title: Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.
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.
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Department of Biochemistry, Faculdade de Medicina do ABC, Av. Príncipe de Gales, SP, Brazil.
authors.forename: Eloah Rabello
authors.initials: ER
authors.lastname: Suarez
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: De Kuan
authors.initials: de K
authors.lastname: Chang
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.affiliation: National Institute of Biological Sciences, ZGC Life Science Park, Changping, Beijing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI), Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002256:Carbonic Anhydrases / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002678:Chimera / Q000276:immunology; D004195:Disease Models, Animal; D053804:Granzymes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D011948:Receptors, Antigen, T-Cell; D053804:Granzymes; C509214:Gzmb protein, mouse; D002256:Carbonic Anhydrases
keywords: T cell exhaustion; carbonic anhydrase IX; chimeric antigen receptor; immune checkpoint inhibitor; interleukin-21