Glioblastoma (GBM) is one of the most lethal and untreatable human tumours, and is characterized by its extremely poor prognosis. Conventional therapies, including surgery, radiotherapy and chemotherapy, have not resulted in major improvements in the survival, due to high recurrence and tumour spreading. Therefore, there is an urgent need to develop new effective therapies to improve patient survival. The establishment of an immunosuppressive tumour microenvironment (TME) in GBM is known to limit the cytotoxic effects of conventional therapies and in this context, myeloid-derived suppressor cells (MDSCs) play a critical role by promoting immune tolerance, tumour growth and spreading. Hyperthermal therapy in GBM has resulted in improved immune reactivity of tumours, despite this, its effectivity has been limited by its inability to overcome the immunosuppressive TME and induce strong systemic antitumour responses. Consequently, targeting MDSCs in combination with thermal ablation therapies appears to be a very promising strategy.
The goal of the MHT-ImmunoEnhancer project is the development of a dual stimuli-responsive hybrid polymer/Iron oxide nanocubes (IONCs) delivery system in order to combine local fever-range Magnetic Hyperthermia (MHT) with MDSC depletion-targeted immunotherapy for intratumoral treatment of GBM. The specific objectives of our strategy are, 1) to exploit the superior heating efficiency of the hybrid polymer/IONCs platforms to induce tumour damage. 2) To turn the immunosuppressive TME into an immunosupportive one, by local delivery of CpG oligonucleotide; along with 5-Fluorouracil (5-FU), a chemotherapeutic agent. 3) To release CpG and 5-FU specifically at the tumour site under the appropriate stimulus (pH or enzymes/temperature), thus enhancing their tumour retention and therapeutic effect. All these actions will result in the reduction of T-cell-suppressive activity of MDSCs, enhancement of antitumour immune response and tumour regression.
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