A Drug‐Gated, Modular STAb‐T Immunotherapy With External Control
12 affiliations
- 1Cancer Immunotherapy Unit (UNICA) Department of Immunology Hospital Universitario 12 de Octubre Madrid Spain
- 2Immuno‐Oncology and Immunotherapy Group Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12) Madrid Spain
- 3CNIO‐HMRIB Cancer Immunotherapy Clinical Research Unit Spanish National Cancer Research Centre (CNIO) Madrid Spain
- 4Centro de Biología Molecular (CBM) Severo Ochoa CSIC‐UAM Madrid Spain
- 5Department of Immunology Ophthalmology and ENT School of Medicine Universidad Complutense Madrid Spain
- 6Lymphocyte Immunobiology Group Instituto De Investigación Sanitaria 12 De Octubre (imas12) Madrid Spain
- 7Experimental Therapeutics Programme Spanish National Cancer Research Centre (CNIO) Madrid Spain
- 8Protein Production Unit Spanish National Cancer Research Center (CNIO) Madrid Spain
- 9Department of Advanced Therapy Drug Development Instituto De Salud Carlos III Madrid Spain
- 10Cancer Immunotherapy Hospital Del Mar Research Institute Barcelona (HMRIB) Barcelona Spain
- 11Advanced Therapies Program Hospital Del Mar Research Institute Barcelona (HMRIB) Barcelona Spain
- 12Banc de Sang i Teixits Barcelona Spain
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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BibTeX
@article{luengoarias2026druggated,
title = {{A Drug‐Gated, Modular STAb‐T Immunotherapy With External Control}},
author = {Susana Luengo‐Arias and Carmen Domínguez‐Alonso and Ivana Zagorac and Antonio Tapia‐Galisteo and Eva García‐Veros and Laura Rubio‐Pérez and Marina Gómez‐Rosel and Patricia Fuentes and Patricia Hernández‐López and Óscar Aguilar‐Sopeña and Laura Almagro‐Puente and Sonia Martínez‐González and Lucía Cañizares‐Moscato and María Rivas‐Sánchez and Belén Blanco and Ángel Ramírez‐Fernández and Laura Díez‐Alonso and Carmen Blanco‐Aparicio and Javier Arroyo‐Ródenas and Jorge Martínez‐Torrecuadrada and María L. Toribio and Pedro Roda‐Navarro and Anaïs Jiménez‐Reinoso and Luis Álvarez‐Vallina},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77236},
url = {https://doi.org/10.1002/advs.77236},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Drug‐Gated, Modular STAb‐T Immunotherapy With External Control
AU - Susana Luengo‐Arias
AU - Carmen Domínguez‐Alonso
AU - Ivana Zagorac
AU - Antonio Tapia‐Galisteo
AU - Eva García‐Veros
AU - Laura Rubio‐Pérez
AU - Marina Gómez‐Rosel
AU - Patricia Fuentes
AU - Patricia Hernández‐López
AU - Óscar Aguilar‐Sopeña
AU - Laura Almagro‐Puente
AU - Sonia Martínez‐González
AU - Lucía Cañizares‐Moscato
AU - María Rivas‐Sánchez
AU - Belén Blanco
AU - Ángel Ramírez‐Fernández
AU - Laura Díez‐Alonso
AU - Carmen Blanco‐Aparicio
AU - Javier Arroyo‐Ródenas
AU - Jorge Martínez‐Torrecuadrada
AU - María L. Toribio
AU - Pedro Roda‐Navarro
AU - Anaïs Jiménez‐Reinoso
AU - Luis Álvarez‐Vallina
PY - 2026
DA - 2026/08/24
JO - Advanced Science
DO - 10.1002/advs.77236
UR - https://doi.org/10.1002/advs.77236
AB - 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.
SN - 2198-3844
ER -