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Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma

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-th...

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Autores principales: Maldonado-Pérez, Noelia, Tristán-Manzano, María, Justicia-Lirio, Pedro, Martínez-Planes, Elena, Muñoz, Pilar, Pavlovic, Kristina, Cortijo-Gutiérrez, Marina, Blanco-Benítez, Carlos, Castella, María, Juan, Manel, Wenes, Mathias, Romero, Pedro, Molina-Estévez, Francisco J., Marañón, Concepción, Herrera, Concha, Benabdellah, Karim, Martin, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585383/
https://www.ncbi.nlm.nih.gov/pubmed/36275777
http://dx.doi.org/10.3389/fimmu.2022.1011858
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author Maldonado-Pérez, Noelia
Tristán-Manzano, María
Justicia-Lirio, Pedro
Martínez-Planes, Elena
Muñoz, Pilar
Pavlovic, Kristina
Cortijo-Gutiérrez, Marina
Blanco-Benítez, Carlos
Castella, María
Juan, Manel
Wenes, Mathias
Romero, Pedro
Molina-Estévez, Francisco J.
Marañón, Concepción
Herrera, Concha
Benabdellah, Karim
Martin, Francisco
author_facet Maldonado-Pérez, Noelia
Tristán-Manzano, María
Justicia-Lirio, Pedro
Martínez-Planes, Elena
Muñoz, Pilar
Pavlovic, Kristina
Cortijo-Gutiérrez, Marina
Blanco-Benítez, Carlos
Castella, María
Juan, Manel
Wenes, Mathias
Romero, Pedro
Molina-Estévez, Francisco J.
Marañón, Concepción
Herrera, Concha
Benabdellah, Karim
Martin, Francisco
author_sort Maldonado-Pérez, Noelia
collection PubMed
description 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.
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spelling pubmed-95853832022-10-22 Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma Maldonado-Pérez, Noelia Tristán-Manzano, María Justicia-Lirio, Pedro Martínez-Planes, Elena Muñoz, Pilar Pavlovic, Kristina Cortijo-Gutiérrez, Marina Blanco-Benítez, Carlos Castella, María Juan, Manel Wenes, Mathias Romero, Pedro Molina-Estévez, Francisco J. Marañón, Concepción Herrera, Concha Benabdellah, Karim Martin, Francisco Front Immunol Immunology 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. Frontiers Media S.A. 2022-10-06 /pmc/articles/PMC9585383/ /pubmed/36275777 http://dx.doi.org/10.3389/fimmu.2022.1011858 Text en Copyright © 2022 Maldonado-Pérez, Tristán-Manzano, Justicia-Lirio, Martínez-Planes, Muñoz, Pavlovic, Cortijo-Gutiérrez, Blanco-Benítez, Castella, Juan, Wenes, Romero, Molina-Estévez, Marañón, Herrera, Benabdellah and Martin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Maldonado-Pérez, Noelia
Tristán-Manzano, María
Justicia-Lirio, Pedro
Martínez-Planes, Elena
Muñoz, Pilar
Pavlovic, Kristina
Cortijo-Gutiérrez, Marina
Blanco-Benítez, Carlos
Castella, María
Juan, Manel
Wenes, Mathias
Romero, Pedro
Molina-Estévez, Francisco J.
Marañón, Concepción
Herrera, Concha
Benabdellah, Karim
Martin, Francisco
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title_full Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title_fullStr Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title_full_unstemmed Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title_short Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma
title_sort efficacy and safety of universal (tcrko) ari-0001 car-t cells for the treatment of b-cell lymphoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585383/
https://www.ncbi.nlm.nih.gov/pubmed/36275777
http://dx.doi.org/10.3389/fimmu.2022.1011858
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