ROCHESTER, Minn. — Mayo Clinic researchers have identified a strategy that could help chimeric antigen receptor-T cell therapy, or CAR-T cell therapy, overcome a major barrier to treating solid tumors: Cancer cells can change in ways that allow them to hide from immune cells designed to attack them.

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 recognize 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."

Making an aggressive cancer visible again

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 recognize, 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.

Turning the target back on

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.

"One of the key discoveries from our work is that antigen density matters. We showed that restoring TSHR expression with combination therapy can sensitize aggressive thyroid tumors to CAR-T cell attack, effectively turning a suboptimal target into a more vulnerable one. This approach may provide a new framework for enhancing CAR-T therapies across solid tumors where target expression is limited," says co-first author Claudia Manriquez Roman, Ph.D., process development engineer at Mayo Clinic in Minnesota.

Researchers also found 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  the CAR-T cells could target cancer cells that had previously escaped detection.

TSHR expression declined after MAPK inhibitor treatment stopped, but two weeks of concurrent treatment was sufficient to improve CAR-T cell activity in the preclinical models.

"What’s exciting about this approach is that we're taking advantage of the cancer cell's own biology to restore TSHR expression by blocking MAPK signaling with molecular targeted drugs," says co-senior author John Copland III, Ph.D., cancer biologist and translational researcher at Mayo Clinic in Florida. Dr. Copland noted that approximately 2,500 Americans die per year from metastatic thyroid cancer disease. 

A potential strategy beyond thyroid cancer

Although the study focused on thyroid cancer, the concept could have implications for other solid tumors where treatments use immune therapy that targets similar surface markers.

Researchers are completing studies needed to support phase 1 clinical trial testing of TSHR-targeted CAR-T cells. The therapy could be studied alone in patients whose tumors continue to express TSHR or in combination with MAPK inhibitors in patients whose tumors have lost TSHR expression.

The researchers hope the approach ultimately could lead to another treatment option for patients with cancers that no longer respond to available therapies.  

For a complete list of authors, disclosures and funding, read the study.

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Media contact:

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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