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

John, Liza B., Devaud, Christel, Duong, Connie P. M., Yong, Carmen S., Beavis, Paul A., Haynes, Nicole M., Chow, Melvyn T., Smyth, Mark J., Kershaw, Michael H. and Darcy, Phillip K. (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clinical Cancer Research, 19 20: 5636-5646. doi:10.1158/1078-0432.CCR-13-0458


Author John, Liza B.
Devaud, Christel
Duong, Connie P. M.
Yong, Carmen S.
Beavis, Paul A.
Haynes, Nicole M.
Chow, Melvyn T.
Smyth, Mark J.
Kershaw, Michael H.
Darcy, Phillip K.
Title Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2013-10-01
Year available 2013
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-13-0458
Open Access Status DOI
Volume 19
Issue 20
Start page 5636
End page 5646
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted 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. 
Keyword Chimeric antigen receptors
Suppressor cells
Adoptive immunotherapy
Future directions
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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