Real-world safety profile of T-cell engagers: evidence from multi-database analysis with CAR-T comparisons

T-cell engagers (TCEs), "off-the-shelf" immunotherapies are seeing widespread clinical application, yet their real-world safety profile is not fully defined. This study aimed to characterize the comprehensive adverse event (AE) profile of TCEs, using chimeric antigen receptor T-cell (CAR-T) therapy as a contextual benchmark.

A pharmacovigilance study was conducted on AE reports for TCE and CAR-T therapies from FAERS and VigiBase. A multi-level analytical framework integrated disproportionality analysis, time-to-onset modeling, occurrence network analysis, and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) analysis to characterize signals, temporal dynamics, and clinical syndromes.

The proportion of fatal outcomes reported with TCEs significantly increased from 14.3% in 2015 to 23.5% in 2025 (P<0.001). Compared to CAR-T, TCEs showed stronger signals for Infection and Tumor Lysis Syndrome (TLS), while CAR-T showed stronger signals for Cytokine Release Syndrome (CRS) and ICANS. TLS and CRS occurred significantly earlier with TCEs. Network analysis quantified the co-occurrence and clinical severity of the CRS-ICANS-infection triad. The TCE class showed profound drug-specific heterogeneity, including severe oral/nail toxicities with talquetamab (oral toxicity ROR = 6066.40) and extramedullary relapse/infiltration with blinatumomab. TCE-associated ICANS revealed a strong overall signal (ROR 197.08), with fatal outcomes reported in 26% of cases, an early-peaking reporting pattern (WSP α = 0.63), and key risk factors including age, indication, target and concurrent CRS.

TCEs are characterized by rapid early CRS/TLS AEs, elevated infection reporting, and target-specific toxicities, while CAR-T exhibits stronger CRS/ICANS signals. These findings support early monitoring and molecule-specific, syndrome-based risk management, advancing precision pharmacovigilance for T-cell redirecting therapies.