@misc{10481/76676,
year = {2022},
month = {5},
url = {http://hdl.handle.net/10481/76676},
abstract = {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.},
organization = {Spanish ISCIII Health Research Fund},
organization = {European Commission	PI15/02015	
PI18/00337	
PI21/00298	
RD21/0017/0004	
PI18/00330	
PI17/00672},
organization = {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},
organization = {Spanish Government	PLEC2021-008094	
00123009/SNEO-20191072},
organization = {Nicolas Monardes contracts from regional Ministry of Health	0006/2018	
C2-0002-2019},
organization = {German Research Foundation (DFG)	FPU16/05467	
FPU17/02268	
FPU17/04327	
MCI	DIN2018-010180},
organization = {Fundacion Andaluza Progreso y Salud},
organization = {German Research Foundation (DFG)	PEJ-2018-001760-A},
organization = {Junta de Andalucia	PE-0223-2018},
organization = {Biomedicine Programme of the University of Granada (Spain)},
publisher = {Cell Press},
title = {Physiological lentiviral vectors for the generation of improved CAR-T cells},
doi = {10.1016/j.omto.2022.05.003},
author = {Tristán Manzano, María and Maldonado Pérez, Noelia and Justicia Lirio, Pedro and Muñoz Fernández, Pilar and Cortijo Gutiérrez, Marina and Pavlovic, Kristina and Sánchez Hernández, Sabina and Aguilar González, Araceli and Marañón, Concepción and Marchal Corrales, Juan Antonio and Benabdellah, Karim and Martín Molina, Francisco},
}