Benutzerspezifische Werkzeuge

Selective Nucleic Acid Carriers for Immunotherapy of Malignant Diseases

European Social Fund (ESF) via Sächsische Aufbaubank (SAB)

Glioblastoma multiforme (GBM), the most common brain tumor of the central nervous system and one of the most aggressive malignant tumors in adults, comprises GBM cells and tumor stroma. Of note, the tumor stroma can account for up to 30% of tumor mass and mostly contains so-called glioma-associated microglia/macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs). The interplay between GBM cells, GAMs and MDSCs finally results in an immunosuppressive environment characterized by enhanced levels of TGF-β, IL-10 and other immunosuppressive factors. Nowadays, immunosuppression in GBM is considered as the main obstacle for several immunotherapeutic treatments including vaccines, antibodies and tumor-reactive T lymphocytes. A promising avenue to increase clinical efficiency of such tumor-selective treatments but also a rationale to achieve an anti-tumor immune response is the re-programming of the tumor environment by tumor-targeted delivery of  an synthetic 50 bp dsRNA-molecule, representing a “Toll-like receptor 3” (TLR3) agonist, exclusively to GBM cells.
In this proof-of-concept study we plan to utilize our newly developed selective TLR3-agonist delivery nanoparticle platform, designated “Rapid Inducer of Cellular Inflammation and Apoptosis” (RICIA) for treatment of EGFRvIII-positive GBM cells as well as orthotopic syngenic tumors. This selective delivery of TLR3-agonists, which is driven by receptor-mediated internalization of the RICIA-nanoparticles is advantageous from the standpoint of lower dosage requirements and reduction of potential “off-target effects” in normal brain areas. Of note, this modular system allows the easy exchange or combination of targeting moieties (scFvs, ligands) for redirection of immunoconjugate-nanoparticles to additional tumor-associated surface structures in order to overcome potential loss of antigen expression and to address heterogeneity of tumors.

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