Reprogramming thyroid tumors with MAPK inhibitors could make them more susceptible to CAR T-cell therapy, according to a preclinical study.
The strategy uses targeted drugs to restore thyroid-stimulating hormone receptor (TSHR) expression on aggressive thyroid cancer cells. Combining the drugs with TSHR-directed CAR T cells improved tumor control and survival in mice compared with either treatment alone.
CAR T-cell therapies depend on cancer cells expressing the antigen that the engineered cells are designed to recognize. Low or heterogeneous antigen expression can therefore limit their activity against solid tumors.
TSHR is highly expressed in normal thyroid tissue and several differentiated forms of thyroid cancer. However, its expression declines as tumors lose their thyroid-like characteristics and become more aggressive. This leaves anaplastic thyroid cancer, one of the most aggressive forms of the disease, poorly suited to TSHR-targeted treatment.
In the study, TSHR-targeted CAR T cells produced durable, antigen-specific activity against differentiated thyroid cancer models with high TSHR expression. Their activity was more limited against tumors with low expression, confirming that antigen density influenced treatment response.
The researchers then tested whether inhibiting MAPK signaling could induce redifferentiation – a process in which tumor cells regain biological features lost during cancer progression. Treatment with the MEK inhibitor trametinib, alone or with the BRAF inhibitor dabrafenib, increased TSHR expression in a patient-derived anaplastic thyroid cancer model.
Concurrent treatment with MAPK inhibitors and TSHR-directed CAR T cells produced stronger tumor control than sequential treatment or either approach alone. The combination maintained tumor control for more than two months in one experiment and prolonged survival in a second.
Two weeks of concurrent MAPK inhibitor treatment after CAR T-cell administration was sufficient to improve activity. However, TSHR expression fell within two days of stopping the inhibitors, indicating that the timing of the treatments will require further investigation.
The inhibitors did not reduce CAR T-cell proliferation, cytotoxicity, cytokine production, or persistence in the experiments.
“One of the key discoveries from our work is that antigen density matters,” said co-first author Claudia Manriquez Roman in a Mayo Clinic press release. “We showed that restoring TSHR expression with combination therapy can sensitize aggressive thyroid tumors to CAR-T cell attack.”
The researchers are completing studies to support a phase I trial of TSHR-directed CAR T cells, both alone and in combination with MAPK inhibitors.
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