A Drug‐Gated, Modular STAb‐T Immunotherapy With External Control

Abstract

ABSTRACT 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.