Trispecific T cell engagers in hematological malignancies: Advancing beyond bispecific antibodies

The success of bispecific T cell engagers (BiTEs) in hematological malignancies has catalyzed the development of trispecific antibodies that simultaneously target 3 molecular entities. These next-generation immunotherapeutics address the key limitations of bispecific constructs including antigen escape, limited T cell activation, and on-target off-tumor toxicity. Trispecific constructs employ 2 primary strategies: dual tumor antigen targeting combined with CD3 engagement to prevent antigen escape, and integration of co-stimulatory signals (CD28, 4-1BB) to enhance T cell function. Early clinical data demonstrated promising efficacy signals, particularly in multiple myeloma where BCMA×CD38×CD3 constructs achieved 90% overall response rates in early-phase trials. Safety profiles mirror bispecific antibodies with cytokine release syndrome and neurotoxicity as primary concerns. Trispecific T cell engagers represent a significant advancement in precision immunotherapy for hematological malignancies. Although early clinical results are encouraging, challenges remain in optimal target selection, manufacturing complexity, and resistance mechanisms. Ongoing clinical trials will define their role in the evolving treatment landscape.