A review on toxicities of T-cell engager-based therapies in solid tumors

T-cell engager (TCE)-based therapies represent an emerging and rapidly expanding class of immunotherapies in oncology. Initially developed for hematologic malignancies, TCEs are now entering the field of solid tumors. To date, two agents have received regulatory approval in this setting: Tebentafusp for metastatic uveal melanoma and Tarlatamab for small-cell lung cancer (SCLC). By physically linking a tumor-associated antigen (TAA) to a T-cell activating domain, most commonly cluster of differentiation (CD) 3, TCEs induce an immunological synapse that promotes targeted T-cell mediated cytotoxicity. This narrative review summarizes the most clinically relevant toxicities associated with TCEs in solid tumors, drawing on data from clinical trials and real-world experience. Tebentafusp exemplifies the safety profile of this therapeutic class, which is dominated by cytokine release syndrome (CRS) and cutaneous adverse events (AEs). These toxicities are typically early in onset, predictable, and reversible, occurring predominantly during the initial step-up dosing phase and decreasing substantially with subsequent administrations, consistent with immune adaptation. Tarlatamab, a Delta-like ligand 3 (DLL3) × CD3 bispecific TCE recently approved for SCLC, displays a toxicity profile similarly driven by immune activation, with CRS as the most frequent AE, generally of low grade and confined to early treatment cycles. In contrast, neurotoxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) occurs more frequently, though events are usually low grade, delayed relative to CRS. Other TCEs currently in clinical development target a wide range of TAAs and display a broadly similar toxicity profile, with CRS emerging as a class effect related to CD3-mediated T-cell activation. The incidence and severity of CRS are influenced by dosing strategies, with step-up dosing mitigating early toxicity. Cutaneous, immune-related, and hematologic AEs are generally infrequent and rarely severe. Continued optimization of antigen selection, molecular engineering, and pharmacokinetic parameters will be critical to improving the safety profile of TCEs gathering data from clinical trials and real-world experience.