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

Cancer Immunol Res. 2018 Nov;6(11):1301-1313. doi: 10.1158/2326-6066.CIR-18-0166. Epub 2018 Aug 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / chemistry
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / pharmacology*
  • Female
  • Lung Neoplasms / secondary
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nanoparticles / chemistry*
  • Neoplasm Recurrence, Local
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / mortality
  • Neoplasms, Experimental / therapy
  • Papillomavirus E7 Proteins / chemistry*
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus E7 Proteins / pharmacology
  • T-Lymphocytes, Regulatory / immunology
  • Treatment Outcome
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
  • Vaginal Neoplasms / immunology
  • Vaginal Neoplasms / pathology
  • Vaginal Neoplasms / prevention & control


  • Antibodies
  • Cancer Vaccines
  • Papillomavirus E7 Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • oncogene protein E7, Human papillomavirus type 16