title: Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors.
abstract: Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFNγ-expressing tumor-infiltrating CD4(+) and CD8(+) T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNγ-inducing cancer vaccines with immune checkpoint blockade.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery.
authors.forename: Juan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery.
authors.forename: Ian-James
authors.initials: IJ
authors.lastname: Malm
authors.affiliation: Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Kadayakkara
authors.affiliation: Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hy
authors.initials: H
authors.lastname: Levitsky
authors.affiliation: Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland ykim76@jhmi.edu.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000906:Antibodies; D019496:Cancer Vaccines; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma