Therapeutic efficacy of a human papillomavirus type 16 E7 bacterial exotoxin fusion protein adjuvanted with CpG or GPI-0100 in a preclinical mouse model for HPV-associated disease

Diane M Da Silva,Joseph G Skeate,Elena Chavez-Juan,Kim P Lühen,Jiun-Ming Wu,Chia-Mao Wu,W Martin Kast,Kinkai Hwang

doi:10.1016/j.vaccine.2019.04.043

Diane M Da Silva, Joseph G Skeate + Show 6 more

Open Access

https://doi.org/10.1016/j.vaccine.2019.04.043

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Journal: Vaccine	Publication Date: Apr 19, 2019
Citations: 22	License type: cc-by

Affiliation: University of Southern California

Abstract

Persistent human papillomavirus (HPV) infection is causally linked to the development of several human cancers, including cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancers. To address the need for a therapeutic vaccine against HPV-associated diseases, here we test and compare the immunogenicity and therapeutic efficacy of a bacterial exotoxin fusion protein covalently linked to the HPV16 E7 oncoprotein adjuvanted with CpG or GPI-0100 in the C3.43 preclinical HPV16-transformed tumor model. We show that TVGV-1 protein vaccine adjuvanted with either CpG or GPI-0100 adjuvant induces a high frequency of E7-specific CD8+ T cells, and both adjuvants are able to assist the immune response in inducing polyfunctional cytokine-secreting lytic T cells that show therapeutic efficacy against well-established C3.43 tumors. CpG-adjuvanted TVGV-1 resulted in higher frequencies of IFNγ secreting and degranulating E7-specific T cells compared to GPI-0100-adjuvanted TVGV-1, resulting in marginally increased in vivo efficacy. Despite minor differences in immune response outcomes, we consider both CpG ODN and GPI-0100 to be promising vaccine adjuvants to increase the immunogenicity and therapeutic efficacy of the TVGV-1 protein for HPV16-driven cancers.

Highlights

Persistent infection with high-risk human papillomaviruses (HPVs) are the causative agent in virtually all cervical cancer cases, a significant number of other anogenital cancers, and a subset of oropharyngeal cancers [1]
TVGV-1 vaccine adjuvanted by CpG induced significantly higher frequencies of HPV16E7-specific CD8+ T cells in vaccinated mice compared to TVGV-1 vaccine adjuvanted by GPI-0100
Prior studies have shown the importance of directing antigen into the cytosol and endoplasmic reticulum (ER) for generation of anti-HPV16 E6 and/or E7 tumor immunity using various strategies, including the use of heat shock protein fusions, calreticulin, and Bordatella pertussis adenylate cyclase, for example [27,28,29]

Summary

Introduction

Persistent infection with high-risk human papillomaviruses (HPVs) are the causative agent in virtually all cervical cancer cases, a significant number of other anogenital cancers, and a subset of oropharyngeal cancers [1]. HPV16 is the most carcinogenic genotype relative to other high risk HPVs, being found in 60% of invasive cervical cancer cases and the predominant genotype found in vulvar, vaginal, anal, penile lesions, and almost all HPV-associated oropharyngeal head and neck cancers [2,3,4]. Among them are DNA, RNA, viral vectors, bacterial vectors, dendritic cells, peptides and proteins in various iterations and combinations. These strategies have been supplemented with different adjuvants, heterologous prime-boost regimens, immunostimulants and immunomodulators. Despite this enormous effort, there are currently no approved therapeutic vaccines for HPV-induced cancers or precancerous lesions, though several candidates are currently in clinical trials (reviewed in [7])

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