@misc{10481/99255,
year = {2024},
url = {https://hdl.handle.net/10481/99255},
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 conventionalCAR-
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 transactivatorfree
anti-CD19 CAR-T cells able to control IL-18 expression
(iTRUCK19.18) under ultra-low doses of doxycycline and
without altering cellularfitness. 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.},
title = {First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B-cell lymphomas},
doi = {doi.org/10.1016/j.omtn.2024.102308},
author = {Justicia Lirio, Pedro and Tristán-Manzano, María and Maldonado Pérez, Noelia and Barbero-Jiménez, Carmen and Cortijo Gutiérrez, Marina and Pavlovic, Kristina and Molina-Estévez, Francisco Javier and Muñoz, Pilar and Hinckley-Boned, Ana and Rodriguez-Madoz, Juan R and Prósper, Felipe and Griñan-Lison, Carmen and Navarro-Marchal, Saúl A and Muñoz-Ballester, Julia and Gonzalez-Sierra, Pedro A and Herrera, Concha and Marchal Corrales, Juan Antonio and Martín, Francisco},
}