Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model
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Eloah Rabello Suarez1,2,3, De-Kuan Chang1,2, Jiusong Sun1,2, Jianhua Sui4, Gordon J. Freeman2,5, Sabina Signoretti6, Quan Zhu1,2, Wayne A. Marasco1,2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA
2Department of Medicine, Harvard Medical School, Boston, MA, USA
3Department of Biochemistry, Faculdade de Medicina do ABC, Av. Príncipe de Gales, SP, Brazil
4National Institute of Biological Sciences, ZGC Life Science Park, Changping, Beijing, China
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
6Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Wayne A. Marasco, email: [email protected]
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
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.
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