Abstract
Among the most aggressive and resistant tumors of the central nervous system, glioblastoma (GBM) has a poor prognosis and few available treatments. Because of the tumor's infiltrative nature, immunosuppressive environment, and resistance mechanisms, traditional treatments such as radiotherapy, chemotherapy, and surgery offer only modest survival benefits. Bispecific T-cell engagers (TCEs) have shown promising preclinical and early clinical results, and immunotherapy has become a feasible strategy. TCEs efficiently promote antigen evasion and strong tumor lysis by directing cytotoxic T lymphocytes (CTLs) to tumor-associated antigens (TAA) such as the EGFRvIII ligands IL-13Rα2, Fn14, and NKG2D ligands (NKG2DLs). Although phase I clinical studies with AMG 596 have shown acceptable safety profiles and early indications of efficacy, preclinical mice have demonstrated prolonged longevity. However, challenges still exist, including the short half-life of TCEs molecules, limited T-cell infiltration, antigen heterogeneity, and the risk of neurotoxicity or cytokine release syndrome (CRS). Promising developments include novel approaches such as multivalent targeting, DNA-encoded or cell-delivered TCEs, and combinations with immune checkpoint inhibitors (ICIs) or CAR-T cells. With an emphasis on its integration into multimodal treatment approaches, this review highlights the safety, effectiveness, and potential uses of TCEs immunotherapy for gliomas.