Dynamic IMaging of IMmune system interaction with glioblastoma boosted by Focus Ultrasons Strategy to improve personalized therapy – IM2FUS

The brain is by far our most precious organ. That is why the brain is the best-protected organ in the body. The key protective element in our brain system is the blood-brain barrier (BBB) that protect our brain against disease-causing pathogens and toxins that may be present in our blood. However, this protection can play against us in the case of some brain diseases. This protection becomes a strong limitation in the way that the BBB limit the drug diffusion that could fight the tumor cells. Glioblastoma (GBM), for instance, a very aggressive brain tumor remains essentially incurable even if the BBB is compromised by the presence of the tumor. The tumor growth induces abnormal tumor vasculature that leads to a compromised BBB (called in this case blood-tumor barrier (BTB)). This alteration could be beneficial for penetration of drug into the tumor; however, the majority of approved anticancer drugs does not improve the survival of GBM patients. Several aspects can explain the failure to propose an efficient treatment option against GBM mainly because the BTB presents some degree of heterogeneity with some regions presenting intact BBB or presenting low alteration of BTB. It can be hypothesized that the failure to deliver an effective therapy to all regions of the GBM is a major cause for treatment failure. It is the case particularly for the immunotherapy that could help to restore the immune system activity inhibited by the tumor cells. Immunotherapy is a tremendous promise as a strategy for eradicating solid tumors. Immunotherapy based on monoclonal antibody (mAb) failed in GBM due to the low mAb capacities to cross the BBB and BTB.
In IM²FUS project, we propose to study completely an innovative theranostic strategy (therapy and diagnostic) to overcome this drug passage limitation based on an ultrasound method. Ultrasound method has been proved to allow various drug diffusion though the brain without inducing any brain damage. Thanks to microbubbles (MB), this non-invasive method creates an interesting localized and transient manner to open the BBB and the BTB. In IM²FUS, we are taking the advantage of this BBB and BTB disruption by ultrasound coupled with MB to create a synergy between the boost of immunological activity by mAb, the tumor cytotoxic T cell activity increase, and the activation of glial cell to fight against the tumor cells. In order to have potentialize the action of this synergy, we propose to develop a functional biomedical imaging method. It will be possible to not only follow the progress of the disease under treatment but also to propose an intelligent scoring based on immune system biomarkers quantification. This scoring could predict the efficacy of ultrasound method coupled with antibodies-based therapy. ImmunoPET, which combine the high affinity of mAb and the high sensitivity of positron emission tomography (PET) will be used to study the immune system activity as well as the boost of mAb passage thanks to the ultasound. In this project, key biological mechanisms involved with ultrasound combined with mAb will be deeply studied using complementary approaches (in vivo PET, immunohistochemistry, molecular biology and biochemistry) in preclinical orthotopic model that mimics many characteristics of the human GBM phenotype.