Gene edited T cell therapies for leukaemia

T cells can be genetically redirected to express recombinant chimeric antigen receptors (CARs) in order to mediate potent anti-leukaemic effects. In certain conditions, high levels of remission have been reported in early phase studies. To date, most clinical trials have manufactured CAR-T cells from autologous cell harvests, but this can be time consuming and expensive, and may not be possible in lymphopenic subjects. Gene editing offers the possibility of circumventing HLA-barriers and producing ‘off-the-shelf’ universal T cells that can be banked and used without matching. Such an approach could extend the application and availability of cell therapies and the first clinical demonstration of this strategy has been in patients with CD19+ B-cell acute lymphoblastic leukemia. Initial applications used lentiviral gene transfer to stably integrate genes encoding for CARs, and Transcription Activator-Like Effector Nucleases (TALENs) were delivered as mRNA by electroporation to target T cell receptor genes (TRAC) and the locus for CD52, the target antigen of Alemtuzumab. Residual TCRab T cells were removed by magnetic bead enrichment, reducing alloreactivity and allowing cells to be used in a mismatched setting. Subsequently, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 systems have been adopted to improve the efficiency of engineering, and vectors that couple transduction and editing effects yield highly homogenous products.  High throughput sequencing analysis and targeted bioinformatics analysis has allowed detailed profiling of CRISPR-CAR modified cells, including quantification of on- and off-target effects.  Early phase studies will help determine the safety and potential of gene edited T cells, and improvements in reagents and manufacturing techniques are promising a wide range of applications.


Waseem Qasim is Professor of Cell and Gene therapy at the Institute of Child Health, and a consultant immunologist at Great Ormond Street hospital, supported by the National Institute of Health Research. He trained in Immunology and Paediatric Medicine, and then completed his PhD at University College London. He is researching blood and marrow stem cell transplantation and the application of T cell therapies for cancer and infection. Waseem heads a research group developing gene based therapies, from basic laboratory development, through GMP manufacturing and into first-in-human trials. His group has a strong focus on lentiviral technology and gene-editing tools including TALENs and CRISPR/Cas reagents for novel therapeutic applications such as universal chimeric antigen receptor T cells for leukaemia.