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Research Articles

Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites

Zachary S. Morris, Emily I. Guy, Lauryn R. Werner, Peter M. Carlson, Clinton M. Heinze, Jasdeep S. Kler, Sara M. Busche, Abigail A. Jaquish, Raghava N. Sriramaneni, Lakeesha L. Carmichael, Hans Loibner, Stephen D. Gillies, Alan J. Korman, Amy K. Erbe, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari and Paul M. Sondel
Zachary S. Morris
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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  • For correspondence: zmorris@humonc.wisc.edu
Emily I. Guy
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Lauryn R. Werner
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Peter M. Carlson
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Clinton M. Heinze
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Jasdeep S. Kler
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Sara M. Busche
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Abigail A. Jaquish
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Raghava N. Sriramaneni
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Lakeesha L. Carmichael
Department of Biostatistics and Bioinformatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Hans Loibner
Apeiron Biologics, Vienna, Austria.
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Stephen D. Gillies
Provenance Biopharmaceuticals, Carlisle, Massachusetts.
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Alan J. Korman
Bristol-Myers Squibb, Redwood City, California.
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Amy K. Erbe
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Jacquelyn A. Hank
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Alexander L. Rakhmilevich
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Paul M. Harari
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Paul M. Sondel
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.Departments of Pediatrics and Genetics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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DOI: 10.1158/2326-6066.CIR-17-0353 Published July 2018
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Abstract

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the “primary” tumor would induce a systemic antitumor response causing regression of the “secondary” tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated “primary” tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic “DEREG” mice or IgG2a anti–CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti–CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825–34. ©2018 AACR.

Footnotes

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

  • Received July 7, 2017.
  • Revision received February 21, 2018.
  • Accepted May 3, 2018.
  • Published first May 10, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Immunology Research: 6 (7)
July 2018
Volume 6, Issue 7
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Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites
Zachary S. Morris, Emily I. Guy, Lauryn R. Werner, Peter M. Carlson, Clinton M. Heinze, Jasdeep S. Kler, Sara M. Busche, Abigail A. Jaquish, Raghava N. Sriramaneni, Lakeesha L. Carmichael, Hans Loibner, Stephen D. Gillies, Alan J. Korman, Amy K. Erbe, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari and Paul M. Sondel
Cancer Immunol Res July 1 2018 (6) (7) 825-834; DOI: 10.1158/2326-6066.CIR-17-0353

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Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites
Zachary S. Morris, Emily I. Guy, Lauryn R. Werner, Peter M. Carlson, Clinton M. Heinze, Jasdeep S. Kler, Sara M. Busche, Abigail A. Jaquish, Raghava N. Sriramaneni, Lakeesha L. Carmichael, Hans Loibner, Stephen D. Gillies, Alan J. Korman, Amy K. Erbe, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari and Paul M. Sondel
Cancer Immunol Res July 1 2018 (6) (7) 825-834; DOI: 10.1158/2326-6066.CIR-17-0353
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