Mayo Clinic strategy restores CAR T targets on aggressive thyroid tumours

Drugs already used to treat advanced thyroid cancer could help make aggressive tumours visible to CAR T cells, potentially overcoming one of the major challenges of using the immune therapy against solid tumours.

Researchers at Mayo Clinic found that blocking a key cancer signalling pathway can restore a target known as TSHR on aggressive thyroid cancer cells. This could allow specially engineered CAR T cells to recognise and attack tumours that had previously become difficult for them to detect.

In their study, amalgamating the drugs with CAR T therapy produced better tumour control and survival in preclinical models than either treatment alone.

Instead of modifying CAR T cells to recognise cancer cells that had lost their targets, the researchers investigated whether they could instead make the cancer cells display the target again.

We often think about engineering the immune cell to overcome resistance, this work shows another possibility.”

Saad Kenderian, Haematologist and Oncologist, Mayo Clinic

Making cancer visible again

CAR T-cell therapy involves genetically engineering T cells, immune cells that help protect the body from disease, to recognise specific targets known as antigens on cancer cells.

The approach has changed the way some blood cancers are treated but has proved more difficult to use against solid tumours. One reason is that cancer cells can lose or reduce the antigens targeted by CAR T cells, making them harder for the engineered immune cells to identify.

To try and combat this, the Mayo Clinic researchers looked at a protein that is usually found on thyroid cells, the thyroid-stimulating hormone receptor (TSHR).

When designing CAR T cells to target TSHR, they demonstrated strong anti-tumour activity against thyroid cancers with high levels of the receptor. However, their effectiveness was weaker against anaplastic thyroid cancer, the most aggressive form of the disease, which often has low levels of TSHR expression or none at all.

Restoring the target

The researchers then looked at whether TSHR could be restored through redifferentiation. This is when aggressive cancer cells regain some biological characteristics they have lost.

They used drugs that block the mitogen-activated protein kinase (MAPK) signalling pathway, including trametinib and dabrafenib, which are approved for treating advanced thyroid cancer.

In models derived from patients with anaplastic thyroid cancer, MAPK inhibition increased TSHR expression on tumour cells. When the drugs were combined with TSHR-targeted CAR T cells, the treatment produced stronger tumour control and improved survival compared with either approach 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 tumours 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 tumours where target expression is limited.”

Claudia Manriquez Roman, Process Development Engineer, Mayo Clinic 

Potential for other cancers

The researchers found that the MAPK inhibitors did not appear to prevent CAR T cells from multiplying or attacking cancer cells. Instead, the drugs appeared to create a temporary period during which the engineered cells could target cancer cells that had previously escaped detection.

TSHR expression declined after treatment with the MAPK inhibitors stopped. However, two weeks of concurrent treatment was sufficient to increase 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,” said co-senior author John Copland III, a cancer biologist and translational researcher at Mayo Clinic.

The researchers are completing studies to support potential Phase I clinical trials of TSHR-targeted CAR T cells. Future testing could examine the therapy alone in patients whose tumours continue to express TSHR or alongside MAPK inhibitors when the receptor has been lost.

Although the research focused on thyroid cancer, the approach could potentially be investigated in other solid tumours where limited target expression restricts the effectiveness of immune therapies.