Anti-Cancer Vaccine for HPV-Associated Neoplasms: Focus on a Therapeutic HPV Vaccine Based on a Novel Tumor Antigen Delivery Method Using Endogenously Engineered Exosomes.

Paola Di Bonito,Luisa Accardi,Flavia Ferrantelli,Luisa Galati,Maurizio Federico

doi:10.3390/cancers11020138

Abstract

Some human papillomavirus (HPV) genotypes are universally recognized as major etiological agents not only of ano-genital tumors but also of head and neck cancers, which show increasing incidence. The evaluation of current and future therapeutic approaches against HPV-induced tumors is a global health priority, despite an effective prophylactic vaccine against 7 of the 12 genotypes involved in the etiology of tumors being currently available. In this review, we present the main anti-HPV therapeutic approaches in clinical experimentation, with a focus on a novel tumor antigen delivery method using engineered exosomes, that we recently developed. Our system allows the induction of an efficient unrestricted cytotoxic T lymphocyte (CTL) immune response against the HPV16-E7 tumor-associated antigen, with the formation of endogenously engineered exosomes, i.e., nanovesicles spontaneously released by all cell types. Immunogenic exosomes are uploaded with HPV16-E7 due to the fusion with a unique exosome-anchoring protein referred to as Nefmut. Intramuscular injection of a DNA vector expressing the fusion protein generates exosomes sufficiently immunogenic to elicit a potent anti-16E7 CTL immune response. The approach is described here and the advantages over other existing methodologies are reported.

Highlights

Despite the significant progress obtained in the past decades in the field of tumor therapy, robust anticancer therapies able to induce effective antitumor responses, namely to clear tumor cells while avoiding adverse effects, are not yet available
Interest in anticancer immunotherapies has grown explosively over the last 5–10 years mainly due to approval of new clinical protocols based on the use of monoclonal antibodies, referred to as immune check-point blockers (ICBs) [2], which foster pre-existing immune response against both tumor-associated antigens (TAAs) and neo-antigens
We developed an innovative strategy based on the induction of an effective anti-human papillomavirus (HPV)-E7 cytotoxic T lymphocyte (CTL) immunity

Summary

Introduction

Despite the significant progress obtained in the past decades in the field of tumor therapy, robust anticancer therapies able to induce effective antitumor responses, namely to clear tumor cells while avoiding adverse effects, are not yet available. Cancer cells can express antigens to which the host does not develop tolerance, the immune response is not sufficiently effective to counteract the growth of cancer cells Such antigens include the so-called tumor-specific neo-antigens as well as antigens normally produced in immune-privileged tissues, such as cancer-testis antigens (CTAs), which in adults are restricted to male germ cells. Active immunotherapies stimulate the immune system by presenting antigens to elicit a specific immune response, while passive immunotherapies attack the tumor directly, without directly engaging the patient’s immune system to target a specific antigen In this context, cancer vaccines can be used to prime or boost the immune system by generating or amplifying tumor antigen-specific immune responses against proteins differentially expressed by tumor cells. We described the most advanced therapeutic approaches against HPV-associated tumors and compared their performance to that of a novel pre-clinical vaccine based on the in vivo engineering of exosomes released spontaneously by muscle cells

HPV-Related Tumors

Current Anti-HPV Therapeutic Strategies

Exosomes in Cancer Immunotherapy

Other Applications of the Nefmut-Based Exosome Technology

Findings

Conclusions