interplay of cancer cells and TME leads to various degrees of immune suppression in all cancers.

Immunotherapy for glioblastoma poses some specific challenges. This is due to an immune-suppressive TME, absence of resident dendritic cells and unique structure of the lymphatic drainage as compared to the rest of the body. Therefore, the recent success of immune checkpoint blockade in several oncological indications has not yet translated into efficacy in treatment of glioblastoma patients.

In my group we use novel models and treatments of human GBM to address the underlying problems in glioma immunotherapy. With this we hope to eventually enable immunotherapy in GBM patients.