Mishra, AK;
Qasim, W;
(2024)
Genome editing approaches for universal chimeric antigen receptor T cells.
EJC Paediatric Oncology
, 3
, Article 100149. 10.1016/j.ejcped.2024.100149.
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Abstract
Autologous chimeric antigen receptor (CAR) T cell therapy has revolutionised the management of certain B-cell malignancies. However, as bespoke therapies, challenges include complex manufacturing logistics and risks ranging from suboptimal harvests to inadvertent transduction and masking of blast populations. Premanufactured, ready -to -use allogeneic CAR T cells could mitigate some of these hurdles if barriers created by HLA (Human leukocyte antigen) mismatching can be addressed. Genome editing to disrupt TCRαβ (T-cell receptor αβ) expression has been shown to be effective in addressing alloreactivity and avoiding graft versus host disease (GVHD). Platforms including transcription activator-like effector nucleases (TALENs), homing endonucleases and clustered regularly interspersed short palindromic repeats (CRISPR) / Cas9 have allowed multiplex editing of TCR genes in combination with CD52, the target antigen of alemtuzumab, as a strategy to evade lymphodepletion used to prevent host v graft rejection effects. Alternative approaches have targeted pathways to prevent HLA expression on donor T cells, and have also allowed targeted insertion of CAR genes, including placing transgene expression under the control of endogenous transcriptional machinery. These tools have rapidly progressed to clinical trials, and applications have extended beyond B-cell malignancies, showing promising early results in other settings, including relapsed/refractory(r/r) T-cell leukaemia. Short term immunological effects and toxicities have been generally manageable, and long-term monitoring is ongoing to help build confidence in safety over time.
| Type: | Article |
|---|---|
| Title: | Genome editing approaches for universal chimeric antigen receptor T cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ejcped.2024.100149 |
| Publisher version: | http://dx.doi.org/10.1016/j.ejcped.2024.100149 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Genome editing, CRISPR/Cas9, Base editor, Allogeneic CAR T, T-cell therapies, Chimeric antigen receptor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10191739 |
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