Suarez, Eloah RabelloChang, De-KuanSun, JiusongSui, JianhuaFreeman, GordonSignoretti, SabinaZhu, QuanMarasco, Wayne2016-11-182016Suarez, Eloah Rabello, De-Kuan Chang, Jiusong Sun, Jianhua Sui, Gordon J. Freeman, Sabina Signoretti, Quan Zhu, and Wayne A. Marasco. 2016. “Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.” Oncotarget 7 (23): 34341-34355. doi:10.18632/oncotarget.9114. http://dx.doi.org/10.18632/oncotarget.9114.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408263Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50–80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.en-USimmune checkpoint inhibitorT cell exhaustionchimeric antigen receptorcarbonic anhydrase IXinterleukin-21Journal Article2016-11-1810.18632/oncotarget.9114