Bispecific Protein Engager-Armed T Cells (BATs): Next-Generation Platforms for Precision Cancer Immunotherapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy and CD3-directed bispecific T-cell engagers (BiTEs) have transformed cancer immunotherapy, particularly for relapsed or refractory hematologic malignancies. However, CAR T-cell therapy remains constrained by complex genetic engineering, individualized manufacturing, specialized infrastructure, high cost, limited accessibility, and treatment-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In contrast, soluble BiTEs frequently require repeated dosing or continuous infusion because of their short serum half-life and may also induce CRS and neurotoxicity. To address these limitations, our research group at the Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT) developed bispecific protein engager (BiPE)-armed T cells (BATs), a non-genetically modified and adaptable platform that combines BiPE-mediated tumor targeting with the intrinsic cytotoxic activity of activated T cells. This review positions BATs within the broader evolution of cancer immunotherapy-including monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), CAR T cells, bispecific antibodies (BsAbs), and BiTEs-and summarizes their structure and mechanism of action. BATs mediate major histocompatibility complex (MHC)-independent T-cell activation, promote immune synapse formation, and enable efficient tumor cell lysis. Clinical studies of bispecific antibody-armed T cells (BsAb-Ts), the closest clinical analogs of BATs, demonstrate feasibility, a consistent absence of dose-limiting toxicities (DLTs), and preliminary biological and clinical activity. Building on this foundation, next-generation BAT platforms targeting tumor-associated antigens and immune checkpoint molecules-including BCMA, CD138, integrin αvβ6, and PD-L1-have shown promising preclinical activity in multiple myeloma, breast cancer, and cholangiocarcinoma. Collectively, BATs represent a flexible, scalable, and potentially safer platform for next-generation precision T-cell immunotherapy.