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Clin Cancer Res. 2013 Oct 15;19(20):5636-46. doi: 10.1158/1078-0432.CCR-13-0458. Epub 2013 Jul 19.

Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells.

Author information

1
Authors' Affiliations: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria; Department of Pathology, University of Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville; Department of Immunology, Monash University, Clayton; Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research; and School of Medicine, University of Queensland, Herston, Queensland, Australia.

Abstract

PURPOSE:

To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression.

EXPERIMENTAL DESIGN:

We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2(+) tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach.

RESULTS:

In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8(+) T cells following antigen-specific stimulation with PD-L1(+) tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2(+) tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1(+) CD11b(+) myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen.

CONCLUSION:

This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer.

PMID:
23873688
DOI:
10.1158/1078-0432.CCR-13-0458
[Indexed for MEDLINE]
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