ROR1 CAR T cells and lenvatinib cooperatively target anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is a rare thyroid malignancy with poor prognosis and very limited treatment options. Therefore, the development of novel therapies is urgently needed. Here, we identified the Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1) protein as a specific CAR T cell target for ATC. ROR1 is part of the Wnt signalling pathway, mainly expressed during embryogenesis, but mostly absent in differentiated adult tissue. In ATCs, ROR1 is strongly overexpressed (RNA/protein level, surface expression) and high expression levels are associated with reduced survival. ROR1 CAR Ts specifically target ATC cell lines in 2D and 3D spheroid cultures, reduce the quantity of circulating tumour cells and block tumour metastases in different ATC mouse models. While small tumours were completely eliminated by ROR1 CAR T cells alone, larger tumours required the combination of ROR1 CAR T cells with the multikinase inhibitor lenvatinib. Lenvatinib blocked primary tumour growth, reduced the quantity of immunosuppressive cancer associated fibroblasts (CAF-S1) in the microenvironment and enhanced CAR T cell functionality and activation. Overall, we validated ROR1 as a prime target for CAR T cell therapies in ATC and identified lenvatinib as highly valuable combination partner, which is able to improve CAR T cell functionality.