First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas

Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators.

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Publication Details

Journal
Molecular Therapy — Nucleic Acids
Published
2024-08-15
DOI
https://doi.org/10.1016/j.omtn.2024.102308
Citations
3
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.85

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article

First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas

Julia Muñoz‐Ballester, Juan R. Rodríguez-Madoz, Saúl A. Navarro-Marchal, Felipe Prósper et al.
3 citations
Molecular Therapy — Nucleic Acids
CAR-T cell therapy research
0.85
article

First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas

Julia Muñoz‐Ballester, Juan R. Rodríguez-Madoz, Saúl A. Navarro-Marchal, Felipe Prósper, María Tristán‐Manzano, Noelia Maldonado‐Pérez, Pedro Antonio González Sierra, Francisco Martı́n, Carmen Griñán‐Lisón, Pedro Justicia-Lirio, Marina Cortijo-Gutierréz, Carla Panisello, Francisco J. Molina-Estévez, Juan Antonio Marchal, Concha Herrera, Ana Hinckley-Boned, Carmen Barbero-Jiménez, Pilar Muñoz, Kristina Pavlovic
article en
3 citations

Abstract

Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators.

Molecular Therapy — Nucleic AcidsVol. 35(4)
Universidad de Granada (ES), Instituto de Salud Carlos III (ES), Edinburgh Cancer Research (GB), Josep Carreras Leukaemia Research Institute (ES), Instituto Maimónides de Investigación Biomédica de Córdoba (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Universitario Virgen de las Nieves (ES), Clinica Universidad de Navarra (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Universidad de Navarra (ES)
European Commission, Centro para el Desarrollo Tecnológico Industrial, Ministerio de Ciencia e Innovación, Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológic, Junta de Andalucía, Cohesion Fund, Instituto de Salud Carlos III, European Regional Development Fund
Zero hunger
Openalex Percentile: Top 23%
CAR-T cell therapy research
0.85
DOIOpen Access PDFOpenAlex
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