Next generation CAR-T cell therapy could fight solid cancers

Written by Alexander Marshall

CAR-T cell therapy could soon combat solid tumors by utilizing exhaustion resistant cells.

Research conducted by a team from Stanford University (CA, USA) has resulted in the production of a new generation of CAR-T cells that show promise in combating solid tumors. The work, led by Crystal Mackall (Stanford University), has been published in Nature and describes the promising use of these new cells in mice with bone cancer.

CAR-T has shown significant advances against blood cancers; however, its effectiveness against solid tumors has been less impressive due to the CAR-T cells naturally exhausting, resulting in shorter-term impact. By overexpressing C-JUN in their CAR-T cells, the team were able to demonstrate an ability to remain active and proliferate under laboratory conditions. The team went on to treat mice that had been injected with human leukemias with either the traditional CAR-T or C-JUN+ CAR-T and demonstrated an increased survival rate among those with the modified C-JUN+ CAR-T.

 “We know that T cells are powerful enough to eradicate cancer, but these same T cells have evolved to have natural brakes that tamp down the potency of their response after a period of prolonged activity” commented Crystal Mackall. “We’ve developed a way to mitigate this exhaustion response and improve the activity of CAR-T cells against blood and solid cancers.”

Following their success against leukemia, the team treated mice with human osteosarcoma — a solid bone cancer — and successfully demonstrated a reduction in tumor burden and an extension in lifespan.

The team focused on C-JUN after utilizing a technique known as ATAC-seq on both exhausted and non-exhausted CAR-T cells. ATAC-seq allowed the researchers to discover which areas of the genome were most accessible and suggested that the difference between the two states was in a major class of genes that regulate protein levels. This led the team to select C-JUN, a protein which is known to be associated with T-cell activation.

“When we used this technique to compare the genomes of healthy and exhausted T cells,” explained Mackall. “We identified some significant differences in gene expression patterns.”

It is now the team’s aim to initiate clinical trials within 18 months against leukemia, with the eventual goal of progressing onto solid tumors.

Source: Lynn R, Weber E, Sotillo E, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. doi:10.1038/s41586-019-1805-z (2019) (Epub ahead of print);

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