Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine.

He Hu,Nicole F Steinmetz

doi:10.3390/cancers13122909

Abstract

Simple SummaryVirus-like particles (VLPs) have attracted significant interest as immunotherapy platforms and cancer vaccines for inducing antigen-specific immune responses against tumors. We prepared a human epidermal growth factor receptor-2 (HER2) cancer vaccine, by conjugating the HER2-derived CH401 epitope to the external surface of Physalis mottle virus (PhMV)-like particles via copper-free click chemistry. Another candidate was prepared by loading Toll-like receptor 9 (TLR9) agonists as adjuvant into the interior cavity of PhMV-CH401—although the addition of the adjuvant conferred no additional immune priming. The VLP-based anti-HER2 vaccine candidate was administered subcutaneously, using a prime-boost immunization schedule and BALB/c mice. The vaccine candidate elicited a strong immune response, including high titers of HER2-specific immunoglobulins and increased the toxicity of antisera to DDHER2 tumor cells. DDHER2 tumor challenge studies demonstrated efficacy, as evident from the delayed onset of tumor growth and the prolonged survival of the vaccinated vs. naïve BALB/C mice.To develop a human epidermal growth factor receptor-2 (HER2)-specific cancer vaccine, using a plant virus-like particle (VLP) platform. Copper-free click chemistry and infusion encapsulation protocols were developed to prepare VLPs displaying the HER2-derived CH401 peptide epitope, with and without Toll-like receptor 9 (TLR9) agonists loaded into the interior cavity of the VLPs; Physalis mottle virus (PhMV)-based VLPs were used. After prime-boost immunization of BALB/c mice through subcutaneous administration of the vaccine candidates, sera were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) for the CH401-specific antibodies; Th1 vs. Th2 bias was determined by antibody subtyping and splenocyte assay. Efficacy was assessed by tumor challenge using DDHER2 tumor cells. We successful developed two VLP-based anti-HER2 vaccine candidates—PhMV-CH401 vs. CpG-PhMV-CH401; however, the addition of the CpG adjuvant did not confer additional immune priming. Both VLP-based vaccine candidates elicited a strong immune response, including high titers of HER2-specific immunoglobulins and increased toxicity of antisera to DDHER2 tumor cells. DDHER2 tumor growth was delayed, leading to prolonged survival of the vaccinated vs. naïve BALB/C mice. The PhMV-based anti-HER2 vaccine PhMV-CH401, demonstrated efficacy as an anti-HER2 cancer vaccine. Our studies highlight that VLPs derived from PhMV are a promising platform to develop cancer vaccines.

Highlights

Virus-like particles (VLPs) have shown exceptional promise as vaccines and immunotherapies targeting cancers and infectious diseases, amongst other target areas [1].virus-like particle (VLP) are protein structures isolated from plant or mammalian viruses or bacteriophages, assembled in the absence of genomic nucleic acid [2]
We further studied the vaccine efficacy of the cowpea mosaic virus (CPMV)-CH401 in different human epidermal growth factor receptor-2 (HER2)+ tumor models, including ectopic and orthotopic primary tumor and metastatic tumor in mice [26]
Physalis mottle virus (PhMV)-based VLPs were prepared by expressing the PhMV coat protein in E. coli, as reported previously [28,35]

Summary

Introduction

Virus-like particles (VLPs) have shown exceptional promise as vaccines and immunotherapies targeting cancers and infectious diseases, amongst other target areas [1].VLPs are protein structures isolated from plant or mammalian viruses or bacteriophages, assembled in the absence of genomic nucleic acid (albeit several VLPs will package host nucleic acids to some degree) [2]. While non-infectious, the repetitive proteinaceous structure of the VLPs mimic pathogen-associated molecular patterns (PAMPs), making them highly visible to the immune system [1]. The VLPs themselves function as an adjuvant and stimulate the immune system to improve vaccine efficacy. Based on their size, VLPs promote antigen localization to dendritic cell-enriched draining lymph nodes and enhance endocytosis of antigens through the antigen presenting cells (APCs); they stimulate. With the well-defined structural knowledge, the VLPs are an adjuvant and a delivery agent, offering high-precision nano-chemistry and an ideal scaffold for vaccine design through chemical or genetic engineering methods [1]

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Conclusion