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

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.

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Publication Details

Journal
Advanced Science
Published
2026-08-24
DOI
https://doi.org/10.1002/advs.77236
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
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article

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

Laura Cebada Almagro, Pedro Roda‐Navarro, Belén Blanco, Laura Rubio‐Pérez et al.
Advanced Science
Monoclonal and Polyclonal Antibodies Research
article

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

Laura Cebada Almagro, Pedro Roda‐Navarro, Belén Blanco, Laura Rubio‐Pérez, E. García-Veros, Carmen Blanco‐Aparicio, Jorge L. Martı́nez-Torrecuadrada, Luis Álvarez‐Vallina, Laura Díez-Alonso, Anaïs Jiménez-Reinoso, Óscar Aguilar-Sopeña, Patricia Fuentes, Ángel Ramírez-Fernández, Carmen Domínguez-Alonso, Sonia Martı́nez, Ivana Zagorac, Marı́a L. Toribio, Antonio Tapia‐Galisteo, Javier Arroyo‐Ródenas, Marina Gómez-Rosel, María Rivas-Sánchez, Patricia Hernández-López, Susana Luengo-Arias, Lucía Cañizares-Moscato
article en

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.

Advanced Science
Universidad Complutense de Madrid (ES), Instituto de Salud Carlos III (ES), Research Institute Hospital 12 de Octubre (ES), Spanish National Cancer Research Centre (ES), Hospital Universitario 12 De Octubre (ES), Hospital Del Mar (ES), Centro de Biología Molecular Severo Ochoa (ES), Banc de Sang i Teixits (ES), Universidad Autónoma de Madrid (ES)
Good health and well-being
Openalex Percentile: Top 10%
Monoclonal and Polyclonal Antibodies Research
DOIOpen Access PDFOpenAlex
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