Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model

Abstract

// Eloah Rabello Suarez 1, 2, 3 , De-Kuan Chang 1, 2 , Jiusong Sun 1, 2 , Jianhua Sui 4 , Gordon J. Freeman 2, 5 , Sabina Signoretti 6 , Quan Zhu 1, 2 , Wayne A. Marasco 1, 2 1 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA 2 Department of Medicine, Harvard Medical School, Boston, MA, USA 3 Department of Biochemistry, Faculdade de Medicina do ABC, Av. Príncipe de Gales, SP, Brazil 4 National Institute of Biological Sciences, ZGC Life Science Park, Changping, Beijing, China 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 6 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Correspondence to: Wayne A. Marasco, email: wayne_marasco@dfci.harvard.edu Keywords: immune checkpoint inhibitor, T cell exhaustion, chimeric antigen receptor, carbonic anhydrase IX, interleukin-21 Received: March 04, 2016      Accepted: April 16, 2016      Published: April 29, 2016 ABSTRACT Advances 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.