ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Real-World Safety Profile of T-Cell Engagers: Evidence from Multi-Database Analysis with CAR-T Comparisons
Jinman Zhong
Chang Chen
Yunman Xu
Yueping He
Changxiu Zhang
Jingwen Luo
Jiewen Tan
Dan Xiong
Shunde Hospital, Southern Medical University, Foshan, China
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Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Summary
Keywords
Chimeric antigen receptor T-cell therapy, Immune Effector Cell-Associated Neurotoxicity Syndrome, Pharmacovigilance, Real-world evidence, t-cell engager
Received
05 November 2025
Accepted
20 February 2026
Copyright
© 2026 Zhong, Chen, Xu, He, Zhang, Luo, Tan and Xiong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dan Xiong
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