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http://hdl.handle.net/2445/209232
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DC Field | Value | Language |
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dc.contributor.author | Maldonado Pérez, Noelia | - |
dc.contributor.author | Tristán Manzano, María | - |
dc.contributor.author | Justicia Lirio, Pedro | - |
dc.contributor.author | Martínez Planes, Elena | - |
dc.contributor.author | Muñoz, Pilar | - |
dc.contributor.author | Pavlovic, Kristina | - |
dc.contributor.author | Cortijo Gutiérrez, Marina | - |
dc.contributor.author | Blanco Benítez, Carlos | - |
dc.contributor.author | Castella, Maria | - |
dc.contributor.author | Juan, Manel | - |
dc.contributor.author | Wenes, Mathias | - |
dc.contributor.author | Romero, Pedro | - |
dc.contributor.author | Molina Estévez, Francisco J. | - |
dc.contributor.author | Marañón, Concepción | - |
dc.contributor.author | Herrera, Concha | - |
dc.contributor.author | Benabdellah, Karim | - |
dc.contributor.author | Martín, Francisco | - |
dc.date.accessioned | 2024-03-27T13:10:43Z | - |
dc.date.available | 2024-03-27T13:10:43Z | - |
dc.date.issued | 2023-07-06 | - |
dc.identifier.issn | 1664-3224 | - |
dc.identifier.uri | http://hdl.handle.net/2445/209232 | - |
dc.description.abstract | Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. Allogeneic off-the-shelf CAR-T cells are an alternative to simplify this complex and time-consuming process. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation alpha CD19 CAR approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) under the Hospital Exemption for treatment of patients older than 25 years with Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption (over 80%) without significant alterations on T cells phenotype and with an increased percentage of energetic mitochondria. However, we also found that efficient TCRKO can lead to on-target large and medium size deletions, indicating a potential safety risk of this procedure that needs monitoring. Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic responses and did not detectably alter their phenotype, while maintaining a similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.3389/fimmu.2022.1011858 | - |
dc.relation.ispartof | Frontiers In Immunology, 2022, vol. 13 | - |
dc.relation.uri | https://doi.org/10.3389/fimmu.2022.1011858 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) | - |
dc.subject.classification | Malalties del sistema limfàtic | - |
dc.subject.classification | Immunoteràpia | - |
dc.subject.other | Lymphatic diseases | - |
dc.subject.other | Immunotheraphy | - |
dc.title | Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2023-07-06T14:26:28Z | - |
dc.rights.accessRights | cc by (c) Maldonado Pérez, Noelia et al, 2022 | - |
dc.identifier.idimarina | 9334008 | - |
dc.identifier.pmid | 36275777 | - |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
Files in This Item:
File | Description | Size | Format | |
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Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment_FrontiersInImmunology.pdf | 7.48 MB | Adobe PDF | View/Open |
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