Restored thyroid receptor makes aggressive tumors more vulnerable to CAR-T cell therapy

Mayo Clinic researchers have discovered a method that could make CAR-T cell therapy more effective against aggressive solid tumors where cancer cells can evade immune cells. The approach involves using drugs approved for advanced thyroid cancer to restore a marker called the thyroid-stimulating hormone receptor (TSHR) on aggressive thyroid cancer cells, making them visible again to CAR-T cells engineered to target this marker.

Preclinical studies published in Molecular Cancer showed that combining the MAPK inhibitors trametinib and dabrafenib with TSHR-targeted CAR-T cells resulted in better tumor control and survival than either treatment alone. CAR-T cell therapy, which engineers immune cells to recognize specific targets on cancer cells, has been successful in treating some blood cancers but less effective against solid tumors due to cancer cells losing or reducing antigens recognized by these engineered cells.

Researchers focused on the TSHR protein primarily found on thyroid cells, discovering that the MAPK pathway inhibitors restored TSHR expression in aggressive cancer cells, making the tumors more susceptible to CAR-T cell attack. The MAPK inhibitors did not interfere with the CAR-T cells' ability to multiply or attack cancer cells, creating a temporary window for the CAR-T cells to target cancer cells that had previously escaped detection.

Although TSHR expression declined after the MAPK inhibitors were stopped, two weeks of concurrent treatment was sufficient to improve CAR-T cell activity in preclinical models. Researchers believe this approach could provide a new framework for enhancing CAR-T therapies for solid tumors where target expression is limited, and the concept could potentially be applicable to other solid tumors where immunotherapy targets similar surface markers.

The study's findings could lead to another treatment option for patients with cancers that no longer respond to available therapies.