Beyond the chimeric antigen receptor T cells and bispecific antibody duopoly: ex vivo armed T cells for solid tumors.

While monoclonal antibodies (mAbs) continue to dominate the overall immunotherapy landscape, the field of T-cell-based therapeutics is rapidly evolving. Although chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs) currently represent the pillars of T-cell-directed therapy, the complexity of solid tumors demands a more diversified therapeutic arsenal. By combining antibody-mediated tumor targeting with the robust effector function of ex vivo expanded T cells, BsAb-armed T cells (BATs)-also referred to as Ex vivo Armed T cell (EATs)-provide a 'third way' that addresses the unmet needs of solid tumor immunotherapy. They can overcome the quantitative and qualitative deficiencies of endogenous immune effector cells in cancer patients. By offering personalized multi-antigen targetability and the prospect of off-the-shelf therapy, EATs have the potential to address critical challenges, such as poor tumor infiltration, immune escape via heterogeneity and target antigen loss, and treatment-related toxicities like cytokine release syndrome. In this review, we discuss the characteristics of EAT therapy, distinct from CAR-T and BsAb therapy, as an independent and alternative niche. We explore strategies to accelerate their clinical translation, encompassing BsAb optimization, modulation of the tumor microenvironment (TME) and cytokines, and simultaneous engagement of multiple antigens, which are essential for boosting EAT potency and overcoming the limitations of solid tumors. In this evolving landscape, EATs could play a unique and independent role, expanding the CAR-T and BsAb-dominated paradigm to address unmet clinical needs.