![]() ![]() 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. 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. 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. 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. We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation αCD19 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). Allogeneic off-the-shelf CAR-T cells are an alternative to simplify this complex and time-consuming process. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. 7Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, SpainĪutologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies.6Department of Oncology, University of Lausanne, Épalinges, Switzerland.5Department of Hematology, ICMHO, Hospital Clínic de Barcelona, Barcelona, Spain.4Cellular Therapy Unit, Maimonides Institute of Biomedical Research in Córdoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.3Department of Celular Biology, Faculty of Sciences, University of Granada, Granada, Spain.2LentiStem Biotech, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), PTS, Granada, Spain.1Department of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Granada, Spain.Molina-Estévez 1, Concepción Marañón 1, Concha Herrera 4, Karim Benabdellah 1‡§ and Francisco Martin 1,7*‡ Noelia Maldonado-Pérez 1†, María Tristán-Manzano 1,2†, Pedro Justicia-Lirio 1,2, Elena Martínez-Planes 1, Pilar Muñoz 1,3, Kristina Pavlovic 1,4, Marina Cortijo-Gutiérrez 1, Carlos Blanco-Benítez 1,2, María Castella 5, Manel Juan 5, Mathias Wenes 6, Pedro Romero 6, Francisco J. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |