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

Juan Fu, Ian James Malm, Deepak K. Kadayakkara, Hy Levitsky, Andrew Mark Pardoll, Young J. Kim

Research output: Contribution to journalArticle

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 IFNg-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 IFNg-inducing cancer vaccines with immune checkpoint blockade.

Original languageEnglish (US)
Pages (from-to)4042-4052
Number of pages11
JournalCancer Research
Volume74
Issue number15
DOIs
StatePublished - Aug 1 2014

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Cancer Vaccines
Neoplasms
Tumor Microenvironment
Up-Regulation
T-Lymphocytes
Blocking Antibodies
Toll-Like Receptors
Granulocyte-Macrophage Colony-Stimulating Factor
Dendritic Cells
Immunity
Vaccines
Biomarkers
Ligands
Antibodies
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. / Fu, Juan; Malm, Ian James; Kadayakkara, Deepak K.; Levitsky, Hy; Pardoll, Andrew Mark; Kim, Young J.

In: Cancer Research, Vol. 74, No. 15, 01.08.2014, p. 4042-4052.

Research output: Contribution to journalArticle

Fu, Juan ; Malm, Ian James ; Kadayakkara, Deepak K. ; Levitsky, Hy ; Pardoll, Andrew Mark ; Kim, Young J. / Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. In: Cancer Research. 2014 ; Vol. 74, No. 15. pp. 4042-4052.
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