Chimeric antigen receptor (CAR) T-cell therapy for glioblastoma (GBM): current clinical insights, challenges, and future directions.

Glioblastoma (GBM) remains the most lethal primary brain cancer with a median survival of under 2 years despite current best treatment practices. Early immunotherapies, including checkpoint blockade and vaccines, showed safety and immunogenicity but no survival benefit. Chimeric antigen receptor (CAR) T treatments in GBM trials have yielded feasibility and antitumor signals but still lack long-term control. This review synthesizes recent clinical and mechanistic data to establish priorities for clinical trial design, patient selection, and treatment development aimed at achieving durable responses in GBM.Recent trials highlight two consistent observations regarding the delivery of CAR T treatment. First, that CAR T cells can be effectively delivered peripherally rather than requiring direct intracranial administration. And second, multi-antigen, regionally delivered products can induce measurable intracranial responses. These findings indicate that access across the blood-brain barrier is feasible, but persistent function is limited by tumor antigen heterogeneity and an immunosuppressive, myeloid-dominated microenvironment that accelerates T-cell exhaustion.Emerging development strategies reflect these constraints. Broader antigen recognition is being pursued through bivalent and engager-secreting constructs. Locoregional delivery through cerebrospinal fluid spaces enables repeated exposure at multifocal sites. Resistance modules targeting TGF-β (Transforming Growth Factor-beta) signaling and myeloid suppression are being investigated to prolong persistence. Cerebrospinal fluid pharmacodynamic monitoring, such as measuring cytokines, chemokines, and CAR cell kinetics, may support adaptive dosing and minimize corticosteroid use. Patient selection criteria increasingly favor individuals with confirmed target expression, sufficient intratumoral T-cell infiltration, and minimal steroid exposure.Advances in manufacturing, including point-of-care platforms, allogeneic products, and in vivo CAR engineering, aim to shorten production timelines and improve access. Collectively, regional delivery, multi-antigen recognition, and microenvironment resistance constitute the current framework for translating CAR T therapy in GBM from transient responses toward sustained benefit.