Volume 3 Supplement 2
An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression
© Rice et al. 2015
Published: 4 November 2015
The prevalence of head and neck cancers in the USA is estimated to be about 370,000 and between 25% to 38% of these are human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). We have developed a viral gene delivery platform to immunize against HPV 16 genes E6 and E7 (Ad5 [E1-, E2b-]-E6/E7) for the treatment of HPV-associated HNSCC. We tested the Ad5 [E1-, E2b-]-E6/E7 immunotherapy alone and in combination with programmed death-ligand 1 (PD-1) blockade in a murine HPV+ tumor model. As a single agent, Ad5 [E1-, E2b-]-E6/E7 induced HPV-E6/E7 cell-mediated immunity and resulted in the clearance of small tumors and an overall survival benefit in mice with larger established tumors. When immunotherapy was combined with PD-1 immune checkpoint blockade, an increased level of anti-tumor activity against large tumors was observed in addition to an improvement in survival. Tumor microenvironment analysis in Ad5 [E1-, E2b-]-E6/E7 treated mice revealed an increase in CD8+ tumor-infiltrating lymphocytes (TILs). In addition, 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 increased level but found that a smaller fraction of these were PD-1+. Furthermore, we observed a reduction in PD-L1 expression on tumor cells, providing a mechanism by which combination therapy favors tumor clearance and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.