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An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression

Cancer Gene Therapy volume 22, pages 454–462 (2015)Cite this article

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Abstract

We have investigated if immunotherapy against human papilloma virus (HPV) using a viral gene delivery platform to immunize against HPV 16 genes E6 and E7 (Ad5 [E1-, E2b-]-E6/E7) combined with programmed death-ligand 1 (PD-1) blockade could increase therapeutic effect as compared to the vaccine alone. Ad5 [E1-, E2b-]-E6/E7 as a single agent induced HPV-E6/E7 cell-mediated immunity. Immunotherapy using Ad5 [E1-, E2b-]-E6/E7 resulted in clearance of small tumors and an overall survival benefit in mice with larger established tumors. When immunotherapy was combined with immune checkpoint blockade, an increased level of anti-tumor activity against large tumors was observed. Analysis of the tumor microenvironment in Ad5 [E1-, E2b-]-E6/E7 treated mice revealed elevated CD8+ tumor infiltrating lymphocytes (TILs); however, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. When Ad5 [E1-, E2b-]-E6/E7 immunotherapy was combined with anti-PD-1 antibody, we observed CD8+ TILs at the same level but a reduction in tumor PD-L1 expression on tumor cells and reduced PD-1+ TILs providing a mechanism by which combination therapy favors a tumor clearance state and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials.

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Acknowledgements

The authors thank Dr Winston Witcomb for management and care of the animals. We also thank Carol Jones for management of grant activities. This study was funded by Small Business Innovative Research (SBIR) Grants 1R43DE021973-01 and 2R44DE021973-02 from the National Institute of Dental and Cranial Research (NIDCR).

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  1. E S Gabitzsch and F R Jones: These authors contributed equally to this work.

Authors and Affiliations

  1. Research and Development, Etubics Corporation, Seattle, WA, USA

    A E Rice, Y E Latchman, J P Balint, E S Gabitzsch & F R Jones

  2. Sanford Cancer Research Center, Sioux Falls, SD, USA

    J H Lee

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  1. A E Rice
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Correspondence to E S Gabitzsch.

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Competing interests

AER, YL, JPB, ESG and FRJ are employees of Etubics and have equity and/or stock options in the company. JHL is a member of the Etubics Scientific Advisory Board and has stock options in the company.

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Rice, A., Latchman, Y., Balint, J. et al. An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression. Cancer Gene Ther 22, 454–462 (2015). https://doi.org/10.1038/cgt.2015.40

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