T cells get tired out by continuous activation, suffering an epigenetic reprogramming of their gene expression that leaves them in a state of sluggish apathy. This condition, known as “exhaustion,” is the bane of T cell-based therapies for cancer, even those that employ chimeric antigen-receptor (CAR) T cells to target cancer cells bearing specific molecular markers. Exhaustion was until recently considered generally irreversible. No longer. Adding to a growing body of evidence that exhausted T cells can in fact be revived (see previous feature), a team of researchers led by Ludwig Stanford investigator Crystal Mackall reported in Science in April that all exhausted CAR-T cells may really need is a little rest. The researchers gave CAR-T cells their time out in two ways: by using synthetic biology to regulate degradation of the chimeric antigen receptor protein, or with the use of an existing small molecule that temporarily suppresses CAR-T activity. In both cases, the CAR-T cells took their time off to rewrite the epigenetic programming of their genomes, reviving vital gene expression programs and regaining their cancer-killing capabilities. Given just four days of rest, the rejuvenated cells leapt back into action, significantly extending survival in mouse models of cancer.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).