Abstract
BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy represents a promising frontier in oncology, but its application to high-grade gliomas (HGG) is challenged by the blood-brain barrier, limited efficacy, and significant toxicities associated with systemic administration. Locoregional delivery has the potential to address these shortcomings. This systematic review evaluates the safety and efficacy of locoregional vs systemic CAR-T cell delivery for HGG. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a total of 112 studies were identified from three separate databases between 2015 and 2024. Of these, 19 articles were assessed for eligibility, resulting in 16 articles meeting the inclusion criteria with 194 treated patients across 14 clinical trials. A comparative meta-analysis was performed to compare the safety and efficacy outcomes of locoregional administration (eg, intracerebroventricular, intratumoral) with systemic (intravenous) delivery. Severe (grade ≥3) adverse event rates and therapeutic responses were pooled to calculate crude incidence, rate ratios, and relative risks (RRs) with 95% CIs. Both fixed-effect and random-effects models were used to evaluate incidence rate ratios. RESULTS: Locoregional delivery was associated with a markedly improved safety profile, demonstrating an over 60% reduction in the incidence of grade ≥3 adverse events compared with systemic infusion (RR=0.39; 95% CI 0.30 to 0.52; p<0.001). Furthermore, locoregional strategies demonstrated encouraging signals of antitumor activity, including rates of disease responses not widely observed with systemic approaches (RR=3.79; 95% CI 1.23 to 11.70; p<0.05). Locoregional delivery also enables the analysis of cerebrospinal fluid to monitor T-cell trafficking and emerging biomarkers of immune activation. CONCLUSION: Intracranial delivery of CAR-T cells helps overcome key barriers that limit the efficacy and safety of systemic therapy in brain tumors. These findings support a paradigm shift that integrates locoregional delivery techniques as a pivotal component in the design of future CAR-T cell trials, offering a safer and potentially more effective therapeutic approach with greater opportunities for longitudinal sampling for patients with HGG.