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Oncotarget. 2016 Jun 7;7(23):34341-55. doi: 10.18632/oncotarget.9114.

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

Author information

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.

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.

KEYWORDS:

T cell exhaustion; carbonic anhydrase IX; chimeric antigen receptor; immune checkpoint inhibitor; interleukin-21

PMID:
27145284
PMCID:
PMC5085160
DOI:
10.18632/oncotarget.9114
[Indexed for MEDLINE]
Free PMC Article

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