Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model

JCI Insight. 2018 Apr 19;3(8):e99488. doi: 10.1172/jci.insight.99488.

Abstract

T cell receptor (TCR) T cell therapy is a promising cancer treatment modality. However, its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is an attractive therapeutic target that is constitutively expressed by HPV+ cancers but not by healthy tissues. It is unknown if genetically engineered TCR T cells that target E7 can mediate regression of HPV+ cancers. We identified an HPV-16 E7-specific, HLA-A*02:01-restricted TCR from a uterine cervix biopsy from a woman with cervical intraepithelial neoplasia. This TCR demonstrated high functional avidity, with CD8 coreceptor-independent tumor targeting. Human T cells transduced to express the TCR specifically recognized and killed HPV-16+ cervical and oropharyngeal cancer cell lines and mediated regression of established HPV-16+ human cervical cancer tumors in a mouse model. These findings support the therapeutic potential of this approach and established the basis for an E7 TCR gene therapy clinical trial in patients with metastatic HPV+ cancers (NCT02858310).

Keywords: Immunology; Immunotherapy; T cells; T-cell receptor.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Cervical Intraepithelial Neoplasia / drug therapy
  • Cervical Intraepithelial Neoplasia / veterinary
  • Cervical Intraepithelial Neoplasia / virology
  • Cervix Uteri / drug effects
  • Cervix Uteri / pathology
  • Cervix Uteri / virology
  • Disease Models, Animal
  • Female
  • Genetic Therapy / methods
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / immunology*
  • Humans
  • Mice
  • Papillomaviridae / drug effects
  • Papillomaviridae / genetics
  • Papillomavirus Infections / drug therapy
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / veterinary
  • Uterine Cervical Neoplasms / virology

Substances

  • CD8 Antigens
  • Receptors, Antigen, T-Cell

Associated data

  • ClinicalTrials.gov/NCT02858310