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Bovine papillomavirus prostate cancer antigen virus-like particle vaccines are efficacious in advanced cancers in the TRAMP mouse spontaneous prostate cancer model

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Abstract

Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-γ secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19–20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.

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Abbreviations

AAY:

Alanine-alanine–tyrosine

BPV:

Bovine papillomavirus

DAB:

Diaminobenzidine

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

GSH:

Glutathione

GSSG:

Glutathione disulfide

IQR:

Interquartile range

ORF:

Open reading frame

PAP:

Prostatic acid phosphatase

PC:

Prostate cancer

PD-1:

Programed death-1

PIN:

Prostatic intraepithelial neoplasia

PSCA:

Prostate stem cell antigen

SPAS:

Stimulator of prostatic adenocarcinoma-specific T cells

TCEP:

Tris(2-carboxyethyl)phosphine

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

VLP:

Virus-like particle

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Acknowledgements

The authors thank the NIH tetramer core facility for provision of dye labeled MHC peptide complexes.

Funding

This work was supported by grants from the Allegheny Health Network, Patrick C. Walsh Prostate Cancer Research Fund, and State of Maryland TEDCO program.

Author information

Author notes

  1. Brian W. Simons

    Present address: Center for Comparative Medicine, Baylor College of Medicine, Houston, TX, USA

  2. Fabiana Cannella

    Present address: Laboratory of Virology, Department of Molecular Medicine, and Institute Pasteur-Cenci Bolognetti Foundation, Sapienza University, Rome, Italy

Authors and Affiliations

  1. Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Brian W. Simons

  2. The Department of Pediatrics, Johns Hopkins University, 600 North Wolfe Street, Blalock Building 1153, Baltimore, MD, 21287, USA

    Fabiana Cannella, Dayana T. Rowley & Raphael P. Viscidi

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  1. Brian W. Simons
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  4. Raphael P. Viscidi
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Contributions

BWS contributed to study design and analysis, and supervised immunization of mice, measurement of tumor size and immunohistochemical analysis of tumor tissue. FC produced VLP vaccines and assisted with measurements of tumor size. DTR produced VLP vaccines and performed flow cytometry analysis of the immune response to vaccination. RPV contributed to study design and analysis, and supervised production of VLP vaccines and analysis of vaccine immunogenicity.

Corresponding author

Correspondence to Raphael P. Viscidi.

Ethics declarations

Conflict of interest

Raphael P Viscidi is the inventor of the bovine VLP vaccine technology and could financially benefit if a product based on the technology is commercialized. All other authors declare that they have no conflicts of interest.

Ethical approval

All animal procedures were performed according to NIH guidelines under protocol MO17M189 approved by the Johns Hopkins University Animal Care and Use Committee.

Animal rights

Breeding pairs of TRAMP mice (C57BL/6-Tg(TRAMP)8247Ng/J)(stock no. 003135) and wild type C57BL/6 J mice (stock no. 000664) were purchased from Jackson Laboratories (Bar Harbor, ME). Tramp mice were bred within our colony on a pure C57BL/6 background.

Cell line authentication

High Five™ Cells (BTI-TN-5B1-4) are a clonal isolate derived from the parental Trichoplusia ni cell line (cabbage looper ovary) and are adapted to serum-free culture (Thermo Fisher Scientific, #B85502). The cells were not further authenticated as they are of insect origin and were used for protein production only.

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Simons, B.W., Cannella, F., Rowley, D.T. et al. Bovine papillomavirus prostate cancer antigen virus-like particle vaccines are efficacious in advanced cancers in the TRAMP mouse spontaneous prostate cancer model. Cancer Immunol Immunother 69, 641–651 (2020). https://doi.org/10.1007/s00262-020-02493-z

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