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Cancer Immunology Research
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Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

Gabriele Galliverti, Mélanie Tichet, Sonia Domingos-Pereira, Sylvie Hauert, Denise Nardelli-Haefliger, Melody A. Swartz, Douglas Hanahan and Stephan Wullschleger
Gabriele Galliverti
1Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
2Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
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Mélanie Tichet
2Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
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Sonia Domingos-Pereira
3Urology Research Unit, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
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  • ORCID record for Sonia Domingos-Pereira
Sylvie Hauert
1Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
4Institute for Molecular Engineering, University of Chicago, Chicago, Illinois.
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Denise Nardelli-Haefliger
3Urology Research Unit, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
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Melody A. Swartz
1Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
4Institute for Molecular Engineering, University of Chicago, Chicago, Illinois.
5The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
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  • For correspondence: stephan.wullschleger@epfl.ch douglas.hanahan@epfl.ch melodyswartz@uchicago.edu
Douglas Hanahan
2Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
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  • For correspondence: stephan.wullschleger@epfl.ch douglas.hanahan@epfl.ch melodyswartz@uchicago.edu
Stephan Wullschleger
2Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
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  • For correspondence: stephan.wullschleger@epfl.ch douglas.hanahan@epfl.ch melodyswartz@uchicago.edu
DOI: 10.1158/2326-6066.CIR-18-0166 Published November 2018
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Abstract

Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV+ cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NP-conjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8+ T cells with increased effector functions than unconjugated free E7LP. At the tumor site, NP-E7LP prompted a robust infiltration of CD8+ T cells that was not accompanied by concomitant accumulation of regulatory T cells (Tregs), resulting in a higher CD8+ T-cell to Treg ratio. Consequently, the amplified immune response elicited by the NP-E7LP formulation led to increased regression of large, well-established tumors, resulting in a significant percentage of complete responses that were not achievable by immunizing with the non-NP–conjugated long-peptide. The partial responses were characterized by distinct phases of regression, stable disease, and relapse to progressive growth, establishing a platform to investigate adaptive resistance mechanisms. The efficacy of NP-E7LP could be further improved by therapeutic activation of the costimulatory receptor 4-1BB. This NP-E7LP formulation illustrates a “solid-phase” antigen delivery strategy that is more effective than a conventional free-peptide (“liquid”) vaccine, further highlighting the potential of using such formulations for therapeutic vaccination against solid tumors. Cancer Immunol Res; 6(11); 1301–13. ©2018 AACR.

Footnotes

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

  • Received March 15, 2018.
  • Revision received June 16, 2018.
  • Accepted August 16, 2018.
  • Published first August 21, 2018.
  • ©2018 American Association for Cancer Research.
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Cancer Immunology Research: 6 (11)
November 2018
Volume 6, Issue 11
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Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice
Gabriele Galliverti, Mélanie Tichet, Sonia Domingos-Pereira, Sylvie Hauert, Denise Nardelli-Haefliger, Melody A. Swartz, Douglas Hanahan and Stephan Wullschleger
Cancer Immunol Res November 1 2018 (6) (11) 1301-1313; DOI: 10.1158/2326-6066.CIR-18-0166

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Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice
Gabriele Galliverti, Mélanie Tichet, Sonia Domingos-Pereira, Sylvie Hauert, Denise Nardelli-Haefliger, Melody A. Swartz, Douglas Hanahan and Stephan Wullschleger
Cancer Immunol Res November 1 2018 (6) (11) 1301-1313; DOI: 10.1158/2326-6066.CIR-18-0166
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