Abstract
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. 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. 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. 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.
Highlights
Adoptive immunotherapy using gene-modified T cells expressing antigen-specific chimeric antigen receptors (CAR) is a promising approach for the treatment of cancer [1,2,3]
To determine whether stimulation of T cells through the chimeric antigen receptor leads to increased expression of programmed death-1 (PD-1), we first evaluated the expression of the PD-1 ligand (PD-L1) on Her-2þ (24JK-Her-2, e0771-Her-2) and parental (24JK, e0771) tumor targets
Further analysis revealed that increased PD-1 expression was only observed on CD8þ T cells when cocultured with 24JK-Her-2 target cells (9.23 Æ 3.77% SEM), compared to stimulation with parental tumor cells (3.40 Æ 0.58% SEM) or in media alone (5.16 Æ 0.84% SEM; Fig. 2A)
Summary
Adoptive immunotherapy using gene-modified T cells expressing antigen-specific chimeric antigen receptors (CAR) is a promising approach for the treatment of cancer [1,2,3]. Recent clinical trials using CARs that target cell surface tumor-associated antigens such as CD20 for the treatment of non-Hodgkin lymphoma [4], GD2 in neuro-. Authors' Affiliations: 1Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria; 2Department of Pathology, University of Melbourne; 3Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville; 4Department of Immunology, Monash University, Clayton; 5Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research; and 6School of Medicine, University of Queensland, Herston, Queensland, Australia. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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