Author:
Gleba Justyna J.,Siegler Elizabeth L.,Manriquez-Roman Claudia,Huynh Truc N.,Mai Long K.,Miller James L.,Miller Erin E.,Pawlush Matthew L.,Demirer Aylin Alasonyalilar,Kimball Brooke L.,Tapper Erin E.,Sakemura R. Leo,Stewart Carli M.,Can Ismail,Sirpilla Olivia L.,Feigin Jennifer M.,Yun Kun,Gutierrez Ruiz Omar L.,Xia Hong,Torghabeh Mehrdad Hefazi,Schick Kendall J.,Ogbodo Ekene J.,Olivier Gloria,Qiu Yushi,Tun Han W.,Smallridge Robert C.,Zubair Abba,Copland John A.,Kenderian Saad S.
Abstract
ABSTRACTMost thyroid cancer deaths are attributed to a subset of poorly differentiated, metastatic tumors. To improve treatment options for these aggressive thyroid cancers, we developed a novel thyroid-stimulating hormone receptor (TSHR)-targeted chimeric antigen receptor T (CART) cell therapy, which demonstrated antigen-specific activation and antitumor efficacy against TSHR-overexpressing cell linesin vitroandin vivo. However, de- differentiated thyroid cancers downregulate TSHR. We therefore developed a potent treatment strategy by combining our novel TSHR-CART cells with mitogen-activated protein kinase (MAPK) inhibitors, which redifferentiate thyroid tumors and upregulate TSHR expression. In patient-derived anaplastic thyroid cancer xenografts, combination therapy of TSHR-CART cells and MAPK inhibitors led to increased TSHR expression on the tumor tissue and significantly enhanced antitumor efficacy and prolonged survival compared to TSHR- CART monotherapy.STATEMENT OF SIGNIFICANCEPoor target selection and antigen escape limit CART cell efficacy in solid tumors. We developed TSHR-CART cells to treat differentiated thyroid cancers but observed TSHR downregulation in dedifferentiated thyroid cancers. We found that MAPK inhibitors restored TSHR expression and sensitized these cancers to TSHR- CART cell therapy.
Publisher
Cold Spring Harbor Laboratory