Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future.
Highlights
Immunotherapy is a fast-evolving field that has gained increased attention in recent years due to its clinical successes, especially that of immune checkpoint blockade
In order to allow delivery of two tumour-associated antigens concurrently, the MUC1 peptide SAPDT(GalNAc)RPAPGST(GalNAc)APPA was conjugated onto surv.virus-like particles (VLPs) via an intracellular reducible linker
The delivery of tumour antigens using virus-like particles (VLPs) has shown promise as an immunotherapy, inducing enhanced anti-tumour immune responses compared to the unformulated delivery of free peptides [29,30,31]
Summary
Immunotherapy is a fast-evolving field that has gained increased attention in recent years due to its clinical successes, especially that of immune checkpoint blockade. Induction of a strong and reliable anti-tumour immune response can be achieved by delivering tumour antigens as well as vaccine adjuvants to the same antigen-presenting cell (APC) [3]. The co-delivery of two antigens to form a multi-target vaccine decreases the risk of tumour escape by targeting a wider range of tumour cell populations, and offers a potential treatment avenue for BCs given their heterogeneity [5]. This concurrent delivery of peptides can be achieved by using nanoparticle vehicles, such as virus-like particles (VLPs). VLPs are amenable to a broad range of modifications, including recombinant insertion, chemical conjugation, encapsulation, and surface adsorption [9]
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