Chimeric Infectious Bursal Disease Virus-Like Particles as Potent Vaccines for Eradication of Established HPV-16 E7–Dependent Tumors

Abstract

Cervical cancer is caused by persistent high-risk human papillomavirus (HR-HPV) infection and represents the second most frequent gynecological malignancy in the world. The HPV-16 type accounts for up to 55% of all cervical cancers. The HPV-16 oncoproteins E6 and E7 are necessary for induction and maintenance of malignant transformation and represent tumor-specific antigens for targeted cytotoxic T lymphocyte–mediated immunotherapy. Therapeutic cancer vaccines have become a challenging area of oncology research in recent decades. Among current cancer immunotherapy strategies, virus-like particle (VLP)–based vaccines have emerged as a potent and safe approach. We generated a vaccine (VLP-E7) incorporating a long C-terminal fragment of HPV-16 E7 protein into the infectious bursal disease virus VLP and tested its therapeutic potential in HLA-A2 humanized transgenic mice grafted with TC1/A2 tumor cells. We performed a series of tumor challenge experiments demonstrating a strong immune response against already-formed tumors (complete eradication). Remarkably, therapeutic efficacy was obtained with a single dose without adjuvant and against two injections of tumor cells, indicating a potent and long-lasting immune response.

Virus‐like particles for vaccination against cancer

“…The exterior or interior surface of VLPs can be functionalized and modified to display the antigens or epitopes of interest by different means: • Chemical coupling • Genetic fusion and engineering • Peptide conjugation , Brune et al (2016); Kaczmarczyk, Sitaraman, Young, Hughes, and Chatterjee (2011); Martin Caballero et al (2012); Pomwised, Intamaso, Teintze, Young, and Pincus (2016); Pumpens (2016); Tegerstedt et al (2005); Zeltins et al (2017) Immunostimulatory molecules Some VLPs assemble around RNA fragments (noninfectious or replication competent) during the expression process in host cells. VLPs can also be disassembled and reassembled in the presence of different TLR-ligands such as oligodeoxynucleotides (CpGs) (TLR-9 ligand), polyGLU, ssRNA (TLR 7/8 ligand) or dsRNA (TLR-3 ligand) Dash, Federica, Ottenbrite, and Chiellini (2011); Kawano, Matsui, and Handa (2018); Sioud (2006); ; Gomes et al (2019).…”

Structural Basis for the Development of Avian Virus Capsids That Display Influenza Virus Proteins and Induce Protective Immunity

“…Tϭ1 SVPs have also been used as vaccine carriers to target diseases such as cancer, after incorporation of a 54-residue E7 oncoprotein fragment of human papillomavirus 16 to the VP2 C terminus (27). The Tϭ1 SVP platform nevertheless entails considerable space limitations, as its cargo space is only 380 nm 3 .…”

Virus like particles as a platform for cancer vaccine development

“…The lack of a therapeutic vaccine makes it impossible to cure pre-existing HPV-associated CC. Nevertheless, an attempt to develop a therapeutic vaccine against HPV was undertaken by inserting the non-structural E7 protein of HPV into infectious bursal disease virus VLPs (VLP E7) ( Martin Caballero et al, 2012 ). The E7 protein is a tumor-specific antigen (TSA), which is highly expressed in HPV-associated CC.…”

“…It is suggested to be an important element in the maintenance of transformed phenotype of cancerous cells ( Baker et al, 1987 ; DeFilippis et al, 2003 ; Psyrri et al, 2004 ). Tumor challenge followed by vaccination of mice with VLP E7 demonstrated a complete rejection of the tumor ( Martin Caballero et al, 2012 ).…”