Rhabdoid tumors as a novel target for PSMA-directed CAR T cell therapy.

Rhabdoid tumor is an ultra-rare and highly aggressive pediatric malignancy with a poor prognosis and limited therapeutic options. To identify novel immunotherapeutic targets, transcriptomic data from the Cancer Cell Line Encyclopedia were analyzed, and we found that two rhabdoid tumor cell lines exhibit high expression of prostate-specific membrane antigen (PSMA), with levels comparable to well-established PSMA-positive prostate cancer cell lines. PSMA expression in rhabdoid tumors was subsequently validated in cell lines and in a subset of primary clinical rhabdoid tumor specimens. While PSMA-directed therapies have primarily been explored in prostate cancer, we evaluated their potential in rhabdoid tumors by employing PSMA-directed chimeric antigen receptor (CAR) T cells. These CAR T cells demonstrated potent and antigen-specific cytotoxicity against PSMA-positive rhabdoid tumor cells in vitro. In addition, the in vivo efficacy was also assessed in xenograft mouse models of non-CNS tumors, where PSMA CAR T cell treatment resulted in significant tumor regression and robust accumulation of CAR T cells within the tumor microenvironment. Together, these findings establish PSMA as a promising surface antigen beyond prostate cancer and provide preclinical evidence supporting the development of PSMA-directed therapies for this highly lethal pediatric cancer.