Innovative 'CAR-T cell' therapies are ushering in a new era of leukaemia treatment, suggests Professor Waseem Qasim.
Survival rates for children with B-cell acute lymphoblastic leukaemia (B-ALL) have improved markedly, thanks to treatments such as chemotherapy and stem cell transplants. However, disease still recurs in some children, and additional effective treatments would be welcomed. CAR-T cell therapies - chimeric antigen receptor T cell therapies - are offering hope to children who have exhausted other therapeutic options, and may even become front-line B-ALL treatments.
CAR-T cell therapy harnesses the destructive power of the immune system, directing it specifically at cancer cells. T cells specialised for cell killing are engineered so that they recognise an antigen (known as CD19) on the surface of B-ALL cells, focusing their destructive powers on these specific cells.
Commonly, the T cells used in CAR-T cell therapy are taken from the patients themselves, but these can be difficult to obtain in large numbers. An alternative is to modify donor T cells, which could then be used 'off the shelf' when the need arose. However, there is a risk that such cells would attack cells other than the B-ALL cells and might themselves be recognised as foreign and be attacked by the patient's immune system.
To overcome these challenges, Professor Qasim and colleagues collected non-matched donor T cells and used a genome-editing technique known as TALEN to disable the cells' existing T cell receptor (to prevent 'off-target' effects) and introduced the receptor targeting CD19. In a world first, these cells were successfully used to treat two children with relapsed CD19 B-ALL .
This study demonstrated the feasibility of genome editing to facilitate the use of donor T cells. Professor Qasim and colleagues are now modifying their approach, adopting the more commonly used CRISPR-Cas9 genome-editing technology to modify T cells, with a view to carrying out further clinical studies in B-ALL.
Professor Qasim and colleagues at Great Ormond Street Hospital were able to adopt the new technology so rapidly in part because of their past clinical experience with genetically manipulated cells, in landmark gene therapy trials. Professor Qasim has established a facility for generating clinical-grade CAR-T cells, which are supplied to other UCL groups pursuing the CAR-T treatment route.
While CAR-T therapy is currently used when other treatments have failed, continuing success and evidence of its safety could see it adopted at early stages. And its use could also be extended to other centres treating childhood cancers. To promote wider uptake, Professor Qasim has worked with a medical device company on equipment for automating aspects of CAR-T cell manufacturing  - something that could both extend their use and bring down the cost of treatment.
- Qasim W et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374).
- Mock U et al. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy. Cytotherapy. 2016;18(8):1002-11.