In a preclinical study published in Molecular Cancer, researchers found that drugs used to treat advanced thyroid cancer can restore a marker on aggressive thyroid cancer cells, making the cancer visible again to specially engineered CAR-T cells. Combining the drugs with CAR-T cell therapy resulted in better tumor control and survival in preclinical models than either approach alone. Rather than further modifying CAR-T cells to recognise cancers that have lost their targets, researchers sought to change the tumor so the target reappears. "We often think about engineering the immune cell to overcome resistance," says co-senior author Saad Kenderian, M.B., Ch.B., a hematologist and oncologist at Mayo Clinic in Minnesota.
"This work shows another possibility." CAR-T cell therapy engineers T cells — immune cells that help protect the body from disease — to recognize a specific target, or antigen, on cancer cells. The approach has transformed treatment for some blood cancers but has been less successful against solid tumors. One reason is that solid tumors can lose or reduce the antigens CAR-T cells are designed to recognise, making it more difficult for the engineered cells to identify and destroy the cancer. The Mayo Clinic team focused on the thyroid-stimulating hormone receptor (TSHR), a protein found primarily on thyroid cells. CAR-T cells targeting this receptor showed strong antitumor activity against thyroid cancers with high TSHR levels. Their effectiveness was more limited against anaplastic thyroid cancer, the most aggressive form of the disease with low or no TSHR expression. Researchers investigated whether they could restore TSHR through a process known as redifferentiation, in which aggressive cancer cells regain some of the biological features they had lost. They used drugs that inhibit the mitogen activated protein kinase (MAPK) signaling pathway, including trametinib and dabrafenib, which are approved to treat advanced thyroid cancer. In patient-derived models of anaplastic thyroid cancer, MAPK inhibition increased TSHR expression on tumor cells. When researchers combined the drugs with TSHR-targeted CAR-T cells, the combination produced stronger tumor control and survival than either treatment alone.
