CAR T-cell therapy has racked up remarkable wins, but it does have its limitations. For one thing, while it works against some blood cancers, it hasn’t yet been shown to be effective against solid tumors. For another, its efficacy can wane after some time even against blood cancers, often due to the T cell exhaustion that naturally kicks in after prolonged T cell activity. In a December Nature paper, researchers led by Ludwig Stanford’s Crystal Mackall report their exploration of the phenomenon, and an approach to its prevention. Using a technique called ATAC-Seq—developed in the laboratory of Ludwig Professor Howard Chang—the researchers explored differences in the activation of the genome between exhausted and active T cells. This revealed an imbalance in the activity of a class of genes that regulate protein levels in the exhausted cells, which led in turn to the inhibition of T-cell activity. The team engineered CAR T-cells to overexpress c-Jun, a protein involved in T-cell activation, and demonstrated in preclinical models of leukemia, and even a (solid) bone cancer, that the modified CAR-T cells could better target cancer than their ordinary counterparts, further extending the lives of mice.
This article appeared in the April 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).