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

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Date

2022-05-07

Authors

Tristan-Manzano, Maria
Maldonado-Perez, Noelia
Justicia-Lirio, Pedro
Muñoz, Pilar
Cortijo-Gutierrez, Marina
Pavlovic, Kristina
Jimenez-Moreno, Rosario
Nogueras, Sonia
Carmona, M Dolores
Sanchez-Hernandez, Sabina

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Cell Press
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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.

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MeSH Terms

Lentiviral vectors
Leukemia
Lymphoma
Physiological expression
Tonic signaling

DeCS Terms

Leucemia
Linfoma
Fenotipo
Genes
Linfocitos T

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Keywords

CAR-T, T cells phenotype, TCR-like expression, WAS gene promoter, Exhaustion

Citation

Tristán-Manzano M, Maldonado-Pérez N, Justicia-Lirio P, Muñoz P, Cortijo-Gutiérrez M, Pavlovic K, et al. Physiological lentiviral vectors for the generation of improved CAR-T cells. Mol Ther Oncolytics. 2022 May 18;25:335-349. doi: 10.1016/j.omto.2022.05.003. Erratum in: Mol Ther Oncolytics. 2022 Jul 21;26:245