An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression.
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.
Research and Development, Etubics Corporation, Seattle, WA, USA.
A E
AE
Rice
Research and Development, Etubics Corporation, Seattle, WA, USA.
Y E
YE
Latchman
Research and Development, Etubics Corporation, Seattle, WA, USA.
J P
JP
Balint
Sanford Cancer Research Center, Sioux Falls, SD, USA.
J H
JH
Lee
Research and Development, Etubics Corporation, Seattle, WA, USA.
E S
ES
Gabitzsch
Research and Development, Etubics Corporation, Seattle, WA, USA.
F R
FR
Jones
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003673:Defective Viruses / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D059016:Tumor Microenvironment; D014412:Tumor Virus Infections / Q000473:pathology / Q000628:therapy*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D007074:Immunoglobulin G; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16