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Title: | Physiological lentiviral vectors for the generation of improved CAR-T cells |
Author: | Tristán Manzano, María Maldonado Pérez, Noelia Justicia Lirio, Pedro Muñoz, Pilar Cortijo Gutiérrez, Marina Pavlovic, Kristina Jiménez Moreno, Rosario Nogueras, Sonia Carmona, M. Dolores Sánchez Hernández, Sabina Aguilar Gonzalez, Araceli Castella, Maria Juan, Manel Marañón, Concepción Marchal, Juan Antonio Benabdellah, Karim Herrera, Concha Martín, Francisco |
Keywords: | Leucèmia Cèl·lules T Leukemia T cells |
Issue Date: | 17-May-2022 |
Publisher: | Elsevier |
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 alpha (EF1 alpha)-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-alpha) and interferon (IFN)-gamma 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 AWLVs for the generation of improved CAR-T products. |
Note: | Reproducció del document publicat a: https://doi.org/10.1016/j.omto.2022.05.003 |
It is part of: | Molecular Therapy-Oncolytics, 2022, vol. 25, p. 335-349 |
URI: | http://hdl.handle.net/2445/201200 |
Related resource: | https://doi.org/10.1016/j.omto.2022.05.003 |
ISSN: | 2372-7705 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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Physiological lentiviral vectors for the generation of improved CAR-T cells_MolecularTherapyOncolytics.pdf | 3.98 MB | Adobe PDF | View/Open |
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