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PMID: 24812273 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors.

Cancer research ·Vol. 74 ·No. 15 ·2014-08-01 ·Pages 4042-52

Fu J, Malm IJ, Kadayakkara DK, Levitsky H, Pardoll D, Kim YJ

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.

MeSH Terms
Animals Antibodies/immunology,pharmacology Cancer Vaccines/immunology,pharmacology Dendritic Cells/immunology Female Interferon-gamma/immunology Melanoma, Experimental/immunology,therapy Mice Mice, Inbred BALB C Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Programmed Cell Death 1 Receptor/antagonists & inhibitors,immunology T-Lymphocytes/immunology T-Lymphocytes, Cytotoxic/immunology
Chemicals
Antibodies Cancer Vaccines Programmed Cell Death 1 Receptor Interferon-gamma
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Fu Juan
Department of Otolaryngology-Head and Neck Surgery.
Malm Ian-James
Department of Otolaryngology-Head and Neck Surgery.
Kadayakkara Deepak K
Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Levitsky Hy
Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Pardoll Drew
Department of Oncology, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Kim Young J
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.
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-13-2685
Email
ykim76@jhmi.edu
Published
2014-08-01
Epub
2014-00-08
Pages
4042-52
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC4396709
Subset
IM
Grants
NIDCR NIH HHS · K23 DE018464 · United States
NCI NIH HHS · P30 CA006973 · United States
NCI NIH HHS · R01 CA178613 · United States
NIDCR NIH HHS · K23-DE018464 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-13-2685 PMC Full Text View journal details
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