RT Journal Article
T1 Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma.
A1 Maldonado-Perez, Noelia
A1 Tristan-Manzano, Maria
A1 Justicia-Lirio, Pedro
A1 Martinez-Planes, Elena
A1 Muñoz, Pilar
A1 Pavlovic, Kristina
A1 Cortijo-Gutierrez, Marina
A1 Blanco-Benitez, Carlos
A1 Castella, Maria
A1 Juan, Manel
A1 Wenes, Mathias
A1 Romero, Pedro
A1 Molina-Estevez, Francisco J
A1 Marañon, Concepcion
A1 Herrera, Concha
A1 Benabdellah, Karim
A1 Martin, Francisco
K1 CAR-T cells
K1 CRISPR/Cas9
K1 TCRKO
K1 Large deletions
K1 Lymphoma
K1 Off-the-shelf
K1 Safety
AB 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 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). 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.
PB Frontiers Research Foundation
YR 2022
FD 2022-09-22
LK http://hdl.handle.net/10668/20594
UL http://hdl.handle.net/10668/20594
LA en
NO Maldonado-Pérez N, Tristán-Manzano M, Justicia-Lirio P, Martínez-Planes E, Muñoz P, Pavlovic K, et al. Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. Front Immunol. 2022 Oct 6;13:1011858
DS RISalud
RD Apr 20, 2025