GTL001, a bivalent therapeutic vaccine against human papillomavirus 16 and 18, induces antigen-specific CD8+ T cell responses leading to tumor regression.

Michaël Esquerré,Anne Goubier,Marie Momot,Hélène Keller,Astrid Navarro,Myriam Bouillette-Marussig,Marie-Christine Bissery,Christophe Gonindard,Craig Meyers

doi:10.1371/journal.pone.0174038

Abstract

BackgroundProphylactic vaccines are available for women and girls not yet infected with HPV, but women already infected with HPV need a treatment to prevent progression to high-grade cervical lesions and cancer. GTL001 is a bivalent therapeutic vaccine for eradicating HPV-infected cells that contains HPV16 E7 and HPV18 E7 both fused to detoxified adenylate cyclase from Bordetella pertussis, which binds specifically to CD11b+ antigen-presenting cells. This study examined the ability of therapeutic vaccination with GTL001 adjuvanted with topical imiquimod cream to induce functional HPV16 E7- and HPV18 E7-specific CD8+ T cell responses.MethodsBinding of GTL001 to human CD11b was assessed by a cell-based competition binding assay. Cellular immunogenicity of intradermal vaccination with GTL001 was assessed in C57BL/6 mice by enzyme-linked immunospot assay and in vivo killing assays. In vivo efficacy of GTL001 vaccination was investigated in the TC-1 murine HPV16 E7-expressing tumor model.ResultsGTL001 bound specifically to the human CD11b/CD18 receptor. GTL001 adjuvanted with topical 5% imiquimod cream induced HPV16 E7 and HPV18 E7-specific CD8+ T cell responses. This CD8+ T-cell response mediated in vivo killing of HPV E7-expressing cells. In the HPV16 E7-expressing tumor model, GTL001 adjuvanted with imiquimod but not imiquimod alone or a combination of unconjugated HPV16 E7 and HPV18 E7 caused complete tumor regression.ConclusionsGTL001 adjuvanted with topical 5% imiquimod is immunogenic and induces HPV16 E7 and HPV18 E7-specific CD8+ T cell responses that can kill HPV E7-expressing cells and eliminate HPV E7-expressing tumors.

Highlights

Most cervical cancer is caused by human papillomavirus (HPV) [1]
In the HPV16 E7-expressing tumor model, GTL001 adjuvanted with imiquimod but not imiquimod alone or a combination of unconjugated HPV16 E7 and HPV18 E7 caused complete tumor regression
We explore whether the HPV E7-specific T cells induced by GTL001 are functional cytotoxic CD8+ T lymphocytes that can promote the regression of HPV16 E7-expressing tumors

Summary

Introduction

Most cervical cancer is caused by human papillomavirus (HPV) [1]. B cell-mediated immunity to the viral capsid proteins L1 and L2 can provide efficient protection against HPV infection [2], but it is not effective for patients who already are infected with HPV [3, 4]. Most target the HPV E7 protein and, in some cases, the E6 protein, which are continuously expressed during the viral cycle, are required for cellular transformation, and are expressed by all cervical cancers and precursor lesions [11,12,13]. Some of these candidate vaccines have shown promise in treating vulvar and highgrade cervical intraepithelial neoplasia, and some induce cellular immunity against HPV, but they have only been tested in women who already have high-grade lesions [14,15,16]. This study examined the ability of therapeutic vaccination with GTL001 adjuvanted with topical imiquimod cream to induce functional HPV16 E7- and HPV18 E7-specific CD8+ T cell responses

Methods

Results

Conclusion