PD1 blockade enhances ICAM1-directed CAR T therapeutic efficacy in advanced thyroid cancer.

Purpose: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of ATC patients have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options. Experimental Design: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of thyroid cancer patients. Next, we studied the tumor targeting efficacy and T cell dynamics of mono- and combination treatments of ICAM1-targeting CAR T cells and anti-PD1 antibody in a xenograft model of ATC. Results: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8+ T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNg-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared to CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model. Conclusions:Targeting two IFNg-inducible, tumor-associated antigens - ICAM1 and PD-L1 - in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers in vivo.