Intranasal Therapeutic Peptide Vaccine Promotes Efficient Induction and Trafficking of Cytotoxic T Cell Response for the Clearance of HPV Vaginal Tumors.

Gloria Sierra,Ananta V Yanamandra,Venkatesh L Hegde,Stephanie Dorta-Estremera,K Jagannadha Sastry,Sita M K Nookala

doi:10.3390/vaccines8020259

Abstract

Human papillomavirus (HPV)-induced cancers continue to affect millions of women around the world, and the five year survival rate under the current standard of care for these cancers is less than 60% in some demographics. Therefore there is still an unmet need to develop an effective therapy that can be easily administered to treat established HPV cervical cancer lesions. We sought to investigate the potential of an intranasal HPV peptide therapeutic vaccine incorporating the combination of α-Galactosylceramide (α-GalCer) and CpG-ODN adjuvants (TVAC) against established HPV genital tumors in a syngeneic C57BL/6J mouse model. We obtained evidence to show that TVAC, delivered by the mucosal intranasal route, induced high frequencies of antigen-specific CD8 T cells concurrent with significant reduction in the immunosuppressive regulatory T cells and myeloid derived suppressor cells in the tumor microenvironment (TME), correlating with sustained elimination of established HPV genital tumors in over 85% of mice. Inclusion of both the adjuvants in the vaccine was necessary for significant increase of antigen-specific CD8 T cells to the tumor and antitumor efficacy because vaccination incorporating either adjuvant alone was inefficient. These results strongly support the utility of the TVAC administered by needle-free intranasal route as a safe and effective strategy for the treatment of established genital HPV tumors.

Highlights

The incidences of human papillomavirus (HPV) driven cancers, including cervical, vulvar, penile, anal, and head and neck cancers continue to increase despite the availability of a prophylactic vaccine targeted at preventing initial infection [1,2,3,4]
Using an orthotopic tumor model for pre-clinical studies, we reported that administration of the therapeutic vaccine consisting of HPV16-E6/E7 peptides and α-GalCer adjuvant (TVA) by the intranasal route along with systemic agonistic 4–1BB antibody immune checkpoint therapy (ICT), was curative against vaginally implanted Human papillomavirus (HPV) tumors in mice [15]
Immune checkpoint therapy (ICT) in the clinical setting was reported to be associated with significant toxicity [16,17,18], we tested therapeutic vaccination in the absence of ICT by intranasal administration of the HPV peptides along with α-GalCer and CpG-ODN, two clinically relevant adjuvants with established safety profiles and proven potency to activate dendritic cells through divergent, but complementary, mechanisms [20,21,22]

Summary

Introduction

The incidences of human papillomavirus (HPV) driven cancers, including cervical, vulvar, penile, anal, and head and neck cancers continue to increase despite the availability of a prophylactic vaccine targeted at preventing initial infection [1,2,3,4]. This is especially true in countries with limited resources and in need for preventative screening measures. There is an urgent need to develop an effective, administered therapy for cervical cancer around the world.

Methods

Results

Conclusion