Introduction: Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of 12 months. This figure remains constant despite progress in all areas of medical research and treatment. The lack of an efficient immune response to the tumor and its microinvasive nature have been explained by its immunosupressive capabilities and the immunosupressed local environment. Our aim was to design a molecule that specifically binds MMP-2 expressed on glioma cells and most abundantly on GBM cells, and through its effector domain mobilize and recruit elements of the immune system to mount an effective anti-tumor reaction.
Methods: The targeting moiety is the small 36-amino acid Chlorotoxin, derived from the venom of the Israeli Yellow scorpion. The effector end of the chimera is a single chain HLA-A2 (Human leukocyte antigen subtype A2) covalently bound to pp65 (phosphoprotein 65) derived from the cytomegalovirus, to which most of the human population has developed a specific immune response.
Results: The entire molecular construct was cloned and expressed in E.Coli. the protein product was isolated and purified, and than folded in vitro. different activity assays designed at proving retained activity of each domain included flow cytometry, intracellular staining, flourescence immunohistochemistry, radiolabeled toxicity assays etc.
Conclusions: This molecular construct represents a new family of molecules which contain a non-antibody compact and highly specific targeting domain, combined with the ability to recruit different lymphocyte populations using HLA-molecules bearing a single, preselected, highly antigenic peptide derived from immunogenic viral or bacterial T cell epitopes. Moreover, the recruitment of potent memory CTL’s to the tumor’s milieu may be resistant to the previously described local immunosuppressive environment created in part by TH2 secretion profile, and may enables the shift to TH1 cytokine profile resulting in specific massive tumor destruction.
Patient Care: A new immunotherapeutic appraoch to battle malignant astrocytoma.
Learning Objectives: A new immunotherapeutic appraoch to battle malignant astrocytoma.