Physiological lentiviral vectors for the generation of improved CAR-T cells
Metadatos
Mostrar el registro completo del ítemAutor
Tristán Manzano, María; Maldonado Pérez, Noelia; Justicia Lirio, Pedro; Muñoz Fernández, Pilar; Cortijo Gutiérrez, Marina; Pavlovic, Kristina; Sánchez Hernández, Sabina; Aguilar González, Araceli; Marañón, Concepción; Marchal Corrales, Juan Antonio; Benabdellah, Karim; Martín Molina, FranciscoEditorial
Cell Press
Fecha
2022-05-18Referencia bibliográfica
María Tristán-Manzano... [et al.]. Physiological lentiviral vectors for the generation of improved CAR-T cells, Molecular Therapy - Oncolytics, Volume 25, 2022, Pages 335-349, ISSN 2372-7705, [https://doi.org/10.1016/j.omto.2022.05.003]
Patrocinador
Spanish ISCIII Health Research Fund; European Commission PI15/02015 PI18/00337 PI21/00298 RD21/0017/0004 PI18/00330 PI17/00672; CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia 2016000073391-TRA 2016000073332-TRA PI-57069 PA IDI-Bio326 CARTPI-0001-201 PECART-0031-2020 Red RANTECAR CAR-T 2019 00400200101918 PLEC2021-008094 PI-0014-2016 PEER-0286-2019; Spanish Government PLEC2021-008094 00123009/SNEO-20191072; Nicolas Monardes contracts from regional Ministry of Health 0006/2018 C2-0002-2019; German Research Foundation (DFG) FPU16/05467 FPU17/02268 FPU17/04327 MCI DIN2018-010180; Fundacion Andaluza Progreso y Salud; German Research Foundation (DFG) PEJ-2018-001760-A; Junta de Andalucia PE-0223-2018; Biomedicine Programme of the University of Granada (Spain)Resumen
Anti-CD19 chimeric antigen receptor (CAR)-T cells have
achieved impressive outcomes for the treatment of relapsed
and refractory B-lineage neoplasms.However, important limitations
still remain due to severe adverse events (i.e., cytokine
release syndrome and neuroinflammation) and relapse of
40%–50%of the treated patients.MostCAR-Tcells are generated
using retroviral vectors with strong promoters that lead to high
CAR expression levels, tonic signaling, premature exhaustion,
and overstimulation, reducing efficacy and increasing side effects.
Here, we show that lentiviral vectors (LVs) expressing the
transgene through a WAS gene promoter (AW-LVs) closely
mimic the T cell receptor (TCR)/CD3 expression kinetic upon
stimulation. These AW-LVs can generate improved CAR-T cells
as a consequence of theirmoderate andTCR-like expression profile.
Compared with CAR-T cells generated with human elongation
factor a (EF1a)-driven-LVs, AW-CAR-T cells exhibited
lower tonic signaling, higher proportion of naive and stem cell
memory T cells, less exhausted phenotype, and milder secretion
of tumor necrosis factor alpha (TNF-a) and interferon (IFN)-ɣ
after efficient destruction of CD19+ lymphoma cells, both
in vitro and in vivo.Moreover, we also showed their improved efficiency
using an in vitro CD19+ pancreatic tumor model. We
finally demonstrated the feasibility of large-scale manufacturing
ofAW-CAR-T cells in good manufacturing practice (GMP)-like
conditions. Based on these data, we propose the use of AW-LVs
for the generation of improved CAR-T products.