4.8 Article

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

期刊

FRONTIERS IN IMMUNOLOGY
卷 13, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.1011858

关键词

CAR-T cells; lymphoma; TCRKO; CRISPR; Cas9; off-the-shelf; safety; large deletions

资金

  1. Spanish ISCIII Health Research Fund
  2. European Regional Development Fund (FEDER) [PI15/02015, PI18/00337, PI21/00298, Red TerAv RD21/ 0017/0004, PI18/ 00330, PI17/00672]
  3. CECEyU and CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia [2016000073391-TRA, 2016000073332-TRA, PI-57069, PAIDIBio326, CARTPI-0001- 201, PECART-0031-2020, PI0014-2016, PEER-0286-2019]
  4. Ministerio de Ciencia, Innovacion y Universidades [00123009/SNEO-20191072, PLEC2021-008094]
  5. regional Ministry of Health [0006/2018, C2-0002-2019]
  6. Spanish Ministry of Education and Science [FPU16/05467, FPU17/02268, FPU17/04327]
  7. CSyF of the Junta de Andalucia [PECART-00312020]
  8. Consejeria de Salud y Familias [PECART-0027-2020]
  9. [MCI DIN2018-010180]
  10. [DIN2020-011550]

向作者/读者索取更多资源

This study investigated the safety and efficacy of knocking out the TCR gene in ARI-0001 CAR-T cells using CRISPR/Cas9. The results showed that TCR disruption efficiently prevented allogeneic responses without altering T cell phenotype and maintained a similar anti-tumor activity compared to unedited CAR-T cells.
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.

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