Bi-, tri-, and multi-specific T-cell engager therapies in glioblastoma: a decade of preclinical innovation

Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a poor prognosis despite advances in treatment options. T-cell-engager therapies, which have an antibody-based structure connecting immune cells to target cancer cells with high affinity, offer a promising strategy but face four key barriers: antigen heterogeneity, immune escape, the blood-brain barrier (BBB), and the immunosuppressive tumor microenvironment (TME). This systematic review synthesizes preclinical developments in bispecific T-cell engager (BiTE), tri-specific T-cell engager (TriTE), and multi-specific T-cell engagers for GBM over the last 10 years, evaluating their capacity to overcome these barriers. Methods: A systematic search was conducted in OVID Medline, Embase, and ClinicalTrials.gov for pre-clinical and clinical studies. A descriptive analysis without meta-analysis was formulated in which data were grouped thematically by the ability of treatments to overcome GBM-specific barriers. Results: Among the 14 studies meeting inclusion criteria, all studies were preclinical, with 12/14 (85.7%) utilizing an in vivo mouse model. BiTEs were used in 12/14 (85.7%) studies, while 4/14 (28.6%) studies targeted multiple antigens through either TriTEs or multivalent BiTEs. There was a range of antigen targets with the most common being interleukin 13 receptor alpha 2 (IL13Rα2) as well as epidermal growth factor receptor (EGFR) or EGFR variant III (EGFRvIII) in 7/14 (50.0%) studies. Most studies (85.7%) addressed two or more barriers, with 13/14 (92.9%) showing evidence of affecting the TME. Discussion: In the last decade, T-cell engager therapies have evolved in both antigenic targets and delivery vehicles used to overcome the key barriers. An emerging area within T-cell engager therapies is targeting multiple antigens through multi-specific T-cell engager therapies, such as the TriTEs. Studies have explored chimeric antigen receptor T-cells (CAR-Ts) as a potential delivery vehicle for BiTEs. A future clinical trial using multi-specific T-cell engager therapies or a CAR-T-secreting BiTE in adult patients is required to determine the potential clinical utility of T-cell engagers.