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Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 reduction after intranasal anti-Gal-1 siRNA administration

par Van Woensel, Matthias
Promoteur Amighi, Karim ;De Vleeschouwer, Steven
Co-Promoteur Wauthoz, Nathalie ;Van Gool, Stefaan Willy V S.W.
Publication Non publié, 2016-12-13

Thèse de doctorat

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Résumé :

High grade gliomas remain a devastating disease, for which a curative therapy is virtually absent. The high medical need is unmet by novel treatment strategies and advances in chemo-and radiotherapy. Patients diagnosed for GBM face a median survival of 15 months after maximal standard-of-care therapy, and relapse is often observed due to micro-metastasis in the direct environment of resection. In part, current treatment modalities such as chemo-and immunotherapy are hampered in their efficacy due to the specialized TME. This area is adequately equipped to withstand the cytotoxic attack of chemo- and immunotherapy. Therefore, we hypothesized that modulation of the TME could decrease these defense mechanisms, and increase susceptibility to tumor lysis.In this respect, we focused on Gal-1 as an ideal target to modulate the TME in the context of GBM. Gal-1 exerts multiple tumor promoting functions. From pre-clinical research, we have learned that Gal-1 is an important mediator for the proliferation and migration of tumor cells, moreover Gal-1 could also promote angiogenesis in the TME, providing nutrients and oxygen for GBM to grow. Gal-1 also maintains the inherent defense mechanisms to chemo and immunotherapy. Gal-1 is crucial for the resistance mechanisms to TMZ by altering the EPR stress response. Moreover, and most important for our purposes, Gal-1 is also a crucial immune suppressor in the TME, which can induce apoptosis in activated T cells, and recruit Tregs. To target Gal-1 in the TME would be clinically most relevant if this could be performed via a non-invasive treatment modality. Therefore, we developed a nanoparticle complex that could deliver siGal-1 from the nasal cavity directly to the CNS, and even the TME. This nose-to-brain delivery bypasses systemic routes, with a higher (and more selective) local bioavailability in the CNS. The major pharmaceutical excipient in this nanoparticle complex consists of chitosan polymers. These polymers are highly interesting agents to promote nose-to-brain delivery due their muco-adhesive and epithelial barrier modulation properties. When applying these particles in vitro on GBM cells, a solid decrease of Gal-1 was noted, and the epithelial modulatory properties were confirmed. Furthermore, we observed a rapid transport from the nasal cavity to the brain upon intranasal administration of a highly-concentrated chitosan nanoparticle siGal-1 suspension and we could even observe the sequence-specific cleavage of Gal-1 mRNA, and a decrease of Gal-1 in the TME. This Gal-1 reduction could modulate the TME from immune suppression to immune activation, as demonstrated by decrease in suppressor cells, and increased stage of activation in rejective immune cells. Moreover, due to decreased Gal-1, also angiogenesis was alleviated, and a reduced size in vasculature was observed, mimicking a morphological vessel normalisation. Reversing the immune and vascular contexture of the TME by Gal-1 reduction seemed a prerequisite to increase the efficacy of TMZ, DC vaccination and PD-1 blocking. In combination experiments, we noticed that siGal-1 on top of these treatments, could further increase the efficiency of chemo and immunotherapy. The findings presented in this thesis can serve as a proof of concept for the feasibility to modulate and re-orchestrate the TME of GBM via intranasal administration. The intranasal administration of siGal-1 could represent a valuable clinically translational treatment to increase the efficiency of chemo- and immunotherapy for GBM patients. In our research facilities, a phase 0 as a first-in-human trial is actively pursued.