Development of a Human Cytomegalovirus (HCMV)-Based Therapeutic Cancer Vaccine Uncovers a Previously Unsuspected Viral Block of MHC Class I Antigen Presentation

Abstract

Human cytomegalovirus (HCMV) induces a uniquely high frequency of virus-specific effector/memory CD8+ T-cells, a phenomenon termed “memory inflation”. Thus, HCMV-based vaccines are particularly interesting in order to stimulate a sustained and strong cellular immune response against cancer. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high lethality and inevitable relapse. The current standard treatment does not significantly improve the desperate situation underlining the urgent need to develop novel approaches. Although HCMV is highly fastidious with regard to species and cell type, GBM cell lines are susceptible to HCMV. In order to generate HCMV-based therapeutic vaccine candidates, we deleted all HCMV-encoded proteins (immunoevasins) that interfere with MHC class I presentation. The aim being to use the viral vector as an adjuvant for presentation of endogenous tumor antigens, the presentation of high levels of vector-encoded neoantigens and finally the repurposing of bystander HCMV-specific CD8+ T cells to fight the tumor. As neoantigen, we exemplarily used the E6 and E7 proteins of human papillomavirus type 16 (HPV-16) as a non-transforming fusion protein (E6/E7) that covers all relevant antigenic peptides. Surprisingly, GBM cells infected with E6/E7-expressing HCMV-vectors failed to stimulate E6-specific T cells despite high level expression of E6/E7 protein. Further experiments revealed that MHC class I presentation of E6/E7 is impaired by the HCMV-vector although it lacks all known immunoevasins. We also generated HCMV-based vectors that express E6-derived peptide fused to HCMV proteins. GBM cells infected with these vectors efficiently stimulated E6-specific T cells. Thus, fusion of antigenic sequences to HCMV proteins is required for efficient presentation via MHC class I molecules during infection. Taken together, these results provide the preclinical basis for development of HCMV-based vaccines and also reveal a novel HCMV-encoded block of MHC class I presentation.

Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies

“… 141 Though there are no current ongoing clinical trials, there are promising preclinical data to suggest that viral-based vaccines may be effective in brain tumors. Abdelaziz et al 142 designed human cytomegalovirus (HCMV)-based vaccine expressing E6-derived peptide fused to HCMV proteins. Patient-derived GBM cells infected with these vectors efficiently stimulated E6-specific T cells.…”

The Association of Human Herpesviruses with Malignant Brain Tumor Pathology and Therapy: Two Sides of a Coin

“…Further, the fact that CMV infection contributes to the accumulation of functional antigen-specific CD8 + T cells with an effector memory phenotype served as the backbone for the development of a novel therapeutic vaccine platform based on human CMV vectors against different cancer types, including brain tumors [ 108 , 109 ]. In a recent preclinical study, a CMV-based therapeutic vaccine expressing the E6 peptide of human papillomavirus type 16 as a neo-epitope and lacking immunoevasins was generated in order to use the viral vector as an adjuvant for the presentation of endogenous tumor antigens and finally to repurpose bystander CMV-specific CD8 + T cells against the tumor [ 110 ]. Glioblastoma cells infected with these vectors were shown to be capable of efficiently stimulating E6-specific T cells.…”

Evasion of the Host Immune Response by Betaherpesviruses

“…A recent advance in the interaction between MHC class I molecules and HCMV came about as an unexpected discovery during research to create a cytomegalovirus-based vaccine for glioblastoma. It was noted that E6-specific T cells were not activated by glioblastoma cells infected with HCMV-based vaccines including the human papillomavirus proteins E6 and E7 [ 122 ]. The proteins US2, US3, US6, and US11, all of which are known to downregulate MHC class I presentation [ 123 , 124 , 125 ], had been removed.…”