CRISPR may lead to improvements in cancer immunotherapies

CRISPR/Cas9 has been used to identify genome editing targets that significantly enhance the efficiency of a targeted therapy for myeloma, a type of cancer.

Researchers from Harvard Medical School, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, all in Massachusetts, discovered key genes that, when disabled, dramatically improve the persistence and function of chimeric antigen receptor T cell (CAR-T) cells. They employed a CRISPR-based genetic screening approach, targeting 135 genes known to regulate T cell biology, and tracked their effects in cell cultures followed by mouse models for up to 21 days.

'Testing individual genetic modifications to find those that enhance CAR-T function would take a huge amount of time and money,' explained Professor Marcela Maus, co-senior author of the study published in Nature. 'Our approach lets us test hundreds of changes at a time.'

CAR-T cells are immune cells – usually the patient's own – which are edited to be more effective at identifying and destroying cancer cells.

The screening revealed that deleting the cell cycle regulator gene CDKN1B produced the most significant improvements. This gene normally acts as a brake on cell division, but removing it allows CAR-T cells to proliferate more rapidly and persist longer in the body. CAR-T cells without the CDKN1B gene demonstrated accelerated expansion, sustained anti-tumour activity, and significantly improved tumour clearance compared to standard treatments.

Some genes that enhanced CAR-T cell activity in culture dishes failed to show the same benefits in mouse models. Other genes promoted the early proliferation of CAR-T cells but did not increase their effectiveness over time.

'We discovered important regulators in vivo that we could not have predicted from the in vitro results,' said co-senior author Dr Robert Manguso.

Beyond CDKN1B, the screens identified several other promising targets. Knocking out some genes improved CAR-T cell in vitro expansion during manufacturing, while removing others conferred early growth advantages in vivo. Each genetic change offered distinct benefits, suggesting potential combination approaches.

A separate study from the Medical University of Vienna, Austria, similarly demonstrates the potential of genome editing to improve the effectiveness of CAR-T cell therapies.

In their study – also published in Nature – the team from Vienna conducted 58 genome-wide screens, again using a CRISPR-based platform. They identified RHOG deletion as another potent CAR-T cell booster, and even more so when combined with deletion of the FAS gene. This combination produced strong therapeutic effects across multiple cancer models.

'By targeting both RHOG and FAS, we saw strikingly synergistic effects – the gene-edited CAR-T cells proliferated faster, stayed more active, were less likely to kill each other, and were able to cure mice from aggressive leukaemia,' said co-first author Dr Cosmas Arnold.