Njoku, Innocent Jr; Boockvar, John A.
Conventional methods for the treatment of glioblastoma multiforme (GBM) are nonspecific and are limited by the consequent damage to normal brain tissue. Such methods including, chemotherapy radiation therapy, and gross total resection, may prolong median survival time to 15 months but can be deleterious to the patient’s quality of life. New treatment modalities arising from novel genetic recombination techniques and cell-mediated immunotherapy may provide a promising treatment strategy to treating patients with GBM.
T cell mediated antitumor immune responses have received notable recent attention. The ability to mount an immune response that discriminately targets a specific antigen provides an eloquent method of targeting cancer cells without the disastrous side effects that accompanies inflammation. Work published by Choi et al (PNAS, November 2012) demonstrates the potential of bispecific antibodies as a tool to elicit cytotoxicity from circulating T cells only in the vicinity of the enticing antigen. These so-called bispecific T-cell engagers (BiTE), have dual functionality whereby their single variable antibody fragment (scFv) can simultaneously target specific tumors cells and the T-cell activation ligand (CD3). The dual nature of these BiTE antibodies provides the capability of inducing an immunologic response without the need for costimulatory signals.
The authors show the therapeutic capabilities of BiTES, via specific targeting against the mutant EGF receptor (EGFRvIII), and its ability to penetrate the CNS. EGFRvIII is a constitutively active tyrosine kinase not found in normal tissue but over expressed in GBM. Their work demonstrates that EGFRvIII-targeted BiTE (bscEGFRvIIIxCD3) molecules are antigen specific, highly cytotoxic, and can activate T cells leading to the exclusive secretion of Th1-type cytokines.
The authors genetically engineered both svFc regions by joining both domains to a flexible linker region to ultimately generate a fusion protein capable of redirecting T cells against cancer cells in vitro. The authors showed localized cytotoxicity and cancer-specific cell lysis which was dependent on the ability of the BiTE antibody to recognize both the target antigen and the effecter T cell.
In vitro data was further supported by data collected in vivo; U87MG glioma cell-line mice with either the mutated EGFRvIII or the wild type EGFR were inoculated with human peripheral blood monocytes and injected with the BiTE antibody. Under these parameters, mice over expressing wild type EGFR did not show significant survival benefit as compared to those expressing the EGFRvIII mutant. Furthermore, localized treatment and antitumor effects were seen in a dose-dependent manner. Taken together, the data points to a promising treatment for GBM—ie, the potential of genetically engineered bispecific monoclonal antibodies.
Since the biology of GBM is so complex, current research is focusing on the theory of the cancer stem cell, the microenvironmental niche, and various unregulated signaling pathways. Genetic therapy, immunotherapy, or perhaps the combination of the two may provide an eloquent, minimally invasive, and highly specific modality of targeting and eradicating cancer cells. Further studies are needed to delineate the plausibility of such treatments in human subjects with GBM.
Figure. Specific tar...Image Tools