{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:42:30Z","timestamp":1776692550078,"version":"3.51.2"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/02015, PI18\/00337, PI21\/00298 , RD21\/0017\/0004 , PI18\/00330 , PI17\/00672"],"award-info":[{"award-number":["PI15\/02015, PI18\/00337, PI21\/00298 , RD21\/0017\/0004 , PI18\/00330 , PI17\/00672"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PI-57069, PAIDI-Bio326, CARTPI-0001-201, PECART-0031-2020 , PI-0014-2016 , PEER-0286-2019"],"award-info":[{"award-number":["PI-57069, PAIDI-Bio326, CARTPI-0001-201, PECART-0031-2020 , PI-0014-2016 , PEER-0286-2019"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["00123009\/SNEO-20191072 , PLEC2021-008094 , (#0006\/2018 , C2-0002-2019 , FPU16\/05467, FPU17\/02268"],"award-info":[{"award-number":["00123009\/SNEO-20191072 , PLEC2021-008094 , (#0006\/2018 , C2-0002-2019 , FPU16\/05467, FPU17\/02268"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 <jats:italic>off-the-shelf<\/jats:italic> 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 \u03b1CD19 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 <jats:italic>TRAC<\/jats:italic> 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 <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1011858","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T06:27:08Z","timestamp":1665037628000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell 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