Carboplatin/paclitaxel, E7-vaccination and intravaginal CpG as tri-therapy towards efficient regression of genital HPV16 tumors

J Immunother Cancer. 2019 May 6;7(1):122. doi: 10.1186/s40425-019-0593-1.

Abstract

High-risk human papillomavirus (HPV) are responsible for genital and oral cancers associated with the expression of the E6/E7 HPV oncogenes. Therapeutic vaccines targeting those oncogenes can only partially control tumor progression, highlighting the necessity to investigate different treatment strategies. Using the genital orthotopic HPV16 TC-1 model, herein we sequentially investigated in progressively more stringent settings the effects of systemic administration of carboplatin/paclitaxel (C + P) chemotherapy combined with HPV16-E7 synthetic long peptide (E7LP) vaccination, followed by intravaginal immunostimulation with the synthetic toll-like-receptor-9 agonist CpG. Our data show that systemic delivery of C + P prior to E7LP vaccination significantly increased mice survival. This survival benefit was associated with both reduced genital tumor growth at the time of vaccination, and a decreased infiltration of Ly6G myeloid cells and tumor-associated macrophages. Adding intravaginal CpG, which results in increased E7-specific CD8 T cells locally, to E7LP vaccination and the chemotherapy formed a tri-therapy, which significantly increased mice survival as compared to any of the dual treatments. When the tri-therapy was further refined by using a recently optimized nanoparticle-conjugated E7LP vaccine, even larger end-stage genital-TC-1 tumors responded, with 90% of mice showing a survival benefit as compared to 30% of mice with the tri-therapy involving the traditional E7LP 'liquid' vaccine. C + P is commonly used to treat cervical cancer patients and its combination with E7/E6 vaccination is currently being tested in a phase I/II trial (NCT02128126). Our data suggests that new vaccine formulations combined with local immunostimulation and standard-of-care chemotherapy have promise to further benefit patients with HPV-associated cancer.

Keywords: Carboplatin/paclitaxel; E7 long peptide and nanoparticle vaccination; HPV genital cancer; Intravaginal CpG immunostimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravaginal
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Combined Modality Therapy / methods
  • Disease Models, Animal
  • Female
  • Genital Neoplasms, Female / immunology
  • Genital Neoplasms, Female / pathology
  • Genital Neoplasms, Female / therapy*
  • Genital Neoplasms, Female / virology
  • Human papillomavirus 16 / immunology
  • Human papillomavirus 16 / isolation & purification
  • Human papillomavirus 16 / pathogenicity
  • Humans
  • Immunotherapy / methods*
  • Injections, Intraperitoneal
  • Injections, Subcutaneous
  • Mice
  • Oligodeoxyribonucleotides / administration & dosage*
  • Paclitaxel / administration & dosage
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / therapy*
  • Papillomavirus Infections / virology
  • Toll-Like Receptor 9 / agonists
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology
  • Vagina / immunology
  • Vagina / pathology
  • Vagina / virology

Substances

  • Cancer Vaccines
  • CpG ODN 1826
  • Oligodeoxyribonucleotides
  • Papillomavirus E7 Proteins
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Vaccines, Synthetic
  • oncogene protein E7, Human papillomavirus type 16
  • Paclitaxel

Associated data

  • ClinicalTrials.gov/NCT02128126