Preclinical thyroid cancer study restores CAR-T target with targeted drugs

Mayo Clinic researchers have identified a drug combination that restored a surface target on aggressive thyroid cancer cells and improved the activity of CAR-T cells in preclinical models. In patient-derived models of anaplastic thyroid cancer, the mitogen-activated protein kinase inhibitors trametinib and dabrafenib increased expression of the thyroid-stimulating hormone receptor, or TSHR. When the drugs were combined with CAR-T cells engineered to target TSHR, the regimen produced stronger tumor control and improved survival compared with either treatment alone. The peer-reviewed study, published in Molecular Cancer, addresses a major obstacle in treating solid tumors with CAR-T therapy: cancer cells can lose or reduce the antigens that engineered immune cells are designed to recognize.

CAR-T cell therapy engineers T cells 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. Solid tumors can lose or reduce their targeted antigens, making them harder for CAR-T cells to identify and destroy. Rather than modifying CAR-T cells further to recognize cancers that have lost their targets, the Mayo Clinic team investigated whether targeted drugs could change the tumor so that the original target reappeared. The strategy uses redifferentiation, a process in which aggressive cancer cells regain some of the biological features they have lost, to restore TSHR expression and make anaplastic thyroid cancer cells vulnerable to existing TSHR-targeted CAR-T cells.

The team focused on 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, which can have low or no TSHR expression. The researchers used drugs that inhibit the MAPK signaling pathway, including trametinib and dabrafenib, both approved to treat advanced thyroid cancer. In patient-derived anaplastic thyroid cancer models, MAPK inhibition increased TSHR expression on tumor cells. Combining the inhibitors with TSHR-targeted CAR-T cells then yielded better tumor control and survival than either approach alone, indicating that restoring antigen density could improve CAR-T activity without requiring the engineered cells to acquire a different target.

The experiments also indicated that the MAPK inhibitors did not appear to interfere with the CAR-T cells’ ability to multiply or attack cancer cells. Instead, the drugs created a temporary window in which CAR-T cells could target cancer cells that had previously escaped detection because of low receptor expression. TSHR expression declined after the inhibitors were stopped, but two weeks of concurrent MAPK-inhibitor and CAR-T treatment was sufficient to improve CAR-T activity in the preclinical models. The findings therefore depended on treatment timing: the receptor increase was temporary, and the enhanced immune attack occurred while the tumor cells were more susceptible to recognition.

Co-first author Claudia Manriquez Roman, Ph.D., a process development engineer at Mayo Clinic in Minnesota, said the study showed that antigen density matters in CAR-T activity against solid tumors. Restoring TSHR through combination therapy sensitized aggressive thyroid tumors to CAR-T attack and turned a previously suboptimal target into a more vulnerable one. Co-senior author Saad Kenderian, M.B., Ch.B., a Mayo hematologist and oncologist, said the work presents another way to overcome resistance alongside engineering the immune cell. Co-senior author John Copland III, Ph.D., a Mayo cancer biologist and translational researcher in Florida, said the approach uses the cancer cell’s own biology to restore TSHR by blocking MAPK signaling with molecular targeted drugs. Although the study focused on thyroid cancer models, the concept may offer a framework for other solid tumors in which limited target expression restricts immune therapy. Mayo Clinic researchers are completing studies needed to support phase 1 clinical testing of TSHR-targeted CAR-T cells, either alone in patients whose tumors continue to express TSHR or with MAPK inhibitors in patients whose tumors have lost it. The results remain preclinical and do not yet establish clinical benefit in people with cancer.

Subject of Research: Preclinical restoration of TSHR expression with MAPK inhibitors to improve CAR-T treatment of anaplastic thyroid cancer.

Article Title: Study shows reprogramming thyroid tumors may improve CAR-T cell therapy

Article References: Study shows reprogramming thyroid tumors may improve CAR-T cell therapy. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: anaplastic thyroid cancer, CAR-T cells, TSHR, MAPK inhibitors, trametinib, dabrafenib, antigen restoration, redifferentiation, solid tumors, preclinical research, shows, reprogramming