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Cancer Therapy: Preclinical

Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice

Elizabeth K. Duperret, Aspen Trautz, Dylan Ammons, Alfredo Perales-Puchalt, Megan C. Wise, Jian Yan, Charles Reed and David B. Weiner
Elizabeth K. Duperret
1Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania.
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Aspen Trautz
1Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania.
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Dylan Ammons
1Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania.
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Alfredo Perales-Puchalt
1Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania.
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Megan C. Wise
2Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania.
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Jian Yan
2Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania.
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Charles Reed
2Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania.
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David B. Weiner
1Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania.
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  • For correspondence: dweiner@wistar.org
DOI: 10.1158/1078-0432.CCR-17-2033 Published March 2018
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Abstract

Purpose: Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is an interesting target for cancer immune therapy, with prior studies indicating a potential to affect the tumor stroma. Our aim was to extend this earlier work through the development of a novel FAP immunogen with improved capacity to break tolerance for use in combination with tumor antigen vaccines.

Experimental Design: We used a synthetic consensus (SynCon) sequence approach to provide MHC class II help to support breaking of tolerance. We evaluated immune responses and antitumor activity of this novel FAP vaccine in preclinical studies, and correlated these findings to patient data.

Results: This SynCon FAP DNA vaccine was capable of breaking tolerance and inducing both CD8+ and CD4+ immune responses. In genetically diverse, outbred mice, the SynCon FAP DNA vaccine was superior at breaking tolerance compared with a native mouse FAP immunogen. In several tumor models, the SynCon FAP DNA vaccine synergized with other tumor antigen–specific DNA vaccines to enhance antitumor immunity. Evaluation of the tumor microenvironment showed increased CD8+ T-cell infiltration and a decreased macrophage infiltration driven by FAP immunization. We extended this to patient data from The Cancer Genome Atlas, where we find high FAP expression correlates with high macrophage and low CD8+ T-cell infiltration.

Conclusions: These results suggest that immune therapy targeting tumor antigens in combination with a microconsensus FAP vaccine provides two-fisted punch-inducing responses that target both the tumor microenvironment and tumor cells directly. Clin Cancer Res; 24(5); 1190–201. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received July 14, 2017.
  • Revision received November 11, 2017.
  • Accepted December 13, 2017.
  • ©2018 American Association for Cancer Research.
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Clinical Cancer Research: 24 (5)
March 2018
Volume 24, Issue 5
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Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice
Elizabeth K. Duperret, Aspen Trautz, Dylan Ammons, Alfredo Perales-Puchalt, Megan C. Wise, Jian Yan, Charles Reed and David B. Weiner
Clin Cancer Res March 1 2018 (24) (5) 1190-1201; DOI: 10.1158/1078-0432.CCR-17-2033

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Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice
Elizabeth K. Duperret, Aspen Trautz, Dylan Ammons, Alfredo Perales-Puchalt, Megan C. Wise, Jian Yan, Charles Reed and David B. Weiner
Clin Cancer Res March 1 2018 (24) (5) 1190-1201; DOI: 10.1158/1078-0432.CCR-17-2033
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Clinical Cancer Research
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