| Data: |
2024 |
| Resum: |
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. |
| Ajuts: |
Instituto de Salud Carlos III PI21/00298
Ministerio de Ciencia e Innovación RD21/0017/0004
Agencia Estatal de Investigación PLEC2021-008094
|
| Nota: |
Altres ajuts: European Union-Next Generation EU: grants 00123009/SNEO-20191072 (to F.M.), PMPTA22/00060 (to F.M. and J.R.-M.), and DIN2018-010180 (to P.J.-L.); Consejería de Salud y Familias (CSyF) - Junta de Andalucía - FEDER/European Cohesion Fund (FSE) for Andalucía: grants 2016000073332-TRA, CARTPI-0001-201, PECART-0031-2020, and CAR-T 2019 00400200101918 (Red RANTECAR) (to F.M. and J.A.M.); Consejería de Economía, conocimiento, empresa y Universidad, grant A-CTS-235-UGR18 (to F.M.); Fellowship Garantía Juvenil (PEJ2018-001760-A); Doctors Galera-Requena in cancer stem cell research" (CMC-CTS963) |
| Drets: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Llengua: |
Anglès |
| Document: |
Article ; recerca ; Versió publicada |
| Publicat a: |
Molecular Therapy. Nucleic Acids, Vol. 35 Núm. 4 (August 2024) , ISSN 2162-2531 |
visitant ::
identificació
(Universidad de Granada)
