Advanced age is a major risk factor for the development of diseases affecting the central nervous system (CNS). Glioblastoma (GBM) is the most common primary malignant brain tumor with a median age of diagnosis at 68-70 years of age, and increasing age is associated with worse prognosis.

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In recent years we have observed astonishing advances in cancer therapy, which have led to increased survival rates for patients with multiple
types of tumors.

 

Unfortunately, that is not the case for GBM, which is still considered incurable and its prognosis remains dismal. Since conventional therapies have not resulted in major improvements in the survival outcomes of patients with GBM, increasing efforts are being devoted to developing new therapeutic strategies, particularly in the field of CAR T-cell immunotherapy. CAR T-cells have shown remarkable success in hematological malignancies, but initial attempts to use the same approach in treating solid tumors have encountered various challenges.

 

These challenges include the lack of unique tumor associated antigens and tumor heterogeneity, that
leads to 'antigen escape', and the highly immunosuppressive and glucose-deprived tumor microenvironment (TME), that can lead to T-cell exhaustion.

 

The aim of this project is to overcome some of these main challenges in order to boost the curative potential of CAR T-cells in GBM. This will be done by modulating the immunosuppressive TME, through in vivo expression of IL-12 using CD68 (Tumor Associated Macrophages)
targeted mRNA lipid nanoparticles (LNPs).

 

Also by enhancing CAR T-cells metabolic fitness, engineering 'metabolically superior' cells capable of using trehalose as an alternative source of energy. Lastly, we will evaluate a potential neoadjuvant therapy based on PD1-expressing NanoGhosts loaded with the anti-GBM drug
Gboxin.

 

Even though GBM is a challenging candidate for CAR T-cell immunotherapy, we consider that using these novel combination strategies we will be able to overcome some of the major hurdles posed by these highly aggressive tumors.