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Physiological lentiviral vectors for the generation of improved CAR-T cells

Authors :
María Tristán-Manzano
Noelia Maldonado-Pérez
Pedro Justicia-Lirio
Pilar Muñoz
Marina Cortijo-Gutiérrez
Kristina Pavlovic
Rosario Jiménez-Moreno
Sonia Nogueras
M. Dolores Carmona
Sabina Sánchez-Hernández
Araceli Aguilar-González
María Castella
Manel Juan
Concepción Marañón
Juan Antonio Marchal
Karim Benabdellah
Concha Herrera
Francisco Martin
Source :
Molecular Therapy: Oncolytics, Vol 25, Iss , Pp 335-349 (2022)
Publication Year :
2022
Publisher :
Elsevier, 2022.

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. Most CAR-T cells 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 their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor α (EF1α)-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-α) 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 of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AW-LVs for the generation of improved CAR-T products.

Details

Language :
English
ISSN :
23727705
Volume :
25
Issue :
335-349
Database :
Directory of Open Access Journals
Journal :
Molecular Therapy: Oncolytics
Publication Type :
Academic Journal
Accession number :
edsdoj.338abdeeff24c2185714739029ce627
Document Type :
article
Full Text :
https://doi.org/10.1016/j.omto.2022.05.003