Epigenome editing could improve CAR-T cell cancer therapies

CAR-T cell cancer treatments could be made safer and more durable by reprogramming T cells without altering their DNA, according to new research.

Scientists at the Arc Institute in Palo Alto, California, and the University of California, San Francisco, have developed an advanced epigenome editing platform. Unlike traditional genome editing, which cuts DNA, epigenome editing uses CRISPR-guided application of chemical tags, such as methylation, to control gene activity: restoring or blocking important functions without altering the DNA sequence.

'The T cells essentially memorise our programming instructions,' Dr Luke Gilbert from the Arc Institute, senior author of the study published in Nature Biotechnology. 'We deliver the epigenetic editors for just a couple of days, but the gene silencing effects remain stable through dozens of cell divisions and multiple rounds of immune activation'.

CAR-T cell therapy is a personalised treatment that involves engineering a patient's own T cells (a type of white blood cell that forms part of the immune system) to find and destroy cancer. While effective against some blood cancers, their effectiveness in solid tumours is limited because those cancers create a hostile environment that starves and exhausts T cells.

Circumventing this often requires making 'armoured' T cells that can survive. Previously, scientists have used genome editing to make T cells more persistent by removing genes (see BioNews 1172). However, the CRISPR/Cas9 approach, which makes multiple cuts, has a higher chance of causing cell death from unintended DNA damage.

By avoiding DNA breaks, the new epigenomic approach can modify up to five genes simultaneously, giving T cells better memory and resilience even after many cycles of division and immune attack. When the researchers silenced a gene called RASA2, which acts as a 'brake' on T cell activity, the resulting CAR-T cells showed improved persistence and tumour control in mouse models of leukaemia, leading to longer survival compared with standard CAR-T cells.

The platform is compatible with existing manufacturing protocols, potentially making it easier to produce more advanced, personalised T cell therapies at scale. The researchers hope that it will lead to more effective treatments for solid tumours, and are now working to refine the technique, with clinical trials in mind.