Major-histocompatibility complex harnessing and lymphocytic recruitment: a new tool for glioblastoma multiforme immunotherapy.
Glioblastoma multiforme (GBM) is the most common malignant primary brain neoplasm, notorious for being able to evade and suppress the immune-system. We present a new immunotherapeutic approach that can potentially overcome or circumvent many of the GBM laden obstacles for an efficient antitumor immune response. In this molecular construct, a soluble major-histocompatibility complex (MHC), presenting an immunogenic peptide is directed towards GBM cells. This soluble complex is known to be able to activate relevant cytotoxic T-lymphocyte (CTL's) populations, mounting an effective local immune response. The chimeric protein consists of a targeting domain, a function that can be fulfilled by an antibody or other small molecule that binds tumor associated antigens, and an effector domain. A single chain MHC directly linked to an immunogenic Cytomegalovirus derived peptide (phosphoprotein 65) can be used as such an effector domain. Targeting MHC complexes to the tumor enables to recruit different lymphocyte populations using MHC-molecules bearing a single, highly antigenic peptide derived from immunogenic T cell epitopes. Moreover, the recruited potent memory CTL's at the tumor's milieu may prove resistant to the previously described local immunosuppressive environment, and may enable the shift to TH1 cytokine profile resulting in specific massive tumor destruction.
Department of Neurological Surgery, Rambam Health Care Center, Haifa, Israel - orcoheni@tx.technion.ac.il.|Molecular Immunology Laboratory, Faculty of Biology, Technion Israel Institute of Technology, Haifa, Israel - orcoheni@tx.technion.ac.il.|Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel - orcoheni@tx.technion.ac.il.|Department of Neurological Surgery and Gamma-Knife Radiosurgical Center, University of Virginia Health Care Center, Charlottesville, VA, USA - orcoheni@tx.technion.ac.il.
Or
O
Cohen-Inbar
Molecular Immunology Laboratory, Faculty of Biology, Technion Israel Institute of Technology, Haifa, Israel.
Yoram
Y
Reiter
Department of Neurological Surgery, Rambam Health Care Center, Haifa, Israel.|Molecular Immunology Laboratory, Faculty of Biology, Technion Israel Institute of Technology, Haifa, Israel.|Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Menashe
M
Zaaroor
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008214:Lymphocytes / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*