Strategies to Reduce Global Health Disparities in Cervical Cancer

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary/Abstract The primary goal of our studies is to employ novel spontaneous HPV cervicovaginal carcinoma models to develop cancer immunotherapeutic vaccines that are highly effective against cervical cancers associated with HPV16 E6/E7 variants. Human papillomavirus (HPV) is detected in more than 90% of all cervical cancer patients and is considered a necessary etiologic factor; HPV type 16 (HPV16), in particular, is present in more than 50% of all HPV-associated cervical cancers. Therapeutic HPV vaccines that target HPV16 E6/E7 viral proteins hold particular promise because E6/E7 are uniquely expressed in all tumor cells, but not in normal cells, and they are functionally required to initiate and maintain cervical cancer growth. However, HPV16 isolates from different populations show differences in E6/E7 sequence. These variants likely evolved because of populations’ distinct HLA patterns, and may contribute to immune evasion. There is compelling data that non- European HPV16 variants influence persistence, progression to precancer, development of cancer, and histologic type of cervical cancer. Most therapeutic HPV vaccines tested clinically were developed based on the European strain of the HPV16 genome. Unfortunately, it recently became evident that therapeutic vaccines based on the ‘prototypical’ European strain are less effective against lesions that express other HPV16 variants. The presence of these variants correlates with both reductions in T cell response and with lower rates of viral clearance in individuals vaccinated with the therapeutic vaccine based on the European strain. Thus, vaccines based on prototypical European strain are likely to be less effective in patients from non-European geographic locations, i.e., races and ethnicities other than White non-Hispanic. Our goal is to develop a therapeutic vaccine that is highly effective at clearing HPV16 in geographically, ethnically, and racially diverse populations, regardless of variant, to comprehensively intercept HPV16-associated carcinogenesis. Our work could substantially mitigate the global problem of racial and ethnic disparities in outcomes observed in HPV16-associated cancers. Specifically, we will: Aim 1: Characterize the immune evasion by studying human MHC-1 presentation of the HPV E6/E7 specific CTL epitope variants identified in different HPV-16 isolates using the activation assay with prototypic HPV16 E6/E7-specific CD8+ T cell lines from different human MHC-1 transgenic mice. Aim 2: Characterize the growth rates and tumor microenvironment of spontaneous carcinomas in the cervicovaginal tract of immunodeficient mice, and mice transgenic for common human MHC-1, that are driven by either the prototypic HPV16 E6/E7, or its variants from different continents. Aim 3: Characterize the efficacy (antigen-specific CD8+ T cell-mediated immune responses and therapeutic antitumor effects) of a novel HPV DNA vaccine that encodes prototype HPV16 E6/E7 protein linked to Fusion Variant Protein (FVP), derived from the mutation portion of E6/E7 variants, against spontaneous cervicovaginal carcinomas driven by either the prototypic HPV16 E6/E7 or variants, in mice that are transgenic for common human MHC-1.