A Drug-Gated, Modular STAb-T Immunotherapy With External Control.

Living cell therapies lack robust, reversible mechanisms for externally controlling therapeutic activity after administration, limiting their safety and clinical adaptability. Here we engineer a drug-gated cellular immunotherapy platform in which T cells function as programmable factories that secrete two inactive antibody modules whose extracellular assembly into a functional bispecific T cell engager (TCE) is controlled by a small-molecule input. Using a rapalog-inducible FKBP-FRB* heterodimerization switch, we design a split CD19 × CD3 engager architecture that remains inactive in the absence of drug and assembles on demand upon rapalog exposure. A 2A-peptide bicistronic construct enables coordinated expression and secretion of both modules, allowing precise drug-dependent control of TCE formation in situ. Drug administration quantitatively regulates T cell activation and cytotoxicity against CD19+ targets in vitro, with stringent OFF-state behavior in the absence of rapalog. In xenograft models, systemic rapalog administration induces on-demand anti-tumor activity without evidence of treatment-related toxicity, demonstrating reversible pharmacological control of a locally secreted therapeutic interface. We further extend this strategy to an EGFR-targeting TCE, demonstrating the modularity and broad adaptability of the platform across distinct antigen specificities. This work introduces a generalizable engineering framework for externally programmable cell therapies, enabling tunable, safety-by-design control of T cell-based immunotherapies.