Periodic Reporting for period 1 - MHT-ImmunoEnhancer (Stimuli-Responsive Nanoplatform to Combine Magnetic Hyperthermia with Immunemodulators Delivery for Glioblastoma Treatment)
Periodo di rendicontazione: 2019-10-01 al 2021-09-30
Glioblastoma (GBM) is the most common primary cancer of the central nervous system and prognosis of patients treated with the current standard care remains extremely poor. Indeed, conventional therapies, including surgery, radiotherapy and chemotherapy, have not resulted in major improvements in the survival outcomes of patients, due to high recurrence and tumor spreading. Because conventional therapies are not effective, there is a clear and urgent need to develop innovative treatments that can be effective at improving the survival expectation of GBM patients.
“MHT-ImmunoEnhancer” focused at advancing the state of the art in GBM management by proposing a novel combinatorial immunotherapy directed to elicit an antitumor immune response capable to induce regression of primary and distant untreated tumors.
To achieve our goal, we designed a multifunctional nanosystem able to combine nanoparticle-mediated hyperthermia with the co-delivery of a potent immunomodulator intended to revert the immunosuppressive microenvironment, which is considered one of the major challenges responsible for the poor prognosis and tumor relapse in GBM.
“MHT-ImmunoEnhancer” focused at advancing the state of the art in GBM management by proposing a novel combinatorial immunotherapy directed to elicit an antitumor immune response capable to induce regression of primary and distant untreated tumors.
To achieve our goal, we designed a multifunctional nanosystem able to combine nanoparticle-mediated hyperthermia with the co-delivery of a potent immunomodulator intended to revert the immunosuppressive microenvironment, which is considered one of the major challenges responsible for the poor prognosis and tumor relapse in GBM.
The work performed during this project led to the proposal of a novel biodegradable and highly biocompatible delivery platform incorporating both iron oxide nanocubes, acting as mediators of mild magnetic hyperthermia (MHT) for thermal therapy, and an immunomodulator driving the re-shaping of tumor microenvironment in GBM. We observed that the proposed approach did not only directly kill GBM cells, but also resulted in the increased expression of molecular signatures that rendered MHT-resistant cells more susceptible to the cytotoxic activity of innate immune cells.
Currently, temozolomide combined with extended focal radiotherapy represents the standard treatment of GBM but, still, the median overall survival of patients is less than 15 months with no significant improvements in recent decades. The establishment of an immunosuppressive tumor microenvironment in GBM is considered responsible for this therapeutic failure by playing a critical role in promoting resistance, immune evasion, tumor growth and spreading. This project demonstrates that a combinatorial approach that simultaneously promotes direct killing of cancer cells and modulates the immune microenvironment can provide a superior alternative to conventional treatments. By making treatment resistant cancer cells more susceptible to immune cell killing, our strategy can potentially overcome tumor recurrence, one of the major hurdles in GBM therapy.